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Tocilizumab for treating giant cell arteritis
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Tocilizumab for treating giant cell arteritis
Evidence-based recommendations on tocilizumab (RoActemra) for treating giant cell arteritis in adults.
# Recommendations
Tocilizumab, when used with a tapering course of glucocorticoids (and when used alone after glucocorticoids), is recommended as an option for treating giant cell arteritis in adults, only if:
they have relapsing or refractory disease
they have not already had tocilizumab
tocilizumab is stopped after 1 year of uninterrupted treatment at most and
the company provides tocilizumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with tocilizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Giant cell arteritis is usually treated with a high dose of glucocorticoids, which is gradually reduced over time. High doses of glucocorticoids may cause a number of problems, including skin problems, weight gain, diabetes and osteoporosis.
Clinical trial results show that after having tocilizumab plus a tapering course of glucocorticoids for 1 year, more people stay in remission and need lower doses of glucocorticoids compared with people having glucocorticoids alone.
In the full population, the most plausible cost-effectiveness estimates were above the range normally considered to be a cost-effective use of NHS resource, even when tocilizumab is used for only 1 year. For the subgroup of people with relapsing or refractory disease, using the committee's preferred assumptions (including that tocilizumab is given for 1 year at most), the most likely cost-effectiveness estimate compared with glucocorticoids alone is £24,977 per quality-adjusted life year gained. This is within the range normally considered to be a cost-effective use of NHS resources, so tocilizumab is recommended.# Information about tocilizumab
# Marketing authorisation indication
Tocilizumab (RoActemra, Roche) has a marketing authorisation for 'the treatment of adults with giant cell arteritis'.
# Dosage in the marketing authorisation
Subcutaneous injection (162 mg) once every week in combination with a tapering course of glucocorticoids. Tocilizumab can be used alone following discontinuation of glucocorticoids, but monotherapy should not be used for the treatment of acute relapses. Treatment beyond 52 weeks should be guided by disease activity, physician discretion and patient choice.
# Price
£913.12 for 4 syringes containing 162 mg tocilizumab (excluding VAT). The company has a commercial arrangement. This makes tocilizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# A new treatment option
## People would welcome a new treatment that reduces the cumulative amount of glucocorticoids needed
Giant cell arteritis causes inflammation in the walls of the arteries in the head and neck, and less commonly the aorta (known as large vessel giant cell arteritis). The patient experts explained that this causes symptoms such as headache, jaw pain, fatigue and muscle and joint pains. More serious complications include vision loss, stroke, aortic aneurysm and dissection, and myocardial infarction. It is with visual symptoms that people often first present to health services. Initial treatment in the NHS is with high-dose glucocorticoids, usually prednisolone. The dose is tapered gradually over 18 to 24 months to minimise the risk of the disease flaring up. The clinical experts explained that although glucocorticoids are effective at managing the disease, large cumulative doses can cause serious side effects such as diabetes and osteoporosis. The patient experts also noted unpleasant side effects with glucocorticoids such as skin changes and weight gain. They highlighted that because the disease is most common among people 50 years and older, these side effects are often in addition to existing health problems. The patient experts emphasised that glucocorticoid-sparing agents are very important for people with giant cell arteritis, especially for those with relapsing or refractory disease, who are subject to excessive cumulative dosage of glucocorticoids. The committee concluded that people with giant cell arteritis would welcome a new treatment option that reduces flares of the disease and the cumulative amount of glucocorticoids needed.
# Subgroups
## People with relapsing or refractory giant cell arteritis have the highest unmet need
Tocilizumab has a UK marketing authorisation for use in adults with giant cell arteritis. At the first committee meeting, the company presented clinical- and cost-effectiveness analyses which divided the overall population into 2 subgroups: people with newly diagnosed disease and people with relapsing disease. The clinical experts explained that newly diagnosed giant cell arteritis is treated differently to relapsing disease. People with a new diagnosis are usually offered high doses of glucocorticoids (40 mg to 60 mg of prednisolone daily). This is because the priority is to prevent vision loss, and at this stage people have not been exposed to a high cumulative dose of glucocorticoids, so there are fewer concerns about glucocorticoid-related adverse events. People with relapsing disease are usually offered lower doses of glucocorticoids in an attempt to manage flares and minimise additional glucocorticoids exposure; as such, the clinical and patient experts considered that tocilizumab would be most valuable to people with relapsing disease. The committee agreed that there were important differences between the 2 subgroups. It considered how many people with newly diagnosed disease would then go on to have relapses. The clinical experts explained that it is difficult to identify people whose disease may relapse, although there are some whose disease does not respond to initial high doses of glucocorticoids and that never achieve remission. The committee also acknowledged differences within the subgroup of people with relapsing disease: for example, some people's disease may relapse frequently, whereas for others relapses may be rare. Furthermore, the clinical experts explained there were differences in the severity of flares in this subgroup. In response to consultation, the company stated that tocilizumab would be most valuable to people with relapsing or refractory giant cell arteritis and therefore amended its cost-effectiveness model to focus on this subgroup only (section 3.14). It was also noted that, although clinician and patient groups also highlighted a high unmet need in patients with newly diagnosed giant cell arteritis with comorbidities, there was no data available for the company to do an analysis in this subgroup. The committee concluded that the relapsing or refractory subgroup was distinct and biologically plausible and had the highest unmet need. Therefore it considered both the full population and the relapsing or refractory subgroup in its decision making.
# Clinical evidence
## The weekly tocilizumab and 52‑week glucocorticoid taper arms of GiACTA reflect the license and British Society for Rheumatology guidelines
The main clinical evidence for tocilizumab came from GiACTA, a multicentre, double-blind, randomised controlled trial. The trial followed patients for 52 weeks, at which point they were enrolled in an open-label extension study which is still ongoing. Patients in the tocilizumab arm had tocilizumab plus glucocorticoids for 26 weeks, followed by tocilizumab alone for the remaining 26 weeks. The primary outcome of the trial investigated whether more people achieve sustained disease remission at 52 weeks with tocilizumab and glucocorticoids compared with glucocorticoids alone. Secondary outcomes included time to first flare after disease remission and cumulative glucocorticoid dose. The trial included 4 arms:
tocilizumab every week with 26‑week prednisone taper (n=100)
tocilizumab every 2 weeks with 26‑week prednisone taper (n=50)
placebo with 26‑week prednisone taper (n=50)
placebo with 52‑week prednisone taper (n=51).The company presented clinical-effectiveness data for all 4 arms, but in its economic model used only the weekly tocilizumab and the placebo with 52‑week prednisone taper arms. This is because weekly tocilizumab reflects the marketing authorisation, and the 52‑week glucocorticoid taper reflects the minimum tapering regimen recommended in British Society for Rheumatology guidelines on giant cell arteritis. The committee noted that splitting the trial into 4 arms meant that the numbers in each arm were small, especially when the population was further divided into newly diagnosed and relapsing subgroups. It also noted that prednisolone, not prednisone, is usually used in the NHS, but considered that the 2 drugs are very similar. The committee concluded that the 2 arms included in the company's economic model (that is, weekly tocilizumab and placebo with 52‑week prednisone taper) are most relevant to clinical practice in England.
## Patients in GiACTA reflect those with giant cell arteritis in England
The committee noted a number of differences in the baseline characteristics between the treatment groups in GiACTA, but the ERG explained that these generally balanced out with no obvious skew. However, the committee was concerned that the mean age in the trial was lower than the mean age of people with the disease in the UK (69 years and 73 years respectively). In addition, 40% of patients in GiACTA had large vessel disease, compared with only around 5% of people with giant cell arteritis seen in clinical practice in England. Large vessel disease tends to be associated with a longer disease duration and more relapses than giant cell arteritis affecting the head and neck. However, the clinical experts explained that most people with giant cell arteritis affecting the head and neck also have large vessel disease. It is less likely to be diagnosed in the NHS because there is a lower utilisation of advanced imaging than in the trial. As such, the proportion in the trial is likely to reflect the true proportion with large vessel disease in England. The committee concluded that the patients in the trial reflect those with giant cell arteritis in England.
## The 52‑week glucocorticoid taper does not reflect clinical practice in England and might bias the results in favour of tocilizumab
The committee was concerned that 52 weeks (12 months) is the shortest glucocorticoid taper recommended in the British Society for Rheumatology guidelines. The clinical experts explained that in clinical practice, glucocorticoids would usually be tapered over 18 to 24 months. The committee considered that this might mean that the number of flares in the comparator arm (that is, placebo with 52‑week glucocorticoid taper) may be higher, and the time to first flare shorter, than in clinical practice in England. In response to consultation, the company proposed a revision to the comparator arm of the cost-effectiveness model to incorporate the slowest tapering regimen (24 months) recommended by the British Society for Rheumatology guidelines. The committee was also aware that 49% of patients in the comparator arm did not have disease remission after the 6‑week screening phase of the trial, but that nonetheless they had to start the 52‑week tapering regimen. The committee was concerned that this might bias the primary end point of the trial (sustained remission at 52 weeks) in favour of tocilizumab, because it is less likely that people whose disease has not responded to high-dose glucocorticoids would achieve remission with lower doses. In response to consultation, the company submitted evidence from a new exploratory analysis that suggested there is no difference in primary end point analysed by remission status at baseline in the trial. However, without any statistical analyses from the company to support this conclusion, the committee remained concerned about potential bias in the primary end point in favour of tocilizumab. It concluded that the 52‑week glucocorticoid taper arm of the trial does not reflect clinical practice in England and might bias the results in favour of tocilizumab.
## Tocilizumab plus a tapering course of glucocorticoids is more effective than glucocorticoids alone
The company presented results for the overall intention-to-treat population of GiACTA, as well as for both the newly diagnosed and relapsing subgroups. The results showed that tocilizumab plus a tapering course of glucocorticoids was more effective than glucocorticoids alone at increasing the proportion of patients sustaining remission at 52 weeks, and increasing the time to first flare for the overall population and both subgroups (see table 1). The committee recalled that in clinical practice, newly diagnosed disease and relapsing disease are managed differently, but the results were similarly effective across both subgroups. The committee concluded that tocilizumab is more effective than glucocorticoids alone at increasing sustained remission and time to first flare.
Population
Sustained remission at 52 weeks (%)
Time to first flare hazard ratio
(99% confidence interval)
Median cumulative glucocorticoids dose (mg)
Overall population:
tocilizumab (n=100)
(0.18 to 0.82)
Overall population: placebo (n=51)
(0.18 to 0.82)
Newly diagnosed subgroup: tocilizumab (n=47)
(0.29 to 1.59)
Newly diagnosed subgroup: placebo (n=23)
(0.29 to 1.59)
Relapsing subgroup: tocilizumab (n=53)
(0.14 to 0.81)
Relapsing subgroup: placebo (n=28)
(0.14 to 0.81)
# Adverse events
## Because tocilizumab is taken with glucocorticoids, the extent to which glucocorticoid-related adverse events are reduced is unclear
The committee considered the benefits of tocilizumab in terms of a reduction in cumulative glucocorticoid dose and risk of glucocorticoid-related adverse events. The committee noted that although the tapering regimen with tocilizumab is shorter than when glucocorticoids are used alone, disease flares are treated by increasing the glucocorticoid dose, and a tapering regimen restarted. As such, people taking tocilizumab could still be exposed to large cumulative doses of glucocorticoids. The committee acknowledged that the median cumulative glucocorticoid dose was lower in the tocilizumab arm of GiACTA (see table 1), but noted that this was over the relatively short 52‑week follow-up. It was concerned that despite the lower median cumulative glucocorticoid dose in the tocilizumab arm, the rate of glucocorticoid-related adverse events was similar between trial arms (50% compared with 49%). The committee acknowledged that this might be because many glucocorticoid-related adverse events only manifest in the longer term. In response to consultation, the company provided new evidence from post-hoc trial analyses that showed a higher rate of glucocorticoid-related adverse events being seen in the comparator arm. However, the committee was concerned that the data were analysed retrospectively and not based on standard or prespecified criteria. In addition, the company did not provide any statistical analyses to support the comparison of glucocorticoid-related adverse events between arms. The committee concluded that because glucocorticoids still need to be taken with tocilizumab, the extent to which glucocorticoid-related adverse events are reduced is unclear.
# The company's economic model
## The structure of the model is adequate for decision making
The company's economic model had a 30-year time horizon and included separate health states for remission based on whether patients are having glucocorticoids or not. Patients in the model could also have a flare, giant cell arteritis-related adverse events and glucocorticoid-related adverse events. Both taking glucocorticoids and disease flares were associated with a utility decrement. The committee concluded that the structure of the model was adequate for decision making.
# Duration of tocilizumab treatment
## A 1-year stopping rule can be implemented in NHS practice
In its original model, the company assumed that treatment with tocilizumab stops after 2 years. The committee was concerned that in clinical practice treatment may continue well beyond 2 years. This is because the risk of relapse continues, and there is no evidence that tocilizumab modifies the underlying disease when treatment stops (it may just supress it for the duration of treatment). In addition, tocilizumab treatment may be stopped and restarted in the event of a relapse. After consultation, however, the company argued that most patients would not need the full 2 years of tocilizumab treatment. It proposed that, based on clinical expert opinion, up to 1 year of treatment would be sufficient to sustain remission in the longer term and to reduce the cumulative glucocorticoid burden. The company therefore implemented a 1-year stopping rule in its revised economic model for people with relapsing or refractory disease. This stopping rule assumed that patients only had 1 course of treatment, even if they had another flare. It supported its position by providing supporting evidence from a literature review of published case reports of tocilizumab in giant cell arteritis, in which most patients had tocilizumab for less than 1 year (range 1 to 53 months). However, the committee was concerned that the evidence was based only on case reports, and that most included no follow-up details. Nevertheless, it noted that GiACTA showed that 1 years' treatment with tocilizumab is effective in sustaining remission and reducing cumulative glucocorticoid burden. It also noted that the 1-year treatment duration provided results that were most internally valid. Both the clinical and patient experts agreed that many patients are likely to need less than 1 year of tocilizumab to achieve sustainable remission, and that a 1-year stopping rule would be acceptable. As a relevant commissioner, NHS England specialised services also stated that a 1-year stopping rule could be implemented in NHS practice. The committee therefore concluded that it would include the 1-year stopping rule in its decision making.
# Extrapolation of time to first flare
## The company's extrapolation after 52 weeks lacks validity
In order to extrapolate time to first flare beyond the 52 weeks of the trial, the company fitted separate parametric models to the 2 arms (weekly tocilizumab with 26‑week prednisone taper and placebo with 52‑week prednisone taper) in its economic model. It used a Weibull distribution for the weekly tocilizumab arm (implying a decreasing risk of flare over time) and an exponential distribution for the comparator arm (implying a constant risk of flare over time). The committee was concerned that extrapolating in this way meant that the benefit of tocilizumab over glucocorticoids alone was assumed to continue for the 30-year time horizon of the model, despite tocilizumab treatment stopping at 2 years. Moreover, the extrapolation for the comparator arm was based on the glucocorticoid taper period, when the risk of flare is highest. The committee was concerned that this would exaggerate the risk of flare for patients in the comparator arm that had successfully completed the 52‑week glucocorticoid taper. The clinical experts explained that after 10 years, they would expect around 25% of people who had successfully completed a glucocorticoid taper to not have disease relapse; in contrast, at the same time point, the company's model predicted that almost all patients in the comparator arm would have disease relapse. Longitudinal cohort data also suggest that at 5 years, 30% to 50% of people having glucocorticoids alone will not have disease relapse; at the same time point, the company's model predicted this to be less than 2%. The committee concluded that the company's extrapolation of time to first flare lacked validity.
## The ERG's approach to extrapolation is more appropriate
The ERG suggested an alternative approach to extrapolating time to first flare for the comparator arm, in which it switches to the same Weibull distribution as the weekly tocilizumab arm after 2 years. The committee considered that this addressed the issue of the relative benefit of tocilizumab continuing after treatment stops, because all patients that have successfully completed the taper in either arm have the same decreasing risk of disease relapse. Using this approach, the ERG predicted that at year 5 around 12% of patients in the comparator arm would not have relapsing disease (falling to 8% by year 10). The committee concluded although the ERG's approach may still overestimate the risk of flare in the comparator arm, it provided more clinically realistic estimates of the proportion of patients with disease relapse after having glucocorticoids alone.
# Estimating rates of subsequent flares
## The ERG's approach results in more realistic estimates of subsequent flares
The company used GiACTA data to estimate rates of subsequent flares that were used in the economic model. The ERG noted that the company's estimate for the tocilizumab newly diagnosed subgroup was higher than for the relapsing subgroup, which is clinically implausible. In addition, the company's model predicted a high number of flares for people having glucocorticoids alone, which lacks validity. For example, over the same period of 10 years, a longitudinal cohort study of people with giant cell arteritis taking glucocorticoids alone (Labarca et al. 2016) reported less than half the flares predicted by the company's model. The ERG derived probabilities based on this study that were logically consistent across the subgroups. The committee considered that when the ERG's probabilities for subsequent flare are combined with its approach to time to first flare extrapolation, the predicted mean number of flares over the model time horizon for the comparator arm is more plausible than the company's approach. In the company's revised model for people with relapsing or refractory disease, it proposed an additional 10% adjustment to the ERG's estimated rates of subsequent flares to provide a better estimate in the control arm of the relapsing subgroup. The ERG stated that this had already been accounted for in its own estimates, so no adjustments were needed. The committee concluded that the ERG's approach to estimating the probability of subsequent flares was more appropriate.
# Utility values in the model
## The company's model adequately captures the negative effect of flares and glucocorticoids on quality of life
The company used a common utility value for the remission health state in both treatment arms, and applied a utility decrement of -0.13 for 4 weeks to capture how a flare negatively affects quality of life. The company accounted for the negative effects of glucocorticoids by including increased probabilities of diabetes and fracture in the model, which are associated with costs and disutilities. In addition, all patients having glucocorticoids in the model were assigned a utility decrement of -0.07 for the duration of their treatment, reflecting the negative effects of common side effects such as weight gain and skin changes. The committee acknowledged that the disutility estimate does not include an exhaustive list of adverse events that can result from glucocorticoid treatment, but considered the source to be the most relevant reference. The ERG noted that within the disutility estimate is a separate 'base' disutility estimate (‑0.03) to capture common side effects for all patients having glucocorticoids. This was applied during each cycle patients were in the subsequent remission state. It assumed, after a relapse, people would continue to incur both the 'base' disutility and the specific side effects for the remainder of their lifetime. The ERG considered that unless patients continued to have lifelong treatment with glucocorticoids, it might not be appropriate to continue applying the 'base' disutility. Nevertheless, the committee concluded that the company's model adequately captures the negative effect of flares and glucocorticoids on quality of life.
# The company's updated economic analysis
## The company's ICER for tocilizumab in relapsing or refractory disease is £18,801 per QALY gained with a 1-year stopping rule
The company's original base-case deterministic incremental cost-effectiveness ratio (ICER) for the overall population was £28,272 per quality-adjusted life year (QALY) gained. This was based on a 2-year stopping rule and included a confidential patient access scheme discount for tocilizumab. In response to consultation, the company updated its economic model to focus only on the subgroup of people with relapsing or refractory giant cell arteritis. The updated economic model included the committee's preferred assumptions, specifically:
a mean age of 73 years (section 3.4)
switching the time to first flare extrapolation for glucocorticoids alone to the same Weibull function as tocilizumab after 2 years (section 3.10)
basing the probabilities of subsequent flares on longitudinal cohort data (section 3.12).The updated model also included a number of company-preferred assumptions and corrections, specifically:
incorporating a 1-year stopping rule for tocilizumab (section 3.9)
incorporating the slowest glucocorticoid taper regimen (24 months) in the comparator arm to match NHS practice
incorporating the costs for emergency department visits
updating the costs of glucocorticoid-related adverse events to reflect 2017 health care utilisation, specifically:
including additional costs for a yearly DEXA scan and prophylaxis medication
inflating diabetes costs from 2005 to 2017 estimates
revising fracture costs (based on Kanis et al. 2007)
revising infection costs (based on Sarnes 2011)
adjusting the ERG's flare rate to better reflect relapsing or refractory giant cell arteritis in the comparator arm of GiACTA
correcting 2 programming errors: using the average weight of the relapsing and refractory population in GiACTA to calculate concomitant medication dosage (instead of the UK population), and correcting the yearly concomitant medication costs applied to the comparator arm.When incorporating these changes, the deterministic ICER for tocilizumab plus prednisolone compared with prednisolone alone, incorporating the confidential patient access scheme, was £18,801 per QALY gained in people with relapsed or refractory giant cell arteritis (a probabilistic ICER was not provided).
# The ERG's updated alternative economic analysis
## The ERG's ICER for tocilizumab in relapsing and refractory disease is £24,977 per QALY gained when a 1-year stopping rule is applied
The ERG's original base-case probabilistic ICER for the overall population was £65,801 per QALY gained. This was based on a 2-year stopping rule and included the committee's preferred assumptions. A confidential patient access scheme discount for tocilizumab was also applied. The ERG's revised economic model included a 1-year stopping rule, and focused only on people with relapsing or refractory disease. It made a number of other changes in its revised model, specifically:
using both the average weight and body surface area estimates of the relapsing or refractory population in GiACTA to calculate the dosages of concomitant medication
incorporating an alternative estimate for emergency department visits based on NHS reference costs
including costs for a single DEXA scan, instead of yearly scans, and using average generic cost estimate for oral therapies (taken from NICE's technology appraisal guidance on bisphosphonates for treating osteoporosis)
using fracture cost estimates that are consistent with those used in NICE's technology appraisal guidance on bisphosphonates for treating osteoporosis.The ERG did not consider the company's proposed change to the glucocorticoid tapering regimen to be appropriate, because only the cost of the comparator glucocorticoid taper regimen was adjusted and no adjustment was made to address the uncertainties about how this may affect the number of flares and time to first flare. The ERG also noted that the reference data used to update the infection costs in the company's updated economic model was taken from a US study (Sarnes 2011), so the generalisability of the findings to the NHS is unclear. In addition, the ERG considered the company's proposed additional adjustment to the ERG's estimated rates of subsequent flares (section 3.12) to be inappropriate. The ERG therefore did not make these changes in its revised analysis. When the ERG made its adjustments, the revised model produced ICERs for tocilizumab plus prednisolone compared with prednisolone alone of £24,977 (deterministic) and £24,032 (probabilistic) per QALY gained in people with relapsed or refractory giant cell arteritis (including the patient access scheme discount).
# The most plausible ICER after consultation
## Tocilizumab is cost-effective only for relapsing or refractory giant cell arteritis and when a 1-year stopping rule is applied
The committee preferred the ERG's estimates for both the overall population and people with relapsing or refractory giant cell arteritis, because they better reflected its preferred assumptions. It therefore concluded that the most plausible ICERs for tocilizumab plus prednisolone compared with prednisolone alone, incorporating the confidential patient access scheme, were £65,501 (2-year treatment duration) and £36,960 (1-year treatment duration) per QALY gained for the overall population and £55,924 (2-tear treatment duration) and £24,977 (1-year treatment duration) per QALY gained for people with relapsing or refractory giant cell arteritis. The ICERs for the overall population were higher than the range normally considered to be a cost-effective use of NHS resources (usually £20,000 to £30,000 per QALY), as were the ICERs when a 2-year treatment duration was applied, so the committee concluded that it would recommend tocilizumab as a cost-effective use of NHS resources only for treating relapsing or refractory giant cell arteritis and if a 1-year stopping rule is applied.
# Other factors
## There are no additional benefits that are not captured in the QALY calculations
The clinical experts highlighted that tocilizumab is the first new treatment for giant cell arteritis in several years. The committee was aware that before its marketing authorisation was granted, tocilizumab received a Promising Innovative Medicines designation for this indication. The patient experts explained that high doses of glucocorticoids are needed to treat flares and afterwards the tapering regimen must be restarted. This can have a large negative effect on quality of life, which may not be captured in the modelling. However, the committee noted that in the model, patients have a substantially lower utility during a flare, which is assumed to last for 4 weeks (section 3.8). In addition, after a disease flare, all patients have glucocorticoids and this is associated with a utility decrement (section 3.13). The committee concluded that there were no additional benefits that had not been captured in the QALY calculation.
## The recommendations do not have a different impact on people protected by equality legislation than on the wider population
The committee discussed equality issues, and agreed that its recommendations apply equally regardless of age. In addition, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. The committee concluded that its recommendations do not have a different impact on people protected by the equality legislation than on the wider population.
|
{'Recommendations': "Tocilizumab, when used with a tapering course of glucocorticoids (and when used alone after glucocorticoids), is recommended as an option for treating giant cell arteritis in adults, only if:\n\nthey have relapsing or refractory disease\n\nthey have not already had tocilizumab\n\ntocilizumab is stopped after 1\xa0year of uninterrupted treatment at most and\n\nthe company provides tocilizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with tocilizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nGiant cell arteritis is usually treated with a high dose of glucocorticoids, which is gradually reduced over time. High doses of glucocorticoids may cause a number of problems, including skin problems, weight gain, diabetes and osteoporosis.\n\nClinical trial results show that after having tocilizumab plus a tapering course of glucocorticoids for 1\xa0year, more people stay in remission and need lower doses of glucocorticoids compared with people having glucocorticoids alone.\n\nIn the full population, the most plausible cost-effectiveness estimates were above the range normally considered to be a cost-effective use of NHS resource, even when tocilizumab is used for only 1\xa0year. For the subgroup of people with relapsing or refractory disease, using the committee's preferred assumptions (including that tocilizumab is given for 1\xa0year at most), the most likely cost-effectiveness estimate compared with glucocorticoids alone is £24,977 per quality-adjusted life year gained. This is within the range normally considered to be a cost-effective use of NHS resources, so tocilizumab is recommended.", 'Information about tocilizumab': "# Marketing authorisation indication\n\nTocilizumab (RoActemra, Roche) has a marketing authorisation for 'the treatment of adults with giant cell arteritis'.\n\n# Dosage in the marketing authorisation\n\nSubcutaneous injection (162\xa0mg) once every week in combination with a tapering course of glucocorticoids. Tocilizumab can be used alone following discontinuation of glucocorticoids, but monotherapy should not be used for the treatment of acute relapses. Treatment beyond 52\xa0weeks should be guided by disease activity, physician discretion and patient choice.\n\n# Price\n\n£913.12 for 4 syringes containing 162\xa0mg tocilizumab (excluding VAT). The company has a commercial arrangement. This makes tocilizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# A new treatment option\n\n## People would welcome a new treatment that reduces the cumulative amount of glucocorticoids needed\n\nGiant cell arteritis causes inflammation in the walls of the arteries in the head and neck, and less commonly the aorta (known as large vessel giant cell arteritis). The patient experts explained that this causes symptoms such as headache, jaw pain, fatigue and muscle and joint pains. More serious complications include vision loss, stroke, aortic aneurysm and dissection, and myocardial infarction. It is with visual symptoms that people often first present to health services. Initial treatment in the NHS is with high-dose glucocorticoids, usually prednisolone. The dose is tapered gradually over 18 to 24\xa0months to minimise the risk of the disease flaring up. The clinical experts explained that although glucocorticoids are effective at managing the disease, large cumulative doses can cause serious side effects such as diabetes and osteoporosis. The patient experts also noted unpleasant side effects with glucocorticoids such as skin changes and weight gain. They highlighted that because the disease is most common among people 50\xa0years and older, these side effects are often in addition to existing health problems. The patient experts emphasised that glucocorticoid-sparing agents are very important for people with giant cell arteritis, especially for those with relapsing or refractory disease, who are subject to excessive cumulative dosage of glucocorticoids. The committee concluded that people with giant cell arteritis would welcome a new treatment option that reduces flares of the disease and the cumulative amount of glucocorticoids needed.\n\n# Subgroups\n\n## People with relapsing or refractory giant cell arteritis have the highest unmet need\n\nTocilizumab has a UK marketing authorisation for use in adults with giant cell arteritis. At the first committee meeting, the company presented clinical- and cost-effectiveness analyses which divided the overall population into 2 subgroups: people with newly diagnosed disease and people with relapsing disease. The clinical experts explained that newly diagnosed giant cell arteritis is treated differently to relapsing disease. People with a new diagnosis are usually offered high doses of glucocorticoids (40\xa0mg to 60\xa0mg of prednisolone daily). This is because the priority is to prevent vision loss, and at this stage people have not been exposed to a high cumulative dose of glucocorticoids, so there are fewer concerns about glucocorticoid-related adverse events. People with relapsing disease are usually offered lower doses of glucocorticoids in an attempt to manage flares and minimise additional glucocorticoids exposure; as such, the clinical and patient experts considered that tocilizumab would be most valuable to people with relapsing disease. The committee agreed that there were important differences between the 2\xa0subgroups. It considered how many people with newly diagnosed disease would then go on to have relapses. The clinical experts explained that it is difficult to identify people whose disease may relapse, although there are some whose disease does not respond to initial high doses of glucocorticoids and that never achieve remission. The committee also acknowledged differences within the subgroup of people with relapsing disease: for example, some people's disease may relapse frequently, whereas for others relapses may be rare. Furthermore, the clinical experts explained there were differences in the severity of flares in this subgroup. In response to consultation, the company stated that tocilizumab would be most valuable to people with relapsing or refractory giant cell arteritis and therefore amended its cost-effectiveness model to focus on this subgroup only (section\xa03.14). It was also noted that, although clinician and patient groups also highlighted a high unmet need in patients with newly diagnosed giant cell arteritis with comorbidities, there was no data available for the company to do an analysis in this subgroup. The committee concluded that the relapsing or refractory subgroup was distinct and biologically plausible and had the highest unmet need. Therefore it considered both the full population and the relapsing or refractory subgroup in its decision making.\n\n# Clinical evidence\n\n## The weekly tocilizumab and 52‑week glucocorticoid taper arms of GiACTA reflect the license and British Society for Rheumatology guidelines\n\nThe main clinical evidence for tocilizumab came from GiACTA, a multicentre, double-blind, randomised controlled trial. The trial followed patients for 52\xa0weeks, at which point they were enrolled in an open-label extension study which is still ongoing. Patients in the tocilizumab arm had tocilizumab plus glucocorticoids for 26\xa0weeks, followed by tocilizumab alone for the remaining 26\xa0weeks. The primary outcome of the trial investigated whether more people achieve sustained disease remission at 52\xa0weeks with tocilizumab and glucocorticoids compared with glucocorticoids alone. Secondary outcomes included time to first flare after disease remission and cumulative glucocorticoid dose. The trial included 4 arms:\n\ntocilizumab every week with 26‑week prednisone taper (n=100)\n\ntocilizumab every 2\xa0weeks with 26‑week prednisone taper (n=50)\n\nplacebo with 26‑week prednisone taper (n=50)\n\nplacebo with 52‑week prednisone taper (n=51).The company presented clinical-effectiveness data for all 4 arms, but in its economic model used only the weekly tocilizumab and the placebo with 52‑week prednisone taper arms. This is because weekly tocilizumab reflects the marketing authorisation, and the 52‑week glucocorticoid taper reflects the minimum tapering regimen recommended in British Society for Rheumatology guidelines on giant cell arteritis. The committee noted that splitting the trial into 4 arms meant that the numbers in each arm were small, especially when the population was further divided into newly diagnosed and relapsing subgroups. It also noted that prednisolone, not prednisone, is usually used in the NHS, but considered that the 2 drugs are very similar. The committee concluded that the 2 arms included in the company's economic model (that is, weekly tocilizumab and placebo with 52‑week prednisone taper) are most relevant to clinical practice in England.\n\n## Patients in GiACTA reflect those with giant cell arteritis in England\n\nThe committee noted a number of differences in the baseline characteristics between the treatment groups in GiACTA, but the ERG explained that these generally balanced out with no obvious skew. However, the committee was concerned that the mean age in the trial was lower than the mean age of people with the disease in the UK (69\xa0years and 73\xa0years respectively). In addition, 40% of patients in GiACTA had large vessel disease, compared with only around 5% of people with giant cell arteritis seen in clinical practice in England. Large vessel disease tends to be associated with a longer disease duration and more relapses than giant cell arteritis affecting the head and neck. However, the clinical experts explained that most people with giant cell arteritis affecting the head and neck also have large vessel disease. It is less likely to be diagnosed in the NHS because there is a lower utilisation of advanced imaging than in the trial. As such, the proportion in the trial is likely to reflect the true proportion with large vessel disease in England. The committee concluded that the patients in the trial reflect those with giant cell arteritis in England.\n\n## The 52‑week glucocorticoid taper does not reflect clinical practice in England and might bias the results in favour of tocilizumab\n\nThe committee was concerned that 52\xa0weeks (12\xa0months) is the shortest glucocorticoid taper recommended in the British Society for Rheumatology guidelines. The clinical experts explained that in clinical practice, glucocorticoids would usually be tapered over 18 to 24\xa0months. The committee considered that this might mean that the number of flares in the comparator arm (that is, placebo with 52‑week glucocorticoid taper) may be higher, and the time to first flare shorter, than in clinical practice in England. In response to consultation, the company proposed a revision to the comparator arm of the cost-effectiveness model to incorporate the slowest tapering regimen (24\xa0months) recommended by the British Society for Rheumatology guidelines. The committee was also aware that 49% of patients in the comparator arm did not have disease remission after the 6‑week screening phase of the trial, but that nonetheless they had to start the 52‑week tapering regimen. The committee was concerned that this might bias the primary end point of the trial (sustained remission at 52\xa0weeks) in favour of tocilizumab, because it is less likely that people whose disease has not responded to high-dose glucocorticoids would achieve remission with lower doses. In response to consultation, the company submitted evidence from a new exploratory analysis that suggested there is no difference in primary end point analysed by remission status at baseline in the trial. However, without any statistical analyses from the company to support this conclusion, the committee remained concerned about potential bias in the primary end point in favour of tocilizumab. It concluded that the 52‑week glucocorticoid taper arm of the trial does not reflect clinical practice in England and might bias the results in favour of tocilizumab.\n\n## Tocilizumab plus a tapering course of glucocorticoids is more effective than glucocorticoids alone\n\nThe company presented results for the overall intention-to-treat population of GiACTA, as well as for both the newly diagnosed and relapsing subgroups. The results showed that tocilizumab plus a tapering course of glucocorticoids was more effective than glucocorticoids alone at increasing the proportion of patients sustaining remission at 52\xa0weeks, and increasing the time to first flare for the overall population and both subgroups (see\xa0table\xa01). The committee recalled that in clinical practice, newly diagnosed disease and relapsing disease are managed differently, but the results were similarly effective across both subgroups. The committee concluded that tocilizumab is more effective than glucocorticoids alone at increasing sustained remission and time to first flare.\n\nPopulation\n\nSustained remission at 52 weeks (%)\n\nTime to first flare hazard ratio\n\n(99% confidence interval)\n\nMedian cumulative glucocorticoids dose (mg)\n\nOverall population:\n\ntocilizumab (n=100)\n\n\n\n\n\n(0.18 to 0.82)\n\n,862\n\nOverall population: placebo (n=51)\n\n\n\n\n\n(0.18 to 0.82)\n\n,818\n\nNewly diagnosed subgroup: tocilizumab (n=47)\n\n\n\n\n\n(0.29 to 1.59)\n\n,942\n\nNewly diagnosed subgroup: placebo (n=23)\n\n\n\n\n\n(0.29 to 1.59)\n\n,817\n\nRelapsing subgroup: tocilizumab (n=53)\n\n\n\n\n\n(0.14 to 0.81)\n\n,385\n\nRelapsing subgroup: placebo (n=28)\n\n\n\n\n\n(0.14 to 0.81)\n\n,785\n\n# Adverse events\n\n## Because tocilizumab is taken with glucocorticoids, the extent to which glucocorticoid-related adverse events are reduced is unclear\n\nThe committee considered the benefits of tocilizumab in terms of a reduction in cumulative glucocorticoid dose and risk of glucocorticoid-related adverse events. The committee noted that although the tapering regimen with tocilizumab is shorter than when glucocorticoids are used alone, disease flares are treated by increasing the glucocorticoid dose, and a tapering regimen restarted. As such, people taking tocilizumab could still be exposed to large cumulative doses of glucocorticoids. The committee acknowledged that the median cumulative glucocorticoid dose was lower in the tocilizumab arm of GiACTA (see\xa0table 1), but noted that this was over the relatively short 52‑week follow-up. It was concerned that despite the lower median cumulative glucocorticoid dose in the tocilizumab arm, the rate of glucocorticoid-related adverse events was similar between trial arms (50% compared with 49%). The committee acknowledged that this might be because many glucocorticoid-related adverse events only manifest in the longer term. In response to consultation, the company provided new evidence from post-hoc trial analyses that showed a higher rate of glucocorticoid-related adverse events being seen in the comparator arm. However, the committee was concerned that the data were analysed retrospectively and not based on standard or prespecified criteria. In addition, the company did not provide any statistical analyses to support the comparison of glucocorticoid-related adverse events between arms. The committee concluded that because glucocorticoids still need to be taken with tocilizumab, the extent to which glucocorticoid-related adverse events are reduced is unclear.\n\n# The company's economic model\n\n## The structure of the model is adequate for decision making\n\nThe company's economic model had a 30-year time horizon and included separate health states for remission based on whether patients are having glucocorticoids or not. Patients in the model could also have a flare, giant cell arteritis-related adverse events and glucocorticoid-related adverse events. Both taking glucocorticoids and disease flares were associated with a utility decrement. The committee concluded that the structure of the model was adequate for decision making.\n\n# Duration of tocilizumab treatment\n\n## A 1-year stopping rule can be implemented in NHS practice\n\nIn its original model, the company assumed that treatment with tocilizumab stops after 2\xa0years. The committee was concerned that in clinical practice treatment may continue well beyond 2\xa0years. This is because the risk of relapse continues, and there is no evidence that tocilizumab modifies the underlying disease when treatment stops (it may just supress it for the duration of treatment). In addition, tocilizumab treatment may be stopped and restarted in the event of a relapse. After consultation, however, the company argued that most patients would not need the full 2\xa0years of tocilizumab treatment. It proposed that, based on clinical expert opinion, up to 1\xa0year of treatment would be sufficient to sustain remission in the longer term and to reduce the cumulative glucocorticoid burden. The company therefore implemented a 1-year stopping rule in its revised economic model for people with relapsing or refractory disease. This stopping rule assumed that patients only had 1 course of treatment, even if they had another flare. It supported its position by providing supporting evidence from a literature review of published case reports of tocilizumab in giant cell arteritis, in which most patients had tocilizumab for less than 1\xa0year (range 1 to 53\xa0months). However, the committee was concerned that the evidence was based only on case reports, and that most included no follow-up details. Nevertheless, it noted that GiACTA showed that 1\xa0years' treatment with tocilizumab is effective in sustaining remission and reducing cumulative glucocorticoid burden. It also noted that the 1-year treatment duration provided results that were most internally valid. Both the clinical and patient experts agreed that many patients are likely to need less than 1\xa0year of tocilizumab to achieve sustainable remission, and that a 1-year stopping rule would be acceptable. As a relevant commissioner, NHS England specialised services also stated that a 1-year stopping rule could be implemented in NHS practice. The committee therefore concluded that it would include the 1-year stopping rule in its decision making.\n\n# Extrapolation of time to first flare\n\n## The company's extrapolation after 52\xa0weeks lacks validity\n\nIn order to extrapolate time to first flare beyond the 52\xa0weeks of the trial, the company fitted separate parametric models to the 2 arms (weekly tocilizumab with 26‑week prednisone taper and placebo with 52‑week prednisone taper) in its economic model. It used a Weibull distribution for the weekly tocilizumab arm (implying a decreasing risk of flare over time) and an exponential distribution for the comparator arm (implying a constant risk of flare over time). The committee was concerned that extrapolating in this way meant that the benefit of tocilizumab over glucocorticoids alone was assumed to continue for the 30-year time horizon of the model, despite tocilizumab treatment stopping at 2\xa0years. Moreover, the extrapolation for the comparator arm was based on the glucocorticoid taper period, when the risk of flare is highest. The committee was concerned that this would exaggerate the risk of flare for patients in the comparator arm that had successfully completed the 52‑week glucocorticoid taper. The clinical experts explained that after 10\xa0years, they would expect around 25% of people who had successfully completed a glucocorticoid taper to not have disease relapse; in contrast, at the same time point, the company's model predicted that almost all patients in the comparator arm would have disease relapse. Longitudinal cohort data also suggest that at 5\xa0years, 30% to 50% of people having glucocorticoids alone will not have disease relapse; at the same time point, the company's model predicted this to be less than 2%. The committee concluded that the company's extrapolation of time to first flare lacked validity.\n\n## The ERG's approach to extrapolation is more appropriate\n\nThe ERG suggested an alternative approach to extrapolating time to first flare for the comparator arm, in which it switches to the same Weibull distribution as the weekly tocilizumab arm after 2\xa0years. The committee considered that this addressed the issue of the relative benefit of tocilizumab continuing after treatment stops, because all patients that have successfully completed the taper in either arm have the same decreasing risk of disease relapse. Using this approach, the ERG predicted that at\xa0year 5 around 12% of patients in the comparator arm would not have relapsing disease (falling to 8% by\xa0year 10). The committee concluded although the ERG's approach may still overestimate the risk of flare in the comparator arm, it provided more clinically realistic estimates of the proportion of patients with disease relapse after having glucocorticoids alone.\n\n# Estimating rates of subsequent flares\n\n## The ERG's approach results in more realistic estimates of subsequent flares\n\nThe company used GiACTA data to estimate rates of subsequent flares that were used in the economic model. The ERG noted that the company's estimate for the tocilizumab newly diagnosed subgroup was higher than for the relapsing subgroup, which is clinically implausible. In addition, the company's model predicted a high number of flares for people having glucocorticoids alone, which lacks validity. For example, over the same period of 10\xa0years, a longitudinal cohort study of people with giant cell arteritis taking glucocorticoids alone (Labarca\xa0et\xa0al.\xa02016) reported less than half the flares predicted by the company's model. The ERG derived probabilities based on this study that were logically consistent across the subgroups. The committee considered that when the ERG's probabilities for subsequent flare are combined with its approach to time to first flare extrapolation, the predicted mean number of flares over the model time horizon for the comparator arm is more plausible than the company's approach. In the company's revised model for people with relapsing or refractory disease, it proposed an additional 10% adjustment to the ERG's estimated rates of subsequent flares to provide a better estimate in the control arm of the relapsing subgroup. The ERG stated that this had already been accounted for in its own estimates, so no adjustments were needed. The committee concluded that the ERG's approach to estimating the probability of subsequent flares was more appropriate.\n\n# Utility values in the model\n\n## The company's model adequately captures the negative effect of flares and glucocorticoids on quality of life\n\nThe company used a common utility value for the remission health state in both treatment arms, and applied a utility decrement of -0.13 for 4\xa0weeks to capture how a flare negatively affects quality of life. The company accounted for the negative effects of glucocorticoids by including increased probabilities of diabetes and fracture in the model, which are associated with costs and disutilities. In addition, all patients having glucocorticoids in the model were assigned a utility decrement of -0.07 for the duration of their treatment, reflecting the negative effects of common side effects such as weight gain and skin changes. The committee acknowledged that the disutility estimate does not include an exhaustive list of adverse events that can result from glucocorticoid treatment, but considered the source to be the most relevant reference. The ERG noted that within the disutility estimate is a separate 'base' disutility estimate (‑0.03) to capture common side effects for all patients having glucocorticoids. This was applied during each cycle patients were in the subsequent remission state. It assumed, after a relapse, people would continue to incur both the 'base' disutility and the specific side effects for the remainder of their lifetime. The ERG considered that unless patients continued to have lifelong treatment with glucocorticoids, it might not be appropriate to continue applying the 'base' disutility. Nevertheless, the committee concluded that the company's model adequately captures the negative effect of flares and glucocorticoids on quality of life.\n\n# The company's updated economic analysis\n\n## The company's ICER for tocilizumab in relapsing or refractory disease is £18,801\xa0per\xa0QALY gained with a 1-year stopping rule\n\nThe company's original base-case deterministic incremental cost-effectiveness ratio (ICER) for the overall population was £28,272\xa0per\xa0quality-adjusted life\xa0year (QALY) gained. This was based on a 2-year stopping rule and included a confidential patient access scheme discount for tocilizumab. In response to consultation, the company updated its economic model to focus only on the subgroup of people with relapsing or refractory giant cell arteritis. The updated economic model included the committee's preferred assumptions, specifically:\n\na mean age of 73\xa0years (section\xa03.4)\n\nswitching the time to first flare extrapolation for glucocorticoids alone to the same Weibull function as tocilizumab after 2\xa0years (section 3.10)\n\nbasing the probabilities of subsequent flares on longitudinal cohort data (section\xa03.12).The updated model also included a number of company-preferred assumptions and corrections, specifically:\n\nincorporating a 1-year stopping rule for tocilizumab (section\xa03.9)\n\nincorporating the slowest glucocorticoid taper regimen (24\xa0months) in the comparator arm to match NHS practice\n\nincorporating the costs for emergency department visits\n\nupdating the costs of glucocorticoid-related adverse events to reflect 2017 health care utilisation, specifically:\n\n\n\nincluding additional costs for a\xa0yearly DEXA scan and prophylaxis medication\n\ninflating diabetes costs from 2005 to 2017 estimates\n\nrevising fracture costs (based on Kanis\xa0et\xa0al.\xa02007)\n\nrevising infection costs (based on Sarnes 2011)\n\n\n\nadjusting the ERG's flare rate to better reflect relapsing or refractory giant cell arteritis in the comparator arm of GiACTA\n\ncorrecting 2 programming errors: using the average weight of the relapsing and refractory population in GiACTA to calculate concomitant medication dosage (instead of the UK population), and correcting the\xa0yearly concomitant medication costs applied to the comparator arm.When incorporating these changes, the deterministic ICER for tocilizumab plus prednisolone compared with prednisolone alone, incorporating the confidential patient access scheme, was £18,801\xa0per\xa0QALY gained in people with relapsed or refractory giant cell arteritis (a probabilistic ICER was not provided).\n\n# The ERG's updated alternative economic analysis\n\n## The ERG's ICER for tocilizumab in relapsing and refractory disease is £24,977\xa0per\xa0QALY gained when a 1-year stopping rule is applied\n\nThe ERG's original base-case probabilistic ICER for the overall population was £65,801\xa0per\xa0QALY gained. This was based on a 2-year stopping rule and included the committee's preferred assumptions. A confidential patient access scheme discount for tocilizumab was also applied. The ERG's revised economic model included a 1-year stopping rule, and focused only on people with relapsing or refractory disease. It made a number of other changes in its revised model, specifically:\n\nusing both the average weight and body surface area estimates of the relapsing or refractory population in GiACTA to calculate the dosages of concomitant medication\n\nincorporating an alternative estimate for emergency department visits based on NHS reference costs\n\nincluding costs for a single DEXA scan, instead of\xa0yearly scans, and using average generic cost estimate for oral therapies (taken from NICE's technology appraisal guidance on bisphosphonates for treating osteoporosis)\n\nusing fracture cost estimates that are consistent with those used in NICE's technology appraisal guidance on bisphosphonates for treating osteoporosis.The ERG did not consider the company's proposed change to the glucocorticoid tapering regimen to be appropriate, because only the cost of the comparator glucocorticoid taper regimen was adjusted and no adjustment was made to address the uncertainties about how this may affect the number of flares and time to first flare. The ERG also noted that the reference data used to update the infection costs in the company's updated economic model was taken from a US study (Sarnes 2011), so the generalisability of the findings to the NHS is unclear. In addition, the ERG considered the company's proposed additional adjustment to the ERG's estimated rates of subsequent flares (section\xa03.12) to be inappropriate. The ERG therefore did not make these changes in its revised analysis. When the ERG made its adjustments, the revised model produced ICERs for tocilizumab plus prednisolone compared with prednisolone alone of £24,977 (deterministic) and £24,032 (probabilistic)\xa0per\xa0QALY gained in people with relapsed or refractory giant cell arteritis (including the patient access scheme discount).\n\n# The most plausible ICER after consultation\n\n## Tocilizumab is cost-effective only for relapsing or refractory giant cell arteritis and when a 1-year stopping rule is applied\n\nThe committee preferred the ERG's estimates for both the overall population and people with relapsing or refractory giant cell arteritis, because they better reflected its preferred assumptions. It therefore concluded that the most plausible ICERs for tocilizumab plus prednisolone compared with prednisolone alone, incorporating the confidential patient access scheme, were £65,501 (2-year treatment duration) and £36,960 (1-year treatment duration)\xa0per\xa0QALY gained for the overall population and £55,924 (2-tear treatment duration) and £24,977 (1-year treatment duration)\xa0per\xa0QALY gained for people with relapsing or refractory giant cell arteritis. The ICERs for the overall population were higher than the range normally considered to be a cost-effective use of NHS resources (usually £20,000 to £30,000\xa0per\xa0QALY), as were the ICERs when a 2-year treatment duration was applied, so the committee concluded that it would recommend tocilizumab as a cost-effective use of NHS resources only for treating relapsing or refractory giant cell arteritis and if a 1-year stopping rule is applied.\n\n# Other factors\n\n## There are no additional benefits that are not captured in the QALY calculations\n\nThe clinical experts highlighted that tocilizumab is the first new treatment for giant cell arteritis in several\xa0years. The committee was aware that before its marketing authorisation was granted, tocilizumab received a Promising Innovative Medicines designation for this indication. The patient experts explained that high doses of glucocorticoids are needed to treat flares and afterwards the tapering regimen must be restarted. This can have a large negative effect on quality of life, which may not be captured in the modelling. However, the committee noted that in the model, patients have a substantially lower utility during a flare, which is assumed to last for 4\xa0weeks (section\xa03.8). In addition, after a disease flare, all patients have glucocorticoids and this is associated with a utility decrement (section\xa03.13). The committee concluded that there were no additional benefits that had not been captured in the QALY calculation.\n\n## The recommendations do not have a different impact on people protected by equality legislation than on the wider population\n\nThe committee discussed equality issues, and agreed that its recommendations apply equally regardless of age. In addition, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal. The committee concluded that its recommendations do not have a different impact on people protected by the equality legislation than on the wider population."}
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https://www.nice.org.uk/guidance/ta518
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Evidence-based recommendations on tocilizumab (RoActemra) for treating giant cell arteritis in adults.
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a3636ec44ea213bdf0a9082e17592793725a84dd
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nice
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Care and support of people growing older with learning disabilities
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Care and support of people growing older with learning disabilities
This guideline covers care and support for adults with learning disabilities as they grow older. It covers identifying changing needs, planning for the future, and delivering services including health, social care and housing. It aims to support people to access the services they need as they get older.
# Context
People with learning disabilities are now living significantly longer. The population of older people with learning disabilities will increase 4 times faster than the overall adult learning disability population (see People with learning disabilities in England. Emerson and Hatton 2008). As they grow older, people with learning disabilities have many of the same age-related health and social care needs as other people but they also face specific challenges associated with their learning disability. Many people with learning disabilities, especially those with milder disability, are not known to health or social services (see People with learning disabilities in England 2013. Public Health England 2014), whereas others may find it difficult to express their needs and be heard. Management of their needs will therefore be more complex than for other populations. This will create substantial pressure on services, which has not yet been fully quantified.
People with learning disabilities have a poorer health profile than the general population. For example, there is a high prevalence of dementia in people with Down's syndrome. Practitioners may have difficulty distinguishing the symptoms of a condition such as dementia from those associated with learning disabilities, or with other mental health difficulties. People with learning disabilities may also have poorer health resulting from lifestyle issues such as diet and exercise for which they have not received enough advice and support.
People with learning disabilities also face barriers to accessing healthcare, including health and dental checks. The Michael report on Healthcare for all: independent inquiry into access to healthcare for people with learning disabilities (2008) and the subsequent Confidential inquiry into premature deaths of people with learning disabilities (CIPOLD, Heslop et al. 2013) identified a failure of services to take account of the needs of people with learning disabilities and make reasonable adjustments. This led to misdiagnosis and, in some instances, premature death. People with learning disabilities may have an increased risk of mortality from conditions associated with their learning disability (for example, epilepsy and aspiration pneumonia). Such conditions are often diagnosed late in the course of illness.
Adults with learning disabilities are far more likely to have sensory impairment compared with the general population, but are less likely to access sight or hearing checks, particularly if they are living independently or with family. Sensory impairment is also a barrier to accessing services.
Older people with learning disabilities also have particular housing and social support needs. Two‑thirds of adults with learning disabilities live with their families, usually their parents. In some instances, they may be caring for an older frail parent while they too are getting older. Eventually, ageing family carers may reluctantly explore alternative care arrangements when they are no longer able to provide long-term care. More serious is when family care ends through parental illness or death and, due to lack of future planning, the person may be moved inappropriately, or have multiple moves.
For people living in homes designed for adults with learning disabilities, these may be considered unsuitable for them as they age, which can lead to a move. Older people with learning disabilities are thus likely to be placed in older people's residential services at a much younger age than the general population, even though this may not meet their preferences or needs, especially in relation to communication, support and activities.
The purpose of this guideline is to help commissioners and providers identify, plan and provide for the care and support needs of people growing older with learning disabilities and their families and carers. It covers integrated commissioning and planning; service delivery and organisation; providing accessible information, advice and support; identifying and assessing people's changing needs; care planning; and supporting access to services including health, social care, housing and end of life care. It aims to ensure that people with learning disabilities are given the help they need to access a range of services as they grow older so they can live healthy and fulfilled lives.
The guideline covers care and support in all settings, including people's homes and family homes, temporary accommodation, supported living (see the KeyRing network and Shared Lives schemes) and specialist accommodation. It also covers day services, residential and nursing homes, and primary and secondary healthcare.
A specific age limit is not used in this guideline because adults with learning disabilities typically experience age-related difficulties at different ages, and at a younger age, than the general population. The guideline does not cover people on the autistic spectrum who do not have a learning disability.
This guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. Relevant legislation and guidance includes:
Care Act 2014 and associated guidance
Equality Act 2010
Mental Capacity Act 2005 (amended 2007) and associated guidance on Deprivation of liberty safeguards
Mental Health Act 2007.
Safeguarding is the responsibility of all practitioners. Practitioners must be familiar with, and follow, their local safeguarding procedures.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Overarching principles
## Access to services and person-centred care
Ensure that people growing older with learning disabilities have the same access to care and support as everyone else. In line with the Equality Act 2010, this must be based on their needs and irrespective of:
age
disability
gender reassignment
marriage and civil partnership
pregnancy and maternity
race, religion and belief
sex and sexual orientation
socioeconomic status
-ther aspects of their identity.
Ensure that care and support for people with learning disabilities is tailored to their needs, strengths and preferences and is not determined solely by their age or learning disability.
Service providers and commissioners must make reasonable adjustments to health, social care and housing services to ensure they are fully accessible to older people with learning disabilities and their family members and carers, in line with the Equality Act 2010.
Recognise that people with learning disabilities may be carers, but may not see themselves as such. Ask the person if they have caring responsibilities and, if so, offer them a carer's assessment to meet their needs (see NICE's guideline on supporting adult carers).
## Communicating and making information accessible
Support people's communication and information needs in line with NHS England's Accessible Information Standard. This could also include:
Seeking advice from, or referring people to, a speech and language therapist whenever needed.
Providing an independent interpreter (that is, someone who does not have a relationship with the person) so that people can communicate in their first language.
Finding out before an appointment how the person prefers to communicate and receive information.
Extending appointment times to give more time for discussion.
Giving people written information (such as appointment letters and reminders) in different languages or in an accessible format of their choice, for example Easy Read, audio books, films or by using online resources such as specialist learning disability websites.
Providing information on advocacy services and, if the person needs it and consents to it, providing an independent advocate who will attend appointments.
Using visual aids and short, clear sentences during consultations and conversations.
Talking to the person's family members and carers if appropriate, and with the person's consent.
Provide people with learning disabilities and their family members, carers and advocates with accessible, tailored information about:
the range and role of different health services (such as health checks and screening)
how to access health, social care and support services
the community and specialist services that are available, and their purpose
housing options that they could think about for the future
planning for end of life care
financial issues, including wills, trusts and benefits
how to raise a safeguarding concern if they have one.
Social care and primary care practitioners should regularly review the communication needs of people with learning disabilities as they grow older to find out if they have changed. This should usually be when:
-ther needs are being assessed, for example, during general health and dental checks
there is reason to believe their communication needs may have changed.
## Decision-making, mental capacity and consent
Health and social care practitioners must understand and take into account the Mental Capacity Act 2005 when working with people with learning disabilities, including:
assuming the person has the mental capacity to take part in decision-making unless it is established that they lack capacity
supporting people to make decisions – finding out their views, encouraging them to take part in the decision-making process and ensuring all steps have been taken to help them express their views and make their own decisions
assessing their capacity to make decisions – this assessment should take place where and with whom the person wishes
undertaking best interests decision-making when it is established that a person does not have capacity to make a decision. (NICE's guideline on decision-making and mental capacity covers supporting people to make decisions, assessing mental capacity and best interests decision-making.)
## Involving people, family members, carers and advocates
Health and social care practitioners should listen to, actively involve and value key members of the person's support network in the planning and delivery of their current and future care and support, if the person agrees to this. Regularly check people's willingness and ability to be involved in this way.
Ask people who they want to involve in planning and providing their support, regardless of whether they have close family. Be aware that some people do not have close family members, friends or carers.
Offer independent advocacy whenever it is wanted or needed by a person with a learning disability. As a minimum, it must be offered as described in the Care Act 2014, Mental Capacity Act 2005 and Mental Health Act 2007.
Find out and prioritise the needs and preferences of the person. Ensure these are not overshadowed by the decisions or preferences of others, including when the person lacks capacity.
Be aware that people with learning disabilities may need support to communicate their needs or retain information. With the person's consent, share information with their family members, carers or advocate, for example about:
any changes that might be needed to their care and support
symptoms, management and prognosis of the person's health conditions.
# Organising and delivering care and support
## Planning and commissioning local services
Health and social care commissioners should have an understanding of the needs of people growing older with learning disabilities in their area and know what mainstream and specialist services are available locally to support people as they grow older.
Commissioners should identify the number of adults in their area with a learning disability (and the number of families and carers), and use this information to identify gaps in provision, organise services and plan future provision. This could be done by encouraging GPs to develop and maintain registers of people with learning disabilities and getting information from other support services, including education and the Department for Work and Pensions.
Commissioners and service providers should ensure family members, carers and advocates of people with learning disabilities have access to age-appropriate community support services and resources such as:
day opportunities
short respite breaks (both at home and away from home)
family placements
support groups for family carers, including siblings, and for older people with learning disabilities who have caring responsibilities
a single point of contact for practical information, emotional support and signposting.
Commissioners and service providers should provide housing options that meet the changing needs of people with learning disabilities as they grow older. This includes:
making reasonable adjustments to support people to stay in their current housing as their physical and emotional needs change, for example providing equipment or housing adaptations
arranging housing for people with learning disabilities who are in unstable housing situations, for example those who are homeless or in temporary accommodation (including people seeking asylum)
supported living
residential and nursing care, which reflect gender, sexual orientation and cultural preferences.
Commissioners should make available locally a wide range of family and community support options to meet the needs of people with learning disabilities as they grow older, including the needs of people in later old age, and their family members and carers. These might include:
ensuring accessible transport links are available to help people access local facilities
access to advocacy services.
Consider the use of technologies such as telehealth and telecare to complement but not replace the support provided by people face to face.
Commissioners should identify where there are gaps in community optometry, audiology and dental services for people with learning disabilities and address those gaps.
Mental health commissioners should develop protocols to ensure that people with learning disabilities, including people in later old age, have access to mainstream mental health services for older people, including dementia support.
Commissioners and service providers should ensure that people with learning disabilities have equal access to a range of community services that reflect the cultural diversity of the local area and people's hopes, preferences, choices and abilities as they grow older.
Commissioners and service providers should establish links between specialist learning disability services and mainstream older people's services. This could be done by bringing them together to help identify gaps and inform service development, sharing information and learning, and linking into voluntary sector umbrella groups.
Commissioners and service providers should provide opportunities for people with learning disabilities to meet up and socialise, for instance through social clubs and support groups.
Commissioners and service providers should ensure there is a wide range of community-based physical activity programmes available and encourage people to take part to promote their health and wellbeing. Examples include dancing, swimming, bowls, using the gym, organised walks and chair-based exercise classes.
Commissioners and service providers should arrange accessible opportunities for people with learning disabilities to engage in education, employment and volunteering.
Local authorities should consider introducing schemes to make transport easier for older people with learning disabilities. For example:
providing free travel such as London's 'Freedom pass'
using minibuses as community transport
starting 'buddy' schemes to enable independent travel
developing transport especially for people living in rural locations
schemes such as 'JAM' cards (Just A Minute) – which can be used to alert transport staff that people have a learning disability
schemes to help people with a personal budget to travel to activities and self-advocacy groups.
# Identifying and assessing care and support needs
## Assessing people's need for care and support
Ensure that all assessments of care and support needs are strengths based, person centred and conducted as early as possible. Follow the recommendations on care and support needs assessment in NICE's guideline on people's experience in adult social care services.
Practitioners carrying out assessments of care and support needs should have:
access to the person's full history (medical, social, psychological and the nature of their learning disability) and
an understanding of their usual behaviour.
Practitioners carrying out assessments of care and support needs should be alert to any changes in the person's usual behaviour. This could include how they are communicating or their activity levels, and symptoms (such as weight loss, changes in sleeping patterns or low mood) that could show something is wrong or they are unwell.
Be aware that people growing older with learning disabilities might have difficulty communicating their health needs. When their needs change, think about whether these changes could be age-related and do not assume they are due to the person's learning disability or pre-existing condition (diagnostic overshadowing).
Practitioners carrying out assessments of care and support needs should help people to think about what they want from life as they age. This should include:
asking people how they would like to spend their time and with whom, and enabling them to explore personal and sexual relationships
encouraging them to develop support networks and to build and maintain links with friends and family and with community groups – these might include social, cultural and faith-based groups.
## Assessing the needs of family members and carers
Practitioners carrying out assessments of care and support needs should take into account the needs, capabilities and wishes of families and carers. Also take into account that there may be mutual caring between people with learning disabilities, and their family members and carers, who are likely to be older themselves and have their own support needs.
Practitioners must offer people who are caring for a person with a learning disability their own carer's assessment, in line with the Care Act 2014.
Based on assessment, provide families and carers with support that meets their needs as carers (see NICE's guideline on supporting adult carers).
Review the needs and circumstances of carers at least once a year and if something significant changes (see NICE's guideline on supporting adult carers).
Actively encourage carers to register themselves as a carer, for example, with their GP.
# Planning and reviewing care and support
## Person-centred planning and review
Practitioners should carry out regular person-centred planning with people growing older with learning disabilities to address their changing needs, wishes and capabilities and promote their independence. This should include planning for the future (see recommendations 1.4.5 to 1.4.13). Involve their family members, carers and advocates as appropriate.
Include transport needs in people's care and support plans, to help them get to services, appointments and activities.
Local authorities should plan people's care and support in a way that meets the needs of all family members, as well as the person themselves. This might include combining the personal budgets of different family members.
Give help and information to families and carers, including siblings, as part of planning and providing support for people growing older with learning disabilities. For example, tell them about sources of support for people after a family bereavement.
## Planning for the future
Health and social care practitioners should work with the person and those most involved in their support to agree a plan for the future. Help them to make decisions before a crisis point or life-changing event is reached (for example, the death of a parent or a move to new housing).
Planning for the future should:
be proactive
be led by the person themselves with input from family members, carers or advocates as appropriate (regardless of whether they provide care and support themselves)
involve a practitioner who has a good relationship with the person and communicates well with them
involve practitioners who have good knowledge of local resources
take into account the whole of the person's life, including their hopes and dreams as well as the things they do not want to happen
include considering the needs of family members and carers
seek to maintain the person's current support and housing arrangements, if this is their preference
be reviewed every year and whenever the person's needs or circumstances change.
Include as key components of a future plan:
Housing needs and potential solutions.
Any home adaptations or technology that may address people's changing needs as they grow older.
Members of the person's support network (both paid and unpaid).
Any help the person gives to family members, whether this will continue as they age, and the impact this may have on their health and wellbeing.
Planning for what will happen if someone who the person relies on dies, or is no longer able to provide care and support.
Financial and legal issues, for example whether someone has been appointed to have lasting power of attorney for the person.
The provision of information on wills, trusts and benefits.
Planning for unexpected changes or emergencies.
Planning for a time when the person may lack capacity to make decisions themselves, in line with the Mental Capacity Act 2005.
Consideration of deprivation of liberty safeguards, for instance if planned changes to care or the care environment are likely to increase restrictions on the person.
End of life care decisions – including where the person wants to be when they die. These decisions should be reviewed at least once a year.
When helping the person plan where they will live in the future and who they will live with, take into account whether other family members rely on them for support.
Encourage and support people to be active and independent at home regardless of their age or learning disability. This might include doing household tasks, making their own decisions and plans or leading group activities.
Make reasonable adjustments to people's homes as they grow older to make it possible for them to stay in their current home if they want to. For example, consider a support phone line, daily living equipment, telehealth monitoring and home adaptations, such as shower room conversion, wider doorways or a lift between floors.
Review at least once a year the housing needs of people who are being supported by social care staff at home.
Ensure that the person is centrally involved in any decisions about moving from where they currently live. Also include an advocate or, if appropriate, a family member or carer.
If a move is agreed with the person, practitioners should work with them and their support network to start planning for this straightaway. Planning could include:
arranging for the person to visit the new setting
discussing how they will maintain their existing support networks and develop new ones.
# Identifying and managing health needs
Healthcare practitioners should encourage people growing older with learning disabilities to choose a family member, carer or advocate to bring with them to medical examinations and appointments if they would like this support.
Explain clearly to people with learning disabilities what will happen during any medical appointments as well as their likely follow‑up care. In line with the Mental Capacity Act 2005, healthcare practitioners must take all reasonable steps to help the person understand this explanation.
As well as explaining to people beforehand what will happen, continue to explain what is happening throughout the appointment and ensure there is enough time set aside to do this. If the person agrees, also explain to their family member, carer or advocate what will happen.
If the person needs a medical examination, give them a choice, wherever possible, about where it takes place. Aim to do it in a place that is familiar to them, which is welcoming and appropriate to their needs.
Support family members and carers, for example by providing information, so that they can help people with learning disabilities to access health services.
Consider commissioning training for people and their family members and carers in recognising changes and managing age-related conditions such as:
blood pressure and cholesterol
cancer
changes to skin condition such as itchy or fragile skin
dementia
diabetes
dysphagia (difficulty swallowing)
epilepsy
hearing loss and sight problems
incontinence
-steoporosis
malnutrition
menopausal symptoms
mental health, including depression
thyroid problems.
## Coordinating care and sharing information
Managers in healthcare settings should identify a single lead practitioner to be the point of contact for people with learning disabilities and their family members, carers and advocates. This practitioner could be a member of the community learning disability team or a nurse with experience in learning disabilities.
Ensure that everyone involved in the person's care and support shares information and communicates regularly about the person's health and any treatment they are having, for example by holding regular multidisciplinary meetings. Involve the person in all discussions.
Primary and secondary healthcare teams should identify at least 1 member of staff who develops specific knowledge and skills in working with people with learning disabilities and acts as a champion, modelling and sharing good practice. Use the expertise of people with learning disabilities to ensure the champion understands their needs.
Record a person's learning disability and any reasonable adjustments in their health records and share this information when making referrals. With the person's consent, make sure all relevant practitioners in community and acute settings can access this. Also record any specific needs or wishes, for example to do with the person's communication or mobility.
## Health checks and screening
Recognise that people with learning disabilities may need additional health surveillance to help them identify and communicate symptoms of age-related conditions.
Offer annual health checks to older people with learning disabilities as long as these are followed by prompt referral to specialist services wherever needed. Explain what annual health checks involve and how to arrange them. Record any actions identified by the annual health check in the person's health action plan.
Offer older people with learning disabilities the same routine screening and health checks as other older people.
Discuss with people the changes that may occur with age. Ask them about and monitor them for symptoms of common age-related conditions or changes in any existing conditions, including:
blood pressure and cholesterol
cancer
dementia (also see recommendations 1.5.36 and 1.5.37).
diabetes
dysphagia (difficulty swallowing)
epilepsy
hearing loss and sight problems
incontinence
-steoporosis
malnutrition
menopausal symptoms
mental health, including depression
thyroid problems.
During a person's annual health check, give them information about other available services, including a care and support assessment under the Care Act 2014 if they have not already had one.
During a person's annual health check, ask if they are registered with a dentist, how often they see the dentist and check that they understand the importance of looking after their teeth and mouth.
Give people clear, accessible and practical information and advice about keeping well as they grow older. Tell them about, and help them access, services such as breast screening, smear tests, testicular and prostate checks, dental checks, hearing and sight tests, and podiatry.
When designing and delivering breast screening services, address specific barriers to accessing breast screening among older women with learning disabilities, including support to:
understand breast cancer
understand the screening procedure
be breast aware and check their breasts regularly
understand any information provided
attend appointments.
## Primary care
Primary care and community services should aim to ensure that older people with learning disabilities can see the same GP and other healthcare practitioners, wherever possible, to help practitioners:
become familiar with the person's medical history, which the person may have difficulty remembering themselves
build good relationships and understand the person's usual behaviour and communication needs.
General practices should allocate a named member of staff to remind people with learning disabilities about appointments for screening and health examinations. This staff member should help the person attend the appointment by:
using each person's preferred method of communication
giving them information in a way they can understand
ensuring the person understands the reason for the appointment and why it is important
finding out their transport needs
making reasonable adjustments to help the person and their carer or supporter to attend.
If the person is diagnosed with a health condition, give them and their family members, carers or advocate accessible information on the following (taking time to explain it to them as well):
symptoms and management
benefits, and potential side effects, of treatment
how to take their prescribed medicines.
Support people to manage their own health conditions by getting to know them and adapting health advice to suit their personal choices and the activities they already enjoy (for example, playing football).
## Dental care
Commissioners and managers should ensure that support staff have knowledge of oral health so they can support people with learning disabilities to maintain good oral health and access dental services.
Dental practices should ensure their services are accessible to people with learning disabilities, for example by:
reminding people about their appointments by phone
sending letters in an accessible format, for example Easy Read
suggesting that the person brings a carer or supporter with them
ensuring staff have the skills to communicate with people with learning disabilities and put them at ease. For further guidance on managing oral health, see the NICE guidelines on:
-ral health promotion: general dental practice
-ral health for adults in care homes.
## Outpatient appointments
Hospitals should offer an opportunity for the person and a family member, carer or advocate to visit the hospital before their outpatient appointment to meet the staff who will conduct any tests or examinations, see the equipment that will be used and identify what adjustments will be needed.
## Before and during a hospital stay
When planning a hospital admission, arrange a pre-admission planning meeting, including the hospital liaison team or liaison nurse, a representative of the community learning disability team, the person and their family members, carers or advocate. At this meeting:
complete the pre-admission documentation, which should include information from the person's hospital passport
discuss any reasonable adjustments needed, for example, arranging for the person to visit the hospital before their admission to meet the learning disability liaison nurse who will be their contact.
Hospitals should actively encourage staff to use pre-admission documents and flagging systems so that all relevant hospital staff know about the person's learning disability. At discharge, review how well this is working.
Hospitals should develop policies and guidance to enable someone chosen by the person to stay with them throughout their inpatient stay, including overnight.
Hospital staff should continue to offer health and personal care (toileting, washing, nutrition and hydration) to people with learning disabilities even if they have a family member, carer or advocate there to support them.
For further guidance on planning admission and admitting adults with identified social care needs to hospital, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.
## Transfer of care from hospital
If the person agrees, invite family members, carers or advocates to pre-discharge meetings, as well as the person themselves.
If the discharge plan involves support from family members or carers, take into account their:
willingness and ability to provide support
circumstances, needs and aspirations
relationship with the person
need for respite (short breaks).
Give the person (and their family members and carers) an accessible copy of their discharge plan when they are discharged, and make sure their GP has a copy within 24 hours. Make sure everyone knows what will happen next in the person's care and support.
After the person is discharged, the hospital learning disability liaison nurse, community learning disability team and primary care practitioners should work together to provide ongoing support to help the person manage their health condition.
For further guidance on discharging adults with identified social care needs from hospital, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.
## Dementia
Explain at an early stage to people with learning disabilities (particularly people with Down's syndrome) and their family members, carers and advocates about the link between learning disabilities and dementia. Explain the signs of dementia, how it usually progresses and what support is available. Give people:
printed information on dementia
-pportunities for one-to-one discussion with a professional
advice on communication strategies for people with dementia.
Commissioners should ensure information is provided to family members, carers and advocates of people with learning disabilities who are being assessed for, or have been diagnosed with dementia. Consider also providing training. Information and training might cover:
types of dementia
how dementia might present in people with different learning disabilities
care pathways for different dementias
practical steps to manage daily life
communication skills
how to find further advice and ongoing support, including support groups and respite services (short breaks).
# End of life care
## Access to end of life care services
Give people growing older with learning disabilities and their family members, carers and advocates accessible, timely and person-centred information about all the potential care options available for end of life care, including hospice services.
## Making sure end of life care is person centred
Practitioners providing end of life care should spend time getting to know the person to understand their needs. Get to know how they communicate, their cultural background, what they like and dislike, how they express pain, their health conditions and the medication they are taking. Be aware that this understanding will make it easier to identify when the person's health is deteriorating.
Identify who the person would like to involve in creating their end of life plan. Include the person themselves and everyone who supports them in discussions and planning.
Ask the person regularly who they would like to involve in discussions about their end of life plan, in case they change their mind. Do this every 6 months, or more often if the person is close to the end of life.
Make it possible for the person to die where they wish. This might include adapting their home, working with other practitioners and advocates, and talking to other residents or family members about changes that could be made (for example, moving the person to a room on the ground floor).
## Involving families and support networks
During end of life care planning, talk to the person and their family members, carers or advocate to understand the person's wishes and any cultural needs at the end of their life.
When providing end of life care, learn from family members, carers or advocates about the person's needs and wishes, including those associated with faith and culture, nutrition, hydration and pain management. This is particularly important if the person has difficulty communicating.
Learning disability providers delivering care at the end of life should work collaboratively and share information with other practitioners and services involved in the person's daily life.
Social care providers should work in partnership with healthcare providers to share knowledge about the person and to develop expertise for end of life care.
Provide training, information and support for family members and carers, for example, in medication, pain, nutrition and hydration, to enable the person to die where they wish.
Make sure that key members of the person's support network have the knowledge, confidence and understanding to communicate with the person about their illness and death. This includes being able to talk to the person about symptoms, pain management and their preferences about resuscitation.
Mainstream end of life care services should make reasonable adjustments to support the person, their family members, friends and carers and other people they live with, throughout palliative and end of life care and bereavement.
For further guidance on end of life care, see NICE's guideline on care of dying adults in the last days of life.
# Staff skills and expertise
Managers in health and social care services should ensure that staff in older people's services have the expertise to support people growing older with learning disabilities from a wide range of backgrounds.
Managers in health and social care services should ensure that learning disability staff have the skills and understanding to support people's changing needs as they grow older. Provide this skilled support in all settings, including people's own homes.
Managers in health and social care services should ensure that all staff working with people with learning disabilities have skills and knowledge in:
communication methods, including non-verbal communication
building good relationships with people with learning disabilities and making them feel at ease
the physical, mental health and sensory needs of older people with learning disabilities, related to both their age and disability
the application of the Mental Capacity Act 2005
safeguarding issues, including how to report concerns and keep people safe
common health conditions to which people with learning disabilities are predisposed, for example, the earlier onset of dementia
assessing people's changing needs as they grow older, and not assuming that any new problems are due to their learning disability when they could be symptoms of other conditions or difficulties (diagnostic overshadowing)
the main causes of early death in people with learning disabilities.
Managers in health and social care services should provide opportunities for learning disability staff and practitioners working with older people to share expertise with each other as part of their knowledge and skills development.
Staff should know what local services are available (including housing options) so they can support people with learning disabilities and their family members, carers and advocates to make informed choices about their care and support.
## Staff skills and expertise for supporting end of life care
Commissioners and providers of end of life care should recognise the complex needs of people with learning disabilities. They should provide ongoing training for staff to ensure they have the expertise to provide good-quality coordinated care, enabling people to die in their own home or another place of their choice. Training should include:
having discussions about resuscitation intentions
finding out and responding to cultural preferences
recognising pain and discomfort
managing symptoms, pain and medication
nutrition and hydration
understanding communication preferences and being able to communicate – this might include using augmentative and alternative communication methods.
Provide in‑service training for learning disability and palliative care practitioners so they have the skills to support people at the end of life. This might include joint study days and training of professionals by people with learning disabilities and their family members and carers.
# Terms used in this guideline
## Annual health check
An NHS initiative for adults and young people aged 14 and over with learning disabilities to provide additional health support and help to identify health conditions that could otherwise go undetected.
## Augmentative and alternative communication
An umbrella term that includes methods of communication to supplement or replace speech or writing for people who need support to understand or express language.
## Diagnostic overshadowing
In this guideline, this is used to mean the tendency to attribute all behavioural, emotional, physical and social issues to a person's learning disability or a pre-existing condition, while overlooking the possibility that they could be symptoms of other conditions or difficulties. An example would be attributing challenging behaviour to a learning disability when it could be a reaction to abdominal pain, which in turn might be symptomatic of a physical health problem.
## Family members and carers
This includes people who are related to the person with a learning disability and anyone else who helps to provide informal support, for example friends. It does not cover staff who are paid to provide care or support.
## Health action plan
A personal plan for people with learning disabilities about how to stay healthy. It should detail what help and support they need to look after their health. This might include support to manage physical or mental health conditions, or actions in relation to lifestyle issues such as diet and exercise.
## Hospital passport
A hospital passport is designed to give hospital staff useful information that is not limited to illness and health. For example, it could include details about what the person likes and dislikes in terms of physical contact or food and drink. The idea is to help hospital staff understand how to make the person feel comfortable.
## Lasting power of attorney
Lasting power of attorney is a legal document that lets someone appoint one or more people to make decisions on their behalf, should they be unable to. Lasting power of attorney can be made in relation to health and welfare, and property and financial affairs.
## People growing older with learning disabilities
For the purpose of this guideline, a learning disability is defined as meeting 3 core criteria:
lower intellectual ability (usually an IQ of less than 70)
significant impairment of social or adaptive functioning
-nset in childhood.
A person's learning disability may be mild, moderate, severe or profound in severity. Learning disabilities are different from specific learning difficulties such as dyslexia, which do not affect intellectual ability.
A specific age limit is not used to define older people because adults with learning disabilities typically experience age-related difficulties at different ages, and at a younger age than the general population. This is reflected in the guideline title 'people growing older with learning disabilities'. Within the recommendations, this long form is used at the beginning of each section but in subsequent recommendations 'people' or 'people with learning disabilities' is used as a short hand. In all cases, the intended population is 'people growing older with learning disabilities'.
## Practitioner
In this guideline, 'practitioner' is used to mean a health or social care practitioner who provides care and support for older people with learning disabilities.
## Support network
All the people who provide emotional and practical help to a person with a learning disability. A person's support network could include their family (including siblings), friends, carers, advocates, non-family members living with the person in supported housing, and members of the person's religious community.
For other social care terms, see the Think Local, Act Personal care and support jargon buster.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Ensuring integrated, person-centred care and support for people growing older with learning disabilities, and their families and carers. This will mean health and social care practitioners and providers involving and listening to the person and their family and carers, and agreeing a care plan that reflects their needs and aspirations. Offering an annual health check, including explaining what it will involve and how to arrange it, is an important part of this. It will also mean challenging assumptions and looking beyond the person's learning disability to provide the support needed to help them live an active, community-involved life.
Ensuring a well-trained and supported workforce, with the knowledge needed to support people growing older with learning disabilities. Health and social care services are structured in a way that tends to mean practitioners work in either learning disability or older people's services, and their training and support reflects this. Moving to a workforce with expertise from across both disciplines may be challenging to achieve.
Planning and commissioning local health, social care and housing services to meet the needs of the local population. Commissioners need to know the size of their local population of adults with learning disabilities, and any likely future growth in this population. Learning disability services are often seen as separate from other services, but all pathways of care and support need to consider the needs of people with learning disabilities in order to improve access and funding.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Recommendations for research
The guideline committee has made the following recommendations for research. The full list of research recommendations is in the full guideline.
# Models of care and support at home
What is the effectiveness and cost effectiveness of care and support models (for example, assistive technology) for people growing older with learning disabilities to enable them to live in the family home?
## Why this is important
There is no evidence from studies published later than 2005 about the effectiveness and cost effectiveness of care and support models for people growing older with learning disabilities living in the family home, or about their experiences of that support. For example, we did not identify any evidence on the effectiveness and cost effectiveness of assistive technology for supporting older people with learning disabilities and their ageing family carers.
Comparative studies are needed to evaluate the costs and impact of different approaches, like assistive technology, on care and support for older people with learning disabilities in the family home. Resource use information, demonstrating the impact on paid and unpaid care (whether it increases or decreases as a result of the different support models) is needed as well as outcome data relating to families and carers. These should be supplemented by qualitative studies to explore the views and experiences of older people with learning disabilities, including those from minority backgrounds, and their families and carers, in relation to different models of support.
# Identifying health conditions
What is the effectiveness and cost effectiveness of different ways of identifying age-related and other physical and mental health conditions, in people growing older with learning disabilities?
What can mainstream and specialist health services do to facilitate:
early identification of health conditions in people with learning disabilities?
equal access to health services in people with learning disabilities?
## Why this is important
Apart from studies on annual health checks, we did not find any evidence about different methods and pathways for identifying health conditions among people growing older with learning disabilities. There is a need for effectiveness and cost-effectiveness studies using longitudinal, comparative designs to evaluate the costs and outcomes, in particular the final health outcomes, of different approaches to identifying health conditions in people with learning disabilities. These should be complemented by qualitative studies to explore the views and experiences of people with learning disabilities, including those from minority backgrounds, and their families, carers and practitioners, on the facilitators and barriers of these approaches. This includes their views on how, where and by whom these services should be provided.
# Education and training programmes: self-management
What is the effectiveness and cost effectiveness of education programmes to improve information and advice and to support self-management of chronic health conditions (for example, obesity, diabetes and cardiovascular disease) for people growing older with learning disabilities, and their family members and carers?
## Why this is important
Evidence suggests that people growing older with learning disabilities value the medical knowledge and authority of health professionals. There is a small amount of evidence that practitioners could play a greater role in providing education and advice to support self-management of health conditions in people with learning disabilities. There is also evidence that families and carers play a central role in supporting and advising people with learning disabilities about their health conditions and promoting healthier lifestyle choices.
There is currently a lack of information about the cost effectiveness of such education programmes. However, there is evidence that people with learning disabilities are more likely to have missed appointments with health professionals, do not have optimal medication management and have problems to access to healthcare more broadly, all of which can have costly consequences; some of those might be avoided or reduced through self-management.
Comparative effectiveness and cost-effectiveness studies are needed to evaluate the impact of education programmes to support self-management for people with learning disabilities. These need to be supplemented with studies exploring the views and experiences of people with learning disabilities, including those from minority backgrounds, and their families, carers and practitioners, on the accessibility and acceptability of different approaches to supporting self-management and communicating health messages.
# Dementia education and training programmes for family members and carers
What is the effectiveness, cost effectiveness and acceptability of training programmes (for example, in the use of life story work) for families of people growing older with learning disabilities who have dementia or are at risk of developing it?
## Why this is important
No evidence was found from studies published later than 2005 about the effectiveness and cost effectiveness of interventions or training programmes for family members and carers of people growing older with learning disabilities who have, or are at risk of developing dementia. There is some evidence that some family members and carers of people with learning disabilities and dementia need specialist training in dementia care.
Comparative effectiveness and cost-effectiveness studies are needed to evaluate the impact of specific interventions or training programmes for families and carers of people with learning disabilities, including for people living with conditions such as dementia. Qualitative studies are needed to explore the views and experiences of family, friends and carers of people with learning disabilities, including those from minority backgrounds, about these training programmes.
# Advance planning about end of life care
What is the effectiveness and cost effectiveness of advance care planning for end of life care for people growing older with learning disabilities, and their family members and carers?
What processes are in place to document and follow the wishes of people growing older with learning disabilities about their decisions on end of life care?
## Why this is important
We identified no studies evaluating the effectiveness or cost effectiveness of advance care planning for end of life care in people growing older with learning disabilities, and their family members and carers. Such studies would help to determine how and what reasonable adjustments should be made to ensure that people with learning disabilities receive appropriate care at the end of life, and the costs and cost consequences associated with those. Longitudinal studies should have a naturalistic design with a control group to follow up families and carers who have used advance care planning for end of life care in people with learning disabilities.
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{'Context': "People with learning disabilities are now living significantly longer. The population of older people with learning disabilities will increase 4\xa0times faster than the overall adult learning disability population (see People with learning disabilities in England. Emerson and Hatton\xa02008). As they grow older, people with learning disabilities have many of the same age-related health and social care needs as other people but they also face specific challenges associated with their learning disability. Many people with learning disabilities, especially those with milder disability, are not known to health or social services (see People with learning disabilities in England\xa02013. Public Health England\xa02014), whereas others may find it difficult to express their needs and be heard. Management of their needs will therefore be more complex than for other populations. This will create substantial pressure on services, which has not yet been fully quantified.\n\nPeople with learning disabilities have a poorer health profile than the general population. For example, there is a high prevalence of dementia in people with Down's syndrome. Practitioners may have difficulty distinguishing the symptoms of a condition such as dementia from those associated with learning disabilities, or with other mental health difficulties. People with learning disabilities may also have poorer health resulting from lifestyle issues such as diet and exercise for which they have not received enough advice and support.\n\nPeople with learning disabilities also face barriers to accessing healthcare, including health and dental checks. The Michael report on Healthcare for all: independent inquiry into access to healthcare for people with learning disabilities (2008) and the subsequent Confidential inquiry into premature deaths of people with learning disabilities (CIPOLD, Heslop et al.\xa02013) identified a failure of services to take account of the needs of people with learning disabilities and make reasonable adjustments. This led to misdiagnosis and, in some instances, premature death. People with learning disabilities may have an increased risk of mortality from conditions associated with their learning disability (for example, epilepsy and aspiration pneumonia). Such conditions are often diagnosed late in the course of illness.\n\nAdults with learning disabilities are far more likely to have sensory impairment compared with the general population, but are less likely to access sight or hearing checks, particularly if they are living independently or with family. Sensory impairment is also a barrier to accessing services.\n\nOlder people with learning disabilities also have particular housing and social support needs. Two‑thirds of adults with learning disabilities live with their families, usually their parents. In some instances, they may be caring for an older frail parent while they too are getting older. Eventually, ageing family carers may reluctantly explore alternative care arrangements when they are no longer able to provide long-term care. More serious is when family care ends through parental illness or death and, due to lack of future planning, the person may be moved inappropriately, or have multiple moves.\n\nFor people living in homes designed for adults with learning disabilities, these may be considered unsuitable for them as they age, which can lead to a move. Older people with learning disabilities are thus likely to be placed in older people's residential services at a much younger age than the general population, even though this may not meet their preferences or needs, especially in relation to communication, support and activities.\n\nThe purpose of this guideline is to help commissioners and providers identify, plan and provide for the care and support needs of people growing older with learning disabilities and their families and carers. It covers integrated commissioning and planning; service delivery and organisation; providing accessible information, advice and support; identifying and assessing people's changing needs; care planning; and supporting access to services including health, social care, housing and end of life care. It aims to ensure that people with learning disabilities are given the help they need to access a range of services as they grow older so they can live healthy and fulfilled lives.\n\nThe guideline covers care and support in all settings, including people's homes and family homes, temporary accommodation, supported living (see the KeyRing network and Shared Lives schemes) and specialist accommodation. It also covers day services, residential and nursing homes, and primary and secondary healthcare.\n\nA specific age limit is not used in this guideline because adults with learning disabilities typically experience age-related difficulties at different ages, and at a younger age, than the general population. The guideline does not cover people on the autistic spectrum who do not have a learning disability.\n\nThis guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. Relevant legislation and guidance includes:\n\n\n\nCare Act\xa02014 and associated guidance\n\nEquality Act\xa02010\n\nMental Capacity Act\xa02005 (amended\xa02007) and associated guidance on Deprivation of liberty safeguards\n\nMental Health Act\xa02007.\n\nSafeguarding is the responsibility of all practitioners. Practitioners must be familiar with, and follow, their local safeguarding procedures.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Overarching principles\n\n## Access to services and person-centred care\n\nEnsure that people growing older with learning disabilities have the same access to care and support as everyone else. In line with the Equality Act\xa02010, this must be based on their needs and irrespective of:\n\nage\n\ndisability\n\ngender reassignment\n\nmarriage and civil partnership\n\npregnancy and maternity\n\nrace, religion and belief\n\nsex and sexual orientation\n\nsocioeconomic status\n\nother aspects of their identity.[This recommendation is adapted from the NICE guideline on service user experience in adult mental health.]\n\nEnsure that care and support for people with learning disabilities is tailored to their needs, strengths and preferences and is not determined solely by their age or learning disability.\n\nService providers and commissioners must make reasonable adjustments to health, social care and housing services to ensure they are fully accessible to older people with learning disabilities and their family members and carers, in line with the Equality Act\xa02010.\n\nRecognise that people with learning disabilities may be carers, but may not see themselves as such. Ask the person if they have caring responsibilities and, if so, offer them a carer's assessment to meet their needs (see NICE's guideline on supporting adult carers).[This recommendation is adapted from the NICE guideline on older people with social care needs and multiple long-term conditions.]\n\n## Communicating and making information accessible\n\nSupport people's communication and information needs in line with NHS England's Accessible Information Standard. This could also include:\n\nSeeking advice from, or referring people to, a speech and language therapist whenever needed.\n\nProviding an independent interpreter (that is, someone who does not have a relationship with the person) so that people can communicate in their first language.\n\nFinding out before an appointment how the person prefers to communicate and receive information.\n\nExtending appointment times to give more time for discussion.\n\nGiving people written information (such as appointment letters and reminders) in different languages or in an accessible format of their choice, for example Easy Read, audio books, films or by using online resources such as specialist learning disability websites.\n\nProviding information on advocacy services and, if the person needs it and consents to it, providing an independent advocate who will attend appointments.\n\nUsing visual aids and short, clear sentences during consultations and conversations.\n\nTalking to the person's family members and carers if appropriate, and with the person's consent.\n\nProvide people with learning disabilities and their family members, carers and advocates with accessible, tailored information about:\n\nthe range and role of different health services (such as health checks and screening)\n\nhow to access health, social care and support services\n\nthe community and specialist services that are available, and their purpose\n\nhousing options that they could think about for the future\n\nplanning for end of life care\n\nfinancial issues, including wills, trusts and benefits\n\nhow to raise a safeguarding concern if they have one.\n\nSocial care and primary care practitioners should regularly review the communication needs of people with learning disabilities as they grow older to find out if they have changed. This should usually be when:\n\nother needs are being assessed, for example, during general health and dental checks\n\nthere is reason to believe their communication needs may have changed.\n\n## Decision-making, mental capacity and consent\n\nHealth and social care practitioners must understand and take into account the Mental Capacity Act\xa02005 when working with people with learning disabilities, including:\n\nassuming the person has the mental capacity to take part in decision-making unless it is established that they lack capacity\n\nsupporting people to make decisions – finding out their views, encouraging them to take part in the decision-making process and ensuring all steps have been taken to help them express their views and make their own decisions\n\nassessing their capacity to make decisions – this assessment should take place where and with whom the person wishes\n\nundertaking best interests decision-making when it is established that a person does not have capacity to make a decision. (NICE's guideline on decision-making and mental capacity covers supporting people to make decisions, assessing mental capacity and best interests decision-making.)\n\n## Involving people, family members, carers and advocates\n\nHealth and social care practitioners should listen to, actively involve and value key members of the person's support network in the planning and delivery of their current and future care and support, if the person agrees to this. Regularly check people's willingness and ability to be involved in this way.\n\nAsk people who they want to involve in planning and providing their support, regardless of whether they have close family. Be aware that some people do not have close family members, friends or carers.\n\nOffer independent advocacy whenever it is wanted or needed by a person with a learning disability. As a minimum, it must be offered as described in the Care Act\xa02014, Mental Capacity Act\xa02005 and Mental Health Act\xa02007.\n\nFind out and prioritise the needs and preferences of the person. Ensure these are not overshadowed by the decisions or preferences of others, including when the person lacks capacity.\n\nBe aware that people with learning disabilities may need support to communicate their needs or retain information. With the person's consent, share information with their family members, carers or advocate, for example about:\n\nany changes that might be needed to their care and support\n\nsymptoms, management and prognosis of the person's health conditions.\n\n# Organising and delivering care and support\n\n## Planning and commissioning local services\n\nHealth and social care commissioners should have an understanding of the needs of people growing older with learning disabilities in their area and know what mainstream and specialist services are available locally to support people as they grow older.\n\nCommissioners should identify the number of adults in their area with a learning disability (and the number of families and carers), and use this information to identify gaps in provision, organise services and plan future provision. This could be done by encouraging GPs to develop and maintain registers of people with learning disabilities and getting information from other support services, including education and the Department for Work and Pensions.\n\nCommissioners and service providers should ensure family members, carers and advocates of people with learning disabilities have access to age-appropriate community support services and resources such as:\n\nday opportunities\n\nshort respite breaks (both at home and away from home)\n\nfamily placements\n\nsupport groups for family carers, including siblings, and for older people with learning disabilities who have caring responsibilities\n\na single point of contact for practical information, emotional support and signposting.\n\nCommissioners and service providers should provide housing options that meet the changing needs of people with learning disabilities as they grow older. This includes:\n\nmaking reasonable adjustments to support people to stay in their current housing as their physical and emotional needs change, for example providing equipment or housing adaptations\n\narranging housing for people with learning disabilities who are in unstable housing situations, for example those who are homeless or in temporary accommodation (including people seeking asylum)\n\nsupported living\n\nresidential and nursing care, which reflect gender, sexual orientation and cultural preferences.\n\nCommissioners should make available locally a wide range of family and community support options to meet the needs of people with learning disabilities as they grow older, including the needs of people in later old age, and their family members and carers. These might include:\n\nensuring accessible transport links are available to help people access local facilities\n\naccess to advocacy services.\n\nConsider the use of technologies such as telehealth and telecare to complement but not replace the support provided by people face to face.\n\nCommissioners should identify where there are gaps in community optometry, audiology and dental services for people with learning disabilities and address those gaps.\n\nMental health commissioners should develop protocols to ensure that people with learning disabilities, including people in later old age, have access to mainstream mental health services for older people, including dementia support.\n\nCommissioners and service providers should ensure that people with learning disabilities have equal access to a range of community services that reflect the cultural diversity of the local area and people's hopes, preferences, choices and abilities as they grow older.\n\nCommissioners and service providers should establish links between specialist learning disability services and mainstream older people's services. This could be done by bringing them together to help identify gaps and inform service development, sharing information and learning, and linking into voluntary sector umbrella groups.\n\nCommissioners and service providers should provide opportunities for people with learning disabilities to meet up and socialise, for instance through social clubs and support groups.\n\nCommissioners and service providers should ensure there is a wide range of community-based physical activity programmes available and encourage people to take part to promote their health and wellbeing. Examples include dancing, swimming, bowls, using the gym, organised walks and chair-based exercise classes.\n\nCommissioners and service providers should arrange accessible opportunities for people with learning disabilities to engage in education, employment and volunteering.\n\nLocal authorities should consider introducing schemes to make transport easier for older people with learning disabilities. For example:\n\nproviding free travel such as London's 'Freedom pass'\n\nusing minibuses as community transport\n\nstarting 'buddy' schemes to enable independent travel\n\ndeveloping transport especially for people living in rural locations\n\nschemes such as 'JAM' cards (Just A Minute) – which can be used to alert transport staff that people have a learning disability\n\nschemes to help people with a personal budget to travel to activities and self-advocacy groups.\n\n# Identifying and assessing care and support needs\n\n## Assessing people's need for care and support\n\nEnsure that all assessments of care and support needs are strengths based, person centred and conducted as early as possible. Follow the recommendations on care and support needs assessment in NICE's guideline on people's experience in adult social care services.\n\nPractitioners carrying out assessments of care and support needs should have:\n\naccess to the person's full history (medical, social, psychological and the nature of their learning disability) and\n\nan understanding of their usual behaviour.\n\nPractitioners carrying out assessments of care and support needs should be alert to any changes in the person's usual behaviour. This could include how they are communicating or their activity levels, and symptoms (such as weight loss, changes in sleeping patterns or low mood) that could show something is wrong or they are unwell.\n\nBe aware that people growing older with learning disabilities might have difficulty communicating their health needs. When their needs change, think about whether these changes could be age-related and do not assume they are due to the person's learning disability or pre-existing condition (diagnostic overshadowing).\n\nPractitioners carrying out assessments of care and support needs should help people to think about what they want from life as they age. This should include:\n\nasking people how they would like to spend their time and with whom, and enabling them to explore personal and sexual relationships\n\nencouraging them to develop support networks and to build and maintain links with friends and family and with community groups – these might include social, cultural and faith-based groups.\n\n## Assessing the needs of family members and carers\n\nPractitioners carrying out assessments of care and support needs should take into account the needs, capabilities and wishes of families and carers. Also take into account that there may be mutual caring between people with learning disabilities, and their family members and carers, who are likely to be older themselves and have their own support needs.\n\nPractitioners must offer people who are caring for a person with a learning disability their own carer's assessment, in line with the Care Act\xa02014.\n\nBased on assessment, provide families and carers with support that meets their needs as carers (see NICE's guideline on supporting adult carers).\n\nReview the needs and circumstances of carers at least once a year and if something significant changes (see NICE's guideline on supporting adult carers).\n\nActively encourage carers to register themselves as a carer, for example, with their GP.\n\n# Planning and reviewing care and support\n\n## Person-centred planning and review\n\nPractitioners should carry out regular person-centred planning with people growing older with learning disabilities to address their changing needs, wishes and capabilities and promote their independence. This should include planning for the future (see recommendations\xa01.4.5 to\xa01.4.13). Involve their family members, carers and advocates as appropriate.\n\nInclude transport needs in people's care and support plans, to help them get to services, appointments and activities.\n\nLocal authorities should plan people's care and support in a way that meets the needs of all family members, as well as the person themselves. This might include combining the personal budgets of different family members.\n\nGive help and information to families and carers, including siblings, as part of planning and providing support for people growing older with learning disabilities. For example, tell them about sources of support for people after a family bereavement.\n\n## Planning for the future\n\nHealth and social care practitioners should work with the person and those most involved in their support to agree a plan for the future. Help them to make decisions before a crisis point or life-changing event is reached (for example, the death of a parent or a move to new housing).\n\nPlanning for the future should:\n\nbe proactive\n\nbe led by the person themselves with input from family members, carers or advocates as appropriate (regardless of whether they provide care and support themselves)\n\ninvolve a practitioner who has a good relationship with the person and communicates well with them\n\ninvolve practitioners who have good knowledge of local resources\n\ntake into account the whole of the person's life, including their hopes and dreams as well as the things they do not want to happen\n\ninclude considering the needs of family members and carers\n\nseek to maintain the person's current support and housing arrangements, if this is their preference\n\nbe reviewed every year and whenever the person's needs or circumstances change.\n\nInclude as key components of a future plan:\n\nHousing needs and potential solutions.\n\nAny home adaptations or technology that may address people's changing needs as they grow older.\n\nMembers of the person's support network (both paid and unpaid).\n\nAny help the person gives to family members, whether this will continue as they age, and the impact this may have on their health and wellbeing.\n\nPlanning for what will happen if someone who the person relies on dies, or is no longer able to provide care and support.\n\nFinancial and legal issues, for example whether someone has been appointed to have lasting power of attorney for the person.\n\nThe provision of information on wills, trusts and benefits.\n\nPlanning for unexpected changes or emergencies.\n\nPlanning for a time when the person may lack capacity to make decisions themselves, in line with the Mental Capacity Act\xa02005.\n\nConsideration of deprivation of liberty safeguards, for instance if planned changes to care or the care environment are likely to increase restrictions on the person.\n\nEnd of life care decisions – including where the person wants to be when they die. These decisions should be reviewed at least once a year.\n\nWhen helping the person plan where they will live in the future and who they will live with, take into account whether other family members rely on them for support.\n\nEncourage and support people to be active and independent at home regardless of their age or learning disability. This might include doing household tasks, making their own decisions and plans or leading group activities.\n\nMake reasonable adjustments to people's homes as they grow older to make it possible for them to stay in their current home if they want to. For example, consider a support phone line, daily living equipment, telehealth monitoring and home adaptations, such as shower room conversion, wider doorways or a lift between floors.\n\nReview at least once a year the housing needs of people who are being supported by social care staff at home.\n\nEnsure that the person is centrally involved in any decisions about moving from where they currently live. Also include an advocate or, if appropriate, a family member or carer.\n\nIf a move is agreed with the person, practitioners should work with them and their support network to start planning for this straightaway. Planning could include:\n\narranging for the person to visit the new setting\n\ndiscussing how they will maintain their existing support networks and develop new ones.\n\n# Identifying and managing health needs\n\nHealthcare practitioners should encourage people growing older with learning disabilities to choose a family member, carer or advocate to bring with them to medical examinations and appointments if they would like this support.\n\nExplain clearly to people with learning disabilities what will happen during any medical appointments as well as their likely follow‑up care. In line with the Mental Capacity Act\xa02005, healthcare practitioners must take all reasonable steps to help the person understand this explanation.\n\nAs well as explaining to people beforehand what will happen, continue to explain what is happening throughout the appointment and ensure there is enough time set aside to do this. If the person agrees, also explain to their family member, carer or advocate what will happen.\n\nIf the person needs a medical examination, give them a choice, wherever possible, about where it takes place. Aim to do it in a place that is familiar to them, which is welcoming and appropriate to their needs.\n\nSupport family members and carers, for example by providing information, so that they can help people with learning disabilities to access health services.\n\nConsider commissioning training for people and their family members and carers in recognising changes and managing age-related conditions such as:\n\nblood pressure and cholesterol\n\ncancer\n\nchanges to skin condition such as itchy or fragile skin\n\ndementia\n\ndiabetes\n\ndysphagia (difficulty swallowing)\n\nepilepsy\n\nhearing loss and sight problems\n\nincontinence\n\nosteoporosis\n\nmalnutrition\n\nmenopausal symptoms\n\nmental health, including depression\n\nthyroid problems.\n\n## Coordinating care and sharing information\n\nManagers in healthcare settings should identify a single lead practitioner to be the point of contact for people with learning disabilities and their family members, carers and advocates. This practitioner could be a member of the community learning disability team or a nurse with experience in learning disabilities.\n\nEnsure that everyone involved in the person's care and support shares information and communicates regularly about the person's health and any treatment they are having, for example by holding regular multidisciplinary meetings. Involve the person in all discussions.\n\nPrimary and secondary healthcare teams should identify at least 1\xa0member of staff who develops specific knowledge and skills in working with people with learning disabilities and acts as a champion, modelling and sharing good practice. Use the expertise of people with learning disabilities to ensure the champion understands their needs.\n\nRecord a person's learning disability and any reasonable adjustments in their health records and share this information when making referrals. With the person's consent, make sure all relevant practitioners in community and acute settings can access this. Also record any specific needs or wishes, for example to do with the person's communication or mobility.\n\n## Health checks and screening\n\nRecognise that people with learning disabilities may need additional health surveillance to help them identify and communicate symptoms of age-related conditions.\n\nOffer annual health checks to older people with learning disabilities as long as these are followed by prompt referral to specialist services wherever needed. Explain what annual health checks involve and how to arrange them. Record any actions identified by the annual health check in the person's health action plan.\n\nOffer older people with learning disabilities the same routine screening and health checks as other older people.\n\nDiscuss with people the changes that may occur with age. Ask them about and monitor them for symptoms of common age-related conditions or changes in any existing conditions, including:\n\nblood pressure and cholesterol\n\ncancer\n\ndementia (also see recommendations 1.5.36 and\xa01.5.37).\n\ndiabetes\n\ndysphagia (difficulty swallowing)\n\nepilepsy\n\nhearing loss and sight problems\n\nincontinence\n\nosteoporosis\n\nmalnutrition\n\nmenopausal symptoms\n\nmental health, including depression\n\nthyroid problems.\n\nDuring a person's annual health check, give them information about other available services, including a care and support assessment under the Care Act\xa02014 if they have not already had one.\n\nDuring a person's annual health check, ask if they are registered with a dentist, how often they see the dentist and check that they understand the importance of looking after their teeth and mouth.\n\nGive people clear, accessible and practical information and advice about keeping well as they grow older. Tell them about, and help them access, services such as breast screening, smear tests, testicular and prostate checks, dental checks, hearing and sight tests, and podiatry.\n\nWhen designing and delivering breast screening services, address specific barriers to accessing breast screening among older women with learning disabilities, including support to:\n\nunderstand breast cancer\n\nunderstand the screening procedure\n\nbe breast aware and check their breasts regularly\n\nunderstand any information provided\n\nattend appointments.\n\n## Primary care\n\nPrimary care and community services should aim to ensure that older people with learning disabilities can see the same GP and other healthcare practitioners, wherever possible, to help practitioners:\n\nbecome familiar with the person's medical history, which the person may have difficulty remembering themselves\n\nbuild good relationships and understand the person's usual behaviour and communication needs.\n\nGeneral practices should allocate a named member of staff to remind people with learning disabilities about appointments for screening and health examinations. This staff member should help the person attend the appointment by:\n\nusing each person's preferred method of communication\n\ngiving them information in a way they can understand\n\nensuring the person understands the reason for the appointment and why it is important\n\nfinding out their transport needs\n\nmaking reasonable adjustments to help the person and their carer or supporter to attend.\n\nIf the person is diagnosed with a health condition, give them and their family members, carers or advocate accessible information on the following (taking time to explain it to them as well):\n\nsymptoms and management\n\nbenefits, and potential side effects, of treatment\n\nhow to take their prescribed medicines.\n\nSupport people to manage their own health conditions by getting to know them and adapting health advice to suit their personal choices and the activities they already enjoy (for example, playing football).\n\n## Dental care\n\nCommissioners and managers should ensure that support staff have knowledge of oral health so they can support people with learning disabilities to maintain good oral health and access dental services.\n\nDental practices should ensure their services are accessible to people with learning disabilities, for example by:\n\nreminding people about their appointments by phone\n\nsending letters in an accessible format, for example Easy Read\n\nsuggesting that the person brings a carer or supporter with them\n\nensuring staff have the skills to communicate with people with learning disabilities and put them at ease. For further guidance on managing oral health, see the NICE guidelines on:\n\noral health promotion: general dental practice\n\noral health for adults in care homes.\n\n## Outpatient appointments\n\nHospitals should offer an opportunity for the person and a family member, carer or advocate to visit the hospital before their outpatient appointment to meet the staff who will conduct any tests or examinations, see the equipment that will be used and identify what adjustments will be needed.\n\n## Before and during a hospital stay\n\nWhen planning a hospital admission, arrange a pre-admission planning meeting, including the hospital liaison team or liaison nurse, a representative of the community learning disability team, the person and their family members, carers or advocate. At this meeting:\n\ncomplete the pre-admission documentation, which should include information from the person's hospital passport\n\ndiscuss any reasonable adjustments needed, for example, arranging for the person to visit the hospital before their admission to meet the learning disability liaison nurse who will be their contact.\n\nHospitals should actively encourage staff to use pre-admission documents and flagging systems so that all relevant hospital staff know about the person's learning disability. At discharge, review how well this is working.\n\nHospitals should develop policies and guidance to enable someone chosen by the person to stay with them throughout their inpatient stay, including overnight.\n\nHospital staff should continue to offer health and personal care (toileting, washing, nutrition and hydration) to people with learning disabilities even if they have a family member, carer or advocate there to support them.\n\nFor further guidance on planning admission and admitting adults with identified social care needs to hospital, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\n## Transfer of care from hospital\n\nIf the person agrees, invite family members, carers or advocates to pre-discharge meetings, as well as the person themselves.\n\nIf the discharge plan involves support from family members or carers, take into account their:\n\nwillingness and ability to provide support\n\ncircumstances, needs and aspirations\n\nrelationship with the person\n\nneed for respite (short breaks). [This recommendation is adapted from the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.]\n\nGive the person (and their family members and carers) an accessible copy of their discharge plan when they are discharged, and make sure their GP has a copy within 24\xa0hours. Make sure everyone knows what will happen next in the person's care and support. [This recommendation is adapted from the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.]\n\nAfter the person is discharged, the hospital learning disability liaison nurse, community learning disability team and primary care practitioners should work together to provide ongoing support to help the person manage their health condition.\n\nFor further guidance on discharging adults with identified social care needs from hospital, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\n## Dementia\n\nExplain at an early stage to people with learning disabilities (particularly people with Down's syndrome) and their family members, carers and advocates about the link between learning disabilities and dementia. Explain the signs of dementia, how it usually progresses and what support is available. Give people:\n\nprinted information on dementia\n\nopportunities for one-to-one discussion with a professional\n\nadvice on communication strategies for people with dementia.\n\nCommissioners should ensure information is provided to family members, carers and advocates of people with learning disabilities who are being assessed for, or have been diagnosed with dementia. Consider also providing training. Information and training might cover:\n\ntypes of dementia\n\nhow dementia might present in people with different learning disabilities\n\ncare pathways for different dementias\n\npractical steps to manage daily life\n\ncommunication skills\n\nhow to find further advice and ongoing support, including support groups and respite services (short breaks).\n\n# End of life care\n\n## Access to end of life care services\n\nGive people growing older with learning disabilities and their family members, carers and advocates accessible, timely and person-centred information about all the potential care options available for end of life care, including hospice services.\n\n## Making sure end of life care is person centred\n\nPractitioners providing end of life care should spend time getting to know the person to understand their needs. Get to know how they communicate, their cultural background, what they like and dislike, how they express pain, their health conditions and the medication they are taking. Be aware that this understanding will make it easier to identify when the person's health is deteriorating.\n\nIdentify who the person would like to involve in creating their end of life plan. Include the person themselves and everyone who supports them in discussions and planning.\n\nAsk the person regularly who they would like to involve in discussions about their end of life plan, in case they change their mind. Do this every 6\xa0months, or more often if the person is close to the end of life.\n\nMake it possible for the person to die where they wish. This might include adapting their home, working with other practitioners and advocates, and talking to other residents or family members about changes that could be made (for example, moving the person to a room on the ground floor).\n\n## Involving families and support networks\n\nDuring end of life care planning, talk to the person and their family members, carers or advocate to understand the person's wishes and any cultural needs at the end of their life.\n\nWhen providing end of life care, learn from family members, carers or advocates about the person's needs and wishes, including those associated with faith and culture, nutrition, hydration and pain management. This is particularly important if the person has difficulty communicating.\n\nLearning disability providers delivering care at the end of life should work collaboratively and share information with other practitioners and services involved in the person's daily life.\n\nSocial care providers should work in partnership with healthcare providers to share knowledge about the person and to develop expertise for end of life care.\n\nProvide training, information and support for family members and carers, for example, in medication, pain, nutrition and hydration, to enable the person to die where they wish.\n\nMake sure that key members of the person's support network have the knowledge, confidence and understanding to communicate with the person about their illness and death. This includes being able to talk to the person about symptoms, pain management and their preferences about resuscitation.\n\nMainstream end of life care services should make reasonable adjustments to support the person, their family members, friends and carers and other people they live with, throughout palliative and end of life care and bereavement.\n\nFor further guidance on end of life care, see NICE's guideline on care of dying adults in the last days of life.\n\n# Staff skills and expertise\n\nManagers in health and social care services should ensure that staff in older people's services have the expertise to support people growing older with learning disabilities from a wide range of backgrounds.\n\nManagers in health and social care services should ensure that learning disability staff have the skills and understanding to support people's changing needs as they grow older. Provide this skilled support in all settings, including people's own homes.\n\nManagers in health and social care services should ensure that all staff working with people with learning disabilities have skills and knowledge in:\n\ncommunication methods, including non-verbal communication\n\nbuilding good relationships with people with learning disabilities and making them feel at ease\n\nthe physical, mental health and sensory needs of older people with learning disabilities, related to both their age and disability\n\nthe application of the Mental Capacity Act\xa02005\n\nsafeguarding issues, including how to report concerns and keep people safe\n\ncommon health conditions to which people with learning disabilities are predisposed, for example, the earlier onset of dementia\n\nassessing people's changing needs as they grow older, and not assuming that any new problems are due to their learning disability when they could be symptoms of other conditions or difficulties (diagnostic overshadowing)\n\nthe main causes of early death in people with learning disabilities.\n\nManagers in health and social care services should provide opportunities for learning disability staff and practitioners working with older people to share expertise with each other as part of their knowledge and skills development.\n\nStaff should know what local services are available (including housing options) so they can support people with learning disabilities and their family members, carers and advocates to make informed choices about their care and support.\n\n## Staff skills and expertise for supporting end of life care\n\nCommissioners and providers of end of life care should recognise the complex needs of people with learning disabilities. They should provide ongoing training for staff to ensure they have the expertise to provide good-quality coordinated care, enabling people to die in their own home or another place of their choice. Training should include:\n\nhaving discussions about resuscitation intentions\n\nfinding out and responding to cultural preferences\n\nrecognising pain and discomfort\n\nmanaging symptoms, pain and medication\n\nnutrition and hydration\n\nunderstanding communication preferences and being able to communicate – this might include using augmentative and alternative communication methods.\n\nProvide in‑service training for learning disability and palliative care practitioners so they have the skills to support people at the end of life. This might include joint study days and training of professionals by people with learning disabilities and their family members and carers.\n\n# Terms used in this guideline\n\n## Annual health check\n\nAn NHS initiative for adults and young people aged 14\xa0and over with learning disabilities to provide additional health support and help to identify health conditions that could otherwise go undetected.\n\n## Augmentative and alternative communication\n\nAn umbrella term that includes methods of communication to supplement or replace speech or writing for people who need support to understand or express language.\n\n## Diagnostic overshadowing\n\nIn this guideline, this is used to mean the tendency to attribute all behavioural, emotional, physical and social issues to a person's learning disability or a pre-existing condition, while overlooking the possibility that they could be symptoms of other conditions or difficulties. An example would be attributing challenging behaviour to a learning disability when it could be a reaction to abdominal pain, which in turn might be symptomatic of a physical health problem.\n\n## Family members and carers\n\nThis includes people who are related to the person with a learning disability and anyone else who helps to provide informal support, for example friends. It does not cover staff who are paid to provide care or support.\n\n## Health action plan\n\nA personal plan for people with learning disabilities about how to stay healthy. It should detail what help and support they need to look after their health. This might include support to manage physical or mental health conditions, or actions in relation to lifestyle issues such as diet and exercise.\n\n## Hospital passport\n\nA hospital passport is designed to give hospital staff useful information that is not limited to illness and health. For example, it could include details about what the person likes and dislikes in terms of physical contact or food and drink. The idea is to help hospital staff understand how to make the person feel comfortable.\n\n## Lasting power of attorney\n\nLasting power of attorney is a legal document that lets someone appoint one\xa0or more people to make decisions on their behalf, should they be unable to. Lasting power of attorney can be made in relation to health and welfare, and property and financial affairs.\n\n## People growing older with learning disabilities\n\nFor the purpose of this guideline, a learning disability is defined as meeting 3\xa0core criteria:\n\nlower intellectual ability (usually an IQ of less than\xa070)\n\nsignificant impairment of social or adaptive functioning\n\nonset in childhood.\n\nA person's learning disability may be mild, moderate, severe or profound in severity. Learning disabilities are different from specific learning difficulties such as dyslexia, which do not affect intellectual ability.\n\nA specific age limit is not used to define older people because adults with learning disabilities typically experience age-related difficulties at different ages, and at a younger age than the general population. This is reflected in the guideline title 'people growing older with learning disabilities'. Within the recommendations, this long form is used at the beginning of each section but in subsequent recommendations 'people' or 'people with learning disabilities' is used as a short hand. In all cases, the intended population is 'people growing older with learning disabilities'.\n\n## Practitioner\n\nIn this guideline, 'practitioner' is used to mean a health or social care practitioner who provides care and support for older people with learning disabilities.\n\n## Support network\n\nAll the people who provide emotional and practical help to a person with a learning disability. A person's support network could include their family (including siblings), friends, carers, advocates, non-family members living with the person in supported housing, and members of the person's religious community.\n\nFor other social care terms, see the Think Local, Act Personal care and support jargon buster.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nEnsuring integrated, person-centred care and support for people growing older with learning disabilities, and their families and carers. This will mean health and social care practitioners and providers involving and listening to the person and their family and carers, and agreeing a care plan that reflects their needs and aspirations. Offering an annual health check, including explaining what it will involve and how to arrange it, is an important part of this. It will also mean challenging assumptions and looking beyond the person's learning disability to provide the support needed to help them live an active, community-involved life.\n\nEnsuring a well-trained and supported workforce, with the knowledge needed to support people growing older with learning disabilities. Health and social care services are structured in a way that tends to mean practitioners work in either learning disability or older people's services, and their training and support reflects this. Moving to a workforce with expertise from across both disciplines may be challenging to achieve.\n\nPlanning and commissioning local health, social care and housing services to meet the needs of the local population. Commissioners need to know the size of their local population of adults with learning disabilities, and any likely future growth in this population. Learning disability services are often seen as separate from other services, but all pathways of care and support need to consider the needs of people with learning disabilities in order to improve access and funding.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research. The full list of research recommendations is in the full guideline.\n\n# Models of care and support at home\n\nWhat is the effectiveness and cost effectiveness of care and support models (for example, assistive technology) for people growing older with learning disabilities to enable them to live in the family home?\n\n## Why this is important\n\nThere is no evidence from studies published later than 2005 about the effectiveness and cost effectiveness of care and support models for people growing older with learning disabilities living in the family home, or about their experiences of that support. For example, we did not identify any evidence on the effectiveness and cost effectiveness of assistive technology for supporting older people with learning disabilities and their ageing family carers.\n\nComparative studies are needed to evaluate the costs and impact of different approaches, like assistive technology, on care and support for older people with learning disabilities in the family home. Resource use information, demonstrating the impact on paid and unpaid care (whether it increases or decreases as a result of the different support models) is needed as well as outcome data relating to families and carers. These should be supplemented by qualitative studies to explore the views and experiences of older people with learning disabilities, including those from minority backgrounds, and their families and carers, in relation to different models of support.\n\n# Identifying health conditions\n\nWhat is the effectiveness and cost effectiveness of different ways of identifying age-related and other physical and mental health conditions, in people growing older with learning disabilities?\n\nWhat can mainstream and specialist health services do to facilitate:\n\nearly identification of health conditions in people with learning disabilities?\n\nequal access to health services in people with learning disabilities?\n\n## Why this is important\n\nApart from studies on annual health checks, we did not find any evidence about different methods and pathways for identifying health conditions among people growing older with learning disabilities. There is a need for effectiveness and cost-effectiveness studies using longitudinal, comparative designs to evaluate the costs and outcomes, in particular the final health outcomes, of different approaches to identifying health conditions in people with learning disabilities. These should be complemented by qualitative studies to explore the views and experiences of people with learning disabilities, including those from minority backgrounds, and their families, carers and practitioners, on the facilitators and barriers of these approaches. This includes their views on how, where and by whom these services should be provided.\n\n# Education and training programmes: self-management\n\nWhat is the effectiveness and cost effectiveness of education programmes to improve information and advice and to support self-management of chronic health conditions (for example, obesity, diabetes and cardiovascular disease) for people growing older with learning disabilities, and their family members and carers?\n\n## Why this is important\n\nEvidence suggests that people growing older with learning disabilities value the medical knowledge and authority of health professionals. There is a small amount of evidence that practitioners could play a greater role in providing education and advice to support self-management of health conditions in people with learning disabilities. There is also evidence that families and carers play a central role in supporting and advising people with learning disabilities about their health conditions and promoting healthier lifestyle choices.\n\nThere is currently a lack of information about the cost effectiveness of such education programmes. However, there is evidence that people with learning disabilities are more likely to have missed appointments with health professionals, do not have optimal medication management and have problems to access to healthcare more broadly, all of which can have costly consequences; some of those might be avoided or reduced through self-management.\n\nComparative effectiveness and cost-effectiveness studies are needed to evaluate the impact of education programmes to support self-management for people with learning disabilities. These need to be supplemented with studies exploring the views and experiences of people with learning disabilities, including those from minority backgrounds, and their families, carers and practitioners, on the accessibility and acceptability of different approaches to supporting self-management and communicating health messages.\n\n# Dementia education and training programmes for family members and carers\n\nWhat is the effectiveness, cost effectiveness and acceptability of training programmes (for example, in the use of life story work) for families of people growing older with learning disabilities who have dementia or are at risk of developing it?\n\n## Why this is important\n\nNo evidence was found from studies published later than 2005 about the effectiveness and cost effectiveness of interventions or training programmes for family members and carers of people growing older with learning disabilities who have, or are at risk of developing dementia. There is some evidence that some family members and carers of people with learning disabilities and dementia need specialist training in dementia care.\n\nComparative effectiveness and cost-effectiveness studies are needed to evaluate the impact of specific interventions or training programmes for families and carers of people with learning disabilities, including for people living with conditions such as dementia. Qualitative studies are needed to explore the views and experiences of family, friends and carers of people with learning disabilities, including those from minority backgrounds, about these training programmes.\n\n# Advance planning about end of life care\n\nWhat is the effectiveness and cost effectiveness of advance care planning for end of life care for people growing older with learning disabilities, and their family members and carers?\n\nWhat processes are in place to document and follow the wishes of people growing older with learning disabilities about their decisions on end of life care?\n\n## Why this is important\n\nWe identified no studies evaluating the effectiveness or cost effectiveness of advance care planning for end of life care in people growing older with learning disabilities, and their family members and carers. Such studies would help to determine how and what reasonable adjustments should be made to ensure that people with learning disabilities receive appropriate care at the end of life, and the costs and cost consequences associated with those. Longitudinal studies should have a naturalistic design with a control group to follow up families and carers who have used advance care planning for end of life care in people with learning disabilities.'}
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https://www.nice.org.uk/guidance/ng96
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This guideline covers care and support for adults with learning disabilities as they grow older. It covers identifying changing needs, planning for the future, and delivering services including health, social care and housing. It aims to support people to access the services they need as they get older.
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59cc6692ec5c20fd512ed5f1ca5248b86102c38f
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nice
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Learning disabilities and behaviour that challenges: service design and delivery
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Learning disabilities and behaviour that challenges: service design and delivery
This guideline covers services for children, young people and adults with a learning disability (or autism and a learning disability) and behaviour that challenges. It aims to promote a lifelong approach to supporting people and their families and carers, focusing on prevention and early intervention and minimising inpatient admissions.
# Context
An estimated 1.2 million children, young people and adults in England have a learning disability, and of these it is estimated that 10–17% display behaviour that challenges (see Predictors, costs and characteristics of out of area placement for people with intellectual disability and challenging behaviour. Allen et al. 2007). A more recent report suggested that there are over 40,000 children with learning disabilities who display behaviour that challenges (see Estimating the number of children with learning disabilities in England whose behaviour challenges. Emerson et al. 2014). In addition, approximately 1% of the adult population has an autism spectrum condition and 60–70% of these also have a learning disability (see Estimating the prevalence of autism spectrum conditions in adults Brugha et al. 2012).
The most commonly used definition of behaviour that challenges is: 'behaviour of such an intensity, frequency or duration that the physical safety of the person or others is likely to be placed in serious jeopardy, or behaviour which is likely to seriously limit or deny access to and use of ordinary community facilities' (Emerson et al. 1987). Later definitions have highlighted the role of cultural context in determining whether behaviour is perceived as challenging (Emerson 1995).
This guideline was developed in a context of changes to policy and practice for children, young people and adults with a learning disability (or autism and a learning disability) and behaviour that challenges. The support needs of these vulnerable groups were set out in 1992 in the Mansell report, which identified the need to invest in developing local services with appropriate levels of skilled staff to meet people's needs. This was restated in a later review, the so‑called 'Mansell 2 report' (see Services for people with learning disabilities and challenging behaviour or mental health needs. Department of Health), which also highlighted the increased use of placements away from people's homes.
The exposure of widespread abuse at Winterbourne View hospital in 2011 led to a review of care provided in this hospital, and across England more widely, for people with a learning disability and behaviour that challenges. The resulting report (see Transforming care: a national response to Winterbourne View hospital. Department of Health) started a programme of work to improve services for people with a learning disability or autism who also have mental health conditions or behaviours described as challenging. In particular, this aimed to shift emphasis from inpatient care in mental health hospitals towards care based on people's individual needs and wishes and those of their families, provided by general and specialist services in the community. The programme did not meet its original targets, as highlighted in a report by the National Audit Office (see Care services for people with learning disabilities and challenging behaviour), and was reconfigured in 2015.
The 'transforming care programme' is now led jointly by NHS England, the Association of Directors of Adult Social Services, the Care Quality Commission, Local Government Association, Health Education England and the Department of Health. The national plan (see Building the right support. 2015) included plans for 48 'transforming care partnerships' to pilot new arrangements of services. The national plan was followed by NHS England's national service model (October 2015) that set out the range of support that should be in place no later than March 2019. To support implementation of the interim service model, NHS England developed 3 model service specifications (see Transforming Care: service model specification. January 2017) and supplementary guidance on Developing support and services for children and young people with a learning disability, autism or both (September 2017). This guidance also supports the recommendations of Dame Christine Lenehan's review (January 2017) on providing care and support for children and young people with complex needs who display challenging behaviour.
This guideline takes into account the direction of travel in the transforming care programme. It complements this work by providing evidence-based recommendations to support children, young people and adults with a learning disability (or autism and a learning disability) and behaviour that challenges to live their lives in the community like everyone else.
It is based on evidence about effectiveness and cost effectiveness of different support and services, and how those services are coordinated. It is also informed by the views of people who use services and their families on what is important to them in their care and support.
The application of the recommendations in this guideline is not mandatory. Although there is no legal obligation to implement our guidance, health and social care practitioners, and practitioners in related services, are actively encouraged to follow our recommendations to help them deliver the highest-quality care.
This guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. Relevant legislation and guidance includes:
Autism Act 2009
Care Act 2014 and associated guidance
Children Act 1989 and associated guidance
Children and Families Act 2014
Children and Young Peoples Act 2008
Chronically Sick and Disabled Persons Act 1970
Human Rights Act 1998
Mental Health Act 1983, 2007
Mental Capacity Act 2005 (amended 2007) and associated guidance on Deprivation of liberty safeguards.
The guideline has been developed by a committee of people who use services; family members and carers of children, young people and adults with a learning disability who display behaviour that challenges; and professionals. It has used information from an extensive review of research evidence, and from expert witnesses. The development followed the methods outlined in developing NICE guidelines: the manual and the interim methods guide for developing service guidance (2014).
Equality and diversity issues have been considered throughout the development of the guideline. The committee also gave careful consideration to the potential resource impact of the recommendations.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Aims and principles
This guideline is based on the principle that children, young people and adults with a learning disability and behaviour that challenges should have the support they need to live where and how they want. It will help local areas shift their focus towards prevention and early intervention, enabling children, young people and adults to live in their communities, and increasing support for families and carers. This should reduce the need for people to move away from their home or community for care, education or treatment.
The guideline recommends ways of designing and delivering services that aim to:
help people to have a good quality of life
support people to have good physical and mental health and emotional wellbeing
maximise people's choice and control
promote person-centred care and support
help children, young people and adults take an active part in all aspects of daily life that they choose, based both on what they can do and what they want to do
respect people's cultural, religious and sexual identity
identify when children, young people and adults are at risk of developing behaviour that challenges, so that support can be offered as early as possible
promote continuity of relationships
take a 'whole life' approach.
# Achieving change: strategic planning and infrastructure
## Local leadership
Local authorities and clinical commissioning groups should jointly designate a lead commissioner to oversee strategic commissioning of health, social care and education services specifically for all children, young people and adults with a learning disability, including those who display, or are at risk of developing, behaviour that challenges.
Ensure that the lead commissioner:
plans and oversees joined‑up commissioning arrangements
has in‑depth knowledge and experience of working with children, young people and adults with a learning disability and behaviour that challenges, including knowledge of local services
plans services that take a 'whole life' approach from early childhood onwards and enable smooth transitions.
## Joint commissioning and funding
The lead commissioner should ensure that budgets and other resources are pooled to develop local and regional services for children, young people and adults with a learning disability and behaviour that challenges. These should be pooled:
across health, social care and education and
with neighbouring authorities.
Consider jointly commissioning the most specialised behaviour support services across areas for children, young people and adults with particularly complex needs.
Ensure that funding mechanisms for service providers support creative and flexible community-based responses, for example, a contingency fund that service providers can draw on quickly if there is a crisis.
## Planning and delivering services according to local need
Ensure that service planning and delivery is based on an assessment of current and future service needs using:
the local population prevalence of learning disabilities in children, young people and adults and the proportion who are likely to display behaviour that challenges
an analysis of assessed needs in education, health and social care plans, to provide an early view of likely service needs and enable prevention and early intervention
-ther sources of information, such as registers of people at risk of admission and other dynamic risk data; disabled children's registers; and records of referrals from liaison and diversion teams, youth offending teams and police.
Ensure that services are planned and delivered in a way that:
is co‑produced with children, young people and adults using services and their families, carers and independent advocates
enables person-centred planning and provision
addresses the needs of different age groups but also takes a 'whole life' approach to planning
includes planning for a range of future housing and employment support needs
integrates health, social care and other relevant services.
Develop local and regional plans that have a single care pathway and point of access for children, young people and adults with a learning disability and behaviour that challenges, and their families and carers. Make sure this is reflected in local authorities' commissioning strategies and key documents such as the Market Position Statement. For further information on how to develop care pathways, see the section on organising effective care in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.
## Managing risk
Take joint responsibility with service providers and other organisations for managing risk when developing and delivering care and support for children, young people and adults with a learning disability and behaviour that challenges. Aim to manage risks and difficulties without resorting to changing placements or putting greater restrictions on the person.
## Quality assurance
Ensure services meet set service-level and individual outcomes, and that service providers show evidence of achieving these outcomes. This evidence could include:
satisfaction and quality-of-life ratings of children, young people and adults who have used the service, and their family members, friends and carers
-utcomes measured by personalised and validated tools such as the 'measure of processes of care' (MPOC) tool, or the 'patient feedback questionnaire' (PFQ)
a reduction in duration and frequency of behaviour that challenges
stability of placements
participation in education by children and young people
reports on the use of restrictive interventions, including medication
contact time with specialist professionals
evidence from quality reviews and spot checking involving experts by experience
quality checks by user-led organisations.
Inpatient services should provide the evidence in recommendation 1.1.10 in addition to evidence of detailed assessments, treatment outcomes and time to discharge.
Commissioners should establish a multi-agency group, or make use of an existing group, including experts by experience and service providers, to monitor the quality of services and the outcomes achieved.
Service providers should use evidence gathered to continuously improve services. They should record the results and make them available to people who use services, and their families and carers.
## Involving people in commissioning and service improvement
Commissioners should make use of expertise from experts by experience to inform decision-making and quality assurance of services.
# Enabling person-centred care and support
## Involving people with a learning disability and behaviour that challenges
Practitioners working with children, young people and adults with a learning disability and behaviour that challenges, and their family members and carers, should get to know the person they support and find out what they want from their lives, not just what they want from services. For more information on involving people in their care and support, see the section on working with people with a learning disability and behaviour that challenges, and their families and carers in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.
Actively involve people with a learning disability in all decisions that affect them. If a person aged 16 or over lacks the capacity to make a decision, staff must follow the Mental Capacity Act 2005.
Assess whether a child or young person under the age of 16 is Gillick competent and work in partnership with all children and young people. Include them in decisions about their treatment and ask them how they would like their families or carers to be involved.
Involve families, friends, carers or independent advocates if this is what the person wants, or where decisions are made in the best interests of a person aged over 16 in line with the Mental Capacity Act 2005. This should be done unless there is a compelling reason not to (for example, if there are safeguarding concerns).
Support children, young people and adults with a learning disability and behaviour that challenges to live where and how they want. Give them support that:
is person-centred, reflecting their individual needs and choices, and maximising their control
helps them take an active part in all aspects of daily life that they choose, based both on what they can do and what they want to do
takes into account the severity of their learning disability; their developmental stage; any communication difficulties or physical or mental health problems; and their life history
respects their cultural, religious and sexual identity
helps them before problems occur or as soon as they emerge, not just when crisis has been reached
encourages people to speak out if they have any worries
promotes continuity of relationships.
Find out children, young people and adults' information and communication needs, record them and share this information with everyone working with them in line with NHS England's Accessible Information Standard.
Ensure that people with a learning disability and behaviour that challenges have access to speech and language therapy when they need it.
## Advocacy
Consider providing access to independent advocacy whenever it is wanted or needed by a person with a learning disability and behaviour that challenges. As a minimum, it must be offered by local authorities as described in the Care Act 2014, Mental Capacity Act 2005 and Mental Health Act 2007.
Ensure that independent advocates working with children, young people and adults with a learning disability and behaviour that challenges have skills and experience in working with these groups, and in working with specialist learning disability services.See also recommendations 1.8.3 and 1.8.4 on independent advocacy in relation to inpatient admissions.
## Coordinating care and support
Local authorities working in partnership with healthcare professionals should assign a single practitioner, for example, a social worker (in a disabled children's team or community learning disability team) or community psychiatric nurse, to be the person's 'named worker'. The named worker should get to know the person and coordinate support to meet their needs over the long term.
The local authority, clinical commissioning group and service providers should liaise regularly with the named worker, keeping them informed and involved in decision-making.
Arrange regular meetings to discuss the person's care and support, and invite people in their support network, including family members, carers, independent advocates and practitioners from all services that support them. This could build on existing processes, for example, the education, health and care planning and review process for children (see Gov.uk's children with special educational needs and disabilities).
Recognise and use the expertise brought by all members of the person's support network (not only those who are paid).
## Care and support planning
Community learning disability teams (or relevant children's services, for example, disabled children's teams) and service providers should work in partnership with the child, young person or adult, their family members, carers and independent advocates and their named worker to develop, deliver and review their care and support plan. Develop a care plan that:
meets the person's needs and preferences
works to support and maximise the person's mental capacity
takes into account people's fluctuating mental capacity and needs
adopts a 'whole life' approach that covers what they want to achieve in both the short and long term, and supports smooth transitions
takes a positive approach to managing risk
sets out what to do to prevent or respond to a crisis.
Service providers and agencies responsible for commissioning and planning services (including specialist services) should match the specific skills of staff to the characteristics of the person with a learning disability and behaviour that challenges. Do this as soon as care and support planning begins.
Community learning disability teams or relevant children's services (for example, disabled children's teams) and service providers should review children, young people and adults' care and support with their named worker:
according to timings agreed in their plan and
whenever there is a significant change, for example, if the person is placed out of area.
When reviewing plans:
involve people as set out in recommendations 1.2.1 to 1.2.4
take account of people's fluctuating mental capacity
check that staff are following the behaviour support plan recommendations in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions
think about plans for the future, including whether changes might be needed to the person's housing or support.
As soon as a child, young person or adult develops behaviour that challenges, community learning disability teams (or relevant children's services, for example, child and adolescent mental health learning disability teams) and service providers should offer to work with them and their family or carers to develop a behaviour support plan. For more information on what this should include, see the recommendations on behaviour support plan in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.
## Supporting people to use personal budgets
Ensure that a range of funding arrangements are available, including direct payments, personal budgets or individual service funds, depending on children, young people and adults' needs and preferences.
Offer people a choice of funding arrangements (see recommendation 1.2.19) and support people to use these budgets, where they wish to, by:
telling them how each element of their support will be funded
telling them how much money is available and how much control they have over how the money is spent
giving them and their families and carers information about different ways of managing their budgets, and how these may affect their carer
supporting them to try out different mechanisms for managing their budget
-ffering information, advice and support to people who pay for or arrange their own care and support, as well as to those whose care and support is publicly funded
-ffering information about benefits entitlement
ensuring that carers' needs are taken fully into account.
## Delivering care and support
In all settings, staff working with children, young people and adults with a learning disability, and their families and carers, should aim to reduce the risk of behaviour that challenges developing by:
identifying health or sensory problems early
providing strategies and interventions to support communication. Follow recommendations on psychological and environmental interventions in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.
For people taking medicines:
follow recommendations in NICE's guideline on managing medicines for adults receiving social care in the community and
if the reason for the medicine relates to the person's behaviour or mental health, ensure it is reviewed regularly in line with recommendations on medication in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions, and recommendations in mental health problems in people with learning disabilities: prevention, assessment and management.
Ensure that children, young people and adults with a learning disability and behaviour that challenges know about and are able to use services to support their health and wellbeing. These should include:
services helping people to make and maintain friends, relationships and social networks in their community and take part in community activities
access to employment and pre-employment opportunities
day opportunities where activities can be tailored to the person's interests, preferences, strengths and abilities
universal healthcare services and health checks
peer support opportunities.
# Early intervention and support for families and carers
See section 1.6 for more recommendations on services for children and young people.
## Recommendations for local authorities
Ensure that families and carers of children, young people and adults with a learning disability and behaviour that challenges are given support that helps them to:
manage their role as carers
care for the person and meet their needs, in relation to behaviour, care and support, communication, physical health, mental health, educational needs or any offending behaviour
access support from specialist services when needed.
Provide information, guidance and ongoing support for families and carers of children, young people and adults with a learning disability and behaviour that challenges, which address different aspects of their life. Sources of support could include:
peer support
parent and carer groups or forums
email support
individual phone and face-to-face support
family networks
independent advocacy
managed email networks (a shared discussion forum)
social media groups.
Give family members and carers information in line with the section on support and interventions for family members or carers in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions. This could be in the form of a 'welcome pack'. Provide this information:
at the first point of contact with families
through the local authority website, local libraries and universal services such as GP surgeries.
## Recommendations for the named worker
Help people and their families to understand information about available support (see recommendation 1.3.3) from first contact onwards.
Advise family members and carers how to access:
short break services
specialist behaviour support
training as set out in recommendations 1.7.1 and 1.7.2 in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions
support in an emergency
community resources, including voluntary organisations, networks and support groups
local safeguarding procedures, including how to raise safeguarding concerns or make a complaint.
Ensure that family members and carers have information such as contact details of staff and key dates and appointments.
# Services in the community – prevention, early intervention and response
## Developing services in the community
The lead commissioner should commission services in the community for people with a learning disability and behaviour that challenges (including for people in contact with, or at risk of contact with, the criminal justice system). These services:
should be able to cater for lower-level needs up to intensive, complex or fluctuating needs
could be set up either as 1 large team with different subteams or as several separate teams
should be provided wherever possible as an alternative to, and to reduce the potential need for:
inpatient care for children, young people and adults or
residential placements for children and young people.
Services in the community should fulfil the following core functions:
specialist prevention and early intervention
developing capacity in non-specialist community services to prevent unnecessary inpatient admissions
giving support and training to families and carers (by following the recommendations on support and interventions for family members or carers in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions)
quality assurance and service development
short-term assessment and intervention
longer-term complex intervention
crisis response and intervention.
Ensure that children, young people and adults with a learning disability can get specialist support through their community learning disability team that meets their needs, for example, in relation to:
behaviour
communication
social care and support needs
physical health
mental health
education
-ffending behaviour. This could be achieved by employing relevant practitioners within the community learning disability team or by developing close links with practitioners in other relevant services.
Services who provide support through the community learning disability team should work together and provide consultancy and support to each other. They should work with children, young people and adults, and their family members and carers, in a way that is:
personalised
flexible
responsive
accessible
reflective.
If a child, young person or adult develops, or is at risk of developing, offending behaviour, community learning disability teams should refer them to appropriate specialists, such as community forensic or youth justice services, as soon as possible (see recommendations 1.4.12 to 1.4.16). These services should:
provide evidence-based early interventions that are adapted for people with a learning disability and address the specific behaviour
work in an ongoing partnership with each other and with the community learning disability team whenever needed.
Community learning disability teams should maintain good communication and links with the police and liaison and diversion teams so that:
they can advise on assessments of vulnerability, particularly for people with mild or borderline learning disabilities who may otherwise not be identified as vulnerable
people who need support can be diverted from the criminal justice service to community learning disability teams.
## Specialist behavioural support
Ensure that specialist assessment and behavioural support are available in the community so that children, young people and adults can stay where they currently live and avoid moving.
Ensure that specialist services for behaviour that challenges are available to everyone with a learning disability and behaviour that challenges, based on an assessment of each person's need and risk and taking into account the benefit of early intervention.
The lead commissioner should:
set local maximum waiting times for initial assessment, and for urgent and routine access to treatment and support
ensure that waiting times for specialist behavioural support do not exceed NHS waiting time standards.
## Intensive behavioural support during a crisis
Provide a local, personalised response to children, young people and adults who need intensive support during a crisis. This response should:
focus on keeping people in their own home
have an out-of-hours helpline as a first option with the capacity to respond rapidly (within 1 hour or in line with local mental health crisis response times), staffed by people with skills and knowledge in learning disabilities and behaviour that challenges, and specialist skills in mental health problems
provide face-to-face support within 4 hours if needed, based on initial triage
involve partnership with other commissioners, service providers and family members and carers
include giving staff access to the person's information if they are already in contact with services
provide short-term support to achieve aims that are agreed with the person
include clear contact details for children's services (as set out in the Local Offer) and adults' services.
Use a clear, coordinated approach to reducing the level of support from more intensive services in line with the person's needs. Learn from what happened and use this knowledge to inform future early intervention and prevention services and support crisis plans.
## Services for people in contact with, or at risk of contact with, the criminal justice system
Commission local community forensic services for children, young people and adults with a learning disability and behaviour that challenges who are in contact with, or at risk of contact with, the criminal justice system to prevent out-of-area hospital placement. These could be provided as stand-alone teams, or as a specialism within an existing team, for example, a community learning disability team, or a learning disability specialism within a community forensic team.
When forensic community learning disability services are supporting children, young people and adults with a learning disability (for example, if they are subject to a forensic community rehabilitation order or a community treatment order), they should enable them to live in the community, as close to home as possible, and in the least restrictive setting.
Forensic community learning disability services should stay in frequent contact with the person they are supporting, including those who are in out-of-area placements or criminal justice settings, and help them build and maintain social links in their community.
Forensic learning disability services and probation services should work together to agree who is best able to support the person in meeting the requirements of their treatment or rehabilitation order.
Forensic learning disability services, mental health, specialist voluntary sector organisations, learning disability services and social care services should establish care pathways and close links with each other to help them refer people quickly between these services to get the right support and effectively manage risk.
# Housing and related support
## Giving people a choice of housing
Commissioners should work with local housing and social care providers to identify the specific housing needs of adults with a learning disability and behaviour that challenges. They should ensure areas have a range of housing and care options available that meet these needs and cater for different preferences and person-centred support needs (see also section 1.2).
Enable adults to live close to their family, friends and community unless they choose not to or there is a compelling reason not to.
Where possible ensure that, wherever people live, they have security of tenure in line with the Real Tenancy Test.
When helping adults with a learning disability and behaviour that challenges choose where to live:
provide information on the range of possible options
take into account their preferences and any specific support needs or risks, including the impact of environmental factors on the person (see the recommendation on environmental factors in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions)
give them advice on adapting their current home if needed.
Offer people the option to live alone with appropriate support if they prefer this and it is suitable for them.
If adults prefer not to live alone with support, or it is not suitable for them, offer them the option of living with a small number of other people in shared housing that has a small-scale domestic feel. Involve people in choosing how many people, and who, they live with.
Offer adults housing outside their local community only:
if it is what the person wants
if it is indicated after a full assessment and planning process, which takes into account the person's preferences, needs and risks
for a specified time that has been agreed with the person, or agreed in their best interests if they lack capacity to decide this – for example, if they are in crisis and there is no local placement available.
If someone is moving outside their local area, local authorities, clinical commissioning groups and commissioners should:
establish the commissioner who is responsible for paying for the person's care and support
ensure they will still have the support they need
make a plan that enables them to return to their local area if they want to, or if it is in their best interests if they lack capacity to decide this.
# Services for children and young people
## Recommendations for local authorities, clinical commissioning groups and the lead commissioner
Local authorities should ensure that parents and carers of children and young people with a learning disability and behaviour that challenges have support to care for their child (see section 1.3).
Local authorities must promote the upbringing of children and young people with a learning disability and behaviour that challenges by their families, in line with section 17 of the Children Act 1989. This should include providing a range of services including education, and general and specialist learning disability support services in the community, as an alternative to residential placements away from home and to reduce the potential need for such placements.
The lead commissioner should ensure that specialist behavioural support in the community for children and young people includes support from education and child and adolescent mental health service (CAMHS) practitioners who have skills and experience in working with children and young people with a learning disability and behaviour that challenges.
## Recommendations for local authorities, service providers and practitioners
Health, mental health and behaviour support practitioners should work with other services, for example, education and social care, to:
deliver the outcomes agreed in a child or young person's education, health and care plan
provide support and interventions in line with NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions
maximise life opportunities for children and young people, including by ensuring they have access to meaningful education
support smooth transitions between services in line with the section on organising effective care in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions
support children and young people to develop skills for independence
take a positive approach to managing risk.This applies to children and young people in residential placements, as well as those living at home.
If a child or young person's behaviour that challenges is deteriorating or causing concern, the local authority should carry out a multi-agency review of their education, health and care plan (or other relevant plan) and involve the child or young person and their parents or carers. Review whether the plan needs to be updated and additional support provided if the child or young person's needs have changed.
## Exploring alternatives to residential placements for children and young people
Support parents and carers to understand the full range of options for education, care and support for their child.
When considering a residential placement, arrange a multi-agency review to explore all options and to review the child or young person's education, health and care plan. Include in this discussion:
the child or young person, and their parents or carers
the lead commissioner on behalf of the local authority and clinical commissioning group
at least 1 practitioner with clinical expertise in learning disability and the specific behaviour that is challenging
an independent expert by experience
special educational needs staff, or staff from their school or college.
Only offer children and young people a residential placement:
if assessment and care planning show that their needs (including their educational needs) cannot be met while they are living at home, and all alternatives to residential care have been considered and exhausted, or
following a request by the child or young person's family, which has been considered under the Children and Families Act 2014.
## Living in residential placements
Commission residential placements for children and young people as close to home as possible. Take into account in local authority contracts that some families may need financial support to help them see their child and for their child to visit them.
Support children and young people to maintain links with their family, friends and community (for example, members of their religious community) while they are in a residential placement.
Local authorities and service providers must promote maximum contact between children and young people living in residential placements and their family members and carers (in line with schedule 2 of the Children Act 1989). If a placement lasts longer than 3 months, the government's Visiting Regulations 2011 must be followed, for both local and out-of-area placements (see The Visits to Children in Long-Term Residential Care Regulations 2011). Help families stay in touch between visits, for example, using Skype.
## Planning and review to support children and young people leaving a residential placement
As soon as a child or young person moves into a residential placement, local authorities and clinical commissioning groups should ensure that:
a plan is developed for how they will progress towards returning to their family home, if appropriate, and towards greater independence
they continue to be supported to meet the outcomes identified in their education, health and care plan.
Review the plan in recommendation 1.6.12 at least every 6 months to check that progress is being made. This could be done as part of a looked-after child review, an education, health and care plan review, or sooner if needed.
Plans should be reviewed by the practitioner responsible for overseeing the child or young person's education health and care plan and all other practitioners involved in their care and support, including a specialist in behaviour that challenges.
If progress towards the outcomes in the plan has not been made, explore and address the reasons for this. If the child, young person or their family disagrees with the decision made at the review meeting, explain how they can challenge the decision if they want to.
# Short break services
## Recommendations for local authorities, commissioners and service providers
Local authorities must, in line with government legislation on Breaks for Carers of Disabled Children Regulations 2011 and the Children and Families Act 2014:
provide a range of short breaks for children and young people with a learning disability and behaviour that challenges and
publish as part of their Local Offer a statement of the range of services available and how eligibility will be assessed.
Commissioners in health and social care should provide sufficient, reliable, flexible and varied short break options, including both breaks away and support at home, for adults with a learning disability and behaviour that challenges.
Ensure that short breaks are:
community-based and close to home
available based on need, and at short notice both in crisis and to prevent a crisis
tailored to the needs of the person and their family or carers, taking into account the person's interests and preferences
able to provide a positive experience for the person being supported
able to deliver what is agreed in the education, health and care plan or care and support plan; carer's assessment; or behaviour support plan
planned in advance wherever possible and involve people and their family members and carers visiting the service first to see if it is suitable and to get to know the staff providing it
provided by staff who understand and respect people's cultural norms and values and their choices about personal care, private life and lifestyle.
# Making the right use of inpatient services
## Exploring alternatives to inpatient admission
Admit children, young people and adults with a learning disability and behaviour that challenges to inpatient units only if assessment and care planning show that their needs cannot be met safely in the community, and all possibilities for doing so have been considered and exhausted.
When thinking about inpatient admission, arrange a discussion to explore all other viable options. Include in this discussion:
the person and their family members and carers
at least 1 practitioner with clinical expertise in learning disability and the specific behaviour that is challenging
at least 1 independent expert by experience. For further guidance, see NHS England's information on community Care and treatment reviews or, for children and young people, community Care, education and treatment reviews.
## Providing information
When there is a possibility that someone will be admitted to hospital, including as an informal admission, local authorities and clinical commissioning groups should give them and their family and carers accessible, independent information and advice about their rights, access to independent advocacy and other possible options for treatment, and care and support.
Service providers must provide information about independent mental health advocacy as required by the Mental Health Act 1983.
## When a placement is needed
Provide an inpatient placement that is as close as possible to where the person usually lives.
The named worker should support the person to maintain links with their family, friends and community (for example, members of their religious community) while they are in hospital, and give their family and friends information about their progress.
If people are admitted as inpatients outside their local area, social workers in the community learning disability team and the named worker should stay in contact with the person, and help them stay in contact with other key practitioners in their own area.
When someone is admitted as an inpatient, offer them interventions in line with recommended psychological and environmental interventions in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions. Ensure that these interventions specifically address their needs and the reason for their admission.
## Planning and review to support discharge
As soon as the person is admitted, the hospital and community learning disability team should work together to develop a discharge plan.
Practitioners involved in the child, young person or adult's care and support should review the person's discharge plan at least every 3 months. Include in these reviews:
the person and their family members or carers
the practitioner responsible for agreeing discharge
a specialist in behaviour that challenges.
Think about using NHS England's Care and treatment review process or the Care programme approach as a framework for reviews to support discharge for adults. For children and young people think about using the Care, education and treatment review or education, health and care planning process.
If the person is not discharged after the meeting with practitioners involved in their care and support, provide sufficient reason for this and develop a new plan towards discharge. Explain to the person and their family or carers how they can challenge the decision if they want to.
Tell people who might apply to, or are referred for, a first-tier mental health tribunal relating to being an inpatient, about their right to request an independent clinician (in line with section 76 of the Mental Health Act 1983) to:
visit them at any reasonable time and examine them in private
inspect any records relating to their conditions and treatment.
# Staff skills and values
## Recommendations for commissioners, local authorities and service providers
As part of staff recruitment and training, ensure that staff have the skills, knowledge and qualities they need to support the children, young people and adults they are working with. This includes:
the skills and knowledge recommended in the section on staff training, supervision and support in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions
being resilient and compassionate
showing that they care
understanding and respecting the person's human rights, faith, culture, identity and values.
Ensure that staff providing direct support to children, young people and adults with a learning disability and behaviour that challenges have the 'direct contact' level competencies of the Positive Behavioural Support Academy's Positive behaviour support competence framework.
Give staff providing direct support access to advice from behaviour support specialists with 'consultant' level competencies of the Positive Behavioural Support Academy's Positive behaviour support competence framework.
Local authorities and clinical commissioning groups should plan for and resource training among service providers who provide day-to-day support about how to work with young people and adults with a learning disability who are at risk of offending.
Organisations should ensure that staff have supervision and support, in line with the recommendations on staff training, supervision and support in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.
Involve young people and adults with a learning disability and behaviour that challenges in staff recruitment. Involve their family members and carers too if the person agrees, unless there is a compelling reason not to.
Think about how to involve children with a learning disability in staff recruitment.
# Terms used in this guideline
The Think Local, Act Personal care and support jargon buster explains many of the social care terms used in this guideline.
## Adult
In this guideline, 'adults' are aged 18 years or older.
## Behaviour support specialist
A practitioner who has training in helping people and their family members and carers to understand and change their behaviour if it is causing problems for them.
## Behaviour that challenges
Behaviour of such an intensity, frequency or duration that the physical safety of the person, or others around them, is likely to be placed in serious jeopardy. It also includes behaviour that is likely to severely limit or deny access to and use of ordinary community facilities.
## Carer
Someone who provides informal care and support to a child, young person or adult with a learning disability. It does not cover staff who are paid to provide care or support.
## Children
In this guideline, 'children' are aged 12 years or younger.
## Contingency fund
A sum of money set aside to fund any unforeseen expenditure, and to respond quickly in an emergency.
## Experts by experience
People with lived experience of using services, including people with a learning disability themselves and their family members and carers.
## Forensic services
Specialist services that work with people in contact with, or at risk of contact with, the criminal justice system.
## Lead commissioner
A commissioner appointed by the local authority and clinical commissioning group who oversees strategic joint commissioning arrangements for health, social care and education services specifically for all children, young people and adults with a learning disability, including those who display, or are at risk of developing, behaviour that challenges.
## Learning disability
In line with NICE's guideline on challenging behaviour and learning disabilities, a learning disability is defined as meeting 3 core criteria:
lower intellectual ability (usually an IQ of less than 70)
significant impairment of social or adaptive functioning
-nset in childhood.
A person's learning disability may be described as mild, moderate, severe or profound. Learning disabilities are different from specific learning difficulties such as dyslexia, which do not affect intellectual ability.
## Positive behaviour support
Positive behavioural support is a person-centred approach that uses a multi-element format to better understand and so reduce behaviour that challenges. It can include changing the person's environment, developing their skills, providing focused support and developing reactive strategies.
## Real Tenancy Test
The Real Tenancy Test is a quick test to check that a person who lives in supported accommodation enjoys the same rights and protections in law as a person who has a full tenancy agreement for their rented home.
## Residential placement
Examples of residential placements include residential care homes for adults and, for children and young people, placements that involve living away from their family home, for example, in residential schools and colleges.
## Service providers
This can be any organisation in the public, private or voluntary sector that offers a service to people with a learning disability and behaviour that challenges. This can include services such as hospitals, care homes and organisations that provide support for people to live in their own homes or with their family.
## Short breaks
Also known as respite care, these involve a person with care and support needs spending regular short periods away from their main carer, to give the carer a break and the person a chance to do something different. These breaks may take place in the person's own home, in the home of an approved carer or in a residential placement.
## Young people
In this guideline, 'young people' are aged 13 to 17 years.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Children, young people and adults with a learning disability and behaviour that challenges are likely to use both health and care services throughout their lives. However, a lack of integration across services, including children's and adults' services, can impact on quality of care. Local authorities, working together with clinical commissioning groups, can provide a more joined‑up and person-centred approach by designating a lead commissioner who is responsible for commissioning health, social care and education services for both adults and children with a learning disability, including for people whose behaviour is described as challenging. For some services, creating this role may involve a significant change in practice.
Family members and carers often play a significant role in supporting people with a learning disability and behaviour that challenges, but they can find it difficult to access information, guidance and support. Many families need ongoing training and support for their caring role from specialist services, including positive behaviour support services. Families may also benefit from services such as peer support. Local authorities and health services need to provide this information and support, and tell families how to get it. For areas that do not currently provide comprehensive support for families, this will involve a significant change in practice.
Developing good general and specialist community services is important for supporting children, young people and adults with a learning disability and behaviour that challenges to live how and where they want, and to avoid the need for hospital admission or residential placements. Developing capacity in services and housing to support people in the community is likely to be a challenge in areas where resources are focused on inpatient care. Clear plans will need to be developed, agreed and put in place to make this change.
Children, young people and adults with a learning disability and behaviour that challenges should not be admitted to inpatient units unless all other possible options have been considered and exhausted. Similarly, children and young people should only be provided with a residential placement if all other possibilities have been considered. Where inpatient care or residential placements are used, planning should begin immediately for the person to return to their family or community. The plan should be reviewed regularly. Where this is not current practice, significant change will be needed.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Models of person-centred support
What models of delivering person-centred support are effective and cost effective for people with a learning disability and behaviour that challenges, and their families and carers?
What are the views and experiences of people with a learning disability and behaviour that challenges and their family members and carers, of different models of delivering person-centred support?
## Why this is important
Person-centred support is the current recommended approach and is at the centre of this service guideline. However, there is little published research about what configurations of services and resources provide the best person-centred support for people with a learning disability and behaviour that challenges, and their families and carers. There is also limited research from the point of view of people with a learning disability and their families and carers on what good person-centred support looks like, how it can be measured or benchmarked or what it means for them.
# Supporting family members, carers and staff
What types of services or approaches are effective in supporting family members, carers and staff to be resilient and able to provide care and support to people with a learning disability and behaviour that challenges?
## Why this is important
Enabling family members, carers and staff to provide continuing care and support can help prevent placements from breaking down, which can lead to out-of-area placements. Investment in carers, support networks, initiatives that support independent living, and community networks are key to helping people develop greater resilience. This is especially important if new approaches to service delivery, such as personalisation, are to succeed. However, there is no direct empirical evidence of the social and economic benefits associated with investment in such approaches and services.
# Models of supported living
What is the effectiveness and cost effectiveness of models of shared, supported living, such as Shared Lives?
What are the views and experiences of people sharing their home and people who live with them under programmes such as Shared Lives?
## Why this is important
It is important that people with a learning disability and behaviour that challenges have more choice and control over where they live. Models of supported living, such as Shared Lives, are promising models for people with a learning disability. However, the support needs of people with a learning disability and behaviour that challenges are more complex and there is very limited evidence about which types of supported living are effective specifically for them. It would be useful to know what kinds of supported living are acceptable and feasible for people with a learning disability and behaviour that challenges and their families and carers, as well as for Shared Lives families.
# Effective components of integrated regional services for people with a learning disability and behaviour that challenges
What are the effective components of an integrated regional service for people with a learning disability and behaviour that challenges across health and social care (including pooling budgets and other resources)?
What are the barriers and facilitators to pooling budgets and other resources across regions?
## Why this is important
The Winterbourne View Review Action Group and the Transforming care programme recommended that health and social care services should pool budgets. However, reports from the National Audit Office highlight that there has been little evidence of this happening in practice. Research is needed to know what mechanisms enable or stop this practice from happening, and whether the practice results in better outcomes for people with a learning disability.
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{'Context': "An estimated 1.2\xa0million children, young people and adults in England have a learning disability, and of these it is estimated that 10–17% display behaviour that challenges (see Predictors, costs and characteristics of out of area placement for people with intellectual disability and challenging behaviour. Allen et al.\xa02007). A more recent report suggested that there are over 40,000\xa0children with learning disabilities who display behaviour that challenges (see Estimating the number of children with learning disabilities in England whose behaviour challenges. Emerson et al.\xa02014). In addition, approximately 1% of the adult population has an autism spectrum condition and 60–70% of these also have a learning disability (see Estimating the prevalence of autism spectrum conditions in adults Brugha et al.\xa02012).\n\nThe most commonly used definition of behaviour that challenges is: 'behaviour of such an intensity, frequency or duration that the physical safety of the person or others is likely to be placed in serious jeopardy, or behaviour which is likely to seriously limit or deny access to and use of ordinary community facilities' (Emerson et al.\xa01987). Later definitions have highlighted the role of cultural context in determining whether behaviour is perceived as challenging (Emerson\xa01995).\n\nThis guideline was developed in a context of changes to policy and practice for children, young people and adults with a learning disability (or autism and a learning disability) and behaviour that challenges. The support needs of these vulnerable groups were set out in 1992 in the Mansell report, which identified the need to invest in developing local services with appropriate levels of skilled staff to meet people's needs. This was restated in a later review, the so‑called 'Mansell\xa02 report' (see Services for people with learning disabilities and challenging behaviour or mental health needs. Department of Health), which also highlighted the increased use of placements away from people's homes.\n\nThe exposure of widespread abuse at Winterbourne View hospital in 2011 led to a review of care provided in this hospital, and across England more widely, for people with a learning disability and behaviour that challenges. The resulting report (see Transforming care: a national response to Winterbourne View hospital. Department of Health) started a programme of work to improve services for people with a learning disability or autism who also have mental health conditions or behaviours described as challenging. In particular, this aimed to shift emphasis from inpatient care in mental health hospitals towards care based on people's individual needs and wishes and those of their families, provided by general and specialist services in the community. The programme did not meet its original targets, as highlighted in a report by the National Audit Office (see Care services for people with learning disabilities and challenging behaviour), and was reconfigured in\xa02015.\n\nThe 'transforming care programme' is now led jointly by NHS England, the Association of Directors of Adult Social Services, the Care Quality Commission, Local Government Association, Health Education England and the Department of Health. The national plan (see Building the right support. 2015) included plans for 48\xa0'transforming care partnerships' to pilot new arrangements of services. The national plan was followed by NHS England's national service model (October 2015) that set out the range of support that should be in place no later than March 2019. To support implementation of the interim service model, NHS England developed 3\xa0model service specifications (see Transforming Care: service model specification. January 2017) and supplementary guidance on Developing support and services for children and young people with a learning disability, autism or both (September 2017). This guidance also supports the recommendations of Dame Christine Lenehan's review (January 2017) on providing care and support for children and young people with complex needs who display challenging behaviour.\n\nThis guideline takes into account the direction of travel in the transforming care programme. It complements this work by providing evidence-based recommendations to support children, young people and adults with a learning disability (or autism and a learning disability) and behaviour that challenges to live their lives in the community like everyone else.\n\nIt is based on evidence about effectiveness and cost effectiveness of different support and services, and how those services are coordinated. It is also informed by the views of people who use services and their families on what is important to them in their care and support.\n\nThe application of the recommendations in this guideline is not mandatory. Although there is no legal obligation to implement our guidance, health and social care practitioners, and practitioners in related services, are actively encouraged to follow our recommendations to help them deliver the highest-quality care.\n\nThis guideline complements statutory duties and good practice as set out in relevant legislation and guidance. The recommendations cross-refer to legislation and other guidance where appropriate. Relevant legislation and guidance includes:\n\n\n\nAutism Act 2009\n\nCare Act 2014 and associated guidance\n\nChildren Act 1989 and associated guidance\n\nChildren and Families Act 2014\n\nChildren and Young Peoples Act 2008\n\nChronically Sick and Disabled Persons Act\xa01970\n\nHuman Rights Act 1998\n\nMental Health Act 1983, 2007\n\nMental Capacity Act 2005 (amended 2007) and associated guidance on Deprivation of liberty safeguards.\n\nThe guideline has been developed by a committee of people who use services; family members and carers of children, young people and adults with a learning disability who display behaviour that challenges; and professionals. It has used information from an extensive review of research evidence, and from expert witnesses. The development followed the methods outlined in developing NICE guidelines: the manual and the interim methods guide for developing service guidance (2014).\n\nEquality and diversity issues have been considered throughout the development of the guideline. The committee also gave careful consideration to the potential resource impact of the recommendations.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Aims and principles\n\nThis guideline is based on the principle that children, young people and adults with a learning disability and behaviour that challenges should have the support they need to live where and how they want. It will help local areas shift their focus towards prevention and early intervention, enabling children, young people and adults to live in their communities, and increasing support for families and carers. This should reduce the need for people to move away from their home or community for care, education or treatment.\n\nThe guideline recommends ways of designing and delivering services that aim to:\n\nhelp people to have a good quality of life\n\nsupport people to have good physical and mental health and emotional wellbeing\n\nmaximise people's choice and control\n\npromote person-centred care and support\n\nhelp children, young people and adults take an active part in all aspects of daily life that they choose, based both on what they can do and what they want to do\n\nrespect people's cultural, religious and sexual identity\n\nidentify when children, young people and adults are at risk of developing behaviour that challenges, so that support can be offered as early as possible\n\npromote continuity of relationships\n\ntake a 'whole life' approach.\n\n# Achieving change: strategic planning and infrastructure\n\n## Local leadership\n\nLocal authorities and clinical commissioning groups should jointly designate a lead commissioner to oversee strategic commissioning of health, social care and education services specifically for all children, young people and adults with a learning disability, including those who display, or are at risk of developing, behaviour that challenges.\n\nEnsure that the lead commissioner:\n\nplans and oversees joined‑up commissioning arrangements\n\nhas in‑depth knowledge and experience of working with children, young people and adults with a learning disability and behaviour that challenges, including knowledge of local services\n\nplans services that take a 'whole life' approach from early childhood onwards and enable smooth transitions.\n\n## Joint commissioning and funding\n\nThe lead commissioner should ensure that budgets and other resources are pooled to develop local and regional services for children, young people and adults with a learning disability and behaviour that challenges. These should be pooled:\n\nacross health, social care and education and\n\nwith neighbouring authorities.\n\nConsider jointly commissioning the most specialised behaviour support services across areas for children, young people and adults with particularly complex needs.\n\nEnsure that funding mechanisms for service providers support creative and flexible community-based responses, for example, a contingency fund that service providers can draw on quickly if there is a crisis.\n\n## Planning and delivering services according to local need\n\nEnsure that service planning and delivery is based on an assessment of current and future service needs using:\n\nthe local population prevalence of learning disabilities in children, young people and adults and the proportion who are likely to display behaviour that challenges\n\nan analysis of assessed needs in education, health and social care plans, to provide an early view of likely service needs and enable prevention and early intervention\n\nother sources of information, such as registers of people at risk of admission and other dynamic risk data; disabled children's registers; and records of referrals from liaison and diversion teams, youth offending teams and police.\n\nEnsure that services are planned and delivered in a way that:\n\nis co‑produced with children, young people and adults using services and their families, carers and independent advocates\n\nenables person-centred planning and provision\n\naddresses the needs of different age groups but also takes a 'whole life' approach to planning\n\nincludes planning for a range of future housing and employment support needs\n\nintegrates health, social care and other relevant services.\n\nDevelop local and regional plans that have a single care pathway and point of access for children, young people and adults with a learning disability and behaviour that challenges, and their families and carers. Make sure this is reflected in local authorities' commissioning strategies and key documents such as the Market Position Statement. For further information on how to develop care pathways, see the section on organising effective care in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.\n\n## Managing risk\n\nTake joint responsibility with service providers and other organisations for managing risk when developing and delivering care and support for children, young people and adults with a learning disability and behaviour that challenges. Aim to manage risks and difficulties without resorting to changing placements or putting greater restrictions on the person.\n\n## Quality assurance\n\nEnsure services meet set service-level and individual outcomes, and that service providers show evidence of achieving these outcomes. This evidence could include:\n\nsatisfaction and quality-of-life ratings of children, young people and adults who have used the service, and their family members, friends and carers\n\noutcomes measured by personalised and validated tools such as the 'measure of processes of care' (MPOC) tool, or the 'patient feedback questionnaire' (PFQ)\n\na reduction in duration and frequency of behaviour that challenges\n\nstability of placements\n\nparticipation in education by children and young people\n\nreports on the use of restrictive interventions, including medication\n\ncontact time with specialist professionals\n\nevidence from quality reviews and spot checking involving experts by experience\n\nquality checks by user-led organisations.\n\nInpatient services should provide the evidence in recommendation 1.1.10 in addition to evidence of detailed assessments, treatment outcomes and time to discharge.\n\nCommissioners should establish a multi-agency group, or make use of an existing group, including experts by experience and service providers, to monitor the quality of services and the outcomes achieved.\n\nService providers should use evidence gathered to continuously improve services. They should record the results and make them available to people who use services, and their families and carers.\n\n## Involving people in commissioning and service improvement\n\nCommissioners should make use of expertise from experts by experience to inform decision-making and quality assurance of services.\n\n# Enabling person-centred care and support\n\n## Involving people with a learning disability and behaviour that challenges\n\nPractitioners working with children, young people and adults with a learning disability and behaviour that challenges, and their family members and carers, should get to know the person they support and find out what they want from their lives, not just what they want from services. For more information on involving people in their care and support, see the section on working with people with a learning disability and behaviour that challenges, and their families and carers in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.\n\nActively involve people with a learning disability in all decisions that affect them. If a person aged 16\xa0or over lacks the capacity to make a decision, staff must follow the Mental Capacity Act\xa02005.\n\nAssess whether a child or young person under the age of\xa016 is Gillick competent and work in partnership with all children and young people. Include them in decisions about their treatment and ask them how they would like their families or carers to be involved.\n\nInvolve families, friends, carers or independent advocates if this is what the person wants, or where decisions are made in the best interests of a person aged over\xa016 in line with the Mental Capacity Act\xa02005. This should be done unless there is a compelling reason not to (for example, if there are safeguarding concerns).\n\nSupport children, young people and adults with a learning disability and behaviour that challenges to live where and how they want. Give them support that:\n\nis person-centred, reflecting their individual needs and choices, and maximising their control\n\nhelps them take an active part in all aspects of daily life that they choose, based both on what they can do and what they want to do\n\ntakes into account the severity of their learning disability; their developmental stage; any communication difficulties or physical or mental health problems; and their life history\n\nrespects their cultural, religious and sexual identity\n\nhelps them before problems occur or as soon as they emerge, not just when crisis has been reached\n\nencourages people to speak out if they have any worries\n\npromotes continuity of relationships.\n\nFind out children, young people and adults' information and communication needs, record them and share this information with everyone working with them in line with NHS England's Accessible Information Standard.\n\nEnsure that people with a learning disability and behaviour that challenges have access to speech and language therapy when they need it.\n\n## Advocacy\n\nConsider providing access to independent advocacy whenever it is wanted or needed by a person with a learning disability and behaviour that challenges. As a minimum, it must be offered by local authorities as described in the Care Act\xa02014, Mental Capacity Act\xa02005 and Mental Health Act\xa02007.\n\nEnsure that independent advocates working with children, young people and adults with a learning disability and behaviour that challenges have skills and experience in working with these groups, and in working with specialist learning disability services.See also recommendations 1.8.3 and 1.8.4 on independent advocacy in relation to inpatient admissions.\n\n## Coordinating care and support\n\nLocal authorities working in partnership with healthcare professionals should assign a single practitioner, for example, a social worker (in a disabled children's team or community learning disability team) or community psychiatric nurse, to be the person's 'named worker'. The named worker should get to know the person and coordinate support to meet their needs over the long term.\n\nThe local authority, clinical commissioning group and service providers should liaise regularly with the named worker, keeping them informed and involved in decision-making.\n\nArrange regular meetings to discuss the person's care and support, and invite people in their support network, including family members, carers, independent advocates and practitioners from all services that support them. This could build on existing processes, for example, the education, health and care planning and review process for children (see Gov.uk's children with special educational needs and disabilities).\n\nRecognise and use the expertise brought by all members of the person's support network (not only those who are paid).\n\n## Care and support planning\n\nCommunity learning disability teams (or relevant children's services, for example, disabled children's teams) and service providers should work in partnership with the child, young person or adult, their family members, carers and independent advocates and their named worker to develop, deliver and review their care and support plan. Develop a care plan that:\n\nmeets the person's needs and preferences\n\nworks to support and maximise the person's mental capacity\n\ntakes into account people's fluctuating mental capacity and needs\n\nadopts a 'whole life' approach that covers what they want to achieve in both the short and long term, and supports smooth transitions\n\ntakes a positive approach to managing risk\n\nsets out what to do to prevent or respond to a crisis.\n\nService providers and agencies responsible for commissioning and planning services (including specialist services) should match the specific skills of staff to the characteristics of the person with a learning disability and behaviour that challenges. Do this as soon as care and support planning begins.\n\nCommunity learning disability teams or relevant children's services (for example, disabled children's teams) and service providers should review children, young people and adults' care and support with their named worker:\n\naccording to timings agreed in their plan and\n\nwhenever there is a significant change, for example, if the person is placed out of area.\n\nWhen reviewing plans:\n\ninvolve people as set out in recommendations 1.2.1 to\xa01.2.4\n\ntake account of people's fluctuating mental capacity\n\ncheck that staff are following the behaviour support plan recommendations in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions\n\nthink about plans for the future, including whether changes might be needed to the person's housing or support.\n\nAs soon as a child, young person or adult develops behaviour that challenges, community learning disability teams (or relevant children's services, for example, child and adolescent mental health learning disability teams) and service providers should offer to work with them and their family or carers to develop a behaviour support plan. For more information on what this should include, see the recommendations on behaviour support plan in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.\n\n## Supporting people to use personal budgets\n\nEnsure that a range of funding arrangements are available, including direct payments, personal budgets or individual service funds, depending on children, young people and adults' needs and preferences.\n\nOffer people a choice of funding arrangements (see recommendation 1.2.19) and support people to use these budgets, where they wish to, by:\n\ntelling them how each element of their support will be funded\n\ntelling them how much money is available and how much control they have over how the money is spent\n\ngiving them and their families and carers information about different ways of managing their budgets, and how these may affect their carer\n\nsupporting them to try out different mechanisms for managing their budget\n\noffering information, advice and support to people who pay for or arrange their own care and support, as well as to those whose care and support is publicly funded\n\noffering information about benefits entitlement\n\nensuring that carers' needs are taken fully into account.[This recommendation is adapted from NICE's guideline on older people with social care needs and multiple long-term conditions.]\n\n## Delivering care and support\n\nIn all settings, staff working with children, young people and adults with a learning disability, and their families and carers, should aim to reduce the risk of behaviour that challenges developing by:\n\nidentifying health or sensory problems early\n\nproviding strategies and interventions to support communication. Follow recommendations on psychological and environmental interventions in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.\n\nFor people taking medicines:\n\nfollow recommendations in NICE's guideline on managing medicines for adults receiving social care in the community and\n\nif the reason for the medicine relates to the person's behaviour or mental health, ensure it is reviewed regularly in line with recommendations on medication in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions, and recommendations in mental health problems in people with learning disabilities: prevention, assessment and management.\n\nEnsure that children, young people and adults with a learning disability and behaviour that challenges know about and are able to use services to support their health and wellbeing. These should include:\n\nservices helping people to make and maintain friends, relationships and social networks in their community and take part in community activities\n\naccess to employment and pre-employment opportunities\n\nday opportunities where activities can be tailored to the person's interests, preferences, strengths and abilities\n\nuniversal healthcare services and health checks\n\npeer support opportunities.\n\n# Early intervention and support for families and carers\n\nSee section\xa01.6 for more recommendations on services for children and young people.\n\n## Recommendations for local authorities\n\nEnsure that families and carers of children, young people and adults with a learning disability and behaviour that challenges are given support that helps them to:\n\nmanage their role as carers\n\ncare for the person and meet their needs, in relation to behaviour, care and support, communication, physical health, mental health, educational needs or any offending behaviour\n\naccess support from specialist services when needed.\n\nProvide information, guidance and ongoing support for families and carers of children, young people and adults with a learning disability and behaviour that challenges, which address different aspects of their life. Sources of support could include:\n\npeer support\n\nparent and carer groups or forums\n\nemail support\n\nindividual phone and face-to-face support\n\nfamily networks\n\nindependent advocacy\n\nmanaged email networks (a shared discussion forum)\n\nsocial media groups.\n\nGive family members and carers information in line with the section on support and interventions for family members or carers in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions. This could be in the form of a 'welcome pack'. Provide this information:\n\nat the first point of contact with families\n\nthrough the local authority website, local libraries and universal services such as GP surgeries.\n\n## Recommendations for the named worker\n\nHelp people and their families to understand information about available support (see recommendation 1.3.3) from first contact onwards.\n\nAdvise family members and carers how to access:\n\nshort break services\n\nspecialist behaviour support\n\ntraining as set out in recommendations 1.7.1 and 1.7.2 in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions\n\nsupport in an emergency\n\ncommunity resources, including voluntary organisations, networks and support groups\n\nlocal safeguarding procedures, including how to raise safeguarding concerns or make a complaint.\n\nEnsure that family members and carers have information such as contact details of staff and key dates and appointments.\n\n# Services in the community – prevention, early intervention and response\n\n## Developing services in the community\n\nThe lead commissioner should commission services in the community for people with a learning disability and behaviour that challenges (including for people in contact with, or at risk of contact with, the criminal justice system). These services:\n\nshould be able to cater for lower-level needs up to intensive, complex or fluctuating needs\n\ncould be set up either as 1\xa0large team with different subteams or as several separate teams\n\nshould be provided wherever possible as an alternative to, and to reduce the potential need for:\n\n\n\ninpatient care for children, young people and adults or\n\nresidential placements for children and young people.\n\n\n\nServices in the community should fulfil the following core functions:\n\nspecialist prevention and early intervention\n\ndeveloping capacity in non-specialist community services to prevent unnecessary inpatient admissions\n\ngiving support and training to families and carers (by following the recommendations on support and interventions for family members or carers in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions)\n\nquality assurance and service development\n\nshort-term assessment and intervention\n\nlonger-term complex intervention\n\ncrisis response and intervention.\n\nEnsure that children, young people and adults with a learning disability can get specialist support through their community learning disability team that meets their needs, for example, in relation to:\n\nbehaviour\n\ncommunication\n\nsocial care and support needs\n\nphysical health\n\nmental health\n\neducation\n\noffending behaviour. This could be achieved by employing relevant practitioners within the community learning disability team or by developing close links with practitioners in other relevant services.\n\nServices who provide support through the community learning disability team should work together and provide consultancy and support to each other. They should work with children, young people and adults, and their family members and carers, in a way that is:\n\npersonalised\n\nflexible\n\nresponsive\n\naccessible\n\nreflective.\n\nIf a child, young person or adult develops, or is at risk of developing, offending behaviour, community learning disability teams should refer them to appropriate specialists, such as community forensic or youth justice services, as soon as possible (see recommendations 1.4.12 to 1.4.16). These services should:\n\nprovide evidence-based early interventions that are adapted for people with a learning disability and address the specific behaviour\n\nwork in an ongoing partnership with each other and with the community learning disability team whenever needed.\n\nCommunity learning disability teams should maintain good communication and links with the police and liaison and diversion teams so that:\n\nthey can advise on assessments of vulnerability, particularly for people with mild or borderline learning disabilities who may otherwise not be identified as vulnerable\n\npeople who need support can be diverted from the criminal justice service to community learning disability teams.\n\n## Specialist behavioural support\n\nEnsure that specialist assessment and behavioural support are available in the community so that children, young people and adults can stay where they currently live and avoid moving.\n\nEnsure that specialist services for behaviour that challenges are available to everyone with a learning disability and behaviour that challenges, based on an assessment of each person's need and risk and taking into account the benefit of early intervention.\n\nThe lead commissioner should:\n\nset local maximum waiting times for initial assessment, and for urgent and routine access to treatment and support\n\nensure that waiting times for specialist behavioural support do not exceed NHS waiting time standards.\n\n## Intensive behavioural support during a crisis\n\nProvide a local, personalised response to children, young people and adults who need intensive support during a crisis. This response should:\n\nfocus on keeping people in their own home\n\nhave an out-of-hours helpline as a first option with the capacity to respond rapidly (within 1\xa0hour or in line with local mental health crisis response times), staffed by people with skills and knowledge in learning disabilities and behaviour that challenges, and specialist skills in mental health problems\n\nprovide face-to-face support within 4\xa0hours if needed, based on initial triage\n\ninvolve partnership with other commissioners, service providers and family members and carers\n\ninclude giving staff access to the person's information if they are already in contact with services\n\nprovide short-term support to achieve aims that are agreed with the person\n\ninclude clear contact details for children's services (as set out in the Local Offer) and adults' services.\n\nUse a clear, coordinated approach to reducing the level of support from more intensive services in line with the person's needs. Learn from what happened and use this knowledge to inform future early intervention and prevention services and support crisis plans.\n\n## Services for people in contact with, or at risk of contact with, the criminal justice system\n\nCommission local community forensic services for children, young people and adults with a learning disability and behaviour that challenges who are in contact with, or at risk of contact with, the criminal justice system to prevent out-of-area hospital placement. These could be provided as stand-alone teams, or as a specialism within an existing team, for example, a community learning disability team, or a learning disability specialism within a community forensic team.\n\nWhen forensic community learning disability services are supporting children, young people and adults with a learning disability (for example, if they are subject to a forensic community rehabilitation order or a community treatment order), they should enable them to live in the community, as close to home as possible, and in the least restrictive setting.\n\nForensic community learning disability services should stay in frequent contact with the person they are supporting, including those who are in out-of-area placements or criminal justice settings, and help them build and maintain social links in their community.\n\nForensic learning disability services and probation services should work together to agree who is best able to support the person in meeting the requirements of their treatment or rehabilitation order.\n\nForensic learning disability services, mental health, specialist voluntary sector organisations, learning disability services and social care services should establish care pathways and close links with each other to help them refer people quickly between these services to get the right support and effectively manage risk.\n\n# Housing and related support\n\n## Giving people a choice of housing\n\nCommissioners should work with local housing and social care providers to identify the specific housing needs of adults with a learning disability and behaviour that challenges. They should ensure areas have a range of housing and care options available that meet these needs and cater for different preferences and person-centred support needs (see also section\xa01.2).\n\nEnable adults to live close to their family, friends and community unless they choose not to or there is a compelling reason not to.\n\nWhere possible ensure that, wherever people live, they have security of tenure in line with the Real Tenancy Test.\n\nWhen helping adults with a learning disability and behaviour that challenges choose where to live:\n\nprovide information on the range of possible options\n\ntake into account their preferences and any specific support needs or risks, including the impact of environmental factors on the person (see the recommendation on environmental factors in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions)\n\ngive them advice on adapting their current home if needed.\n\nOffer people the option to live alone with appropriate support if they prefer this and it is suitable for them.\n\nIf adults prefer not to live alone with support, or it is not suitable for them, offer them the option of living with a small number of other people in shared housing that has a small-scale domestic feel. Involve people in choosing how many people, and who, they live with.\n\nOffer adults housing outside their local community only:\n\nif it is what the person wants\n\nif it is indicated after a full assessment and planning process, which takes into account the person's preferences, needs and risks\n\nfor a specified time that has been agreed with the person, or agreed in their best interests if they lack capacity to decide this – for example, if they are in crisis and there is no local placement available.\n\nIf someone is moving outside their local area, local authorities, clinical commissioning groups and commissioners should:\n\nestablish the commissioner who is responsible for paying for the person's care and support\n\nensure they will still have the support they need\n\nmake a plan that enables them to return to their local area if they want to, or if it is in their best interests if they lack capacity to decide this.\n\n# Services for children and young people\n\n## Recommendations for local authorities, clinical commissioning groups and the lead commissioner\n\nLocal authorities should ensure that parents and carers of children and young people with a learning disability and behaviour that challenges have support to care for their child (see section\xa01.3).\n\nLocal authorities must promote the upbringing of children and young people with a learning disability and behaviour that challenges by their families, in line with section\xa017 of the Children Act\xa01989. This should include providing a range of services including education, and general and specialist learning disability support services in the community, as an alternative to residential placements away from home and to reduce the potential need for such placements.\n\nThe lead commissioner should ensure that specialist behavioural support in the community for children and young people includes support from education and child and adolescent mental health service (CAMHS) practitioners who have skills and experience in working with children and young people with a learning disability and behaviour that challenges.\n\n## Recommendations for local authorities, service providers and practitioners\n\nHealth, mental health and behaviour support practitioners should work with other services, for example, education and social care, to:\n\ndeliver the outcomes agreed in a child or young person's education, health and care plan\n\nprovide support and interventions in line with NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions\n\nmaximise life opportunities for children and young people, including by ensuring they have access to meaningful education\n\nsupport smooth transitions between services in line with the section on organising effective care in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions\n\nsupport children and young people to develop skills for independence\n\ntake a positive approach to managing risk.This applies to children and young people in residential placements, as well as those living at home.\n\nIf a child or young person's behaviour that challenges is deteriorating or causing concern, the local authority should carry out a multi-agency review of their education, health and care plan (or other relevant plan) and involve the child or young person and their parents or carers. Review whether the plan needs to be updated and additional support provided if the child or young person's needs have changed.\n\n## Exploring alternatives to residential placements for children and young people\n\nSupport parents and carers to understand the full range of options for education, care and support for their child.\n\nWhen considering a residential placement, arrange a multi-agency review to explore all options and to review the child or young person's education, health and care plan. Include in this discussion:\n\nthe child or young person, and their parents or carers\n\nthe lead commissioner on behalf of the local authority and clinical commissioning group\n\nat least 1\xa0practitioner with clinical expertise in learning disability and the specific behaviour that is challenging\n\nan independent expert by experience\n\nspecial educational needs staff, or staff from their school or college.\n\nOnly offer children and young people a residential placement:\n\nif assessment and care planning show that their needs (including their educational needs) cannot be met while they are living at home, and all alternatives to residential care have been considered and exhausted, or\n\nfollowing a request by the child or young person's family, which has been considered under the Children and Families Act\xa02014.\n\n## Living in residential placements\n\nCommission residential placements for children and young people as close to home as possible. Take into account in local authority contracts that some families may need financial support to help them see their child and for their child to visit them.\n\nSupport children and young people to maintain links with their family, friends and community (for example, members of their religious community) while they are in a residential placement.\n\nLocal authorities and service providers must promote maximum contact between children and young people living in residential placements and their family members and carers (in line with schedule\xa02 of the Children Act\xa01989). If a placement lasts longer than 3\xa0months, the government's Visiting Regulations\xa02011 must be followed, for both local and out-of-area placements (see The Visits to Children in Long-Term Residential Care Regulations 2011). Help families stay in touch between visits, for example, using Skype.\n\n## Planning and review to support children and young people leaving a residential placement\n\nAs soon as a child or young person moves into a residential placement, local authorities and clinical commissioning groups should ensure that:\n\na plan is developed for how they will progress towards returning to their family home, if appropriate, and towards greater independence\n\nthey continue to be supported to meet the outcomes identified in their education, health and care plan.\n\nReview the plan in recommendation 1.6.12 at least every 6\xa0months to check that progress is being made. This could be done as part of a looked-after child review, an education, health and care plan review, or sooner if needed.\n\nPlans should be reviewed by the practitioner responsible for overseeing the child or young person's education health and care plan and all other practitioners involved in their care and support, including a specialist in behaviour that challenges.\n\nIf progress towards the outcomes in the plan has not been made, explore and address the reasons for this. If the child, young person or their family disagrees with the decision made at the review meeting, explain how they can challenge the decision if they want to.\n\n# Short break services\n\n## Recommendations for local authorities, commissioners and service providers\n\nLocal authorities must, in line with government legislation on Breaks for Carers of Disabled Children Regulations\xa02011 and the Children and Families Act\xa02014:\n\nprovide a range of short breaks for children and young people with a learning disability and behaviour that challenges and\n\npublish as part of their Local Offer a statement of the range of services available and how eligibility will be assessed.\n\nCommissioners in health and social care should provide sufficient, reliable, flexible and varied short break options, including both breaks away and support at home, for adults with a learning disability and behaviour that challenges.\n\nEnsure that short breaks are:\n\ncommunity-based and close to home\n\navailable based on need, and at short notice both in crisis and to prevent a crisis\n\ntailored to the needs of the person and their family or carers, taking into account the person's interests and preferences\n\nable to provide a positive experience for the person being supported\n\nable to deliver what is agreed in the education, health and care plan or care and support plan; carer's assessment; or behaviour support plan\n\nplanned in advance wherever possible and involve people and their family members and carers visiting the service first to see if it is suitable and to get to know the staff providing it\n\nprovided by staff who understand and respect people's cultural norms and values and their choices about personal care, private life and lifestyle.\n\n# Making the right use of inpatient services\n\n## Exploring alternatives to inpatient admission\n\nAdmit children, young people and adults with a learning disability and behaviour that challenges to inpatient units only if assessment and care planning show that their needs cannot be met safely in the community, and all possibilities for doing so have been considered and exhausted.\n\nWhen thinking about inpatient admission, arrange a discussion to explore all other viable options. Include in this discussion:\n\nthe person and their family members and carers\n\nat least 1\xa0practitioner with clinical expertise in learning disability and the specific behaviour that is challenging\n\nat least 1\xa0independent expert by experience. For further guidance, see NHS England's information on community Care and treatment reviews or, for children and young people, community Care, education and treatment reviews.\n\n## Providing information\n\nWhen there is a possibility that someone will be admitted to hospital, including as an informal admission, local authorities and clinical commissioning groups should give them and their family and carers accessible, independent information and advice about their rights, access to independent advocacy and other possible options for treatment, and care and support.\n\nService providers must provide information about independent mental health advocacy as required by the Mental Health Act\xa01983.\n\n## When a placement is needed\n\nProvide an inpatient placement that is as close as possible to where the person usually lives.\n\nThe named worker should support the person to maintain links with their family, friends and community (for example, members of their religious community) while they are in hospital, and give their family and friends information about their progress.\n\nIf people are admitted as inpatients outside their local area, social workers in the community learning disability team and the named worker should stay in contact with the person, and help them stay in contact with other key practitioners in their own area.\n\nWhen someone is admitted as an inpatient, offer them interventions in line with recommended psychological and environmental interventions in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions. Ensure that these interventions specifically address their needs and the reason for their admission.\n\n## Planning and review to support discharge\n\nAs soon as the person is admitted, the hospital and community learning disability team should work together to develop a discharge plan.\n\nPractitioners involved in the child, young person or adult's care and support should review the person's discharge plan at least every 3\xa0months. Include in these reviews:\n\nthe person and their family members or carers\n\nthe practitioner responsible for agreeing discharge\n\na specialist in behaviour that challenges.\n\nThink about using NHS England's Care and treatment review process or the Care programme approach as a framework for reviews to support discharge for adults. For children and young people think about using the Care, education and treatment review or education, health and care planning process.\n\nIf the person is not discharged after the meeting with practitioners involved in their care and support, provide sufficient reason for this and develop a new plan towards discharge. Explain to the person and their family or carers how they can challenge the decision if they want to.\n\nTell people who might apply to, or are referred for, a first-tier mental health tribunal relating to being an inpatient, about their right to request an independent clinician (in line with section\xa076 of the Mental Health Act 1983) to:\n\nvisit them at any reasonable time and examine them in private\n\ninspect any records relating to their conditions and treatment.\n\n# Staff skills and values\n\n## Recommendations for commissioners, local authorities and service providers\n\nAs part of staff recruitment and training, ensure that staff have the skills, knowledge and qualities they need to support the children, young people and adults they are working with. This includes:\n\nthe skills and knowledge recommended in the section on staff training, supervision and support in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions\n\nbeing resilient and compassionate\n\nshowing that they care\n\nunderstanding and respecting the person's human rights, faith, culture, identity and values.\n\nEnsure that staff providing direct support to children, young people and adults with a learning disability and behaviour that challenges have the 'direct contact' level competencies of the Positive Behavioural Support Academy's Positive behaviour support competence framework.\n\nGive staff providing direct support access to advice from behaviour support specialists with 'consultant' level competencies of the Positive Behavioural Support Academy's Positive behaviour support competence framework.\n\nLocal authorities and clinical commissioning groups should plan for and resource training among service providers who provide day-to-day support about how to work with young people and adults with a learning disability who are at risk of offending.\n\nOrganisations should ensure that staff have supervision and support, in line with the recommendations on staff training, supervision and support in NICE's guideline on challenging behaviour and learning disabilities: prevention and interventions.\n\nInvolve young people and adults with a learning disability and behaviour that challenges in staff recruitment. Involve their family members and carers too if the person agrees, unless there is a compelling reason not to.\n\nThink about how to involve children with a learning disability in staff recruitment.\n\n# Terms used in this guideline\n\nThe Think Local, Act Personal care and support jargon buster explains many of the social care terms used in this guideline.\n\n## Adult\n\nIn this guideline, 'adults' are aged 18\xa0years or older.\n\n## Behaviour support specialist\n\nA practitioner who has training in helping people and their family members and carers to understand and change their behaviour if it is causing problems for them.\n\n## Behaviour that challenges\n\nBehaviour of such an intensity, frequency or duration that the physical safety of the person, or others around them, is likely to be placed in serious jeopardy. It also includes behaviour that is likely to severely limit or deny access to and use of ordinary community facilities.\n\n## Carer\n\nSomeone who provides informal care and support to a child, young person or adult with a learning disability. It does not cover staff who are paid to provide care or support.\n\n## Children\n\nIn this guideline, 'children' are aged 12\xa0years or younger.\n\n## Contingency fund\n\nA sum of money set aside to fund any unforeseen expenditure, and to respond quickly in an emergency.\n\n## Experts by experience\n\nPeople with lived experience of using services, including people with a learning disability themselves and their family members and carers.\n\n## Forensic services\n\nSpecialist services that work with people in contact with, or at risk of contact with, the criminal justice system.\n\n## Lead commissioner\n\nA commissioner appointed by the local authority and clinical commissioning group who oversees strategic joint commissioning arrangements for health, social care and education services specifically for all children, young people and adults with a learning disability, including those who display, or are at risk of developing, behaviour that challenges.\n\n## Learning disability\n\nIn line with NICE's guideline on challenging behaviour and learning disabilities, a learning disability is defined as meeting 3\xa0core criteria:\n\nlower intellectual ability (usually an IQ of less than\xa070)\n\nsignificant impairment of social or adaptive functioning\n\nonset in childhood.\n\nA person's learning disability may be described as mild, moderate, severe or profound. Learning disabilities are different from specific learning difficulties such as dyslexia, which do not affect intellectual ability.\n\n## Positive behaviour support\n\nPositive behavioural support is a person-centred approach that uses a multi-element format to better understand and so reduce behaviour that challenges. It can include changing the person's environment, developing their skills, providing focused support and developing reactive strategies.\n\n## Real Tenancy Test\n\nThe Real Tenancy Test is a quick test to check that a person who lives in supported accommodation enjoys the same rights and protections in law as a person who has a full tenancy agreement for their rented home.\n\n## Residential placement\n\nExamples of residential placements include residential care homes for adults and, for children and young people, placements that involve living away from their family home, for example, in residential schools and colleges.\n\n## Service providers\n\nThis can be any organisation in the public, private or voluntary sector that offers a service to people with a learning disability and behaviour that challenges. This can include services such as hospitals, care homes and organisations that provide support for people to live in their own homes or with their family.\n\n## Short breaks\n\nAlso known as respite care, these involve a person with care and support needs spending regular short periods away from their main carer, to give the carer a break and the person a chance to do something different. These breaks may take place in the person's own home, in the home of an approved carer or in a residential placement.\n\n## Young people\n\nIn this guideline, 'young people' are aged 13\xa0to 17\xa0years.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nChildren, young people and adults with a learning disability and behaviour that challenges are likely to use both health and care services throughout their lives. However, a lack of integration across services, including children's and adults' services, can impact on quality of care. Local authorities, working together with clinical commissioning groups, can provide a more joined‑up and person-centred approach by designating a lead commissioner who is responsible for commissioning health, social care and education services for both adults and children with a learning disability, including for people whose behaviour is described as challenging. For some services, creating this role may involve a significant change in practice.\n\nFamily members and carers often play a significant role in supporting people with a learning disability and behaviour that challenges, but they can find it difficult to access information, guidance and support. Many families need ongoing training and support for their caring role from specialist services, including positive behaviour support services. Families may also benefit from services such as peer support. Local authorities and health services need to provide this information and support, and tell families how to get it. For areas that do not currently provide comprehensive support for families, this will involve a significant change in practice.\n\nDeveloping good general and specialist community services is important for supporting children, young people and adults with a learning disability and behaviour that challenges to live how and where they want, and to avoid the need for hospital admission or residential placements. Developing capacity in services and housing to support people in the community is likely to be a challenge in areas where resources are focused on inpatient care. Clear plans will need to be developed, agreed and put in place to make this change.\n\nChildren, young people and adults with a learning disability and behaviour that challenges should not be admitted to inpatient units unless all other possible options have been considered and exhausted. Similarly, children and young people should only be provided with a residential placement if all other possibilities have been considered. Where inpatient care or residential placements are used, planning should begin immediately for the person to return to their family or community. The plan should be reviewed regularly. Where this is not current practice, significant change will be needed.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Models of person-centred support\n\nWhat models of delivering person-centred support are effective and cost effective for people with a learning disability and behaviour that challenges, and their families and carers?\n\nWhat are the views and experiences of people with a learning disability and behaviour that challenges and their family members and carers, of different models of delivering person-centred support?\n\n## Why this is important\n\nPerson-centred support is the current recommended approach and is at the centre of this service guideline. However, there is little published research about what configurations of services and resources provide the best person-centred support for people with a learning disability and behaviour that challenges, and their families and carers. There is also limited research from the point of view of people with a learning disability and their families and carers on what good person-centred support looks like, how it can be measured or benchmarked or what it means for them.\n\n# Supporting family members, carers and staff\n\nWhat types of services or approaches are effective in supporting family members, carers and staff to be resilient and able to provide care and support to people with a learning disability and behaviour that challenges?\n\n## Why this is important\n\nEnabling family members, carers and staff to provide continuing care and support can help prevent placements from breaking down, which can lead to out-of-area placements. Investment in carers, support networks, initiatives that support independent living, and community networks are key to helping people develop greater resilience. This is especially important if new approaches to service delivery, such as personalisation, are to succeed. However, there is no direct empirical evidence of the social and economic benefits associated with investment in such approaches and services.\n\n# Models of supported living\n\nWhat is the effectiveness and cost effectiveness of models of shared, supported living, such as Shared Lives?\n\nWhat are the views and experiences of people sharing their home and people who live with them under programmes such as Shared Lives?\n\n## Why this is important\n\nIt is important that people with a learning disability and behaviour that challenges have more choice and control over where they live. Models of supported living, such as Shared Lives, are promising models for people with a learning disability. However, the support needs of people with a learning disability and behaviour that challenges are more complex and there is very limited evidence about which types of supported living are effective specifically for them. It would be useful to know what kinds of supported living are acceptable and feasible for people with a learning disability and behaviour that challenges and their families and carers, as well as for Shared Lives families.\n\n# Effective components of integrated regional services for people with a learning disability and behaviour that challenges\n\nWhat are the effective components of an integrated regional service for people with a learning disability and behaviour that challenges across health and social care (including pooling budgets and other resources)?\n\nWhat are the barriers and facilitators to pooling budgets and other resources across regions?\n\n## Why this is important\n\nThe Winterbourne View Review Action Group and the Transforming care programme recommended that health and social care services should pool budgets. However, reports from the National Audit Office highlight that there has been little evidence of this happening in practice. Research is needed to know what mechanisms enable or stop this practice from happening, and whether the practice results in better outcomes for people with a learning disability."}
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https://www.nice.org.uk/guidance/ng93
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This guideline covers services for children, young people and adults with a learning disability (or autism and a learning disability) and behaviour that challenges. It aims to promote a lifelong approach to supporting people and their families and carers, focusing on prevention and early intervention and minimising inpatient admissions.
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5b57bd58602ae8f5fe2b02bc97ec46b62d91a6d7
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nice
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Emergency and acute medical care in over 16s: service delivery and organisation
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Emergency and acute medical care in over 16s: service delivery and organisation
This guideline covers organising and delivering emergency and acute medical care for people aged over 16 in the community and in hospital. It aims to reduce the need for hospital admissions by giving advanced training to paramedics and providing community alternatives to hospital care. It also promotes good-quality care in hospital and joint working between health and social services.
# Context
NICE's service guidance on emergency and acute medical care supports the next steps in the NHS five year forward view. It presents a survey of the best available evidence on a range of questions across the emergency and acute care pathway, which reaffirms key aspects of care articulated in the NHS seven day services clinical standards, including the role of early consultant review after admission to hospital, daily consultant review in hospital, multidisciplinary care, structured handovers and liaison mental health services.
This guideline covers service organisation and delivery in the following topic areas referred to NICE by the Department of Health in 2012:
urgent and emergency care
-ut-of-hours care
-day services
consultant review within 12 hours of admission
acute medical admissions within the first 48 hours
discharge planning to reduce readmissions.
Hospitals have found it increasingly challenging to maintain the flow of patients through from admission to discharge. The guideline committee considered interventions that avoid hospital admission and facilitate earlier discharge, when this can be achieved safely and without an increase in readmissions.
A comprehensive review of the evidence was conducted on sometimes complex interventions within this field. The guideline committee also took account of national initiatives such as the Keogh urgent and emergency care review that began in January 2013.
The guideline contains recommendations for practice and for research. Commissioners of services should take note of both types of recommendation when planning services.
Commissioners are encouraged to read the evidence reviews, particularly the sections headed 'Recommendations and link to evidence', for more details about the interventions, references to other national initiatives and the committee's deliberations. A link to the relevant evidence review is at the end of each recommendation.
The guideline committee did not include detail in the recommendations about how they should be implemented (such as how many staff are needed or the exact content of an intervention) because the most cost-effective solution is likely to vary depending on local systems.
The recommendations for practice are grouped into 3 sections covering services in the community, services in hospital and service planning.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Emergency and acute medical care in the community
## Recommendations for commissioners and providers of health and social care in the community
Providing emergency and acute medical care in the community can reduce the need for hospital admissions. The recommendations in this section cover the first points of contact with healthcare services, and services that provide alternatives to hospital care or permit earlier discharge back to the community.
Provide specialist and advanced paramedic practitioners who have extended training in assessing and treating people with medical emergencies.
Provide point-of-care C-reactive protein testing for people with suspected lower respiratory tract infections.
For people who are at increased risk of developing a medical emergency:
provide advanced community pharmacy-based services
consider providing advanced pharmacist services in general practices.
For people at risk of an acute medical emergency, do not commission pharmacists to conduct medication reviews in the home unless needed for logistical or clinical reasons.
Full details of the evidence and the committee's discussion are in:
evidence review 3: paramedics with enhanced competencies
evidence review 7: GP access to laboratory investigations
evidence review 10: community-based pharmacists.
Provide nurse-led support in the community for people at increased risk of hospital admission or readmission. The nursing team should work with the team providing specialist care.
Provide multidisciplinary intermediate care as an alternative to hospital care to prevent admission and promote earlier discharge. Ensure that the benefits and risks of the various types of intermediate care are discussed with the person and their family or carer.NICE has published guidelines on transition between inpatient hospital settings and community or care home settings for adults with social care needs and intermediate care including reablement
Provide a multidisciplinary community-based rehabilitation service for people who have had a medical emergency.
Provide specialist multidisciplinary community-based palliative care as an option for people in the terminal phase of an illness.
Offer advance care planning to people in the community and in hospital who are approaching the end of life and are at risk of a medical emergency. Ensure that there is close collaboration between the person, their families and carers, and the professionals involved in their care.See also the NICE guideline on end of life care for adults: service delivery.
Full details of the evidence and the committee's discussion are in:
evidence review 9: community nursing
evidence review 12: alternatives to hospital care
evidence review 13: community rehabilitation
evidence review 14: community palliative care
evidence review 15: advance care planning.
Recommendations for research
The guideline committee made recommendations for research in the following areas:
clinical call handlers
remote decision-support technologies for paramedics
extended access to GP services
primary care-led assessment models for suspected medical emergencies
GP access to same-day plain X-ray radiology or ultrasound
extended access to community nursing
extended access to social care services.
For the full list of research recommendations see recommendations for research.
# Emergency and acute medical care in hospital
## Recommendations for commissioners, providers and healthcare professionals in secondary care
Optimising the quality of care in hospitals can improve the flow of patients from admission to discharge. The recommendations in this section address hospital services for emergency and acute care.
Use validated risk stratification tools to inform clinical decisions about hospital admission for people with medical emergencies.
Assess and treat people who are admitted with undifferentiated medical emergencies in an acute medical unit.
Provide access to liaison psychiatry services for people with medical emergencies who have mental health problems.
Start discharge planning at the time of admission for a medical emergency.
Full details of the evidence and the committee's discussion are in:
evidence review 21: standardised criteria for hospital admission
evidence review 23: liaison psychiatry
evidence review 24: assessment through acute medical units
evidence review 35: discharge planning.
For people admitted to hospital with a medical emergency, consider providing the following, accompanied by local evaluation that takes into account current staffing models, case mix and severity of illness:
consultant assessment within 14 hours of admission to determine the person's care pathway
daily consultant review, including weekends and bank holidays
more frequent (for example, twice daily) consultant review based on clinical need.
Full details of the evidence and the committee's discussion are in:
evidence review 19: early versus late consultant review
evidence review 26: frequency of consultant review.
Provide coordinated multidisciplinary care for people admitted to hospital with a medical emergency.
Include ward-based pharmacists in the multidisciplinary care of people admitted to hospital with a medical emergency.NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.
Provide access to physiotherapy and occupational therapy 7 days a week for people admitted to hospital with a medical emergency.
Consider providing access to critical care outreach teams (CCOTs) for people in hospital who have, or are at risk of, acute deterioration, accompanied by local evaluation of the CCOT service.
Full details of the evidence and the committee's discussion are in:
evidence review 27 critical care outreach teams
evidence review 29: multidisciplinary team meetings
evidence review 30: pharmacist support
evidence review 31: enhanced inpatient access to physiotherapy and occupational therapy.
Use standardised and structured approaches to ward rounds, for example with checklists or other clinical decision support tools. NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.
Use structured handovers during transitions of care and follow the recommendations on transferring patients in the NICE guideline on acutely ill adults in hospital. NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.
Use standardised systems of care (including checklists, staffing and equipment) when transferring critically ill patients within or between hospitals. NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.
Full details of the evidence and the committee's discussion are in:
evidence review 28: structured ward rounds
evidence review 32: structured patient handovers
evidence review 34: standardised systems of care for intra- and inter-hospital transfers.
Recommendations for research
The guideline committee made recommendations for research in the following areas:
emergency department opening hours
GPs located in or near emergency departments
minor injury units, urgent care centres and walk-in centres
hospital diagnostic radiology services
specialised units for older people
the role of 'physician extenders'
integrated patient information systems
standardised criteria for hospital discharge
post-discharge early follow-up clinics.
For the full list of research recommendations see recommendations for research.
# Planning emergency and acute care services
## Recommendations for commissioners and providers of health and social care
The recommendations in this section cover hospital bed capacity and escalation policies, and the development of integrated care models.
Healthcare providers should:
monitor total acute hospital bed occupancy, capacity, flow and outcomes in real time, taking account of changes in a 24-hour period and the occupancy levels and needs of specific wards and units
plan capacity to minimise the risks associated with occupancy rates exceeding 90%.
Health and social care systems should develop and evaluate integrated care pathways.
Full details of the evidence and the committee's discussion are in:
evidence review 38: integrated care
evidence review 39: bed occupancy.
Recommendation for research
The guideline committee made a recommendation for research on hospital escalation policies. For the full list of research recommendations see recommendations for research.# Putting this guideline into practice
# Phased implementation and relation to other national initiatives
This guideline has a wide scope and covers a large number of points in the emergency and acute care pathway. Putting the recommendations into practice will take time, with additional infrastructure and training needed in some areas. In the meantime, services should implement what they can of the guideline, using currently available infrastructure and taking account of local priorities such as those identified by the sustainability and transformation partnerships (STPs) between the NHS and local councils, and relevant national initiatives such as NHS England's seven day services clinical standards.
For more advice and information on implementation see:
NICE's into practice pages for general advice
NICE tools and resources to help you put this guideline into practice
NHS England's work to improve urgent and emergency care
NHS Improvement's support to improve emergency care in accident and emergency departments
the NHS seven day services clinical standards (updated September 2017).# Recommendations for research
The guideline committee made the following recommendations for research. The evidence reviews contain the methods and evidence that were used to develop these recommendations, and a summary of the guideline committee's reasoning for making the recommendations. Each recommendation includes a link to the relevant evidence review on the NICE website.
# Priority recommendations for research
## Extended access to GP services
Is extended access to GP services, for example during early mornings, evenings and weekends, more clinically and cost effective than standard access?
Continuity of care improves patient experience, aids clinical decision‑making and could reduce hospital admissions. GPs' knowledge of patients enhances trust and promotes patient-centred care, especially when dealing with complex conditions. Currently, outside of standard GP hours (Monday to Friday, 08:00 to 18:30), people who need urgent primary care are triaged and treated by an out-of-hours GP provider and will usually be seen by a primary care clinician who is not familiar with them or their history, and who might not have access to their complete clinical records. Extended weekday and weekend access to their usual primary care team might reduce people's unscheduled use of secondary care emergency services. It might also increase opportunities to prevent exacerbations of chronic disease and thus reduce emergency hospital admissions. There is also likely to be less movement to secondary care if there is greater access to usual primary care because GP surgeries are often more conveniently located than more distant out-of-hours centres. Many extended access schemes currently in operation for general practice are for prebooked appointments only and do not provide emergency care. The focus of this research recommendation is on extending opening hours of practices for the full spectrum of GPs' clinical work.
Full details of the evidence and the committee's discussion are in evidence review 5: GP extended hours.
## Extended access to social care services
What is the clinical and cost effectiveness of providing extended access to social care services, for example during early mornings and evenings, and 7 days a week?
A person with social care needs is defined as someone needing personal care and other practical assistance because of their age, illness, disability, dependence on alcohol or drugs, or any other similar circumstances. This is based on the definition of social care in section 65 of the Health and Social Care Act 2012.
At present access to social care differs throughout the country. Some areas have access to all social care services whereas others have very limited access. When social care services are substantially reduced, such as during weekends, collaboration and multidisciplinary planning between hospital, community health services and social care is difficult to achieve. This increases the number of avoidable hospital admissions and readmissions, and delays discharges.
NHS England has stated that community care services in hospitals, primary care, community care and mental healthcare must be available 7 days a week. This will support people to stay in the community and allow those in hospital to leave earlier. Extended access to community care has a direct impact on bed occupancy rates. Current figures suggest that 22% of hospital patients are waiting for a social care assessment so that they can be discharged. Extended access to social care would play an important role in alleviating this problem, particularly for the frail elderly.
Full details of the evidence and the committee's discussion are in evidence review 11: social care extended access.
## GPs located in or near emergency departments
What is the clinical and cost effectiveness of having GPs within or adjoining emergency departments?
Royal College of Emergency Medicine survey data suggest that around 20% of people who attend emergency departments could be treated by GPs. Extended access to GPs in their surgeries is a requirement of current health policy, but the impact of such provision on reducing emergency department attendances of people with acute illnesses is unknown. An alternative approach, proposed in a joint report from the Royal College of Emergency Medicine, Royal College of Paediatrics and Child Health, Royal College of Physicians, and Royal College of Surgeons, is that every emergency department should include a primary care out-of-hours facility. This approach deserves systematic research evaluation focused on the specific impact of GPs on secondary care and the wider urgent and emergency care system.
Full details of the evidence and the committee's discussion are in evidence review 17: GPs within or on the same site as emergency departments.
## Specialised units for older people
What is the most clinically and cost effective way to configure services to assess frail older people who present to hospital with a medical emergency?
Older people are more likely to be admitted for medical emergencies, and to stay longer in hospital, than younger people. This is because there is more multimorbidity, frailty and polypharmacy in older people. Hospital services have adapted to the growing population of older patients by introducing liaison services such as Frail Older Persons' Assessment and Liaison (FOPAL) services. These are now widespread, and share characteristics such as medication reviews and the use of comprehensive geriatric assessments.
However, it is not clear whether there are additional benefits from admitting older people with multimorbidity and frailty to a specialised elderly care assessment unit or an acute frailty unit. Theoretical advantages could include better planning of investigation and diagnosis, multidisciplinary working, dedicated discharge teams, and direct links with community and social care. The question is important because of the potential for large reductions in length of hospital stays and readmissions, and improved quality of care. New units with varying designs are emerging throughout the NHS but there is currently no strong evidence for their effectiveness.
Full details of the evidence and the committee's discussion are in evidence review 25: admission through elderly care assessment units.
## Integrated patient information systems
What is the clinical and cost effectiveness of different methods for integrating patient information throughout the emergency medical care pathway?
Good clinical decision-making depends on the provision of accurate information at the point of care delivery. Paper-based information systems cannot adequately serve the complex needs of people with frailty or multimorbidity. However, the experience of the NHS National Programme for IT has shown the need for an evolutionary and evidence-based approach to developing electronic systems with the capacity for clinical decision support. Examples of where such an approach could be used include managing cognitive impairment, polypharmacy, caring for people with multidisciplinary or complex care needs, and recognising a person's preferred place of death in palliative care. In many locations around the country, web-based patient information systems integrated between primary and secondary care are currently being set up. This research recommendation aims to ensure that where information systems are developed they undergo systematic parallel research evaluation.
Full details of the evidence and the committee's discussion are in evidence review 33: integrated patient information systems.
# Other recommendations for research
## Clinical call handlers
What is the most clinically and cost-effective use of clinical call handlers in a telephone advisory service in terms of i) the ratio of clinical to non-clinical call handlers and ii) point of access to clinical call handlers in a telephone advisory service pathway?
## Remote decision-support technologies
Are paramedic remote decision-support technologies clinically and cost effective?
## Primary care-led assessment models
Which primary care-led models of assessment of people with a suspected medical emergency in the community, such as GP home visits, are most clinically and cost effective?
## Same-day plain X-ray radiology or ultrasound
What is the clinical and cost effectiveness of providing GPs with access to plain X‑ray radiology or ultrasound with same-day results?
## Extended access to community nursing
What is the clinical and cost effectiveness of providing extended access to community nursing, for example during evenings and weekends?
## Limiting emergency department opening hours
What is the clinical and cost effectiveness of limiting emergency department opening hours, and what effect does this have on local healthcare provision and outcomes for people with medical emergencies?
## Minor injury units, urgent care centres and walk-in centres
Is a minor injury unit, urgent care or walk-in centre clinically and cost effective i) as a stand-alone unit and ii) when located on the same site as an emergency department?
## Hospital diagnostic radiology services
What is the optimal configuration in terms of clinical and cost effectiveness of hospital diagnostic radiology services to support 7-day care of people presenting with medical emergencies?
## Standardised criteria for hospital discharge
Are standardised criteria for hospital discharge clinically and cost effective in specific medical emergencies?
## 'Physician extenders'
What is the clinical and cost effectiveness of providing 'physician extenders' such as advanced nurse practitioners, 'physician associates' and advanced clinical practitioners in secondary care?
## Post-discharge early follow-up clinics
What is the clinical and cost effectiveness of post-discharge early follow-up clinics for people who have had a medical emergency and are at risk of unscheduled hospital readmission?
## Hospital escalation policies
Which components of a hospital escalation policy to deal with surges in demand are the most clinically and cost effective?
Full details of the evidence and the committee's discussion are in:
evidence review 2: non-emergency telephone access and call handlers
evidence review 4: paramedic remote support
evidence review 6: GP-led home visits
evidence review 8: GP access to radiology
evidence review 9: community nursing
evidence review 16: emergency department opening hours
evidence review 18: minor injury unit, urgent care centre or walk-in centre
evidence review 20: physician extenders
evidence review 22: 7-day diagnostic radiology
evidence review 36: standardised discharge criteria
evidence review 37: post-discharge early follow-up clinics
evidence review 40: escalation measures.
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{'Context': "NICE's service guidance on emergency and acute medical care supports the next steps in the NHS five year forward view. It presents a survey of the best available evidence on a range of questions across the emergency and acute care pathway, which reaffirms key aspects of care articulated in the NHS seven day services clinical standards, including the role of early consultant review after admission to hospital, daily consultant review in hospital, multidisciplinary care, structured handovers and liaison mental health services.\n\nThis guideline covers service organisation and delivery in the following topic areas referred to NICE by the Department of Health in 2012:\n\nurgent and emergency care\n\nout-of-hours care\n\n-day services\n\nconsultant review within 12 hours of admission\n\nacute medical admissions within the first 48 hours\n\ndischarge planning to reduce readmissions.\n\nHospitals have found it increasingly challenging to maintain the flow of patients through from admission to discharge. The guideline committee considered interventions that avoid hospital admission and facilitate earlier discharge, when this can be achieved safely and without an increase in readmissions.\n\nA comprehensive review of the evidence was conducted on sometimes complex interventions within this field. The guideline committee also took account of national initiatives such as the Keogh urgent and emergency care review that began in January\xa02013.\n\nThe guideline contains recommendations for practice and for research. Commissioners of services should take note of both types of recommendation when planning services.\n\nCommissioners are encouraged to read the evidence reviews, particularly the sections headed 'Recommendations and link to evidence', for more details about the interventions, references to other national initiatives and the committee's deliberations. A link to the relevant evidence review is at the end of each recommendation.\n\nThe guideline committee did not include detail in the recommendations about how they should be implemented (such as how many staff are needed or the exact content of an intervention) because the most cost-effective solution is likely to vary depending on local systems.\n\nThe recommendations for practice are grouped into 3 sections covering services in the community, services in hospital and service planning.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Emergency and acute medical care in the community\n\n## Recommendations for commissioners and providers of health and social care in the community\n\nProviding emergency and acute medical care in the community can reduce the need for hospital admissions. The recommendations in this section cover the first points of contact with healthcare services, and services that provide alternatives to hospital care or permit earlier discharge back to the community.\n\nProvide specialist and advanced paramedic practitioners who have extended training in assessing and treating people with medical emergencies.\n\nProvide point-of-care C-reactive protein testing for people with suspected lower respiratory tract infections.\n\nFor people who are at increased risk of developing a medical emergency:\n\nprovide advanced community pharmacy-based services\n\nconsider providing advanced pharmacist services in general practices.\n\nFor people at risk of an acute medical emergency, do not commission pharmacists to conduct medication reviews in the home unless needed for logistical or clinical reasons.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 3: paramedics with enhanced competencies\n\nevidence review 7: GP access to laboratory investigations\n\nevidence review 10: community-based pharmacists.\n\nProvide nurse-led support in the community for people at increased risk of hospital admission or readmission. The nursing team should work with the team providing specialist care.\n\nProvide multidisciplinary intermediate care as an alternative to hospital care to prevent admission and promote earlier discharge. Ensure that the benefits and risks of the various types of intermediate care are discussed with the person and their family or carer.NICE has published guidelines on transition between inpatient hospital settings and community or care home settings for adults with social care needs and intermediate care including reablement\n\nProvide a multidisciplinary community-based rehabilitation service for people who have had a medical emergency.\n\nProvide specialist multidisciplinary community-based palliative care as an option for people in the terminal phase of an illness.\n\nOffer advance care planning to people in the community and in hospital who are approaching the end of life and are at risk of a medical emergency. Ensure that there is close collaboration between the person, their families and carers, and the professionals involved in their care.See also the NICE guideline on end of life care for adults: service delivery.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 9: community nursing\n\nevidence review 12: alternatives to hospital care\n\nevidence review 13: community rehabilitation\n\nevidence review 14: community palliative care\n\nevidence review 15: advance care planning.\n\nRecommendations for research\n\nThe guideline committee made recommendations for research in the following areas:\n\nclinical call handlers\n\nremote decision-support technologies for paramedics\n\nextended access to GP services\n\nprimary care-led assessment models for suspected medical emergencies\n\nGP access to same-day plain X-ray radiology or ultrasound\n\nextended access to community nursing\n\nextended access to social care services.\n\nFor the full list of research recommendations see recommendations for research.\n\n# Emergency and acute medical care in hospital\n\n## Recommendations for commissioners, providers and healthcare professionals in secondary care\n\nOptimising the quality of care in hospitals can improve the flow of patients from admission to discharge. The recommendations in this section address hospital services for emergency and acute care.\n\nUse validated risk stratification tools to inform clinical decisions about hospital admission for people with medical emergencies.\n\nAssess and treat people who are admitted with undifferentiated medical emergencies in an acute medical unit.\n\nProvide access to liaison psychiatry services for people with medical emergencies who have mental health problems.\n\nStart discharge planning at the time of admission for a medical emergency.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 21: standardised criteria for hospital admission\n\nevidence review 23: liaison psychiatry\n\nevidence review 24: assessment through acute medical units\n\nevidence review 35: discharge planning.\n\nFor people admitted to hospital with a medical emergency, consider providing the following, accompanied by local evaluation that takes into account current staffing models, case mix and severity of illness:\n\nconsultant assessment within 14\xa0hours of admission to determine the person's care pathway\n\ndaily consultant review, including weekends and bank holidays\n\nmore frequent (for example, twice daily) consultant review based on clinical need.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 19: early versus late consultant review\n\nevidence review 26: frequency of consultant review.\n\nProvide coordinated multidisciplinary care for people admitted to hospital with a medical emergency.\n\nInclude ward-based pharmacists in the multidisciplinary care of people admitted to hospital with a medical emergency.NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.\n\nProvide access to physiotherapy and occupational therapy 7\xa0days a week for people admitted to hospital with a medical emergency.\n\nConsider providing access to critical care outreach teams (CCOTs) for people in hospital who have, or are at risk of, acute deterioration, accompanied by local evaluation of the CCOT service.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 27 critical care outreach teams\n\nevidence review 29: multidisciplinary team meetings\n\nevidence review 30: pharmacist support\n\nevidence review 31: enhanced inpatient access to physiotherapy and occupational therapy.\n\nUse standardised and structured approaches to ward rounds, for example with checklists or other clinical decision support tools. NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.\n\nUse structured handovers during transitions of care and follow the recommendations on transferring patients in the NICE guideline on acutely ill adults in hospital. NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.\n\nUse standardised systems of care (including checklists, staffing and equipment) when transferring critically ill patients within or between hospitals. NICE's guideline on medicines optimisation includes recommendations on medicines-related communication systems when patients move from one care setting to another, medicines reconciliation, clinical decision support, and medicines-related models of organisational and cross‑sector working.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 28: structured ward rounds\n\nevidence review 32: structured patient handovers\n\nevidence review 34: standardised systems of care for intra- and inter-hospital transfers.\n\nRecommendations for research\n\nThe guideline committee made recommendations for research in the following areas:\n\nemergency department opening hours\n\nGPs located in or near emergency departments\n\nminor injury units, urgent care centres and walk-in centres\n\nhospital diagnostic radiology services\n\nspecialised units for older people\n\nthe role of 'physician extenders'\n\nintegrated patient information systems\n\nstandardised criteria for hospital discharge\n\npost-discharge early follow-up clinics.\n\nFor the full list of research recommendations see recommendations for research.\n\n# Planning emergency and acute care services\n\n## Recommendations for commissioners and providers of health and social care\n\nThe recommendations in this section cover hospital bed capacity and escalation policies, and the development of integrated care models.\n\nHealthcare providers should:\n\nmonitor total acute hospital bed occupancy, capacity, flow and outcomes in real time, taking account of changes in a 24-hour period and the occupancy levels and needs of specific wards and units\n\nplan capacity to minimise the risks associated with occupancy rates exceeding 90%.\n\nHealth and social care systems should develop and evaluate integrated care pathways.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 38: integrated care\n\nevidence review 39: bed occupancy.\n\nRecommendation for research\n\nThe guideline committee made a recommendation for research on hospital escalation policies. For the full list of research recommendations see recommendations for research.", 'Putting this guideline into practice': "# Phased implementation and relation to other national initiatives\n\nThis guideline has a wide scope and covers a large number of points in the emergency and acute care pathway. Putting the recommendations into practice will take time, with additional infrastructure and training needed in some areas. In the meantime, services should implement what they can of the guideline, using currently available infrastructure and taking account of local priorities such as those identified by the sustainability and transformation partnerships (STPs) between the NHS and local councils, and relevant national initiatives such as NHS England's seven day services clinical standards.\n\nFor more advice and information on implementation see:\n\nNICE's into practice pages for general advice\n\nNICE tools and resources to help you put this guideline into practice\n\nNHS England's work to improve urgent and emergency care\n\nNHS Improvement's support to improve emergency care in accident and emergency departments\n\nthe NHS seven day services clinical standards (updated September 2017).", 'Recommendations for research': "The guideline committee made the following recommendations for research. The evidence reviews contain the methods and evidence that were used to develop these recommendations, and a summary of the guideline committee's reasoning for making the recommendations. Each recommendation includes a link to the relevant evidence review on the NICE website.\n\n# Priority recommendations for research\n\n## Extended access to GP services\n\nIs extended access to GP services, for example during early mornings, evenings and weekends, more clinically and cost effective than standard access?\n\nContinuity of care improves patient experience, aids clinical decision‑making and could reduce hospital admissions. GPs' knowledge of patients enhances trust and promotes patient-centred care, especially when dealing with complex conditions. Currently, outside of standard GP hours (Monday to Friday, 08:00 to 18:30), people who need urgent primary care are triaged and treated by an out-of-hours GP provider and will usually be seen by a primary care clinician who is not familiar with them or their history, and who might not have access to their complete clinical records. Extended weekday and weekend access to their usual primary care team might reduce people's unscheduled use of secondary care emergency services. It might also increase opportunities to prevent exacerbations of chronic disease and thus reduce emergency hospital admissions. There is also likely to be less movement to secondary care if there is greater access to usual primary care because GP surgeries are often more conveniently located than more distant out-of-hours centres. Many extended access schemes currently in operation for general practice are for prebooked appointments only and do not provide emergency care. The focus of this research recommendation is on extending opening hours of practices for the full spectrum of GPs' clinical work.\n\nFull details of the evidence and the committee's discussion are in evidence review 5: GP extended hours.\n\n## Extended access to social care services\n\nWhat is the clinical and cost effectiveness of providing extended access to social care services, for example during early mornings and evenings, and 7\xa0days a week?\n\nA person with social care needs is defined as someone needing personal care and other practical assistance because of their age, illness, disability, dependence on alcohol or drugs, or any other similar circumstances. This is based on the definition of social care in section 65 of the Health and Social Care Act 2012.\n\nAt present access to social care differs throughout the country. Some areas have access to all social care services whereas others have very limited access. When social care services are substantially reduced, such as during weekends, collaboration and multidisciplinary planning between hospital, community health services and social care is difficult to achieve. This increases the number of avoidable hospital admissions and readmissions, and delays discharges.\n\nNHS England has stated that community care services in hospitals, primary care, community care and mental healthcare must be available 7\xa0days a week. This will support people to stay in the community and allow those in hospital to leave earlier. Extended access to community care has a direct impact on bed occupancy rates. Current figures suggest that 22% of hospital patients are waiting for a social care assessment so that they can be discharged. Extended access to social care would play an important role in alleviating this problem, particularly for the frail elderly.\n\nFull details of the evidence and the committee's discussion are in evidence review 11: social care extended access.\n\n## GPs located in or near emergency departments\n\nWhat is the clinical and cost effectiveness of having GPs within or adjoining emergency departments?\n\nRoyal College of Emergency Medicine survey data suggest that around 20% of people who attend emergency departments could be treated by GPs. Extended access to GPs in their surgeries is a requirement of current health policy, but the impact of such provision on reducing emergency department attendances of people with acute illnesses is unknown. An alternative approach, proposed in a joint report from the Royal College of Emergency Medicine, Royal College of Paediatrics and Child Health, Royal College of Physicians, and Royal College of Surgeons, is that every emergency department should include a primary care out-of-hours facility. This approach deserves systematic research evaluation focused on the specific impact of GPs on secondary care and the wider urgent and emergency care system.\n\nFull details of the evidence and the committee's discussion are in evidence review 17: GPs within or on the same site as emergency departments.\n\n## Specialised units for older people\n\nWhat is the most clinically and cost effective way to configure services to assess frail older people who present to hospital with a medical emergency?\n\nOlder people are more likely to be admitted for medical emergencies, and to stay longer in hospital, than younger people. This is because there is more multimorbidity, frailty and polypharmacy in older people. Hospital services have adapted to the growing population of older patients by introducing liaison services such as Frail Older Persons' Assessment and Liaison (FOPAL) services. These are now widespread, and share characteristics such as medication reviews and the use of comprehensive geriatric assessments.\n\nHowever, it is not clear whether there are additional benefits from admitting older people with multimorbidity and frailty to a specialised elderly care assessment unit or an acute frailty unit. Theoretical advantages could include better planning of investigation and diagnosis, multidisciplinary working, dedicated discharge teams, and direct links with community and social care. The question is important because of the potential for large reductions in length of hospital stays and readmissions, and improved quality of care. New units with varying designs are emerging throughout the NHS but there is currently no strong evidence for their effectiveness.\n\nFull details of the evidence and the committee's discussion are in evidence review 25: admission through elderly care assessment units.\n\n## Integrated patient information systems\n\nWhat is the clinical and cost effectiveness of different methods for integrating patient information throughout the emergency medical care pathway?\n\nGood clinical decision-making depends on the provision of accurate information at the point of care delivery. Paper-based information systems cannot adequately serve the complex needs of people with frailty or multimorbidity. However, the experience of the NHS National Programme for IT has shown the need for an evolutionary and evidence-based approach to developing electronic systems with the capacity for clinical decision support. Examples of where such an approach could be used include managing cognitive impairment, polypharmacy, caring for people with multidisciplinary or complex care needs, and recognising a person's preferred place of death in palliative care. In many locations around the country, web-based patient information systems integrated between primary and secondary care are currently being set up. This research recommendation aims to ensure that where information systems are developed they undergo systematic parallel research evaluation.\n\nFull details of the evidence and the committee's discussion are in evidence review 33: integrated patient information systems.\n\n# Other recommendations for research\n\n## Clinical call handlers\n\nWhat is the most clinically and cost-effective use of clinical call handlers in a telephone advisory service in terms of i) the ratio of clinical to non-clinical call handlers and ii) point of access to clinical call handlers in a telephone advisory service pathway?\n\n## Remote decision-support technologies\n\nAre paramedic remote decision-support technologies clinically and cost effective?\n\n## Primary care-led assessment models\n\nWhich primary care-led models of assessment of people with a suspected medical emergency in the community, such as GP home visits, are most clinically and cost effective?\n\n## Same-day plain X-ray radiology or ultrasound\n\nWhat is the clinical and cost effectiveness of providing GPs with access to plain X‑ray radiology or ultrasound with same-day results?\n\n## Extended access to community nursing\n\nWhat is the clinical and cost effectiveness of providing extended access to community nursing, for example during evenings and weekends?\n\n## Limiting emergency department opening hours\n\nWhat is the clinical and cost effectiveness of limiting emergency department opening hours, and what effect does this have on local healthcare provision and outcomes for people with medical emergencies?\n\n## Minor injury units, urgent care centres and walk-in centres\n\nIs a minor injury unit, urgent care or walk-in centre clinically and cost effective i) as a stand-alone unit and ii) when located on the same site as an emergency department?\n\n## Hospital diagnostic radiology services\n\nWhat is the optimal configuration in terms of clinical and cost effectiveness of hospital diagnostic radiology services to support 7-day care of people presenting with medical emergencies?\n\n## Standardised criteria for hospital discharge\n\nAre standardised criteria for hospital discharge clinically and cost effective in specific medical emergencies?\n\n## 'Physician extenders'\n\nWhat is the clinical and cost effectiveness of providing 'physician extenders' such as advanced nurse practitioners, 'physician associates' and advanced clinical practitioners in secondary care?\n\n## Post-discharge early follow-up clinics\n\nWhat is the clinical and cost effectiveness of post-discharge early follow-up clinics for people who have had a medical emergency and are at risk of unscheduled hospital readmission?\n\n## Hospital escalation policies\n\nWhich components of a hospital escalation policy to deal with surges in demand are the most clinically and cost effective?\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review 2: non-emergency telephone access and call handlers\n\nevidence review 4: paramedic remote support\n\nevidence review 6: GP-led home visits\n\nevidence review 8: GP access to radiology\n\nevidence review 9: community nursing\n\nevidence review 16: emergency department opening hours\n\nevidence review 18: minor injury unit, urgent care centre or walk-in centre\n\nevidence review 20: physician extenders\n\nevidence review 22: 7-day diagnostic radiology\n\nevidence review 36: standardised discharge criteria\n\nevidence review 37: post-discharge early follow-up clinics\n\nevidence review 40: escalation measures."}
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https://www.nice.org.uk/guidance/ng94
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This guideline covers organising and delivering emergency and acute medical care for people aged over 16 in the community and in hospital. It aims to reduce the need for hospital admissions by giving advanced training to paramedics and providing community alternatives to hospital care. It also promotes good-quality care in hospital and joint working between health and social services.
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ef63af86615177715074efee197d6b3cb37af8f8
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nice
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Eribulin for treating locally advanced or metastatic breast cancer after 1 chemotherapy regimen
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Eribulin for treating locally advanced or metastatic breast cancer after 1 chemotherapy regimen
Evidence-based recommendations on eribulin (Halaven) for treating locally advanced or metastatic (secondary) breast cancer in adults who have had only 1 course of chemotherapy.
# Recommendations
Eribulin is not recommended for treating locally advanced or metastatic breast cancer in adults who have had only 1 chemotherapy regimen.A positive recommendation on eribulin for treating locally advanced or metastatic breast cancer in adults who have had 2 or more chemotherapy regimens is given in a separate NICE technology appraisal guidance.
This guidance is not intended to affect treatment with eribulin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with advanced breast cancer who have had 1 chemotherapy regimen are usually then offered an anthracycline, a taxane or capecitabine, depending on what they have had already. The clinical trial results for eribulin showed that it did not increase progression-free survival, but there was an average overall survival increase of 4.6 months compared with capecitabine. Since treatment is changed when the disease progresses, and eribulin would have been stopped at that stage, it is not clear whether the increase in overall survival is because of eribulin, or related to the treatments given after eribulin. Eribulin is already recommended after 2 previous chemotherapy treatments, and there are no trials which compare its effectiveness given after 1 or 2 previous treatments, so this remains uncertain.
Eribulin meets NICE's criteria to be considered a life-extending treatment at the end of life. The estimates of cost effectiveness for eribulin range from £36,200 to £82,700 per quality-adjusted life year (QALY) gained. The most plausible estimate of cost effectiveness, based on a revised company model and the committee's preferred assumptions, is £69,800 per QALY gained. This is above what NICE normally considers to be acceptable for end-of-life treatments. Therefore, eribulin cannot be recommended as a cost-effective option for locally advanced or metastatic breast cancer in adults who have had only 1 chemotherapy regimen.# The technology
# Marketing authorisation
Eribulin (Halaven, Eisai) is indicated for 'the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease… Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments'.
# Recommended dose and schedule
1.23 mg/m2 is administered intravenously over 2 to 5 minutes on days 1 and 8 of every 21‑day cycle.
# Price
£361.00 per 0.88 mg/2 ml solution for injection vial and £541.50 per 1.32 mg/3 ml solution for injection vial (excluding VAT; British national formulary online, accessed October 2017). The company has agreed a patient access scheme with the Department of Health. If eribulin had been recommended, this scheme would provide a simple discount to the list price of eribulin with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Eisai and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Symptoms and management of advanced breast cancer
## Patients and their families value additional treatment options
The committee heard from a patient expert that locally advanced or metastatic breast cancer is a debilitating condition that can affect people of all ages, and leads to premature death. It also heard that the symptoms of advanced breast cancer can differ substantially, depending on the type of disease and the site of metastases. The patient expert emphasised that living with advanced breast cancer is very difficult for patients and their families. The life expectancy of people for whom eribulin is licensed is short, and quality of life is very important. The committee heard that having more treatment options available would be very important for patients, giving hope to them and their families. It recognised that having additional treatment options for advanced breast cancer would be valued by patients and their families.
## Capecitabine is the relevant comparator for most people at this stage in the treatment pathway
The clinical expert explained that most patients with locally advanced or metastatic breast cancer have had either an anthracycline and/or a taxane for early breast cancer, and have usually had whichever drug they did not have for early disease as the first chemotherapy regimen for advanced or metastatic disease. The committee understood that some patients with more aggressive disease are likely to have had an anthracycline and a taxane at an earlier stage, so would have capecitabine as the first treatment in the advanced or metastatic setting. A smaller number may be offered vinorelbine. The committee noted that the comparator in the company's original submission was capecitabine, which was used in study 301, from which people who had previously had capecitabine were excluded (see section 3.3). The committee concluded that, although treatment sequences in the adjuvant and advanced setting could vary, in clinical practice, capecitabine is the relevant comparator for most people with locally advanced or metastatic breast cancer who have had 1 chemotherapy regimen.
# Clinical trial evidence
## The relevant evidence is from a post-hoc subgroup
The evidence for eribulin came from study 301, a phase 3 randomised controlled trial comparing eribulin with capecitabine in 1,102 patients with locally advanced or metastatic breast cancer who had had up to 3 chemotherapy regimens (up to 2 for advanced disease), including an anthracycline and a taxane. The company presented results for subgroup 1, which was a post-hoc defined subgroup comprising patients with HER2‑negative disease who had received 1 chemotherapy regimen (186 in the eribulin arm and 206 in the capecitabine arm). The committee was aware that eribulin's marketing authorisation includes people with HER2-positive and HER2-negative disease. However, it noted that people with HER2-positive disease would be treated with specific HER2-targeted therapies rather than being considered for eribulin at this stage of the disease, and accepted that only patients with HER2-negative disease were relevant for the current appraisal. The committee were aware that 2 predefined patient characteristics (HER2-negative disease and line of therapy) had been combined to form this new post-hoc subgroup. It was mindful that post-hoc subgroup analyses could be unreliable (for example, because of reduced statistical power), and expressed concern about whether this subgroup was sufficiently robust for decision-making. After receiving consultation comments from the company, the committee accepted that, despite some limitations, the subgroup data are the only appropriate evidence that is currently available to assess the effectiveness of eribulin compared with capecitabine.
## The trial results show improved overall survival but no statistically significant progression-free survival benefit
The median progression-free results from subgroup 1 of study 301 showed a very small numerical difference of 6 days in the progression-free survival between eribulin (4.2 months) and capecitabine (4.0 months), but the difference was not statistically significant (hazard ratio 0.86, p=0.192). However, the overall-survival results did show a statistically significant benefit with eribulin compared with capecitabine (16.1 months and 13.5 months respectively, hazard ratio 0.77, p=0.026). The ERG explained that these results were consistent with results in the subgroup of patients with HER2-negative disease who had had at least 1 (and up to 3) chemotherapy regimens, in whom there was no statistically significant difference in progression-free survival or overall survival benefit. The committee noted that the overall survival benefit for eribulin had only reached statistical significance in the post-hoc subgroup 1. In the appraisal consultation document the committee had queried whether there was any progression-free survival benefit for eribulin compared with capecitabine. At the second appraisal meeting, the committee further considered the difference between progression-free survival and overall survival benefit.
## The overall survival benefit in study 301 may not be directly attributable to eribulin alone
The committee considered the plausibility of the statistically significant overall survival gain in light of no significant progression-free survival gain. It noted that this discrepancy would indicate that most, if not all, of the survival gain occurred after the disease had progressed, when the patient was no longer having eribulin but would have switched to a subsequent treatment. It was aware that 57.5% of patients in the eribulin arm of the trial had capecitabine after their disease had progressed, which may have contributed to the improvement in overall survival in the treatment arm, whereas only 1 patient in the capecitabine arm (0.5%) had eribulin post progression. The clinical expert explained that eribulin is well tolerated but has a different side-effect profile to capecitabine. In clinical practice patients whose disease responds to eribulin tend to have subsequent treatments to which the disease also responds. The committee therefore concluded that eribulin is well tolerated but the survival benefit in the trial may not be directly attributable to eribulin alone.
## The available data do not address the most clinically relevant question
The clinical expert hypothesised that, although eribulin did not delay disease progression (and therefore transition to subsequent treatment), it might enhance the effect of subsequent treatment with capecitabine. However, the committee noted that a direct comparison of the clinical effectiveness of eribulin then capecitabine with that of capecitabine then eribulin would be needed to substantiate this hypothesis. It considered that the most clinically relevant question was therefore whether having eribulin before capecitabine was more clinically and cost effective than the current practice of having eribulin second line after capecitabine, as recommended in NICE's technology appraisal guidance on eribulin after 2 or more chemotherapy regimens. The committee concluded that the available data did not address this question.
## Post-progression treatment has a substantial effect on overall survival
During consultation the company presented additional evidence on the overall survival benefit of eribulin compared with capecitabine in the intention-to-treat population of study 301 and in the HER2‑negative subgroup of study 301, to support the overall survival benefit of eribulin compared with capecitabine in subgroup 1. It also presented the Kaplan–Meier curves for the effect of different post-progression treatments on overall survival (which the European Medicines Agency had requested from the company). The committee was particularly interested in the impact of post-progression treatments on overall survival. It noted that eribulin or capecitabine followed by no further treatment had the worst prognosis and resulted in survival curves for eribulin and capecitabine that were closely aligned. It also noted that there was little difference in the overall survival for patients having eribulin followed by capecitabine, compared with capecitabine followed by any active treatment (which most closely, although not specifically relates to the question of whether overall survival is better with eribulin followed by capecitabine, compared with capecitabine followed by eribulin, as is currently used in the NHS).The best overall survival gain with eribulin was for patients who went on to have an active treatment other than capecitabine. The committee noted that recommendations on subsequent treatments that should be used are outside the scope of this appraisal. The committee concluded that patients with disease that progresses on eribulin would be very likely to have capecitabine on progression, and the company's evidence suggested that this not likely to result in better overall survival than current clinical practice (that is, capecitabine followed by another active treatment). The committee was not persuaded that a clear benefit had been shown for offering eribulin second line compared with third line, as recommended in NICE's guidance on eribulin after 2 or more chemotherapy regimens.
# The economic model
## The company's economic model is suitable for decision-making
The company presented a partitioned survival economic model comparing eribulin with capecitabine in subgroup 1 (that is HER2‑negative adults whose disease has progressed after 1 chemotherapy regimen in the advanced setting). The base-case incremental cost-effectiveness ratio (ICER) for this model was £36,244 per quality-adjusted life year (QALY) gained. The ERG made several amendments to the original model. These comprised corrections for logic errors and errors relating to discounting and unit costs of eribulin and other chemotherapies, as well as assumptions that included alternative progression-free survival benefit, post-progression utility and subsequent treatment costs. The base-case ICER, which incorporated all of the ERG's corrections and preferred assumptions, was £82,743 per QALY gained. The committee considered that the company's economic model, with the ERG's error corrections and assumptions, was most suitable for its decision-making. During consultation the company submitted a revised model with 4 changes: a new comparator (mix of capecitabine and vinorelbine), continued inclusion of a progression-free survival benefit (which had been excluded by the ERG), an updated post-progression utility value, and a different cap on treatment duration. The company's base-case ICER for the revised model, which incorporated all of the changes, was £50,808 per QALY gained. The committee considered the appropriateness of each of the updated model parameters and the subsequent impact on the ERG's amended model.
# Clinical parameters
## Capecitabine is the most relevant comparator for use in the economic model
The company's original model assumed that all patients in the comparator arm had capecitabine but the revised model, received during consultation, changed the comparator in the base case to an equal split of capecitabine and vinorelbine (with all of the vinorelbine administered intravenously). This assumption reduced the ERG's original ICER of £82,743 by £11,094 per QALY gained. The committee noted that the new 'blended' comparator was based on the advice of 1 expert (who attended the first meeting), but it is not consistent with the comparator in study 301. The company assumed that it had the same effectiveness as capecitabine (based on clinical expert opinion). The committee considered that the company could suggest an alternative comparator, in this case, vinorelbine, particularly if it was included in the scope of the appraisal. However, the modelling of eribulin compared with the new comparator should be supported by evidence of the effectiveness of that comparator. The company did not provide this for vinorebine. In addition, the company's blended comparator used an equal split of capecitabine and vinorelbine, with no supporting evidence for the proportions used. The company also suggested that only intravenous, not oral, vinorelbine should be considered as a comparator, but did not provide any comparative evidence of the effectiveness of the 2 routes of administration, or clear rationale for this. The committee accepted that not all patients in the NHS would have capecitabine as second-line treatment, but it considered that an equal split of capecitabine and intravenous vinorelbine was arbitrary, and not adequately supported by evidence. It concluded that capecitabine is the most relevant comparator for the majority of patients in the NHS, and there is direct trial evidence available to inform that comparison.
## Modelling no progression-free survival benefit increases the ICER substantially
The committee was aware that the trial results did not show a statistically significant progression-free survival benefit for eribulin compared with capecitabine (see section 3.4). Using the Kaplan–Meier data from study 301, the company modelled a small mean progression-free benefit of 0.57 months in their original base-case model. The ERG, when re-examining the data, found a close correspondence between the timing of disease progression in each arm of the trial (which was statistically confirmed when tested), and so assumed no progression-free survival benefit for eribulin in its base case (resulting in an ICER of £82,743 per QALY gained). The committee noted the continued difference of opinion between the company's assumption of progression-free survival benefit of approximately 17 days with eribulin in its revised model, and the ERG's assumption of no progression-free survival benefit. It noted that the inclusion of this very modest, and not statistically significant progression-free survival benefit, has a substantial effect on the ICER, reducing the ERG's preferred ICER by £5,905 per QALY gained. The company representative agreed that the progression-free survival gain with eribulin was small and not statistically significant. The committee noted the ERG's exploratory analysis of a small progression-free survival gain in the first 17 months, which only reduced the ICER by £408 per QALY gained. The committee concluded that no significant progression-free survival benefit had been demonstrated in study 301 (see section 3.4). On this basis, a substantial reduction in the ICER of nearly £6,000 from incorporating a very small progression-free survival benefit, did not seem reasonable.
## The post-progression utility value could be between the company's and ERG's estimates
The company estimated utility values by applying a mapping algorithm to the health-related quality-of-life data from the trial. The committee noted that the algorithm, published by Crott and Briggs (2010), had been developed using data from people with locally advanced but not metastatic breast cancer, and who had good baseline health status. It noted that this resulted in only a small decrease in the utility between the progression-free and post-progression health states in the company's original model (about 3%), which the ERG considered to be implausible. The ERG instead used utility values from a study by Lloyd et al. (2006), which the committee noted were derived from general population estimates using Standard Gamble rather than the time trade-off method preferred in the NICE guide to the methods of technology appraisal (section 5.3) have been used in other NICE appraisals. This method resulted in a decline in utility of about 20% between the pre- and post-progression states, which increased the ICER for the original model by about £11,000 per QALY gained. The committee was mindful of its conclusion in NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens, which accepted the use of the Lloyd study but concluded that while some decline would be expected, an immediate decrease of 20% in health-related quality of life on progression may be an overestimate. The committee concluded that the most plausible utility value could be somewhere between the company's and ERG's estimates. The company updated the utility for progressive disease from 0.679 in its original model to 0.59 in the revised model. This represents the midpoint of the utility values in the company's and ERG's original models (0.679 and 0.496 respectively). This is consistent with the committee's preferred assumption for progressive disease in the appraisal consultation document. The committee noted the uncertainty about the most appropriate utility values to use in advanced breast cancer but accepted the updated utility for progressive disease in the revised company model, which reduced the ERG's preferred ICER by £12,900 per QALY gained.
# Costs
## The costs of subsequent treatments are likely to be closer to the ERG's estimates than the company's
The original company model applied an 8‑month cap on the total treatments a patient could have in the model, meaning that all treatment costs ended after 8 months. The ERG considered that this underestimated the costs of subsequent treatments. Instead, it assumed that, after progression, 60% of patients would go on to have subsequent therapy until death, based on data on the proportion of breast cancer patients progressing from first- to fifth-line therapy (Kantar Health, 2014). The clinical expert commented that treatment duration varied between individuals, but that it was realistic to assume that most patients would still be having active treatment more than 8 months after starting eribulin. The exception would be a small proportion of patients with aggressive disease such as those whose disease was 'triple negative' (HER2 and hormone-receptor negative). The committee agreed at its first meeting that an 8‑month cap on total treatment was not clinically plausible. In its revised model the company changed the cap on the duration of treatment in both arms of the model from 8 months to 21.3 months (the average survival in the eribulin arm). This reduced the ERG's preferred ICER by £8,289 per QALY gained. The ERG noted that a substantial number of people in the eribulin arm of study 301 had more than 21 months of treatment. The committee concluded that in clinical practice patients who live longer than 21 months would still have treatment and therefore it did not accept this assumption.
# Cost-effectiveness estimates
## The most plausible ICER for eribulin is higher than the range normally considered cost effective
The committee considered the cost-effectiveness results for eribulin compared with capecitabine. The committee considered the appropriateness of all changes in the revised company model and their impact on the ICER. It considered only the updated utility value for progressive disease to be justified. It noted that the ICER for eribulin only approached a level that might be considered cost effective when all of the changes to the company's revised model were accepted and if the criteria for special consideration of life-extending treatment at the end of life were met. The committee did not consider that the 17 day improvement in progression-free survival in the model (non-significant 6 days benefit in the trial), which resulted in a large reduction in the ICER of £6,000 per QALY, was justified. In addition, the committee did not accept the blended comparator of capecitabine and intravenous vinorelbine (section 3.9). Even if the blended comparator had been accepted, along with the updated utility for progressive disease, the ICER would have been £58,749 per QALY gained, and so the committee did not consider it further. The committee concluded that the most plausible ICER for eribulin compared with capecitabine, using the revised company model with the committee's preferred assumptions, is approximately £69,843 per QALY gained which does not represent a cost-effective use of NHS resources. It also noted that eribulin is already recommended after 2 previous chemotherapy regimens, and there remained considerable doubt about whether giving it earlier in the treatment pathway conferred a true benefit.
# End of life
## Eribulin met the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee noted the company's model predicted a mean overall survival with capecitabine of about 17 months. The trial showed a mean overall survival benefit of more than 3 months for eribulin compared with capecitabine in the intention-to-treat population. The committee concluded that eribulin met the end-of-life criteria.
# Other factors
## The committee did not identify any other factors that would affect its recommendations
No equality issues were identified. The committee heard from the company that it considered eribulin to be innovative because of its mechanism of action and convenient administration method. However, the committee concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation.
|
{'Recommendations': "Eribulin is not recommended for treating locally advanced or metastatic breast cancer in adults who have had only 1\xa0chemotherapy regimen.A positive recommendation on eribulin for treating locally advanced or metastatic breast cancer in adults who have had 2 or more chemotherapy regimens is given in a separate NICE technology appraisal guidance.\n\nThis guidance is not intended to affect treatment with eribulin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with advanced breast cancer who have had 1\xa0chemotherapy regimen are usually then offered an anthracycline, a taxane or capecitabine, depending on what they have had already. The clinical trial results for eribulin showed that it did not increase progression-free survival, but there was an average overall survival increase of 4.6\xa0months compared with capecitabine. Since treatment is changed when the disease progresses, and eribulin would have been stopped at that stage, it is not clear whether the increase in overall survival is because of eribulin, or related to the treatments given after eribulin. Eribulin is already recommended after 2\xa0previous chemotherapy treatments, and there are no trials which compare its effectiveness given after 1\xa0or\xa02 previous treatments, so this remains uncertain.\n\nEribulin meets NICE's criteria to be considered a life-extending treatment at the end of life. The estimates of cost effectiveness for eribulin range from £36,200 to £82,700 per quality-adjusted life year (QALY) gained. The most plausible estimate of cost effectiveness, based on a revised company model and the committee's preferred assumptions, is £69,800 per QALY gained. This is above what NICE normally considers to be acceptable for end-of-life treatments. Therefore, eribulin cannot be recommended as a cost-effective option for locally advanced or metastatic breast cancer in adults who have had only 1\xa0chemotherapy regimen.", 'The technology': "# Marketing authorisation\n\nEribulin (Halaven, Eisai) is indicated for 'the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease… Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments'.\n\n# Recommended dose and schedule\n\n1.23\xa0mg/m2 is administered intravenously over 2\xa0to\xa05\xa0minutes on days\xa01 and\xa08 of every 21‑day cycle.\n\n# Price\n\n£361.00 per 0.88\xa0mg/2\xa0ml solution for injection vial and £541.50 per 1.32\xa0mg/3\xa0ml solution for injection vial (excluding VAT; British national formulary [BNF] online, accessed October 2017). The company has agreed a patient access scheme with the Department of Health. If eribulin had been recommended, this scheme would provide a simple discount to the list price of eribulin with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Eisai and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Symptoms and management of advanced breast cancer\n\n## Patients and their families value additional treatment options\n\nThe committee heard from a patient expert that locally advanced or metastatic breast cancer is a debilitating condition that can affect people of all ages, and leads to premature death. It also heard that the symptoms of advanced breast cancer can differ substantially, depending on the type of disease and the site of metastases. The patient expert emphasised that living with advanced breast cancer is very difficult for patients and their families. The life expectancy of people for whom eribulin is licensed is short, and quality of life is very important. The committee heard that having more treatment options available would be very important for patients, giving hope to them and their families. It recognised that having additional treatment options for advanced breast cancer would be valued by patients and their families.\n\n## Capecitabine is the relevant comparator for most people at this stage in the treatment pathway\n\nThe clinical expert explained that most patients with locally advanced or metastatic breast cancer have had either an anthracycline and/or a taxane for early breast cancer, and have usually had whichever drug they did not have for early disease as the first chemotherapy regimen for advanced or metastatic disease. The committee understood that some patients with more aggressive disease are likely to have had an anthracycline and a taxane at an earlier stage, so would have capecitabine as the first treatment in the advanced or metastatic setting. A smaller number may be offered vinorelbine. The committee noted that the comparator in the company's original submission was capecitabine, which was used in study\xa0301, from which people who had previously had capecitabine were excluded (see section\xa03.3). The committee concluded that, although treatment sequences in the adjuvant and advanced setting could vary, in clinical practice, capecitabine is the relevant comparator for most people with locally advanced or metastatic breast cancer who have had 1\xa0chemotherapy regimen.\n\n# Clinical trial evidence\n\n## The relevant evidence is from a post-hoc subgroup\n\nThe evidence for eribulin came from study\xa0301, a phase\xa03 randomised controlled trial comparing eribulin with capecitabine in 1,102\xa0patients with locally advanced or metastatic breast cancer who had had up to 3\xa0chemotherapy regimens (up to\xa02 for advanced disease), including an anthracycline and a taxane. The company presented results for subgroup\xa01, which was a post-hoc defined subgroup comprising patients with HER2‑negative disease who had received 1\xa0chemotherapy regimen (186\xa0in the eribulin arm and 206\xa0in the capecitabine arm). The committee was aware that eribulin's marketing authorisation includes people with HER2-positive and HER2-negative disease. However, it noted that people with HER2-positive disease would be treated with specific HER2-targeted therapies rather than being considered for eribulin at this stage of the disease, and accepted that only patients with HER2-negative disease were relevant for the current appraisal. The committee were aware that 2\xa0predefined patient characteristics (HER2-negative disease and line of therapy) had been combined to form this new post-hoc subgroup. It was mindful that post-hoc subgroup analyses could be unreliable (for example, because of reduced statistical power), and expressed concern about whether this subgroup was sufficiently robust for decision-making. After receiving consultation comments from the company, the committee accepted that, despite some limitations, the subgroup data are the only appropriate evidence that is currently available to assess the effectiveness of eribulin compared with capecitabine.\n\n## The trial results show improved overall survival but no statistically significant progression-free survival benefit\n\nThe median progression-free results from subgroup\xa01 of study\xa0301 showed a very small numerical difference of 6\xa0days in the progression-free survival between eribulin (4.2\xa0months) and capecitabine (4.0\xa0months), but the difference was not statistically significant (hazard ratio 0.86, p=0.192). However, the overall-survival results did show a statistically significant benefit with eribulin compared with capecitabine (16.1\xa0months and 13.5\xa0months respectively, hazard ratio [HR] 0.77, p=0.026). The ERG explained that these results were consistent with results in the subgroup of patients with HER2-negative disease who had had at least 1\xa0(and up to 3) chemotherapy regimens, in whom there was no statistically significant difference in progression-free survival or overall survival benefit. The committee noted that the overall survival benefit for eribulin had only reached statistical significance in the post-hoc subgroup\xa01. In the appraisal consultation document the committee had queried whether there was any progression-free survival benefit for eribulin compared with capecitabine. At the second appraisal meeting, the committee further considered the difference between progression-free survival and overall survival benefit.\n\n## The overall survival benefit in study\xa0301 may not be directly attributable to eribulin alone\n\nThe committee considered the plausibility of the statistically significant overall survival gain in light of no significant progression-free survival gain. It noted that this discrepancy would indicate that most, if not all, of the survival gain occurred after the disease had progressed, when the patient was no longer having eribulin but would have switched to a subsequent treatment. It was aware that 57.5% of patients in the eribulin arm of the trial had capecitabine after their disease had progressed, which may have contributed to the improvement in overall survival in the treatment arm, whereas only 1\xa0patient in the capecitabine arm (0.5%) had eribulin post progression. The clinical expert explained that eribulin is well tolerated but has a different side-effect profile to capecitabine. In clinical practice patients whose disease responds to eribulin tend to have subsequent treatments to which the disease also responds. The committee therefore concluded that eribulin is well tolerated but the survival benefit in the trial may not be directly attributable to eribulin alone.\n\n## The available data do not address the most clinically relevant question\n\nThe clinical expert hypothesised that, although eribulin did not delay disease progression (and therefore transition to subsequent treatment), it might enhance the effect of subsequent treatment with capecitabine. However, the committee noted that a direct comparison of the clinical effectiveness of eribulin then capecitabine with that of capecitabine then eribulin would be needed to substantiate this hypothesis. It considered that the most clinically relevant question was therefore whether having eribulin before capecitabine was more clinically and cost effective than the current practice of having eribulin second line after capecitabine, as recommended in NICE's technology appraisal guidance on eribulin after 2 or more chemotherapy regimens. The committee concluded that the available data did not address this question.\n\n## Post-progression treatment has a substantial effect on overall survival\n\nDuring consultation the company presented additional evidence on the overall survival benefit of eribulin compared with capecitabine in the intention-to-treat population of study\xa0301 and in the HER2‑negative subgroup of study\xa0301, to support the overall survival benefit of eribulin compared with capecitabine in subgroup\xa01. It also presented the Kaplan–Meier curves for the effect of different post-progression treatments on overall survival (which the European Medicines Agency had requested from the company). The committee was particularly interested in the impact of post-progression treatments on overall survival. It noted that eribulin or capecitabine followed by no further treatment had the worst prognosis and resulted in survival curves for eribulin and capecitabine that were closely aligned. It also noted that there was little difference in the overall survival for patients having eribulin followed by capecitabine, compared with capecitabine followed by any active treatment (which most closely, although not specifically relates to the question of whether overall survival is better with eribulin followed by capecitabine, compared with capecitabine followed by eribulin, as is currently used in the NHS).The best overall survival gain with eribulin was for patients who went on to have an active treatment other than capecitabine. The committee noted that recommendations on subsequent treatments that should be used are outside the scope of this appraisal. The committee concluded that patients with disease that progresses on eribulin would be very likely to have capecitabine on progression, and the company's evidence suggested that this not likely to result in better overall survival than current clinical practice (that is, capecitabine followed by another active treatment). The committee was not persuaded that a clear benefit had been shown for offering eribulin second line compared with third line, as recommended in NICE's guidance on eribulin after 2 or more chemotherapy regimens.\n\n# The economic model\n\n## The company's economic model is suitable for decision-making\n\nThe company presented a partitioned survival economic model comparing eribulin with capecitabine in subgroup\xa01 (that is HER2‑negative adults whose disease has progressed after 1\xa0chemotherapy regimen in the advanced setting). The base-case incremental cost-effectiveness ratio (ICER) for this model was £36,244 per quality-adjusted life year (QALY) gained. The ERG made several amendments to the original model. These comprised corrections for logic errors and errors relating to discounting and unit costs of eribulin and other chemotherapies, as well as assumptions that included alternative progression-free survival benefit, post-progression utility and subsequent treatment costs. The base-case ICER, which incorporated all of the ERG's corrections and preferred assumptions, was £82,743 per QALY gained. The committee considered that the company's economic model, with the ERG's error corrections and assumptions, was most suitable for its decision-making. During consultation the company submitted a revised model with 4\xa0changes: a new comparator (mix of capecitabine and vinorelbine), continued inclusion of a progression-free survival benefit (which had been excluded by the ERG), an updated post-progression utility value, and a different cap on treatment duration. The company's base-case ICER for the revised model, which incorporated all of the changes, was £50,808 per QALY gained. The committee considered the appropriateness of each of the updated model parameters and the subsequent impact on the ERG's amended model.\n\n# Clinical parameters\n\n## Capecitabine is the most relevant comparator for use in the economic model\n\nThe company's original model assumed that all patients in the comparator arm had capecitabine but the revised model, received during consultation, changed the comparator in the base case to an equal split of capecitabine and vinorelbine (with all of the vinorelbine administered intravenously). This assumption reduced the ERG's original ICER of £82,743 by £11,094 per QALY gained. The committee noted that the new 'blended' comparator was based on the advice of 1 expert (who attended the first meeting), but it is not consistent with the comparator in study\xa0301. The company assumed that it had the same effectiveness as capecitabine (based on clinical expert opinion). The committee considered that the company could suggest an alternative comparator, in this case, vinorelbine, particularly if it was included in the scope of the appraisal. However, the modelling of eribulin compared with the new comparator should be supported by evidence of the effectiveness of that comparator. The company did not provide this for vinorebine. In addition, the company's blended comparator used an equal split of capecitabine and vinorelbine, with no supporting evidence for the proportions used. The company also suggested that only intravenous, not oral, vinorelbine should be considered as a comparator, but did not provide any comparative evidence of the effectiveness of the 2 routes of administration, or clear rationale for this. The committee accepted that not all patients in the NHS would have capecitabine as second-line treatment, but it considered that an equal split of capecitabine and intravenous vinorelbine was arbitrary, and not adequately supported by evidence. It concluded that capecitabine is the most relevant comparator for the majority of patients in the NHS, and there is direct trial evidence available to inform that comparison.\n\n## Modelling no progression-free survival benefit increases the ICER substantially\n\nThe committee was aware that the trial results did not show a statistically significant progression-free survival benefit for eribulin compared with capecitabine (see section\xa03.4). Using the Kaplan–Meier data from study\xa0301, the company modelled a small mean progression-free benefit of 0.57\xa0months in their original base-case model. The ERG, when re-examining the data, found a close correspondence between the timing of disease progression in each arm of the trial (which was statistically confirmed when tested), and so assumed no progression-free survival benefit for eribulin in its base case (resulting in an ICER of £82,743 per QALY gained). The committee noted the continued difference of opinion between the company's assumption of progression-free survival benefit of approximately 17\xa0days with eribulin in its revised model, and the ERG's assumption of no progression-free survival benefit. It noted that the inclusion of this very modest, and not statistically significant progression-free survival benefit, has a substantial effect on the ICER, reducing the ERG's preferred ICER by £5,905 per QALY gained. The company representative agreed that the progression-free survival gain with eribulin was small and not statistically significant. The committee noted the ERG's exploratory analysis of a small progression-free survival gain in the first 17\xa0months, which only reduced the ICER by £408 per QALY gained. The committee concluded that no significant progression-free survival benefit had been demonstrated in study\xa0301 (see section 3.4). On this basis, a substantial reduction in the ICER of nearly £6,000 from incorporating a very small progression-free survival benefit, did not seem reasonable.\n\n## The post-progression utility value could be between the company's and ERG's estimates\n\nThe company estimated utility values by applying a mapping algorithm to the health-related quality-of-life data from the trial. The committee noted that the algorithm, published by Crott and Briggs (2010), had been developed using data from people with locally advanced but not metastatic breast cancer, and who had good baseline health status. It noted that this resulted in only a small decrease in the utility between the progression-free and post-progression health states in the company's original model (about 3%), which the ERG considered to be implausible. The ERG instead used utility values from a study by Lloyd et al. (2006), which the committee noted were derived from general population estimates using Standard Gamble rather than the time trade-off method preferred in the NICE guide to the methods of technology appraisal (section 5.3) have been used in other NICE appraisals. This method resulted in a decline in utility of about 20% between the pre- and post-progression states, which increased the ICER for the original model by about £11,000 per QALY gained. The committee was mindful of its conclusion in NICE's technology appraisal guidance on eribulin for treating locally advanced or metastatic breast cancer after 2 or more chemotherapy regimens, which accepted the use of the Lloyd study but concluded that while some decline would be expected, an immediate decrease of 20% in health-related quality of life on progression may be an overestimate. The committee concluded that the most plausible utility value could be somewhere between the company's and ERG's estimates. The company updated the utility for progressive disease from 0.679 in its original model to 0.59 in the revised model. This represents the midpoint of the utility values in the company's and ERG's original models (0.679 and 0.496 respectively). This is consistent with the committee's preferred assumption for progressive disease in the appraisal consultation document. The committee noted the uncertainty about the most appropriate utility values to use in advanced breast cancer but accepted the updated utility for progressive disease in the revised company model, which reduced the ERG's preferred ICER by £12,900 per QALY gained.\n\n# Costs\n\n## The costs of subsequent treatments are likely to be closer to the ERG's estimates than the company's\n\nThe original company model applied an 8‑month cap on the total treatments a patient could have in the model, meaning that all treatment costs ended after 8\xa0months. The ERG considered that this underestimated the costs of subsequent treatments. Instead, it assumed that, after progression, 60% of patients would go on to have subsequent therapy until death, based on data on the proportion of breast cancer patients progressing from first- to fifth-line therapy (Kantar Health, 2014). The clinical expert commented that treatment duration varied between individuals, but that it was realistic to assume that most patients would still be having active treatment more than 8\xa0months after starting eribulin. The exception would be a small proportion of patients with aggressive disease such as those whose disease was 'triple negative' (HER2 and hormone-receptor negative). The committee agreed at its first meeting that an 8‑month cap on total treatment was not clinically plausible. In its revised model the company changed the cap on the duration of treatment in both arms of the model from 8\xa0months to 21.3\xa0months (the average survival in the eribulin arm). This reduced the ERG's preferred ICER by £8,289 per QALY gained. The ERG noted that a substantial number of people in the eribulin arm of study\xa0301 had more than 21\xa0months of treatment. The committee concluded that in clinical practice patients who live longer than 21\xa0months would still have treatment and therefore it did not accept this assumption.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER for eribulin is higher than the range normally considered cost effective\n\nThe committee considered the cost-effectiveness results for eribulin compared with capecitabine. The committee considered the appropriateness of all changes in the revised company model and their impact on the ICER. It considered only the updated utility value for progressive disease to be justified. It noted that the ICER for eribulin only approached a level that might be considered cost effective when all of the changes to the company's revised model were accepted and if the criteria for special consideration of life-extending treatment at the end of life were met. The committee did not consider that the 17\xa0day improvement in progression-free survival in the model (non-significant 6\xa0days benefit in the trial), which resulted in a large reduction in the ICER of £6,000 per QALY, was justified. In addition, the committee did not accept the blended comparator of capecitabine and intravenous vinorelbine (section 3.9). Even if the blended comparator had been accepted, along with the updated utility for progressive disease, the ICER would have been £58,749 per QALY gained, and so the committee did not consider it further. The committee concluded that the most plausible ICER for eribulin compared with capecitabine, using the revised company model with the committee's preferred assumptions, is approximately £69,843 per QALY gained which does not represent a cost-effective use of NHS resources. It also noted that eribulin is already recommended after 2\xa0previous chemotherapy regimens, and there remained considerable doubt about whether giving it earlier in the treatment pathway conferred a true benefit.\n\n# End of life\n\n## Eribulin met the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee noted the company's model predicted a mean overall survival with capecitabine of about 17\xa0months. The trial showed a mean overall survival benefit of more than 3\xa0months for eribulin compared with capecitabine in the intention-to-treat population. The committee concluded that eribulin met the end-of-life criteria.\n\n# Other factors\n\n## The committee did not identify any other factors that would affect its recommendations\n\nNo equality issues were identified. The committee heard from the company that it considered eribulin to be innovative because of its mechanism of action and convenient administration method. However, the committee concluded that it could not identify any specific health-related benefit that had not already been captured in the QALY calculation."}
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https://www.nice.org.uk/guidance/ta515
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Evidence-based recommendations on eribulin (Halaven) for treating locally advanced or metastatic (secondary) breast cancer in adults who have had only 1 course of chemotherapy.
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09c88850a4b0e2a99c362b86007908ab23ab9719
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nice
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Cabozantinib for treating medullary thyroid cancer
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Cabozantinib for treating medullary thyroid cancer
Evidence-based recommendations on cabozantinib (Cometriq) for treating medullary thyroid cancer in adults.
# Recommendations
Cabozantinib is recommended, within its marketing authorisation, as an option for treating progressive medullary thyroid cancer in adults with unresectable, locally advanced or metastatic disease, only if the company provides cabozantinib with the discount agreed in the patient access scheme.
Why the committee made these recommendations
Cabozantinib and vandetanib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer. Both drugs are currently available through the Cancer Drugs Fund for progressive and symptomatic disease. Best supportive care is the only other available option for people who cannot have cabozantinib or vandetanib.
Clinical trial evidence suggests that cabozantinib is effective in delaying disease progression compared with best supportive care, but may not prolong survival. Without reliable comparative data, it was considered that cabozantinib and vandetanib are likely to be similarly effective.
The cost-effectiveness estimates for cabozantinib compared with best supportive care and vandetanib are less than £30,000 per quality-adjusted life year gained. Therefore, cabozantinib can be recommended as a cost-effective use of NHS resources.# Information about cabozantinib
# Marketing authorisation indication
Cabozantinib (Cometriq) is indicated for use in 'adults with progressive, unresectable locally advanced or metastatic medullary thyroid cancer. For patients in whom rearranged during transfection mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision'.
# Dosage in the marketing authorisation
140 mg taken orally once daily until patient is no longer clinically benefitting from therapy or until unacceptable toxicity occurs. Dose reductions of 100 mg or 60 mg are available if needed.
# Price
£4,800 per 84×20-mg pack, 28×20-mg + 28×80-mg pack and 84×20-mg + 28×80-mg pack (excluding VAT; British national formulary July 2017). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of cabozantinib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# The condition and current treatment
## There is a clinical need for active treatments for unresectable, locally advanced or metastatic medullary thyroid cancer
Medullary thyroid cancer is rare and around 25% of cases are hereditary. The most common symptoms, such as diarrhoea and fatigue, can significantly affect patients' quality of life and wellbeing. The patient experts commented that in the absence of a cure, patients would welcome treatments that delay disease progression and control symptoms. The committee noted that cabozantinib and vandetanib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer, and are only available through the Cancer Drugs Fund for people with progressive and symptomatic disease. The clinical experts explained that both treatments are associated with side effects, so not all patients can tolerate them. The only alternative for these people is best supportive care. Furthermore the toxicity profile of cabozantinib differs to that of vandetanib, so some people who can have cabozantinib may not be able to have vandetanib. The committee agreed that the relevant comparators were therefore vandetanib and best supportive care. It concluded that there is a clinical need for active treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer.
# Clinical trial evidence
## The clinical trial evidence is relevant to clinical practice in England
Evidence for the clinical effectiveness of cabozantinib was from EXAM, a double-blind, randomised controlled trial comparing cabozantinib with placebo. The trial included 330 patients with unresectable, locally advanced, metastatic and progressive medullary thyroid cancer. The clinical experts advised that in practice, targeted treatment is only considered for progressive and symptomatic disease, so the patients in EXAM represented those that would be seen in clinical practice. The committee concluded that the EXAM trial was relevant to clinical practice in England.
# Subgroups
## RET mutation status is not an appropriate subgroup for consideration
The marketing authorisation for cabozantinib specifies that a possible lower benefit should be taken into account for patients in whom rearranged during transfection (RET) mutation status is negative or unknown. The committee was aware that germline RET mutation testing is standard practice to identify hereditary disease, but that somatic RET mutation testing (to identify RET mutations in those with sporadic or non-hereditary disease) is not funded in the NHS. The clinical experts explained that RET mutation testing is not reliable enough to inform treatment decisions and remains subject to further research. The committee therefore concluded that it was not appropriate to consider the clinical or cost effectiveness of cabozantinib based on patients' RET mutation status alone, meaning that its recommendations would cover the whole population regardless of RET mutation status.
# Clinical trial results
## Cabozantinib improves progression-free survival compared with placebo but the exact overall survival benefit is unclear
The results of EXAM showed a statistically significant benefit for cabozantinib compared with placebo for the primary outcome of centrally assessed median progression-free survival: this was 11.2 months for cabozantinib and 4.0 months for placebo (hazard ratio 0.28; 95% confidence interval 0.19 to 0.40), with a median trial follow-up of 13.9 months. The investigator-assessed progression-free survival results were similar (median 13.8 months for cabozantinib and 3.1 months for placebo ). Median overall survival was 26.6 months for cabozantinib and 21.1 months for placebo but this was not statistically significant (HR 0.85; 95% CI 0.64 to 1.12), with a median trial follow-up of 52 months. The committee noted that the trial design did not allow for cabozantinib treatment after disease progression, which it agreed reflected clinical practice in England. It was aware, however, that patients in both arms had subsequent cancer treatments after progression which may have confounded the overall survival results, although it was not clear to what extent. The committee concluded that cabozantinib improved progression-free survival compared with placebo, but that the exact overall survival benefit is difficult to establish.
# Indirect treatment comparison
## Clinical trial evidence for overall survival with vandetanib is confounded by crossover and the exact benefit is difficult to establish
There was no head-to-head evidence comparing cabozantinib with vandetanib. Evidence for the clinical effectiveness of vandetanib was from ZETA, a double-blind, randomised controlled trial comparing vandetanib with placebo in 331 patients with unresectable, locally advanced and metastatic medullary thyroid cancer. The trial inclusion criteria were not limited to patients with progressive and symptomatic disease, so a subgroup analysis was needed to assess the treatment effect in patients that would be considered for targeted treatment in clinical practice. The committee considered this subgroup to be similar to the intention-to-treat population in EXAM. ZETA was designed in such a way that patients with progressed disease (at investigator-assessed progression) in the placebo arm could switch to open-label vandetanib, and those in the vandetanib arm could continue with open-label vandetanib. The committee considered that this did not represent how vandetanib would actually be used in clinical practice in England. It also noted the substantial difference between the centrally reviewed and investigator-assessed progression-free survival results in the placebo arm (median of 16.4 months compared with 8.3 months respectively), which introduced further uncertainty into the evidence. The committee concluded that the overall survival results, which did not show a statistically significant benefit for vandetanib compared with placebo, were confounded by extensive crossover such that the overall survival benefit is difficult to establish.
## Cabozantinib and vandetanib are likely to be similarly effective
The assessment group conducted an indirect treatment comparison of cabozantinib with vandetanib using a network meta-analysis, which showed that in terms of progression-free survival the 2 treatments were broadly similar. However, the assessment group did not include overall survival in the analysis because of the extensive crossover in ZETA. Because the network only contained data from the EXAM and ZETA trials and was subject to uncertainty, the assessment group did not consider the results robust enough to use in the economic model. The clinical experts stated that in their opinion, both drugs have similar effectiveness in terms of delaying progression and controlling symptoms, although there is no evidence to show that they prolong survival. They explained that the decision about whether to use cabozantinib or vandetanib in clinical practice related more to their differing toxicity profiles than their relative effectiveness. The committee considered that an indirect comparison using data from ZETA would not be sufficiently robust to inform its decision-making. It therefore concluded that in the absence of more robust comparative data, cabozantinib and vandetanib were likely to be similarly effective.
# Adverse events
## Adverse events are common and the decision to use cabozantinib is based on careful consideration of the risks and benefits
All patients in EXAM had an adverse event while having cabozantinib. The committee was aware that patients with unresectable, locally advanced or metastatic medullary thyroid cancer have a substantial disease burden, demonstrated by high levels of adverse events in the placebo arm of the trial and the comorbidities of patients shown in the baseline characteristics data. The patient expert described side effects such as frequent diarrhoea, rash and fatigue, but considered that the disease would have had a more severe effect without treatment. The clinical experts explained that treatment toxicities tend to occur soon after treatment starts, and that for most patients the dosage is reduced after the initial treatment period. The experts explained the importance of balancing the risks and benefits when considering starting treatment with cabozantinib, and that treatment is usually started only when the disease becomes symptomatic to the extent that the benefits of treatment outweigh the burden of side effects.
# Economic model
## The assessment group's economic model is appropriate for decision-making
The assessment group presented 3 analyses for the cost effectiveness of cabozantinib compared with best supportive care and vandetanib, using a partitioned survival model:
a pairwise comparison of cabozantinib and best supportive care
an incremental comparison of all treatment options using EXAM trial data, applying the vandetanib progression-free survival treatment effect from ZETA to the placebo arm of EXAM and assuming the same overall survival benefit for both vandetanib and cabozantinib
an incremental comparison of all treatment options using EXAM trial data (assuming the same progression-free and overall survival benefit for both vandetanib and cabozantinib).The committee had agreed that the overall survival results of the ZETA trial were confounded by crossover, and that cabozantinib and vandetanib were likely to be similarly effective (section 3.6). It therefore considered that the most appropriate incremental analysis of all treatment options was the analysis that used treatment effect data from the EXAM trial and assumed the same progression-free and overall survival benefit for both vandetanib and cabozantinib.
# Costs
## Monitoring costs used by the assessment group are appropriate
The assessment group assumed monitoring costs in the subsequent years after the first year to include 6 outpatient appointments per year. The clinical experts confirmed that in clinical practice patients were seen about once a month, although this varies because open-access clinics are also available. Having heard all relevant clinical expert advice, the committee concluded that the monitoring costs estimated by the assessment group were reasonable.
# Utility values
## Utility values for medullary thyroid cancer are unknown but the approach used by the assessment group is acceptable
There are no direct estimates of health utilities for people with medullary thyroid cancer. The assessment group stated its preference to use the same source of data for both pre- and post-progression utility values, and so used values from Fordham et al. (2015), a study of differentiated thyroid cancer, for both. The committee noted that differentiated thyroid cancer was different to medullary thyroid cancer, but acknowledged that the only other potentially relevant study available was in melanoma, which is more uncertain. It noted that Fordham et al. had been used in a previous health technology assessment submission relating to thyroid cancer, and heard from the assessment group that because of low post-progression utility values it was the most favourable source of utility data for cabozantinib. The committee agreed that in the absence of any data relevant to medullary thyroid cancer it would accept the assessment group's estimates.
# Cost-effectiveness estimates
## The most plausible ICER for cabozantinib is within the range normally considered cost effective
Including the updated confidential patient access scheme discount, the probabilistic incremental cost-effectiveness ratios (ICERs) for cabozantinib compared with best supportive care and with vandetanib were less than £30,000 per quality-adjusted life year (QALY) gained (the exact ICERs are commercial in confidence and cannot be reported here). The committee concluded that the most plausible ICER was within the range that NICE normally considers to be a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained).
# Uncaptured benefits
## There are no health-related benefits that are not captured in the analyses
The committee recognised that medullary thyroid cancer is rare, and that cabozantinib is 1 of only 2 targeted treatments available in this indication. However, it heard from the clinical experts that the survival benefit of both drugs is unknown, and so treatment aims to delay disease progression and improve quality of life. The committee acknowledged that although cabozantinib may work well for some people, for many others there may be a substantial side-effect burden. It therefore concluded that there are no additional health-related quality-of-life benefits not already captured in the QALY calculations.
# End of life
## Cabozantinib meets the end-of-life criterion for extension to life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The EXAM trial showed overall survival benefit of more than 3 months for cabozantinib compared with placebo. The model estimated a mean survival benefit of about 7 months, and so the committee agreed that the end-of-life criterion for extension to life was met for cabozantinib.
## Cabozantinib does not meet the short life expectancy criterion so the end-of-life criteria do not apply
For the short life expectancy criterion, the assessment group's model predicted a mean overall survival with best supportive care of over 24 months (about 47 months in the base-case analysis), regardless of the parametric function used to extrapolate survival. The committee was aware that in EXAM, median overall survival in the placebo arm was 21 months. It acknowledged that some patients with unresectable, locally advanced or metastatic medullary thyroid cancer live for a long time. This may have skewed the median estimate, and may explain the difference between the median and mean estimates. Having considered that it had not seen any reliable data on which to consider any subgroups, the committee agreed that the mean estimate from the model was more relevant for end-of-life considerations. Taking this into account, the committee concluded that cabozantinib did not meet the criterion for short life expectancy, and therefore the end-of-life criteria did not apply.
# Recommendations
The committee recommended cabozantinib as a cost-effective use of NHS resources for treating medullary thyroid cancer, because the ICERs for cabozantinib compared with best supportive care and vandetanib were within the range that NICE normally considers to be a cost-effective use of NHS resources.
# Equalities
No equality issues were identified.
|
{'Recommendations': 'Cabozantinib is recommended, within its marketing authorisation, as an option for treating progressive medullary thyroid cancer in adults with unresectable, locally advanced or metastatic disease, only if the company provides cabozantinib with the discount agreed in the patient access scheme.\n\nWhy the committee made these recommendations\n\nCabozantinib and vandetanib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer. Both drugs are currently available through the Cancer Drugs Fund for progressive and symptomatic disease. Best supportive care is the only other available option for people who cannot have cabozantinib or vandetanib.\n\nClinical trial evidence suggests that cabozantinib is effective in delaying disease progression compared with best supportive care, but may not prolong survival. Without reliable comparative data, it was considered that cabozantinib and vandetanib are likely to be similarly effective.\n\nThe cost-effectiveness estimates for cabozantinib compared with best supportive care and vandetanib are less than £30,000\xa0per\xa0quality-adjusted life year gained. Therefore, cabozantinib can be recommended as a cost-effective use of NHS resources.', 'Information about cabozantinib': "# Marketing authorisation indication\n\nCabozantinib (Cometriq) is indicated for use in 'adults with progressive, unresectable locally advanced or metastatic medullary thyroid cancer. For patients in whom rearranged during transfection mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision'.\n\n# Dosage in the marketing authorisation\n\n140\xa0mg taken orally once daily until patient is no longer clinically benefitting from therapy or until unacceptable toxicity occurs. Dose reductions of 100\xa0mg or 60\xa0mg are available if needed.\n\n# Price\n\n£4,800\xa0per\xa084×20-mg pack, 28×20-mg + 28×80-mg pack and 84×20-mg + 28×80-mg pack (excluding VAT; British national formulary July 2017). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of cabozantinib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\n## There is a clinical need for active treatments for unresectable, locally advanced or metastatic medullary thyroid cancer\n\nMedullary thyroid cancer is rare and around 25% of cases are hereditary. The most common symptoms, such as diarrhoea and fatigue, can significantly affect patients' quality of life and wellbeing. The patient experts commented that in the absence of a cure, patients would welcome treatments that delay disease progression and control symptoms. The committee noted that cabozantinib and vandetanib are the only systemic treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer, and are only available through the Cancer Drugs Fund for people with progressive and symptomatic disease. The clinical experts explained that both treatments are associated with side effects, so not all patients can tolerate them. The only alternative for these people is best supportive care. Furthermore the toxicity profile of cabozantinib differs to that of vandetanib, so some people who can have cabozantinib may not be able to have vandetanib. The committee agreed that the relevant comparators were therefore vandetanib and best supportive care. It concluded that there is a clinical need for active treatment options for unresectable, locally advanced or metastatic medullary thyroid cancer.\n\n# Clinical trial evidence\n\n## The clinical trial evidence is relevant to clinical practice in England\n\nEvidence for the clinical effectiveness of cabozantinib was from EXAM, a double-blind, randomised controlled trial comparing cabozantinib with placebo. The trial included 330 patients with unresectable, locally advanced, metastatic and progressive medullary thyroid cancer. The clinical experts advised that in practice, targeted treatment is only considered for progressive and symptomatic disease, so the patients in EXAM represented those that would be seen in clinical practice. The committee concluded that the EXAM trial was relevant to clinical practice in England.\n\n# Subgroups\n\n## RET mutation status is not an appropriate subgroup for consideration\n\nThe marketing authorisation for cabozantinib specifies that a possible lower benefit should be taken into account for patients in whom rearranged during transfection (RET) mutation status is negative or unknown. The committee was aware that germline RET mutation testing is standard practice to identify hereditary disease, but that somatic RET mutation testing (to identify RET mutations in those with sporadic or non-hereditary disease) is not funded in the NHS. The clinical experts explained that RET mutation testing is not reliable enough to inform treatment decisions and remains subject to further research. The committee therefore concluded that it was not appropriate to consider the clinical or cost effectiveness of cabozantinib based on patients' RET mutation status alone, meaning that its recommendations would cover the whole population regardless of RET mutation status.\n\n# Clinical trial results\n\n## Cabozantinib improves progression-free survival compared with placebo but the exact overall survival benefit is unclear\n\nThe results of EXAM showed a statistically significant benefit for cabozantinib compared with placebo for the primary outcome of centrally assessed median progression-free survival: this was 11.2\xa0months for cabozantinib and 4.0\xa0months for placebo (hazard ratio [HR] 0.28; 95% confidence interval [CI]\xa00.19\xa0to\xa00.40), with a median trial follow-up of 13.9\xa0months. The investigator-assessed progression-free survival results were similar (median 13.8\xa0months for cabozantinib and 3.1\xa0months for placebo [HR 0.29; 95% CI\xa00.21\xa0to\xa00.42]). Median overall survival was 26.6\xa0months for cabozantinib and 21.1\xa0months for placebo but this was not statistically significant (HR\xa00.85; 95%\xa0CI\xa00.64\xa0to\xa01.12), with a median trial follow-up of 52\xa0months. The committee noted that the trial design did not allow for cabozantinib treatment after disease progression, which it agreed reflected clinical practice in England. It was aware, however, that patients in both arms had subsequent cancer treatments after progression which may have confounded the overall survival results, although it was not clear to what extent. The committee concluded that cabozantinib improved progression-free survival compared with placebo, but that the exact overall survival benefit is difficult to establish.\n\n# Indirect treatment comparison\n\n## Clinical trial evidence for overall survival with vandetanib is confounded by crossover and the exact benefit is difficult to establish\n\nThere was no head-to-head evidence comparing cabozantinib with vandetanib. Evidence for the clinical effectiveness of vandetanib was from ZETA, a double-blind, randomised controlled trial comparing vandetanib with placebo in 331 patients with unresectable, locally advanced and metastatic medullary thyroid cancer. The trial inclusion criteria were not limited to patients with progressive and symptomatic disease, so a subgroup analysis was needed to assess the treatment effect in patients that would be considered for targeted treatment in clinical practice. The committee considered this subgroup to be similar to the intention-to-treat population in EXAM. ZETA was designed in such a way that patients with progressed disease (at investigator-assessed progression) in the placebo arm could switch to open-label vandetanib, and those in the vandetanib arm could continue with open-label vandetanib. The committee considered that this did not represent how vandetanib would actually be used in clinical practice in England. It also noted the substantial difference between the centrally reviewed and investigator-assessed progression-free survival results in the placebo arm (median of 16.4\xa0months compared with 8.3\xa0months respectively), which introduced further uncertainty into the evidence. The committee concluded that the overall survival results, which did not show a statistically significant benefit for vandetanib compared with placebo, were confounded by extensive crossover such that the overall survival benefit is difficult to establish.\n\n## Cabozantinib and vandetanib are likely to be similarly effective\n\nThe assessment group conducted an indirect treatment comparison of cabozantinib with vandetanib using a network meta-analysis, which showed that in terms of progression-free survival the 2 treatments were broadly similar. However, the assessment group did not include overall survival in the analysis because of the extensive crossover in ZETA. Because the network only contained data from the EXAM and ZETA trials and was subject to uncertainty, the assessment group did not consider the results robust enough to use in the economic model. The clinical experts stated that in their opinion, both drugs have similar effectiveness in terms of delaying progression and controlling symptoms, although there is no evidence to show that they prolong survival. They explained that the decision about whether to use cabozantinib or vandetanib in clinical practice related more to their differing toxicity profiles than their relative effectiveness. The committee considered that an indirect comparison using data from ZETA would not be sufficiently robust to inform its decision-making. It therefore concluded that in the absence of more robust comparative data, cabozantinib and vandetanib were likely to be similarly effective.\n\n# Adverse events\n\n## Adverse events are common and the decision to use cabozantinib is based on careful consideration of the risks and benefits\n\nAll patients in EXAM had an adverse event while having cabozantinib. The committee was aware that patients with unresectable, locally advanced or metastatic medullary thyroid cancer have a substantial disease burden, demonstrated by high levels of adverse events in the placebo arm of the trial and the comorbidities of patients shown in the baseline characteristics data. The patient expert described side effects such as frequent diarrhoea, rash and fatigue, but considered that the disease would have had a more severe effect without treatment. The clinical experts explained that treatment toxicities tend to occur soon after treatment starts, and that for most patients the dosage is reduced after the initial treatment period. The experts explained the importance of balancing the risks and benefits when considering starting treatment with cabozantinib, and that treatment is usually started only when the disease becomes symptomatic to the extent that the benefits of treatment outweigh the burden of side effects.\n\n# Economic model\n\n## The assessment group's economic model is appropriate for decision-making\n\nThe assessment group presented 3 analyses for the cost effectiveness of cabozantinib compared with best supportive care and vandetanib, using a partitioned survival model:\n\na pairwise comparison of cabozantinib and best supportive care\n\nan incremental comparison of all treatment options using EXAM trial data, applying the vandetanib progression-free survival treatment effect from ZETA to the placebo arm of EXAM and assuming the same overall survival benefit for both vandetanib and cabozantinib\n\nan incremental comparison of all treatment options using EXAM trial data (assuming the same progression-free and overall survival benefit for both vandetanib and cabozantinib).The committee had agreed that the overall survival results of the ZETA trial were confounded by crossover, and that cabozantinib and vandetanib were likely to be similarly effective (section 3.6). It therefore considered that the most appropriate incremental analysis of all treatment options was the analysis that used treatment effect data from the EXAM trial and assumed the same progression-free and overall survival benefit for both vandetanib and cabozantinib.\n\n# Costs\n\n## Monitoring costs used by the assessment group are appropriate\n\nThe assessment group assumed monitoring costs in the subsequent years after the first year to include 6 outpatient appointments\xa0per\xa0year. The clinical experts confirmed that in clinical practice patients were seen about once a month, although this varies because open-access clinics are also available. Having heard all relevant clinical expert advice, the committee concluded that the monitoring costs estimated by the assessment group were reasonable.\n\n# Utility values\n\n## Utility values for medullary thyroid cancer are unknown but the approach used by the assessment group is acceptable\n\nThere are no direct estimates of health utilities for people with medullary thyroid cancer. The assessment group stated its preference to use the same source of data for both pre- and post-progression utility values, and so used values from Fordham\xa0et\xa0al. (2015), a study of differentiated thyroid cancer, for both. The committee noted that differentiated thyroid cancer was different to medullary thyroid cancer, but acknowledged that the only other potentially relevant study available was in melanoma, which is more uncertain. It noted that Fordham\xa0et\xa0al. had been used in a previous health technology assessment submission relating to thyroid cancer, and heard from the assessment group that because of low post-progression utility values it was the most favourable source of utility data for cabozantinib. The committee agreed that in the absence of any data relevant to medullary thyroid cancer it would accept the assessment group's estimates.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER for cabozantinib is within the range normally considered cost effective\n\nIncluding the updated confidential patient access scheme discount, the probabilistic incremental cost-effectiveness ratios (ICERs) for cabozantinib compared with best supportive care and with vandetanib were less than £30,000\xa0per\xa0quality-adjusted life year (QALY) gained (the exact ICERs are commercial in confidence and cannot be reported here). The committee concluded that the most plausible ICER was within the range that NICE normally considers to be a cost-effective use of NHS resources (that is, between £20,000 and £30,000\xa0per\xa0QALY gained).\n\n# Uncaptured benefits\n\n## There are no health-related benefits that are not captured in the analyses\n\nThe committee recognised that medullary thyroid cancer is rare, and that cabozantinib is 1 of only 2 targeted treatments available in this indication. However, it heard from the clinical experts that the survival benefit of both drugs is unknown, and so treatment aims to delay disease progression and improve quality of life. The committee acknowledged that although cabozantinib may work well for some people, for many others there may be a substantial side-effect burden. It therefore concluded that there are no additional health-related quality-of-life benefits not already captured in the QALY calculations.\n\n# End of life\n\n## Cabozantinib meets the end-of-life criterion for extension to life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The EXAM trial showed overall survival benefit of more than 3\xa0months for cabozantinib compared with placebo. The model estimated a mean survival benefit of about 7\xa0months, and so the committee agreed that the end-of-life criterion for extension to life was met for cabozantinib.\n\n## Cabozantinib does not meet the short life expectancy criterion so the end-of-life criteria do not apply\n\nFor the short life expectancy criterion, the assessment group's model predicted a mean overall survival with best supportive care of over 24\xa0months (about 47\xa0months in the base-case analysis), regardless of the parametric function used to extrapolate survival. The committee was aware that in EXAM, median overall survival in the placebo arm was 21\xa0months. It acknowledged that some patients with unresectable, locally advanced or metastatic medullary thyroid cancer live for a long time. This may have skewed the median estimate, and may explain the difference between the median and mean estimates. Having considered that it had not seen any reliable data on which to consider any subgroups, the committee agreed that the mean estimate from the model was more relevant for end-of-life considerations. Taking this into account, the committee concluded that cabozantinib did not meet the criterion for short life expectancy, and therefore the end-of-life criteria did not apply.\n\n# Recommendations\n\nThe committee recommended cabozantinib as a cost-effective use of NHS resources for treating medullary thyroid cancer, because the ICERs for cabozantinib compared with best supportive care and vandetanib were within the range that NICE normally considers to be a cost-effective use of NHS resources.\n\n# Equalities\n\nNo equality issues were identified."}
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https://www.nice.org.uk/guidance/ta516
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Evidence-based recommendations on cabozantinib (Cometriq) for treating medullary thyroid cancer in adults.
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Physical activity and the environment
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Physical activity and the environment
This guideline covers how to improve the physical environment to encourage and support physical activity. The aim is to increase the general population’s physical activity levels.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Strategies, policies and plans to increase physical activity in the local environment
Develop and use local strategies, policies and plans to encourage and enable people to be more physically active. Use information from sources such as the joint strategic needs assessment and local cycling and walking implementation plans. Follow established best practice to ensure everyone's needs are identified and addressed, including those of people with limited mobility.
Use community engagement approaches to develop and review these local strategies, policies and plans:
Take account of the views and needs of people who walk, cycle, drive or use public transport in the local area, particularly in relation to shared or contested space. (For example, space shared by pedestrians and cyclists, or cyclists and motorists.)
Take account of the views and needs of people with limited mobility who may be adversely affected by the design and maintenance of streets, footways and footpaths and urban and rural public open spaces.
Take account of the views of voluntary and community sector organisations.
Assess whether initiatives successfully adopted elsewhere are appropriate locally and, if they are, how they can be adapted to local needs. For more information, see NICE's guideline on community engagement.
Develop and put policies into place to ensure people with limited mobility can safely move along and across streets and in public open spaces:
Adopt a consistent approach to permanent or temporary obstructions. This may include vegetation, vending boards, bins, parked cars, scaffolding and street furniture.
Ensure that there are enough pedestrian-controlled crossings, and that they all incorporate accessibility features. Also ensure that signal-controlled crossings give enough time to cross the road safely.
Provide accessible temporary crossings during street and road works (see the Department for Transport's Safety at street works and road works).
Use and maintain tactile paving and dropped kerbs correctly (see the Department for Transport's guidance on the use of tactile paving surfaces).
Provide step-free access or, where this is not possible, clearly signposted accessible alternatives.
Ensure planning permissions always prioritise the need for people (including people with limited mobility) to be physically active as a routine part of their daily life, for example ensuring access on foot to local services such as shops and public transport stops. For more information, see Public Health England's Spatial planning for health report.
Ensure children, young people and their families and carers can be physically active, for example when playing and when travelling to school, college and early years settings.
Use existing health impact assessment tools to assess in advance what impact (both intended and unintended) any proposed changes are likely to have on physical activity levels. For example, will local services be accessible on foot, by bike, and by people with limited mobility? Make the results publicly available and accessible.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on strategies, policies and plans to increase physical activity in the local environment.
# Active travel
Identify and prioritise local areas where there is a high potential to increase travel on foot, by bicycle, or by other forms of active travel. Base this on demographic data, travel surveys, land use mix and other sources of local information. Take into account views identified through community engagement (see recommendation 1.1.2).
Increase physical activity associated with using public transport services. This includes encouraging use of these services by:
Ensuring available services are reliable, particularly in rural areas where public transport may be more limited.
Making information about public transport services accessible to people with visual and hearing impairments, for example provide spoken and visual announcements about destinations and stops on board services, and at stops and stations.
Making public transport physically accessible to everyone (see the Department for Transport's guidance on inclusive mobility).
Improving public transport to parks and other green and blue spaces.
Ensure new and refurbished footways, footpaths and cycle routes link to existing routes and improve the connectivity of the network as a whole. Aim to make it as easy as possible for people to walk, cycle or use other forms of active travel rather than making short journeys by car. This includes journeys between residential areas and:
public transport stops and stations
places of work
public open spaces
schools, colleges and early years settings
healthcare services
shops, and leisure sites.
Ensure footways, footpaths and cycle routes are convenient, safe and appealing to users, and are built and maintained to a high standard. For example, ensure:
they are even and do not include any hazards, for example from tree roots, pot-holes, broken paving slabs or seasonal and weather-related obstructions
they have enough lighting to make people feel secure
they are free from permanent or temporary obstructions, where possible (see recommendation 1.1.3)
they are not hidden by overgrown or poorly managed vegetation
they have clear signs to help people find their way.Work in association with relevant third sector organisations and volunteers to plan and carry out this work. For more details, see the Department for Transport's guidance on inclusive mobility and the Traffic signs manual.
Ensure pedestrians, cyclists and users of other modes of transport that involve physical activity are given the highest priority when developing or maintaining streets and roads. (This includes people with limited mobility.) Use 1 or more of the following methods:
Re-allocate road space to support physically active modes of transport (for example, by widening footways and introducing cycle lanes). For more detail on designing these routes, see the recommendations on walking and cycling in NICE's guideline on air pollution: outdoor air quality and health, and the Department for Transport's guidance on Shared use routes for pedestrians and cyclists.
Restrict motor vehicle access (for example, by closing or narrowing roads to reduce capacity).
Introduce road-user charging schemes. For more detail on charging schemes, see the recommendations on clean air zones in NICE's guideline on air pollution: outdoor air quality and health.
Introduce traffic-calming schemes to restrict vehicle speeds (using signage and changes to highway design). For more detail on traffic calming, see the recommendations on smooth driving and speed reduction in NICE's guideline on air pollution: outdoor air quality and health, measures to reduce speed in NICE's guideline on unintentional injuries on the road, and the Department for Transport's guidance on Traffic calming.
Improve cycling infrastructure using information from people who walk, cycle, and drive in the local area, including those with limited mobility (see recommendation 1.1.2). Improvements may include:
establishing cycle lanes, tracks and trails in line with best practice
installing secure cycle parking facilities in public places, on public transport and at public transport stops. For more details see NICE's guideline on physical activity: walking and cycling, and other guidance such as Transport for London's London cycling design standards and Highways England's Cycle traffic and the strategic road network.
Make it as easy as possible for people with limited mobility to move around their local area, and work with relevant third sector organisations to achieve this. For example:
Ensure footways:
have even, non-reflective, anti-glare surfaces
are free from unauthorised and unnecessary obstructions (whether permanent or temporary) including being free from pavement parking (see recommendation 1.1.3)
are set back from traffic, if possible (for example, by a grass verge).
Ensure footways that have a kerb clearly define the kerb with a change in level (apart from pedestrian crossings).
Ensure pedestrian crossings have flush kerbs and tactile paving (see the Department for Transport's guidance on the use of tactile paving surfaces).
Ensure signal-controlled crossings have tactile rotating cones and, if appropriate, an audible beep, and give enough time to cross the road safely.
Ensure tactile paving is correctly installed and maintained where it is needed, for example at all crossing places, at the top and bottom of stairs, on the edge of railway platforms and on shared use routes (see the Department for Transport's guidance on tactile paving surfaces).
Ensure seating is provided at regular intervals along footways that are key walking routes (see the Department for Transport's guidance on inclusive mobility).
Improve routes that children, young people and their families and carers use, or could use, for active travel to school, college and early years settings. Focus on improving safety, accessibility, connectivity, sustainability and appeal to users.
Consider improving access routes to school, college and early years settings by:
improving footways and pedestrian crossings (see recommendations 1.2.4 and 1.2.7)
introducing measures to reduce vehicle speed (see NICE's guidelines on air pollution: outdoor air quality and health and unintentional injuries on the road).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on active travel.
# Public open spaces
Consider ways to enhance the accessibility, quality and appeal to users of local open spaces, especially green and blue spaces, to increase their use. Focus particularly on communities who may not currently use them, for example those with low mobility, low income communities and some black and minority ethnic communities. Consider, for example, providing:
facilities that help people of all cultures and backgrounds to feel safe and welcome, for example by providing safe areas in which children can play and picnic facilities
lighting and other measures to prevent or reduce antisocial behaviour, such as maintaining vegetation
clear signs that can be understood by everyone, including people with visual impairments and learning disabilities
seats with arms and backrests, sited at frequent intervals
shelter and shade
accessible toilets that are clean, well maintained and unlocked during daylight hours
footpaths with even, non-reflective, anti-glare surfaces and tactile paving
access by public transport, on foot and by bike (including providing cycle parking)
car parking for blue badge holders and other people with limited mobility.
Ensure open spaces and footpaths are maintained to a high standard.
Involve community groups and volunteers in decisions on how to design and manage public open spaces, including trails, footpaths and towpaths. Encourage them to help maintain them, for example by reporting any problems affecting use and accessibility (see NICE's guideline on community engagement).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on public open spaces.
# Buildings
Ensure different parts of campus sites (including those in hospitals and universities) are linked by accessible walking and cycling routes.
Ensure new workplaces are linked to walking and cycling networks. Where possible, these links should improve the existing walking and cycling infrastructure by creating new through routes (and not just links to the new facility).
During building design or refurbishment, ensure staircases are designed and positioned to encourage people to use them.
Ensure staircases are clearly signposted and are attractive to use. For example, they should be well lit and well decorated.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on buildings.
# Schools
Ensure school playgrounds are designed to encourage varied, physically active play.
Primary schools should create areas (for instance, by using different colours) to promote individual and group physical activities such as hopscotch and other games.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on schools.
# Terms used in this guideline
This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.
## Campus
Two or more related buildings set together in the grounds of a defined site.
## Crossings
Signal-controlled crossings: these include puffin, pelican and toucan crossings. They have traffic signals for both vehicles on the carriageway and people crossing it.
Pedestrian-controlled crossings: these include both signal-controlled crossings and zebra crossings.
Accessible crossings: these have dropped kerbs that are flush with the carriageway, and tactile paving. Those with signals also have tactile rotating cones and, if appropriate, an audible beep. These characteristics are accessibility features.
Although these are the definitions of crossings which are used in this guideline, various other definitions exist with more detailed technical specifications. For these, see Schedule 1 of the Traffic Signs Regulations and General Directions 2016.
## Contested space
A geographical space that is used for different purposes, potentially causing conflict because each type of user has differing priorities.
## Limited mobility
People whose mobility is limited, either temporarily or in the long term, because their environment is not adapted to meet their needs. Examples may include:
some disabled people, including people with sensory impairments or learning disabilities
people using wheelchairs, cycles or other mobility aids, or those supporting people using these aids
some older or frail people
people using buggies, prams or cargo cycles for transporting children
people with conditions such as chronic pain or neurological conditions
some people with mental health conditions.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Training on the links between transport and health for council staff and elected members.
Partnership working between local government authority departments responsible for public health, transport and planning and other departments that affect people's ability to be active in the built or natural environment.
Public health knowledge and leadership in local transport departments, and in local authorities' parks and recreation departments.
Access to examples of good practice on physical activity and the environment.
Local links to academic centres for translational research.
Whether and how behavioural interventions may be combined with the environmental interventions covered in this guideline (for more information, see NICE's guidelines on physical activity: walking and cycling and behaviour change: individual approaches).
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Physical activity can help people to prevent and manage over 20 chronic health conditions (Department of Health: Start active, stay active). The benefits of physical activity vary across ages and include improvements to physical and mental development and functioning. (Department of Health: Start active, stay active: infographics on physical activity).
Physical inactivity costs the NHS in the UK around £1 billion per year (The King's Fund: Making the case for public health interventions and Scarborough et al. 2011). Including costs to wider society, this rises to around £7.4 billion a year (Public Health England: Everybody active, every day: an evidence based approach to physical activity).
In 2015, 34% of men over 16 and 42% of women over 16 reported that they did not meet UK guidelines on physical activity, and the number of people meeting the recommended levels decreased with age (NHS Digital: Health Survey for England – 2016). In 2015, only 23% of boys and 20% of girls aged 5 to 15, and in 2012 only 10% of boys and 9% of girls aged 2 to 4 met the UK Chief Medical Officer's guidelines on physical activity for their age group (NHS Digital: Health Survey for England, 2016: children's health; NHS Digital: Health Survey for England 2015: children's physical activity). For children aged 5 to 15, figures exclude physical activity done during school lessons. When this is included, 24% of boys and 18% of girls who had attended school in the past week met the UK Chief Medical Officers' guidelines on physical activity for their age group. For both reports, data was collected from parental report for children aged 2 to 12. For 13 to 15 year olds, data was self-reported.
The environment can influence people's ability to be active (Foster and Hillsdon 2004). The design and layout of towns and cities can enable and encourage walking and cycling, and using public transport may also mean people build physical activity into their daily lives (Beavis and Moodie 2014).
For people with limited mobility, the environment can make it particularly difficult to be active. For example, they may not have easy access to public transport, or may find it difficult to cross roads if the crossings are not accessible.
The government's Sporting Future sets out a strategy for a healthy nation based on 5 outcomes, including physical and mental wellbeing. The government's Cycling and walking investment strategy aims to make cycling and walking the natural choices for shorter journeys, or as part of a longer journey. Objectives for these policies include:
increasing the proportion of the population meeting the physical activity guidelines
decreasing the proportion doing less than 30 minutes of physical activity a week
increasing cycling and walking activity
decreasing fatalities and serious injuries in cyclists.
Supporting people of all ages and abilities to be more physically active can help local authorities meet their public health responsibilities. Specifically, it will affect indicators identified in the Public Health Outcomes Framework 2016 to 2019 and the NHS Outcomes Framework 2016 to 2017.# The committee's discussion
Evidence statement numbers are given in square brackets. See 'The evidence' at the end of each section for details.
# The evidence – overall strengths and limitations
The committee noted that the evidence as a whole indicated that the proposed environmental changes to open spaces and public transport provision appear to increase physical activity.
Of the 70 studies included in reviews 1, 2 and 3, only 2 (both qualitative) were rated as having no risk of bias and 16 were rated as having low risk of bias . The remaining 52 studies were rated as having high risk of bias . No economic evaluations were included in review 1, 5 were included in review 2 and 2 studies in review 3 included a small amount of economic data.
All included studies were based on interventions used as natural experiments, in response to pre-planned infrastructure changes. For many interventions, this study design was deemed to be the most feasible and valid approach. However, individual studies had limitations. Many did not use objective measures of physical activity or report whether they were adequately powered. But the small sample sizes of some studies suggest that they would not have had the power to detect changes in physical activity behaviours. For several types of intervention, self-selection bias may have occurred.
Many studies did not use a control group. Control groups can help to minimise bias or confounding that could influence a study outcome. Of studies using a control, around half were thought to be sufficient to reduce confounding. Around half of the remaining studies did not include enough information to determine whether the control group was appropriate, for example how well it was matched to the intervention group or whether contamination occurred. Some used control groups that were unlikely to effectively reduce confounding. Normally this was because the intervention was geographically close to the control area or there was no buffer between them. Many interventions had behavioural elements that may have affected the outcomes reported but could not be separated from environmental aspects.
Many studies:
were unclear about the length of follow-up periods and when they took place in relation to the intervention and baseline data collection
had very short follow-up periods
were at varying stages of completion when follow-up measures were taken.
The committee recognised that delays to completing infrastructure changes, over which the researchers would have little control, may have reduced follow-up periods. So they may have been too short to detect long-term changes in commuting decisions and physical activity behaviours. The committee also recognised that as follow-up times lengthen, the possibility of other factors influencing outcomes increases.
Finally, some studies report findings for those who are least active. However for those with limited mobility, which is a group distinct from the least active, there was a lack of reporting of the impact of interventions.
The quality of the evidence was also assessed using the Grading of Recommendations Assessment, Development and Evaluation process (GRADE). The committee noted that the complexity and scale of the interventions makes this an extremely challenging area of research.
It may not be possible, practical or ethical to undertake a randomised controlled trial for some interventions and natural experiments may be the most valid approach. So a modified version of GRADE was agreed by the committee and used. Outcomes from studies for which the natural experiment study design was the most feasible and valid approach started the GRADE process as 'high quality'. If a randomised controlled trial was feasible and optimal for answering the study aims but a natural experiment design was used, outcomes started the GRADE process as 'low quality'.
Strong recommendations may be made if there is clear evidence of benefit, and if it is cost effective. Evidence may be derived from published literature, from expert testimony (if sought) and from committee experience. Low and very low quality evidence from published literature may still support strong recommendations if there are transparent and strong rationales to do so, and if benefits and harms have been considered. The committee also noted that variations in the methodology used to evaluate the impact of interventions, in different groups, over different time points meant that the committee did not feel comfortable pooling the heterogeneous outcome data.
Many of the studies were not carried out in the UK so the applicability of the findings to the UK needed to be taken into account. However, the committee agreed that most studies were conducted in a broadly similar context so the findings were likely to be transferable.
The committee agreed that the recommendations in this guideline should be applied to all new changes to the environment, and to existing features when they are being refurbished.
# Cost effectiveness evidence
There was little published evidence on cost effectiveness, so NICE carried out a new economic analysis. Overall, the analysis showed that interventions could be cost effective if modest numbers of people increased their physical activity. For example, in a town with a population of 100,000 people, an intervention that cost £1,000,000 (the equivalent of £10 per person) would be beneficial if it motivated 1,000 people to cycle for an additional hour per week, or 2,500 people to walk for an extra 30 minutes per week.
It also assessed 8 case studies of interventions that were effective in increasing physical activity. It found 7 of these interventions to also be highly cost effective. But both the effect and cost of any intervention will depend on factors specific to the local setting, so this may differ from the case studies. The analysis focused on a limited number of health conditions and did not consider non-health benefits, suggesting that the overall benefits are likely to be greater than the estimates given. So the committee concluded that these types of interventions could offer good value for money.
The committee considered there is not enough evidence to apply a decay rate to the impact of environmental interventions. Because they involve structural changes to the environment, they are likely to remain in place for relatively long periods of time. The committee noted that this differs from the approach taken in previous guidelines on behavioural interventions to increase physical activity. These type of interventions are usually delivered over a finite period and their impact tends to diminish over time. In those guidelines the economic analysis typically used a range of annual decay rate rates from 0% (no decay) to 100% (no intervention effect beyond the first year).
The committee noted the importance of maintaining open spaces to encourage local communities to use them to be physically active. They highlighted that some environmental interventions may need more regular, ongoing maintenance than others, particularly some interventions in open spaces. For example, if footpaths become overgrown with vegetation or become muddy because of poor drainage, they may become unusable relatively quickly. They agreed that ongoing maintenance should be factored into the costs of implementing such interventions. Provided they are adequately maintained, the committee thought their impact (for example, the use of footpaths and cycle paths) would be maintained and could possibly increase over time.
# Strategies, policies and plans to increase physical activity in the local environment
Recommendations 1.1.1 to 1.1.6
## Rationale and impact
Based on their experience and expertise, the committee agreed that increasing most people's physical activity levels is important. They also agreed that it is particularly important to help people who are the least active to be more physically active, because it will benefit their health and wellbeing the most. A well-designed local environment can help to encourage people to be more active. The committee agreed that local strategies, policies and plans which take account of local needs and follow best practice are an important way of creating such an environment.
Some evidence suggested that initiatives to help people be more active locally are more likely to be effective if local communities and groups are involved from the start. The committee recognised that different groups, for example people who walk, cycle or drive, or people with limited mobility, may have different views and needs. They also agreed that some people may use several modes of transport. For example, many adult cyclists may also drive, but not all drivers will be cyclists. The committee noted that it is important to be aware of the range of views and needs when aiming to increase physically active travel.
Experts suggested that initiatives that work well in one locality may not always work in another. In particular, different approaches may be needed in urban and rural areas. The evidence was uncertain. But the committee recognised the importance of seeking the views of local people and voluntary and community organisations on local needs and priorities. They made a recommendation based on their expertise and NICE's guideline on community engagement: improving health and wellbeing and reducing health inequalities.
The committee agreed that it is important for people with limited mobility to be able to move around their local area. Some experts suggested that both temporary and permanent obstructions on footways are not only inconvenient but can cause injuries. But some items, such as seating, may be needed to enable some groups to be physically active.
Even if there is a policy in place to address these issues, the way it is interpreted and put into practice may vary both between areas, and over time in the same area. Some experts also suggested that the number of crossings and their accessibility, for example whether they have tactile paving and (on signal-controlled crossings) rotating cones, may not always meet people's needs. Additionally, temporary street and road works may disrupt people's access, as can a lack of step-free routes. These types of obstructions and issues can put people off going out and about. This is particularly true for people with limited mobility, including those with sensory impairments.
Because several experts highlighted the importance of these issues and because the committee were conscious that everyone should be able to move around in their local environment as easily as possible, they felt there was a strong basis for this recommendation. They also made a recommendation for research to find out more about what type of environmental changes can encourage this group to be more physically active.
These recommendations are taken from NICE's guideline PH8. Please see the evidence for details and why the recommendations were made. The committee examined new evidence and agreed that all planning permissions should prioritise people doing active travel, whether they are new developments or improvements to existing ones.
A lack of physical activity increases the risk of developing conditions such as type 2 diabetes, coronary heart disease, stroke and some types of cancer. People whose mobility is limited may find it particularly difficult to be active and could spend more time being inactive. Strategies, policies and plans that help to create local environments that lead to people becoming more active will benefit everyone but, in particular, those who are least active.
People have varying needs and it can be difficult to achieve a balance in meeting them all, particularly where space is shared between different types of user. For example, dropped kerbs that are flush with the carriageway are important for wheelchair users, but if they have no tactile paving they may prove a problem for people with a visual impairment.
Views and needs may vary depending on whether people walk, cycle or drive in the local area. Where there are conflicting needs, the space may become contested. So it is important to involve the community to ensure everyone's needs are considered and to try to resolve any potential conflicts.
Developing and implementing strategies, policies and plans and consulting with communities is a core part of local authorities' work. So putting these recommendations into practice is not expected to cost more than is already spent in this area. An environment that encourages people to be more active will help prevent a range of chronic health conditions, leading to savings for the NHS, local authorities and society at large.
## Evidence discussion
The outcomes that matter most
Physical activity is a broad concept that includes everyday activities such as housework, gardening and carrying shopping bags, as well as recreational or employment-related activities such as sports, manual work and active travel to work.
The committee were aware that various outcomes can be used to capture changes in physical activity levels. These include: total physical activity, total sedentary time and physical activity in daily life. These outcomes can be measured in different ways. For example, the proportion of participants meeting physical activity guidelines, the time spent in moderate to vigorous physical activity, or changes to 'metabolic equivalents' or METs per unit of time. However, the recommendations in this section are based on expert testimony rather than evidence from the reviews because little published evidence was identified in relation to these recommendations, meaning that expert testimony provided the best available evidence.
The committee agreed that when considering the population as a whole, the objective is to increase the amount of moderate to vigorous activity most people do. However, they noted that there is a continuum of benefits from being physically active. For people who are least active, moving from being inactive to having low levels of activity, or replacing sedentary behaviour with physical activity, would bring the greatest health benefits. (Matthews et al. 2015, Department of Health's Start active, stay active: a report on physical activity in the UK and Kyu et al. 2016).
The quality of the evidence
A key limitation of the evidence from the reviews is that there was a dearth of information on changes to the environment to enable those with limited mobility to be more physically active. However, the committee heard expert testimony from a range of sources that supported these recommendations . Expert testimony is usually considered to be more susceptible to bias than the published evidence. But the committee thought that in this case the expert testimony gave valuable information about barriers or facilitators to physical activity among these groups, and they agreed with it. Likewise, the reviews did not provide any insight into identifying and addressing the needs of different groups, but expert testimony identified the importance of engaging with communities . This is consistent with existing NICE guidance on community engagement.
Benefits and harms of strategies, policies and plans to increase physical activity
The whole local population is considered in these recommendations. But to reduce health inequalities there is a particular focus on those who could gain most benefit from increasing their physical activity. This includes people who are currently inactive or have very low levels of physical activity, particularly those for whom environmental factors are barriers to physical activity.
The committee also recognised that if resources are limited it is best to target areas and groups of people who are likely to benefit most – such as those with limited mobility or low levels of physical activity.
The committee recognised that people may use different modes of transport at different times, potentially being a 'walker', a 'cyclist', a 'motorist' and a 'public transport user' at various points. They also recognised that the needs or preferences of people who are walking, cycling, using public transport, or driving may not always align. This can result in contested space, where one geographical space is used for different purposes, potentially causing conflict because of the different priorities for each type of user. They agreed that it is important to identify solutions that take account of the views of each of these groups, although solutions should aim to increase physical activity. Details about the road design user hierarchy can be found in the government's Manual for streets and Manual for streets 2.
No additional economic analysis was carried out for the review question underpinning this recommendation. However, the committee considered each of the case studies included in the economic analysis to be relevant to this recommendation.
Overall the committee considered the use of strategies, plans and policies to increase levels of physical activity good value for money. This is an integral part of most local authorities' work so would not be expected to need significant extra resources. Costs related to the content of these strategies are not expected to be significant, and may be spread over time as they are rolled out.
However, if the strategies, plans and policies lead to the creation of an environment that results in increased physical activity, then any additional investment would be expected to result in improved health outcomes in the longer term and potential future cost savings and benefits to the health and social care systems.
The committee agreed that examples of effective interventions in other parts of the world, such as those proven to increase cycling in parts of northern Europe, should be assessed to determine whether they are likely to be effective locally (Watts et al. 2011).
The committee were aware that local providers are encouraged to monitor and evaluate the impact of interventions using standard tools if possible.
The committee recognised that there is an overlap between interventions to create green infrastructure and this guideline. This is because this guideline focuses on green, blue and grey spaces which, in turn, can be conducive to physical activity. Green infrastructure interventions tend to focus on natural and ecological processes, which include urban drainage, climate change mitigation, biodiversity, air quality and other environmental factors. Although this guideline also focuses on open spaces it does so with the specific aim of encouraging physical activity.
Therefore interventions that could be defined as green infrastructure are embedded in this guideline because of their effects on physical activity, but green infrastructure is not discussed further. More information can be found in Natural England's Green infrastructure guidance.
## The evidence
The committee looked at evidence in:
Expert testimony on active travel in London: Expert paper 1
Expert testimony on disability and the built environment: Expert paper 2
Expert testimony on environmental support for physical activity in older people, urban deprived populations and black and minority ethnic groups: Expert paper 4
Expert testimony on improving the environment to encourage people to walk: Expert paper 6
Expert testimony on learning from Paths for All: Expert paper 7
Expert testimony on transport planning: Expert paper 9
Physical activity and the environment: Economic modelling report
# Active travel
Recommendations 1.2.1 to 1.2.9
## Rationale and impact
Some evidence suggested that there is more potential to increase active travel – and more benefit to be gained – in some areas than others. For example, interventions to increase active travel in areas where many short car journeys are made may be more effective than in areas where most destinations are much more easily reached by motor vehicle. The committee agreed that it was important to identify and prioritise these areas, along with ways to get more people using active modes of travel. The evidence was limited to expert opinion but the committee agreed that such an assessment was an important step towards a more active population.
Some evidence suggested that if public transport is improved more people may use it, particularly if they live close to the improvements. This may encourage those who are inactive, or who usually drive, to be more active because they will be walking to and from bus stops and stations. The committee agreed with an expert that both spoken and visual announcements on public transport could encourage people who have visual or hearing impairments to use services. They also agreed that public transport should be accessible to everyone, including people with limited mobility.
An expert told the committee that it should be as easy as possible for people to get to parks and other open spaces from where they live, to encourage them to be active. They noted that some open spaces, particularly green or blue spaces, may not be within walking distance and agreed that public transport to these locations should be available. But they also agreed that more evidence is needed to see whether improvements to the public transport system lead to a sustained increase in physical activity levels and made a recommendation for research.
Evidence suggested that if walking and cycling routes connect residential and commercial areas and other destinations, such as schools, then the number of people using them increases – as do their activity levels. The evidence also suggested that trails and footpaths that do not connect to transport links or a central hub were less likely to encourage people to walk or cycle. Regular points where people can get onto these routes are also important.
Experts confirmed that it was important to make it as easy as possible for people to take a short walk from where they live to parks and other local amenities. The committee agreed that ensuring people can walk or cycle to a range of local destinations is important to encourage them to be physically active.
They also agreed that the focus should be on networks of routes rather than looking at each route in isolation. Additionally, improvements should be made when existing routes are refurbished, as well as being incorporated when planning new routes.
Several experts highlighted the importance of ensuring footways and footpaths are well maintained to avoid falls and to ensure people feel safe when using them. They also highlighted the need for clear signs to help people find their way. Although the evidence was uncertain and focused on the needs of older people or those with limited mobility, the committee agreed that well-maintained footways and footpaths are important for everyone. They also agreed that these issues apply equally to cycle routes and that it was important to work with third sector organisations to ensure the recommendation is implemented.
This recommendation is from the 2008 guideline. Some new evidence for this update reinforced that introducing congestion charging increased the number of people using public transport and cycling. The committee heard that traffic-calming schemes had mixed effects on physical activity, and they agreed that some methods of traffic calming can affect air quality. However, the committee also agreed that carefully implemented traffic-calming measures and restricted vehicle access were important ways to encourage active travel.
Some evidence suggested that improvements to cycling infrastructure do encourage more people to cycle regularly. If carefully implemented, they should also improve safety for cyclists and pedestrians.
But the committee were uncertain about how many people would benefit. They agreed that the needs of people who walk and drive in the local area need to be taken into account, as well as those of people who cycle. The views of people who do not cycle because of the current infrastructure and people with limited mobility also need to be taken into account. That is because there may be conflict when space is shared by people using different types of travel. An expert confirmed that it is important to do this when improving the local area for cycling. The committee were aware that there are various best practice guidelines that may be helpful when improving cycling infrastructure.
Some experts suggested that people with limited mobility find it easier to move around their local area if, for example, footways include features such as tactile paving and even surfaces. Non-reflective, anti-glare paving surfaces can make it easier for people with visual impairments to interpret their surroundings. Seating could make it easier for people who need to rest regularly. The committee agreed that sometimes audible beeps at crossings may not be appropriate, for example if several crossings are close to each other audible beeps could cause confusion.
The committee agreed with experts that these actions should be recommended to encourage everyone, particularly people with limited mobility, to be physically active. But they also agreed that more evidence was needed on the effectiveness and cost effectiveness of environmental changes to increase physical activity among this group and made a recommendation for research.
Some evidence suggested that improving routes for active travel to school could increase the number of children who walk and cycle to school. Evidence about the best ways to do this was mixed . But the committee agreed that safety improvements near schools, including measures to reduce vehicle speed and more pedestrian crossings, could perhaps help. Some evidence suggested that parents, teachers and bus drivers approve of these safety measures. And other evidence showed that it also helps if routes are connected and accessible.
## Why we need recommendations on this topic
Experts told the committee that using public transport can help people build physical activity into their daily lives. But they also said that in some areas, particularly rural areas, public transport services may not be available or may be unreliable. Experts also said that some groups, especially those with limited mobility or with sensory impairments, may find it difficult to use services, particularly if they do not give spoken and visual announcements.
The environment can make it difficult for some groups to be active. For example, older people and others with limited mobility may find it difficult to cross the road in the time allowed. In addition, obstructions on footways can make it difficult to walk around an area and may cause injuries, particularly for those with visual impairments. For children, a lack of walking or cycling opportunities and fears of busy roads may stop them being physically active as part of their daily routine.
Putting these recommendations into practice may involve additional costs for local authorities. Some changes – such as providing spoken and visual announcements about destinations and stops on public transport – may be more expensive than others. However, if these changes help to create an environment in which people are more active, it will help to prevent a range of chronic health conditions. This, in turn, will lead to savings for the NHS and local authorities as well as society at large. Also, costs may be spread over time as they are rolled out.
## Evidence discussion
The outcomes that matter most
Recommendations in this section aim to increase physical activity. Therefore, relevant outcomes include total physical activity, total sedentary time, physical activity in everyday life and active travel.
A wide range of outcomes was used in the studies included in the reviews. In addition to physical activity being measured in several different ways (for example, proportion of participants meeting physical activity guidelines, time spent in moderate to vigorous physical activity, and change to 'metabolic equivalents' or METs per unit of time), time spent on specific activities such as walking and cycling were also used as outcomes. Some studies reported changes in 'mode' share, for example whether people changed from using cars to walking or cycling.
Public transport use was also reported as an outcome measure. Because using public transport can increase incidental physical activity when walking or cycling to or between stops and stations, the committee agreed it could be considered a proxy measure for physical activity.
Each of the outcomes above were reported both as observed outcomes and as self-reported outcomes in the studies. Because of social desirability bias, recall bias and interpretation issues, the committee considered that observed outcomes were more reliable than self-reported measures.
The committee discussed which measure was most appropriate for considering the change to total physical activity. They agreed that when considering the population as a whole, the objective is to increase the amount of moderate to vigorous activity most people do. However, they noted that there is a continuum of benefits from being physically active and that for people who are least active, moving from being inactive to having low levels of activity, or replacing sedentary behaviour with physical activity would bring the greatest health benefits. (Matthews et al. 2015, Department of Health's Start active, stay active: a report on physical activity in the UK and Kyu et al. 2016).
The committee agreed that these small changes in physical activity are best captured by the use of METs. The economic modelling carried out to support this guidance also uses this approach.
Because the reviews used GRADE to assess the quality of the evidence, the committee identified which outcomes they considered to be critical or important. They considered all measures of physical activity, time spent in physical activity and public transport use to be critical outcomes. They also considered changes in transport mode share to be important.
The quality of the evidence
The certainty in the evidence base supporting this set of recommendations (29 evidence statements summarising evidence from 45 studies) was generally graded 'very low' or 'low', which means NICE has low confidence that the results would not change if more evidence became available.
In general the evidence showed that improvements to public transport may increase its use particularly for those who live close-by . Five studies suggested that public transport interventions increase participants' total physical activity. However, this increase depended on their existing travelling behaviour – new users of the intervention spent more time being moderately or vigorously active than existing or former users. But there was an exception. A small amount of evidence showed that those living near a new light rail line did not use it any more than anyone else and that it did not have an effect on moderate to vigorous physical activity . However, this study may have used a control group that was located too close to the intervention and so its effect may have been underestimated.
Expert paper 8 considered public transport services in rural areas and highlighted that buses are considered the most flexible service in meeting the needs of more rural communities. Expert papers 2 and 8 included a focus on the use of spoken announcements on public transport and their importance for people with visual impairments. Although these papers did not provide evidence that directly linked such announcements to physical activity levels, it was clear that a lack of them in some areas is a barrier to people with visual impairments feeling able to use public transport.
Expert paper 3 noted that the incidental physical activity people accrue when using public transport can make a significant contribution to their overall physical activity levels. The committee felt that everyone should have an equal opportunity to increase their physical activity levels in this way and that such barriers should be addressed.
Some evidence suggested that connectivity between areas can help increase physical activity. Two studies examined the effect of introducing greenways between residential and commercial areas. One found an increase in the number of people who walked or cycled and the other an increase in the proportion of people who were being moderately or vigorously active .
Another study considered the effect of 'Liveable Neighbourhoods', which included interconnected street networks, public transport stops and a range of different destinations within a 15-minute walk. It found that an increased number and diversity of destinations within walking distance was associated with increased active travel .
Two studies noted the importance of routes connecting to central transport hubs and another the importance of connecting to feeder routes . Expert testimony also supported these findings .
Some evidence suggested that congestion charging may increase use of public transport , although public transport services were also improved as part of the change. Some studies reported mixed evidence showing that traffic-calming measures along school routes may increase active travel to school and that traffic-calming measures in neighbourhood areas may improve perceptions of street safety among older people . The committee felt that design of traffic-calming measures, and parallel improvements to pedestrian and cycling infrastructure and public transport provision, should be carefully considered to ensure that active travel is not reduced.
The 2008 guideline included a recommendation on road-user charging schemes. The committee felt it was still relevant. The new evidence identified by this review and through expert testimony makes an additional contribution to the evidence base for that recommendation.
The evidence suggested that, in general, improvements to footways may increase walking . Some evidence showed no change in walking after extension of a greenway , but these studies used a threshold of 30 minutes of walking per day so did not capture smaller changes in activity that may still be valuable.
One study considering the general population found that introducing wayfinding signs on a trail had no impact on the number of people who used it . But several expert papers highlighted the importance of clear, inclusive signs in both urban and rural areas , particularly for people with disabilities. The committee considered the equity aspects of this intervention and agreed that poor signage was a potential barrier to physical activity and so made a recommendation in this area, so that increased equality in outcomes might be achieved.
Experts also highlighted that lack of regular seating on streets could be a barrier to physical activity for older adults and disabled people .
Another study found that lack of lighting was a concern for potential pedestrians and cyclists using an unlit footway and cycle path that ran parallel to a guided busway . Expert paper 4 noted that lighting footways and ensuring they are not obscured by poorly-managed vegetation was important to ensure people feel secure when using them.
Evidence from the reviews suggested that improvements to cycling infrastructure can increase bicycle trips . This includes the number of people who commute by bicycle and the number who cycle regularly . Improvements can also increase the proportion of all journeys that are made by bicycle . Improvements included off-street cycle routes, motor-vehicle-free bridges and the provision of bicycle racks in public places and on public transport. The committee were aware of tools such as the Propensity to Cycle tool to assess potential for increasing cycling.
The committee recognised that flexible seating arrangements could be used when adding cycle parking to public transport, to help ensure that enough seating is retained for those who need it.
Four studies found that introducing on-street cycle lanes increased the number of cyclists counted each day. But the absolute numbers remained relatively small, with numbers at the beginning of the study ranging from 9 to 91 and at follow-up from 10 to 257 .
Four studies suggested that Safe Routes to Schools have mixed effects on children walking and cycling to school . Two studies found active commuting to school increased, but 1 of these studies (which reported on total physical activity) found no overall increase in activity levels. One study found no effect on the proportion of children who cycled to school whereas 2 others found an increase in the proportion walking and cycling . One qualitative study found that parents, students, school staff and school bus operators approved of the improvements . Interventions included improving footways and road crossings, speed reduction measures and drop-off zones.
The committee agreed that recommending drop-off zones may not be appropriate in the UK, because sometimes 'park and stride' or other drop-off methods are considered safer and may ease congestion. Some behavioural interventions were also included, which are beyond the scope of this guideline but it was not possible to separate the effects on outcomes .
Expert paper 6 included improvements to footways and pedestrian crossings used as part of walking routes to school and some behavioural interventions. Improvements led to an increase in walking that was more or less sustained at 1- and 2-year follow-up (22% increase at year 1 and 19% increase at year 2).
The committee decided not to make a recommendation about extending motorways because only 1 study was identified. This looked at both the beneficial and adverse effects on local residents of extending a motorway that bisected the local area . The committee also decided that there was insufficient certainty in the evidence to make recommendations on temporary road closures to allow events to promote physical activity (including Ciclovia interventions) .
As with recommendations in section 1.1, a key limitation for section 1.2 is the lack of evidence specifically considering interventions that allow those with limited mobility to increase their active travel. So the committee sought expert testimony to address these gaps in the evidence. Expert paper 2 focused in particular on the experience of people with visual impairments. Expert papers 4, 6 and 7 all included a focus on older people or people with limited mobility. These 4 expert papers all raised similar barriers or facilitators to mobility for these groups, including footway surfaces, tactile paving and pedestrian crossings.
Despite generally low or very low quality evidence from the reviews, the committee noted that the evidence from reviews was consistent. Supplementary evidence from expert testimony was internally consistent. The committee considered that the available evidence combined with the fact that these recommendations address equity issues was sufficient to make some strong recommendations, so that increased equality in outcomes might be achieved.
Benefits and harms of active travel
The committee were mindful that some groups may benefit more than others from incidental physical activity accrued through the regular use of public transport. They noted, for example, that people of working age, in employment and living in urban areas may be more likely to benefit than older people or those living in rural areas where transport stops are less available and services may be less frequent.
The committee were aware that increasing active travel may have some unintended consequences or adverse effects. The previously discussed concept of shared or contested space (see benefits and harms in the section on 'strategies, policies and plans to increase physical activity in the local environment') is also relevant here. The committee recognised that interventions benefiting some have the potential to deter others, if not well implemented. They noted the need for carefully designed interventions, for example cycle routes that minimise the risk of creating contested space.
Contested space may create conflict that could affect some groups, such as older people, disproportionately. For roads with possible conflicts, the WHO recommends a safe motor vehicle speed limit of 30 km/h or 20 mph.
A second potential harm is around road traffic collisions. Improving cycle infrastructure may increase the number of cyclists. That, in turn, could result in an increase in the absolute number of cyclists being involved in road traffic collisions. However, the committee did note evidence that dedicated infrastructure for cyclists – in 1 case a tarmacked cycle route with regular junctions – may reduce cyclist collisions in the area around the cycle route .
In addition, the committee were aware that increasing the amount of active travel people do may increase their exposure to outdoor air pollution. They were aware that the physical activity benefits generally outweigh the risk of increased exposure to air pollution. (Cepeda et al. 2017 and Tainio et al. 2016). They also noted that a shift from motorised transport to walking and cycling could improve levels of air pollution. From a broader public health perspective, tackling outdoor air pollution is an important part of creating healthier environments in which people can be physically active. See NICE's guideline on air pollution: outdoor air quality and health.
The committee also noted that increased active travel may generally increase the numbers of people on the streets. This could, in turn, strengthen a feeling of security.
Some cost effectiveness evidence about interventions relevant to these recommendations was identified from the reviews. Overall, the evidence showed that interventions could be cost effective if modest numbers of people increased their physical activity.
One study with high risk of bias, found the Department for Transport's Cycle Demonstration Towns cost effective, with a benefit–cost ratio of between £2.60 and £3.50 for every £1 spent . Another study, with high risk of bias, found Living Streets' Fitter for Walking programmes cost effective in most locations, with benefit–cost ratios larger than £1. Benefit–cost ratios were higher if initial costs were lower . One study, with low risk of bias, found the World Health Organization's Safe Routes to School programmes to be cost effective by both creating savings and gaining quality-adjusted life years (QALYs) .
Economic modelling was also undertaken. Economic analysis of case studies on Active living by Design, Cycle Demonstration Towns, the Paths for All Smarter Choices, Smarter Places and greenways found all 4 to be highly cost effective. The incremental cost effectiveness ratios (ICERs) were £1,397 for Active living by Design, £2,496 for Cycling Demonstration Towns, £4,423 for Paths for All Smarter Choices, Smarter Places and £7,652 for greenways. The analysis of Fitter for Walking found it could be cost effective up to a cost of £100 per person.
There may be additional resource implications for encouraging use of public transport by ensuring available services are reliable, providing information about public transport services, and ensuring footways, footpaths and off-road cycle routes are well maintained.
There are also resource implications for measures such as providing spoken and visual announcements about destinations and stops on bus services and at stops and stations. Guide Dogs for the Blind Association's Installing audio-visual equipment on buses – cost and practicality issues highlighted that installing audio-visual technology could cost £2,100 for a single-decker vehicle, or £2,550 for a double-decker. However, the committee noted that such technology need not be installed on all vehicles at once, but could be introduced as vehicles are replaced.
In addition, lower technology approaches such as spoken announcements by drivers were noted as being easily implementable with relatively small training costs. However, if such approaches create an environment that results in increased physical activity, then that will lead to improved health outcomes in the longer term and potential future cost savings to the healthcare and social care systems.
The committee did not make recommendations on car ownership or parking restrictions. They heard that, in London, car owners are 2 to 3 times less likely to do half an hour of active travel in a day than those who don't own cars . They recognised the benefits of incidental physical activity accrued through using public transport and that some studies highlighted other potential benefits, for example drivers perceiving use of public transport as being less stressful than driving. .
Although 2 studies highlighted a lack of parking at work as being associated with increased use of public transport or increased active travel , the committee were conscious that these studies also included other aspects, such as providing a subsidised travel pass and access to a new transit link or providing workplace travel plans, and so did not make recommendations on this intervention.
The committee were conscious that not all areas have the same level of public transport access as London or other urban areas. They noted that the studies that included parking were done in workplaces and that the findings may not be transferable to other settings. They were also aware that for certain groups, such as some older people, having access to a car and being able to park outside their home was a key factor in determining whether people could get out of the house. This in turn resulted in opportunities to be physically active at destinations reached by car .
The committee noted that although using public transport may help people to build physical activity into their daily lives, it incurs a cost for most people. They noted that certain groups, such as older people and children and young people, have access to free or discounted travel on some public transport services (although the age of eligibility varies). However, fiscal measures such as ticket pricing were beyond the scope of this guidance, so the committee have not made recommendations in this area.
The committee noted that some guidance on increasing active travel already exists. But this is often restricted to walking and cycling as the most common methods of active travel (for example, the Chartered Institution of Highways and Transportation's guidance on Planning for walking and Planning for cycling).
## The evidence
The committee looked at evidence in:
Evidence review 1 on public transport interventions: ES1.1, ES1.2, ES1.3, ES1.4, ES1.5, ES1.6, ES1.7, ES1.8, ES1.9, ES1.10
Evidence review 2 on Ciclovia, trails and safe routes to school interventions: ES2.3; ES2.4; ES2.6, ES2.7; ES 2.8; ES2.9; ES2.10; ES2.11; ES2.12, ES2.13, ES2.14, ES2.15, ES2.16; ES2.17, ES 2.18; ES2.19
Evidence review 3 on parks, neighbourhood and multicomponent interventions: ES3.6, ES3.7, ES3.8
Expert testimony on active travel in London: Expert paper 1
Expert testimony on disability and the built environment: Expert paper 2
Expert testimony on changes in scientific knowledge and transport practice since 2008: Expert paper 3
Expert testimony on environmental support for physical activity in older people, urban deprived populations and black and minority ethnic groups: Expert paper 4
Expert testimony on encouraging physical activity in the natural environment: Expert paper 5
Expert testimony on improving the environment to encourage people to walk: Expert paper 6
Expert testimony on learning from Paths for All: Expert paper 7
Expert testimony on the Strathclyde Partnership for Transport: Expert paper 8
Expert testimony on transport planning: Expert paper 9
Physical activity and the environment: Economic modelling report
# Public open spaces
Recommendations 1.3.1 to 1.3.3
## Rationale and impact
The committee heard from an expert that the quality of green space is an important factor in encouraging people to use it, particularly in deprived urban areas. An expert told the committee that clear signs are important so that people know where they can walk, including where public access is allowed.
Some evidence suggested that people, including those with limited mobility, might use outdoor open spaces if the facilities are improved. For example, improving park facilities like toilets and lighting, and better landscape design may encourage people to use parks, and increase the amount of physical activity they do there. Experts told the committee that facilities such as toilets, seating and footpath surfaces are particularly important for encouraging older people and those with limited mobility to use these spaces. Parking for blue badge holders is also important for these groups along with access on foot, by bike and using public transport.
Despite little evidence on specific actions, the committee made suggestions based on their expertise. They also recommended research into how effective such changes are at creating and sustaining physical activity over the long term among the general population.
Recommendation 1.3.2 is from the 2008 guideline. The committee reviewed this in the light of new evidence for this update, and decided it was still relevant. Experts also highlighted how community groups and volunteers can help design and manage public open spaces, footpaths and trails, as well as support the authorities responsible for maintaining them.
Good quality local open green or blue space that is attractive, feels safe and welcoming and is easy to access may encourage a range of different groups and ages to be physically active.
For most older people walking is by far the most important activity. Getting out of the house at all, even by car or public transport, helps people to do some activity, even if it is a small amount. It may also bring about benefits through improved social connectedness. Pleasant and well-maintained destinations that provide facilities such as accessible toilets and appropriate seating can encourage them to use public open spaces.
Some low income communities in the UK, including many black and minority ethnic communities, have less access to open green spaces than other groups, and the spaces available tend to be of poorer quality. People who don't have the use of a car may find green and blue spaces more difficult to access, particularly if there are no regular public transport services.
Using routine maintenance and refurbishment of facilities such as toilets in parks, to increase their accessibility, would be an efficient way of ensuring that existing facilities are of a high standard.
Providing and maintaining facilities may cost money, but if they create an environment in which people are more active and their health improves as a result, this will lead to savings for the NHS and local authorities as well as society at large.
## Evidence discussion
The outcomes that matter most
The studies supporting this recommendation used various different outcomes. These included total physical activity, which was measured in different ways (for example, proportion of participants meeting physical activity guidelines, time spent in moderate to vigorous physical activity, and change in 'metabolic equivalents' or METs per unit of time); sedentary behaviour; and use of, or visits to, parks and open spaces. Some studies reported the views on and perceptions of factors such as personal safety and security, antisocial behaviour, ease of getting around, maintenance and appearance of open spaces.
Because the reviews used GRADE to assess the quality of the evidence, the committee considered which outcomes were critical or important. They considered all of the outcomes listed above to be critical.
The committee noted that perceptions of personal safety and security and concerns about antisocial behaviour were often commented on in the studies . These could be a strong deterrent to people who might use or visit an area. The committee recognised the importance of addressing these concerns but noted from their experience that in practice, if the area is attractive and the benefits outweigh the perceived risks, enthusiasm for an intervention may override such concerns.
Expert paper 4 reported on studies of the impact of the quality of open spaces on physical activity levels. It reported on a survey that compared physical activity levels of different black and minority ethnic households with access to similar amounts, but varying quality, of open green space. Respondents were asked to rate: how satisfied they were with the quality of the green space nearest to their home; how attractive and pleasant it was to use; and how safe and secure they felt using the space. It found that satisfaction with green space was significantly associated with physical activity levels.
The committee recognised that there is no national definition of 'quality' or 'high standard' in relation to green space. The committee noted that other studies on the quality of green space have used measures such as the number of parks per urban authority awarded Green Flags and Best Value Performance Indicators (Commission for Architecture and the Built Environment's Urban green nation: building the evidence base).
The quality of the evidence
The certainty in the evidence base supporting this set of recommendations (6 evidence statements summarising evidence from 15 studies) was generally graded 'very low' or 'low', which means NICE has low confidence that the results would not change if more evidence became available.
Three evidence statements summarised evidence from 12 studies on effectiveness of open space interventions . Nine of these studies considered the effects of improvements to existing parks on total physical activity and physical activity in everyday life. They were graded 'very low' but because there were a number of studies that generally showed similar effects, NICE can have a moderate level of confidence in the findings. Two studies graded low or very low, presented evidence about the creation of new parks . One study, graded very low, presented evidence from woodland projects .
For existing parks, 9 studies showed that improvements had mixed effects on total physical activity. However, most showed either an increase or no effect. Of 9 studies, 6 reported an increase; 2 no effect; 1 a decrease in number or proportion of people engaging in moderate or vigorous physical activity. The 3 studies reporting change in MET hours showed an increase. The 2 studies reporting on meeting the recommended amounts of physical activity showed no effect for children or adults . Likewise, although the evidence on the effect of interventions on using or visiting parks was mixed, most found either an increase or no effect. Of the 9 studies, 8 reported on park use. Six of these reported an increase, the other 2 reported either no difference or a decrease .
After creation of new parks, 1 study showed that reports by local survey participants of visiting any park once a week increased. A second study reported that after a new park was constructed on an undeveloped green space, visit frequency and energy expended during visits increased .
After interventions to improve 3 woodland areas by improving facilities, 1 study found that visitor numbers increased, but the proportion of visitors who had blue badges did not change. The proportion of visitors from black and minority ethnic groups also increased .
One study considering the general population suggested that removing seating and picnic tables reduced the amount of time people spent sitting down . But several expert papers suggested that providing appropriate seating is an important way to encourage some groups to use outdoor spaces , particularly those with limited mobility.
The committee considered the equity aspects of removing seating and agreed that it could be a barrier to some groups using open spaces. They also drew on evidence that it is particularly important to help people who are least active to be more physically active, because their health and wellbeing will benefit the most. They therefore made a recommendation that adequate seating be provided to make open spaces accessible, so that increased equality in outcomes might be achieved.
Two evidence statements summarised evidence from 3 studies providing qualitative information on people's views of parks or Home Zone interventions . Of these studies, 1 had high risk of bias, and the remaining 2 had low risk of bias. The study reporting people's views of parks that had undergone improvements had high risk of bias, and reported that antisocial behaviour was still a concern after the interventions . The 2 studies reporting people's views of a Home Zone intervention reported that residents did not consider increased opportunity for physical activity to be important and were more concerned about security of the area. Perceptions of personal physical activity levels did not change, but participants mentioned increased outdoor play by children.
Three evidence statements summarised evidence from 3 studies of multicomponent interventions . Two of these included renovating existing parks, or creating new ones . However, all 3 studies featured multiple changes to the local environment, for example improvements to public transport and to paths and pedestrian crossings and 2 included a behavioural intervention . Because both the nature and findings of these studies were mixed, the committee were unable to draw any clear conclusions from them and did not use them as a basis for their recommendations.
Most evidence from the reviews focused on interventions in parks as opposed to open green spaces more broadly. One UK study focused on woodlands and none considered blue space. The committee therefore sought expert testimony to address these gaps.
References cited in expert testimony reported on associations between the quality of local green space and physical activity levels in deprived urban communities, which included a high proportion of people from black and minority ethnic groups. It also reported on a study of interventions in woodlands and their use for outdoor activity by deprived urban communities.
Expert paper 4 also reported on factors that encourage older people to walk and to use open spaces. The quality of footways to open spaces, and facilities such as seating and toilets were important. Expert papers 2, 6 and 7 highlighted similar issues. Expert papers 5 and 7 highlighted the importance of wayfinding signs in rural areas and Expert papers 4, 6 and 7 noted the importance of these being clear and inclusive.
Expert paper 5 provided a small amount of information about access to blue space, specifically coastal areas. Survey data showed that a third of the population would be more likely to visit the coast if access were improved. The paper noted that some areas of the coast are inaccessible to walkers and work is in progress to improve this with the construction of a coastal footpath around England.
Benefits and harms of creating or improving public open spaces
The committee considered that the benefits of improving public open space considerably outweigh any potential harms. Benefits may include mental as well as physical health, and also potential benefits to the ecosystem. For example, urban green spaces are thought to affect not only physical activity but also mental wellbeing, and to provide opportunities for social interactions. The potential for these interventions to disproportionately benefit people in lower socioeconomic groups is important in terms of reducing health inequalities (World Health Organization's Urban green space interventions and health: A review of impacts and effectiveness).
The reviews identified some cost effectiveness evidence about interventions relevant to these recommendations. One US study with high risk of bias found that, when cost effectiveness was defined as less than $0.50 to $1.00 per MET-hour gained, refurbishing parks was cost effective in a large and busy park but not in a small one. A second study with high risk of bias, using the same definition of cost effectiveness, found that introduction of new, small parks was cost effective if parks were very busy but not if they were quiet.
Economic modelling was also undertaken. Economic analysis of case studies on Active living by Design and greenways found both to be highly cost effective, with ICERs of £1,397 and £7,652 respectively. The analysis of a new greenway extension and Fitter for Walking found both could be cost effective up to a cost of £950 per person for the former, £100 per person for the latter.
A US-based park renovation intervention estimated to cost over £200 per person was not cost effective, with an ICER of £207,316 per QALY gained. The analysis reported that the intervention could be cost effective if the cost of the renovation could be reduced from £200 to £25 per person. The committee were aware that some interventions included both a physical and a social element, and some interventions may have combined these two elements without explicitly reporting it.
Increasing use of local public open spaces – especially green and blue spaces – by enhancing accessibility, quality and maintenance may have additional resource implications associated with providing, for example, clear signage, facilities, shelter and shade, or accessible toilets that are clean, well maintained and unlocked during daylight hours. However, if such approaches lead to the creation of an environment that results in increased physical activity, then that will lead to improved health outcomes in the longer term and potential future cost savings to the healthcare system.
The committee discussed the importance of attracting people of all ages and cultural backgrounds to open green spaces by providing a range of facilities to meet the needs of older people, and areas where children and their families can safely play.
Although there was no evidence on effectiveness from the reviews, they noted from experience that providing points of interest such as nature trails and sculptures, and facilities such as picnic areas, may attract people to use open green spaces.
The committee also noted the importance of identifying where access to green space could be increased. One way of doing this is using the Accessible Natural Greenspace Standard, although the committee recognised its limitations (Natural England's Nature nearby: accessible natural greenspace guidance).
## The evidence
The committee looked at evidence in:
Evidence review 3 on parks, neighbourhood and multicomponent interventions: ES3.1, ES 3.2, ES3.3, ES 3.4, ES3.5, ES 3.8, ES 3.9, ES 3.10, ES 3.11, ES3.12
Expert testimony on disability and the built environment: Expert paper 2
Expert testimony on environmental support for physical activity in older people, urban deprived populations and black and minority ethnic groups: Expert paper 4
Expert testimony on encouraging physical activity in the natural environment: Expert paper 5
Expert testimony on improving the environment for people to walk in: Expert paper 6
Expert testimony on learning from Paths for All: Expert paper 7
Physical activity and the environment: Economic modelling report
# Buildings
The recommendations in the section on buildings are taken from the 2008 guideline and the evidence has not been reviewed for this update. For details of the evidence they were based on please see the evidence for PH8.
# Schools
The recommendations in the section on schools are taken from the 2008 guideline and the evidence has not been reviewed for this update. For details of the evidence they were based on please see the evidence for PH8.
# Issues beyond the scope of this guideline
The committee were aware that, in practice, if behaviour change is to be achieved some environmental interventions to encourage people to be more physically active may also need to be accompanied by social interventions to encourage the use of green, blue and grey spaces.
Some studies included in the reviews reported that they included promotional activities and the committee were mindful that others may have done so but not specifically mentioned them. They were conscious that there is some evidence that environmental interventions alone may support existing physical activity behaviours, but not be sufficient to change behaviours (Sugiyama et al. 2013). Additionally, the same intervention may affect groups differently, changing behaviours in some but not others (Panter and Ogilvie 2017). But they noted for some groups, such as older people, maintaining existing activity levels is important.
The committee noted that an area for future research may be the relative effectiveness of interventions to change the environment alone, and interventions to change the environment that are supported by interventions to change people's behaviour. In the meantime they stressed the importance of these recommendations being implemented together with other NICE guidelines, for example those on physical activity: walking and cycling and behaviour change: individual approaches.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Public transport provision and ticketing
How effective and cost effective are changes to public transport provision and ticketing in creating and sustaining an increase in physical activity at a population level?
## Why this is important
Increased use of public transport increases physical activity at a population level, and use can be increased by interventions to improve provision and facilities. But there is little information on how effective changes to public transport provision or ticketing policies (such as age of eligibility for passes and fare integration) are at sustaining an increase, and whether this is cost effective.
Longitudinal research of public transport and ticketing interventions is needed, using objective measures of physical activity with a follow-up period of at least a year and preferably with a matched control group.
Research is also needed on the effects on physical activity of:
location, such as rural or urban, and how easy it is for people to walk around the local area
individual characteristics, such as mobility, health, age, ethnicity
service characteristics, such as density and coverage, frequency, reliability, journey time
accessibility of public transport, in terms of physical access, information, and affordability
links with other forms of transport (cycling, walking, other modes of public transport)
-verall quality of service and infrastructure.
# Changes to public open spaces
How effective and cost effective are environmental changes to public open spaces (including blue, green and grey spaces) in creating and sustaining an increase in physical activity at a population level?
## Why this is important
There is evidence that open space that is accessible, well maintained, and engaging will be used more often by more people, and so could increase physical activity at a population level. But we found little information on how effective changes to public open spaces are at sustaining an increase, and whether this is cost effective.
Longitudinal research of interventions to increase the use of public open spaces, with a follow-up period of at least a year and preferably with a matched control group, is needed to provide a better understanding of how investment in public open space can best enable increases in physical activity at a population level. Objective measures of physical activity are valuable even if increasing activity is not a focus of the intervention.
Research is also needed on the effects on physical activity of:
accessibility by active travel
availability and quality of public transport to open space
features and activities available
involvement of local community in designing changes
-ngoing 'ownership' by local community
management and maintenance.
# Use of public open spaces by particular groups
How effective and cost effective are environmental changes to increase physical activity through use of public open spaces (including blue, green and grey spaces) by the following groups:
black and minority ethnic groups
groups with low socioeconomic status
groups experiencing other forms of disadvantage, for example carers, people with severe mental health conditions?
Are effects maintained over time?
## Why this is important
Some groups, such as those listed above, use open spaces less than others even when these are publicly available. However, we found very little good quality evidence on environmental interventions that influence physical activity in these groups. We also found no cost effectiveness data for interventions among these population groups.
Longitudinal research is needed of environmental interventions specifically targeting groups who use open spaces less than others, with a follow-up period of at least a year and preferably with a matched control group. This should provide a better understanding of how changes can best promote the use of public open spaces and so increase physical activity in these groups. Objective measures of physical activity are valuable even if increasing activity is not a focus of the intervention.
Research is also needed on the effects of cultural acceptability of environmental interventions to increase physical activity.
# People with limited mobility
How effective and cost effective are environmental changes to increase physical activity among people with limited mobility because of either enduring or life-stage specific factors (for example, small children, parents with prams or buggies, disabled people including those with sensory impairments and learning disabilities, older people, people with dementia and their carers)? Are effects maintained over time?
## Why this is important
People who do little physical activity benefit most from becoming more active, and this may include people with limited mobility. But we found very little evidence on interventions specifically targeting them.
Longitudinal research is needed on environmental interventions specifically targeting those with limited mobility, with a follow-up period of at least a year, and preferably with a matched control group. Objective measures of physical activity are valuable even if increasing activity is not a focus of the intervention.
Research is also needed to determine other factors affecting the observed results. This includes variation in the effectiveness of interventions among people with different needs, for example those with sensory impairments and learning disabilities. Interventions might include:
audio-visual announcements on public transport services and at stops or stations
changes to the design of pedestrian crossings, for example increasing the length of time given for crossing
solutions to allow comfortable use of contested space by various groups, including those with limited mobility.
# Reducing car ownership
Does reducing car use or ownership change physical activity levels? Are effects maintained over time?
## Why this is important
People who use more public transport can build physical activity into their daily lives through walking or cycling between stops and stations. There was some evidence from expert testimony that in London people who own cars are less likely to do half an hour of active travel in a day than those who don't own them. However, this evidence is limited and did not consider factors such as the effects on different groups, and in different areas. For example not all areas have ready access to public transport; and for some groups, such as some older people, having access to a car may provide an opportunity for incidental physical activity at destinations reached by car.
Longitudinal research on interventions to reduce car ownership or use, with a follow-up period of at least a year and a matched control group, is needed to understand how it interacts with physical activity and, in the longer term, health status. An objective measure of physical activity is valuable even if that is not a focus of the intervention.
Research is needed on the effects of:
the location – for example, rural or urban, and how easy it is for people to walk around their local area; and availability of public transport
individual characteristics, such as baseline mobility, health, age, ethnicity.
# Interaction between behavioural and environmental interventions
What is the effectiveness and cost effectiveness of interventions to change the environment alone, compared with interventions to change the environment that are supported by interventions to change people's behaviour?
## Why this is important
Behavioural and environmental interventions are sometimes conducted in isolation. But there is some evidence that environmental interventions alone may support existing physical activity behaviours but may not be enough to change behaviour. Conversely, behavioural interventions implemented without any supporting environmental interventions may not be enough to change behaviours.
Longitudinal research is needed on the relative effectiveness and cost effectiveness of environmental interventions – that include system changes such as congestion charging and street closures – in isolation compared with those supported by behavioural interventions. Research should have a follow-up period of at least a year because there is currently little evidence on whether changes are sustained in the longer term.# Glossary
# Active travel
Getting from place to place by a physically active means, such as walking or cycling, non-motorised scooters or rollerblades. This can be commuting, for example to work or school; a journey to other destinations, for example between home and shops and local amenities; or walking and cycling for leisure.
# Blue spaces
These include the sea, rivers, lakes and canals.
# Built environment
This includes roads (carriageways), pavements (footways), the external areas of buildings and open 'grey' space, such as urban squares and pedestrianised areas.
# Connectivity
The extent to which routes connect with other routes and destinations to allow an unbroken journey.
# Cycling
Using cycles for transport or leisure, including bikes, tricycles, tandems or hand cycles.
# Footpaths
Paths that are separate from a road, over which the public have a right of way on foot only (see section 329(1) of the Highways Act 1980).
# Footways
Paths that runs alongside a road, over which the public have a right of way on foot only (see section 329(1) of the Highways Act 1980). Commonly referred to as pavements.
# Green spaces
These include urban parks, open green areas, woods and forests, coastland and countryside, and paths and routes connecting them.
# Greenways
Some studies examined greenway interventions. These studies were conducted in the USA and, in this context, greenways referred to strips of land that form open-space corridors, usually connecting urban areas. They tended to be reserved for recreational use or environmental conservation.
# Grey spaces
Areas of developed land, including urban squares and pedestrian areas.
# Home Zones
Home Zones aim to improve the quality of life in residential roads by making them places for people, instead of just being thoroughfares for vehicles. The key elements to a Home Zone are: community involvement to encourage a change in user behaviour; and for the road to be designed in such a way as to allow it to be used for a range of activities and to encourage very slow vehicle speeds (usually involving sensitively designed traffic calming. (The quiet lanes and home zones (England) regulations 2006).
# Inactivity
Low levels of physical activity, often quantified as less than 30 minutes of moderate-intensity activity per week.
# Land use mix
The variety of uses for land in an area, and the degree to which these are balanced. This can include residential, commercial, employment, recreational, and open space.
# Metabolic equivalents or METs per unit of time
Metabolic equivalents or METs per unit of time. METs are a measure used to estimate the energy expenditure of physical activity and can be used to categorise activities into different intensities – the higher the MET, the higher the intensity. The committee discussed which measure was most appropriate for considering the change to total physical activity.
# Natural environment
All areas of land that would occur naturally and are not artificial. This includes areas of undeveloped land and water.
# Pavement parking
Parking part, or the whole, of a motorised vehicle on a pavement.
# Physical activity
Physical activity is: Any force exerted by skeletal muscle that results in energy expenditure above resting level (Caspersen et al. 1985). It includes the full range of human movement and can encompass everything from competitive sport and active hobbies to walking, cycling and the general activities involved in daily living (such as housework and gardening).
# Physical activity measurements
Physical activity is measured in terms of:
the time it takes (duration)
how often it occurs (frequency)
its intensity (the rate of energy expenditure – or rate at which calories are burnt).
The intensity of an activity is usually measured either in kcals per kg per minute or in METs (metabolic equivalents – multiples of resting metabolic rate). Depending on the intensity, the activity will be described as moderate intensity or vigorous intensity. Moderate-intensity activities increase the heart and breathing rates but, at the same time, allow someone to have a normal conversation. An example is brisk walking.
# Public transport
Shared modes of transport that can be used by members of the public and are not owned by any individual member. They generally have fixed routes and schedules. This may include buses, coaches, trains, rapid transit systems, trams, and ferries.
# Sedentary behaviour
'Activities that do not increase energy expenditure much above resting levels. There is a difference between sedentary and light physical activities. Activities considered sedentary include sitting, lying down and sleeping because they do not require any muscle recruitment. Associated activities, such as watching TV and reading, are also in the sedentary category. (Department of Health's Start Active, Stay Active).
# Street furniture
Permanent or temporary items located on footways and pedestrianised areas. These may include chairs, hanging baskets and planters.
# Translational research
Applies the findings of scientific research to practice to improve people's health and wellbeing.
# Vending boards
Portable advertising boards placed on footways and in pedestrianised areas.
For other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Strategies, policies and plans to increase physical activity in the local environment\n\nDevelop and use local strategies, policies and plans to encourage and enable people to be more physically active. Use information from sources such as the joint strategic needs assessment and local cycling and walking implementation plans. Follow established best practice to ensure everyone's needs are identified and addressed, including those of people with limited mobility. \n\nUse community engagement approaches to develop and review these local strategies, policies and plans:\n\nTake account of the views and needs of people who walk, cycle, drive or use public transport in the local area, particularly in relation to shared or contested space. (For example, space shared by pedestrians and cyclists, or cyclists and motorists.)\n\nTake account of the views and needs of people with limited mobility who may be adversely affected by the design and maintenance of streets, footways and footpaths and urban and rural public open spaces.\n\nTake account of the views of voluntary and community sector organisations.\n\nAssess whether initiatives successfully adopted elsewhere are appropriate locally and, if they are, how they can be adapted to local needs. For more information, see NICE's guideline on community engagement.\n\nDevelop and put policies into place to ensure people with limited mobility can safely move along and across streets and in public open spaces:\n\nAdopt a consistent approach to permanent or temporary obstructions. This may include vegetation, vending boards, bins, parked cars, scaffolding and street furniture.\n\nEnsure that there are enough pedestrian-controlled crossings, and that they all incorporate accessibility features. Also ensure that signal-controlled crossings give enough time to cross the road safely.\n\nProvide accessible temporary crossings during street and road works (see the Department for Transport's Safety at street works and road works).\n\nUse and maintain tactile paving and dropped kerbs correctly (see the Department for Transport's guidance on the use of tactile paving surfaces).\n\nProvide step-free access or, where this is not possible, clearly signposted accessible alternatives. \n\nEnsure planning permissions always prioritise the need for people (including people with limited mobility) to be physically active as a routine part of their daily life, for example ensuring access on foot to local services such as shops and public transport stops. For more information, see Public Health England's Spatial planning for health report. \n\nEnsure children, young people and their families and carers can be physically active, for example when playing and when travelling to school, college and early years settings. \n\nUse existing health impact assessment tools to assess in advance what impact (both intended and unintended) any proposed changes are likely to have on physical activity levels. For example, will local services be accessible on foot, by bike, and by people with limited mobility? Make the results publicly available and accessible. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on strategies, policies and plans to increase physical activity in the local environment.\n\n# Active travel\n\nIdentify and prioritise local areas where there is a high potential to increase travel on foot, by bicycle, or by other forms of active travel. Base this on demographic data, travel surveys, land use mix and other sources of local information. Take into account views identified through community engagement (see recommendation 1.1.2). \n\nIncrease physical activity associated with using public transport services. This includes encouraging use of these services by:\n\nEnsuring available services are reliable, particularly in rural areas where public transport may be more limited.\n\nMaking information about public transport services accessible to people with visual and hearing impairments, for example provide spoken and visual announcements about destinations and stops on board services, and at stops and stations.\n\nMaking public transport physically accessible to everyone (see the Department for Transport's guidance on inclusive mobility).\n\nImproving public transport to parks and other green and blue spaces. \n\nEnsure new and refurbished footways, footpaths and cycle routes link to existing routes and improve the connectivity of the network as a whole. Aim to make it as easy as possible for people to walk, cycle or use other forms of active travel rather than making short journeys by car. This includes journeys between residential areas and:\n\npublic transport stops and stations\n\nplaces of work\n\npublic open spaces\n\nschools, colleges and early years settings\n\nhealthcare services\n\nshops, and leisure sites. \n\nEnsure footways, footpaths and cycle routes are convenient, safe and appealing to users, and are built and maintained to a high standard. For example, ensure:\n\nthey are even and do not include any hazards, for example from tree roots, pot-holes, broken paving slabs or seasonal and weather-related obstructions\n\nthey have enough lighting to make people feel secure\n\nthey are free from permanent or temporary obstructions, where possible (see recommendation 1.1.3)\n\nthey are not hidden by overgrown or poorly managed vegetation\n\nthey have clear signs to help people find their way.Work in association with relevant third sector organisations and volunteers to plan and carry out this work. For more details, see the Department for Transport's guidance on inclusive mobility and the Traffic signs manual. \n\nEnsure pedestrians, cyclists and users of other modes of transport that involve physical activity are given the highest priority when developing or maintaining streets and roads. (This includes people with limited mobility.) Use 1 or more of the following methods:\n\nRe-allocate road space to support physically active modes of transport (for example, by widening footways and introducing cycle lanes). For more detail on designing these routes, see the recommendations on walking and cycling in NICE's guideline on air pollution: outdoor air quality and health, and the Department for Transport's guidance on Shared use routes for pedestrians and cyclists.\n\nRestrict motor vehicle access (for example, by closing or narrowing roads to reduce capacity).\n\nIntroduce road-user charging schemes. For more detail on charging schemes, see the recommendations on clean air zones in NICE's guideline on air pollution: outdoor air quality and health.\n\nIntroduce traffic-calming schemes to restrict vehicle speeds (using signage and changes to highway design). For more detail on traffic calming, see the recommendations on smooth driving and speed reduction in NICE's guideline on air pollution: outdoor air quality and health, measures to reduce speed in NICE's guideline on unintentional injuries on the road, and the Department for Transport's guidance on Traffic calming. \n\nImprove cycling infrastructure using information from people who walk, cycle, and drive in the local area, including those with limited mobility (see recommendation 1.1.2). Improvements may include:\n\nestablishing cycle lanes, tracks and trails in line with best practice\n\ninstalling secure cycle parking facilities in public places, on public transport and at public transport stops. For more details see NICE's guideline on physical activity: walking and cycling, and other guidance such as Transport for London's London cycling design standards and Highways England's Cycle traffic and the strategic road network.\n\nMake it as easy as possible for people with limited mobility to move around their local area, and work with relevant third sector organisations to achieve this. For example:\n\nEnsure footways:\n\n\n\nhave even, non-reflective, anti-glare surfaces\n\nare free from unauthorised and unnecessary obstructions (whether permanent or temporary) including being free from pavement parking (see recommendation 1.1.3)\n\nare set back from traffic, if possible (for example, by a grass verge).\n\n\n\nEnsure footways that have a kerb clearly define the kerb with a change in level (apart from pedestrian crossings).\n\nEnsure pedestrian crossings have flush kerbs and tactile paving (see the Department for Transport's guidance on the use of tactile paving surfaces).\n\nEnsure signal-controlled crossings have tactile rotating cones and, if appropriate, an audible beep, and give enough time to cross the road safely.\n\nEnsure tactile paving is correctly installed and maintained where it is needed, for example at all crossing places, at the top and bottom of stairs, on the edge of railway platforms and on shared use routes (see the Department for Transport's guidance on tactile paving surfaces).\n\nEnsure seating is provided at regular intervals along footways that are key walking routes (see the Department for Transport's guidance on inclusive mobility). \n\nImprove routes that children, young people and their families and carers use, or could use, for active travel to school, college and early years settings. Focus on improving safety, accessibility, connectivity, sustainability and appeal to users. \n\nConsider improving access routes to school, college and early years settings by:\n\nimproving footways and pedestrian crossings (see recommendations 1.2.4 and 1.2.7)\n\nintroducing measures to reduce vehicle speed (see NICE's guidelines on air pollution: outdoor air quality and health and unintentional injuries on the road). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on active travel.\n\n# Public open spaces\n\nConsider ways to enhance the accessibility, quality and appeal to users of local open spaces, especially green and blue spaces, to increase their use. Focus particularly on communities who may not currently use them, for example those with low mobility, low income communities and some black and minority ethnic communities. Consider, for example, providing:\n\nfacilities that help people of all cultures and backgrounds to feel safe and welcome, for example by providing safe areas in which children can play and picnic facilities\n\nlighting and other measures to prevent or reduce antisocial behaviour, such as maintaining vegetation\n\nclear signs that can be understood by everyone, including people with visual impairments and learning disabilities\n\nseats with arms and backrests, sited at frequent intervals\n\nshelter and shade\n\naccessible toilets that are clean, well maintained and unlocked during daylight hours\n\nfootpaths with even, non-reflective, anti-glare surfaces and tactile paving\n\naccess by public transport, on foot and by bike (including providing cycle parking)\n\ncar parking for blue badge holders and other people with limited mobility. \n\nEnsure open spaces and footpaths are maintained to a high standard. \n\nInvolve community groups and volunteers in decisions on how to design and manage public open spaces, including trails, footpaths and towpaths. Encourage them to help maintain them, for example by reporting any problems affecting use and accessibility (see NICE's guideline on community engagement). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on public open spaces.\n\n# Buildings\n\nEnsure different parts of campus sites (including those in hospitals and universities) are linked by accessible walking and cycling routes. \n\nEnsure new workplaces are linked to walking and cycling networks. Where possible, these links should improve the existing walking and cycling infrastructure by creating new through routes (and not just links to the new facility). \n\nDuring building design or refurbishment, ensure staircases are designed and positioned to encourage people to use them. \n\nEnsure staircases are clearly signposted and are attractive to use. For example, they should be well lit and well decorated. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on buildings.\n\n# Schools\n\nEnsure school playgrounds are designed to encourage varied, physically active play. \n\nPrimary schools should create areas (for instance, by using different colours) to promote individual and group physical activities such as hopscotch and other games. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on schools.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the glossary.\n\n## Campus\n\nTwo or more related buildings set together in the grounds of a defined site.\n\n## Crossings\n\nSignal-controlled crossings: these include puffin, pelican and toucan crossings. They have traffic signals for both vehicles on the carriageway and people crossing it.\n\nPedestrian-controlled crossings: these include both signal-controlled crossings and zebra crossings.\n\nAccessible crossings: these have dropped kerbs that are flush with the carriageway, and tactile paving. Those with signals also have tactile rotating cones and, if appropriate, an audible beep. These characteristics are accessibility features.\n\nAlthough these are the definitions of crossings which are used in this guideline, various other definitions exist with more detailed technical specifications. For these, see Schedule 1 of the Traffic Signs Regulations and General Directions 2016.\n\n## Contested space\n\nA geographical space that is used for different purposes, potentially causing conflict because each type of user has differing priorities.\n\n## Limited mobility\n\nPeople whose mobility is limited, either temporarily or in the long term, because their environment is not adapted to meet their needs. Examples may include:\n\nsome disabled people, including people with sensory impairments or learning disabilities\n\npeople using wheelchairs, cycles or other mobility aids, or those supporting people using these aids\n\nsome older or frail people\n\npeople using buggies, prams or cargo cycles for transporting children\n\npeople with conditions such as chronic pain or neurological conditions\n\nsome people with mental health conditions.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nTraining on the links between transport and health for council staff and elected members.\n\nPartnership working between local government authority departments responsible for public health, transport and planning and other departments that affect people's ability to be active in the built or natural environment.\n\nPublic health knowledge and leadership in local transport departments, and in local authorities' parks and recreation departments.\n\nAccess to examples of good practice on physical activity and the environment.\n\nLocal links to academic centres for translational research.\n\nWhether and how behavioural interventions may be combined with the environmental interventions covered in this guideline (for more information, see NICE's guidelines on physical activity: walking and cycling and behaviour change: individual approaches).\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': "Physical activity can help people to prevent and manage over 20 chronic health conditions (Department of Health: Start active, stay active). The benefits of physical activity vary across ages and include improvements to physical and mental development and functioning. (Department of Health: Start active, stay active: infographics on physical activity).\n\nPhysical inactivity costs the NHS in the UK around £1\xa0billion per year (The King's Fund: Making the case for public health interventions and Scarborough et al. 2011). Including costs to wider society, this rises to around £7.4\xa0billion a year (Public Health England: Everybody active, every day: an evidence based approach to physical activity).\n\nIn 2015, 34% of men over 16 and 42% of women over 16 reported that they did not meet UK guidelines on physical activity, and the number of people meeting the recommended levels decreased with age (NHS Digital: Health Survey for England – 2016). In 2015, only 23% of boys and 20% of girls aged 5 to 15, and in 2012 only 10% of boys and 9% of girls aged 2 to 4 met the UK Chief Medical Officer's guidelines on physical activity for their age group (NHS Digital: Health Survey for England, 2016: children's health; NHS Digital: Health Survey for England 2015: children's physical activity). For children aged 5 to 15, figures exclude physical activity done during school lessons. When this is included, 24% of boys and 18% of girls who had attended school in the past week met the UK Chief Medical Officers' guidelines on physical activity for their age group. For both reports, data was collected from parental report for children aged 2 to 12. For 13 to 15 year olds, data was self-reported.\n\nThe environment can influence people's ability to be active (Foster and Hillsdon 2004). The design and layout of towns and cities can enable and encourage walking and cycling, and using public transport may also mean people build physical activity into their daily lives (Beavis and Moodie 2014).\n\nFor people with limited mobility, the environment can make it particularly difficult to be active. For example, they may not have easy access to public transport, or may find it difficult to cross roads if the crossings are not accessible.\n\nThe government's Sporting Future sets out a strategy for a healthy nation based on 5 outcomes, including physical and mental wellbeing. The government's Cycling and walking investment strategy aims to make cycling and walking the natural choices for shorter journeys, or as part of a longer journey. Objectives for these policies include:\n\nincreasing the proportion of the population meeting the physical activity guidelines\n\ndecreasing the proportion doing less than 30\xa0minutes of physical activity a week\n\nincreasing cycling and walking activity\n\ndecreasing fatalities and serious injuries in cyclists.\n\nSupporting people of all ages and abilities to be more physically active can help local authorities meet their public health responsibilities. Specifically, it will affect indicators identified in the Public Health Outcomes Framework 2016 to 2019 and the NHS Outcomes Framework 2016 to 2017.", "The committee's discussion": "Evidence statement numbers are given in square brackets. See 'The evidence' at the end of each section for details.\n\n# The evidence – overall strengths and limitations\n\nThe committee noted that the evidence as a whole indicated that the proposed environmental changes to open spaces and public transport provision appear to increase physical activity.\n\nOf the 70 studies included in reviews 1, 2 and 3, only 2 (both qualitative) were rated as having no risk of bias [++] and 16 were rated as having low risk of bias [+]. The remaining 52 studies were rated as having high risk of bias [−]. No economic evaluations were included in review 1, 5 were included in review 2 and 2 studies in review 3 included a small amount of economic data.\n\nAll included studies were based on interventions used as natural experiments, in response to pre-planned infrastructure changes. For many interventions, this study design was deemed to be the most feasible and valid approach. However, individual studies had limitations. Many did not use objective measures of physical activity or report whether they were adequately powered. But the small sample sizes of some studies suggest that they would not have had the power to detect changes in physical activity behaviours. For several types of intervention, self-selection bias may have occurred.\n\nMany studies did not use a control group. Control groups can help to minimise bias or confounding that could influence a study outcome. Of studies using a control, around half were thought to be sufficient to reduce confounding. Around half of the remaining studies did not include enough information to determine whether the control group was appropriate, for example how well it was matched to the intervention group or whether contamination occurred. Some used control groups that were unlikely to effectively reduce confounding. Normally this was because the intervention was geographically close to the control area or there was no buffer between them. Many interventions had behavioural elements that may have affected the outcomes reported but could not be separated from environmental aspects.\n\nMany studies:\n\nwere unclear about the length of follow-up periods and when they took place in relation to the intervention and baseline data collection\n\nhad very short follow-up periods\n\nwere at varying stages of completion when follow-up measures were taken.\n\nThe committee recognised that delays to completing infrastructure changes, over which the researchers would have little control, may have reduced follow-up periods. So they may have been too short to detect long-term changes in commuting decisions and physical activity behaviours. The committee also recognised that as follow-up times lengthen, the possibility of other factors influencing outcomes increases.\n\nFinally, some studies report findings for those who are least active. However for those with limited mobility, which is a group distinct from the least active, there was a lack of reporting of the impact of interventions.\n\nThe quality of the evidence was also assessed using the Grading of Recommendations Assessment, Development and Evaluation process (GRADE). The committee noted that the complexity and scale of the interventions makes this an extremely challenging area of research.\n\nIt may not be possible, practical or ethical to undertake a randomised controlled trial for some interventions and natural experiments may be the most valid approach. So a modified version of GRADE was agreed by the committee and used. Outcomes from studies for which the natural experiment study design was the most feasible and valid approach started the GRADE process as 'high quality'. If a randomised controlled trial was feasible and optimal for answering the study aims but a natural experiment design was used, outcomes started the GRADE process as 'low quality'.\n\nStrong recommendations may be made if there is clear evidence of benefit, and if it is cost effective. Evidence may be derived from published literature, from expert testimony (if sought) and from committee experience. Low and very low quality evidence from published literature may still support strong recommendations if there are transparent and strong rationales to do so, and if benefits and harms have been considered. The committee also noted that variations in the methodology used to evaluate the impact of interventions, in different groups, over different time points meant that the committee did not feel comfortable pooling the heterogeneous outcome data.\n\nMany of the studies were not carried out in the UK so the applicability of the findings to the UK needed to be taken into account. However, the committee agreed that most studies were conducted in a broadly similar context so the findings were likely to be transferable.\n\nThe committee agreed that the recommendations in this guideline should be applied to all new changes to the environment, and to existing features when they are being refurbished.\n\n# Cost effectiveness evidence\n\nThere was little published evidence on cost effectiveness, so NICE carried out a new economic analysis. Overall, the analysis showed that interventions could be cost effective if modest numbers of people increased their physical activity. For example, in a town with a population of 100,000 people, an intervention that cost £1,000,000 (the equivalent of £10 per person) would be beneficial if it motivated 1,000 people to cycle for an additional hour per week, or 2,500 people to walk for an extra 30\xa0minutes per week.\n\nIt also assessed 8 case studies of interventions that were effective in increasing physical activity. It found 7 of these interventions to also be highly cost effective. But both the effect and cost of any intervention will depend on factors specific to the local setting, so this may differ from the case studies. The analysis focused on a limited number of health conditions and did not consider non-health benefits, suggesting that the overall benefits are likely to be greater than the estimates given. So the committee concluded that these types of interventions could offer good value for money.\n\nThe committee considered there is not enough evidence to apply a decay rate to the impact of environmental interventions. Because they involve structural changes to the environment, they are likely to remain in place for relatively long periods of time. The committee noted that this differs from the approach taken in previous guidelines on behavioural interventions to increase physical activity. These type of interventions are usually delivered over a finite period and their impact tends to diminish over time. In those guidelines the economic analysis typically used a range of annual decay rate rates from 0% (no decay) to 100% (no intervention effect beyond the first year).\n\nThe committee noted the importance of maintaining open spaces to encourage local communities to use them to be physically active. They highlighted that some environmental interventions may need more regular, ongoing maintenance than others, particularly some interventions in open spaces. For example, if footpaths become overgrown with vegetation or become muddy because of poor drainage, they may become unusable relatively quickly. They agreed that ongoing maintenance should be factored into the costs of implementing such interventions. Provided they are adequately maintained, the committee thought their impact (for example, the use of footpaths and cycle paths) would be maintained and could possibly increase over time.\n\n# Strategies, policies and plans to increase physical activity in the local environment\n\nRecommendations 1.1.1 to 1.1.6\n\n## Rationale and impact\n\nBased on their experience and expertise, the committee agreed that increasing most people's physical activity levels is important. They also agreed that it is particularly important to help people who are the least active to be more physically active, because it will benefit their health and wellbeing the most. A well-designed local environment can help to encourage people to be more active. The committee agreed that local strategies, policies and plans which take account of local needs and follow best practice are an important way of creating such an environment.\n\nSome evidence suggested that initiatives to help people be more active locally are more likely to be effective if local communities and groups are involved from the start. The committee recognised that different groups, for example people who walk, cycle or drive, or people with limited mobility, may have different views and needs. They also agreed that some people may use several modes of transport. For example, many adult cyclists may also drive, but not all drivers will be cyclists. The committee noted that it is important to be aware of the range of views and needs when aiming to increase physically active travel.\n\nExperts suggested that initiatives that work well in one locality may not always work in another. In particular, different approaches may be needed in urban and rural areas. The evidence was uncertain. But the committee recognised the importance of seeking the views of local people and voluntary and community organisations on local needs and priorities. They made a recommendation based on their expertise and NICE's guideline on community engagement: improving health and wellbeing and reducing health inequalities.\n\nThe committee agreed that it is important for people with limited mobility to be able to move around their local area. Some experts suggested that both temporary and permanent obstructions on footways are not only inconvenient but can cause injuries. But some items, such as seating, may be needed to enable some groups to be physically active.\n\nEven if there is a policy in place to address these issues, the way it is interpreted and put into practice may vary both between areas, and over time in the same area. Some experts also suggested that the number of crossings and their accessibility, for example whether they have tactile paving and (on signal-controlled crossings) rotating cones, may not always meet people's needs. Additionally, temporary street and road works may disrupt people's access, as can a lack of step-free routes. These types of obstructions and issues can put people off going out and about. This is particularly true for people with limited mobility, including those with sensory impairments.\n\nBecause several experts highlighted the importance of these issues and because the committee were conscious that everyone should be able to move around in their local environment as easily as possible, they felt there was a strong basis for this recommendation. They also made a recommendation for research to find out more about what type of environmental changes can encourage this group to be more physically active.\n\nThese recommendations are taken from NICE's guideline PH8. Please see the evidence for details and why the recommendations were made. The committee examined new evidence and agreed that all planning permissions should prioritise people doing active travel, whether they are new developments or improvements to existing ones.\n\nA lack of physical activity increases the risk of developing conditions such as type\xa02 diabetes, coronary heart disease, stroke and some types of cancer. People whose mobility is limited may find it particularly difficult to be active and could spend more time being inactive. Strategies, policies and plans that help to create local environments that lead to people becoming more active will benefit everyone but, in particular, those who are least active.\n\nPeople have varying needs and it can be difficult to achieve a balance in meeting them all, particularly where space is shared between different types of user. For example, dropped kerbs that are flush with the carriageway are important for wheelchair users, but if they have no tactile paving they may prove a problem for people with a visual impairment.\n\nViews and needs may vary depending on whether people walk, cycle or drive in the local area. Where there are conflicting needs, the space may become contested. So it is important to involve the community to ensure everyone's needs are considered and to try to resolve any potential conflicts.\n\nDeveloping and implementing strategies, policies and plans and consulting with communities is a core part of local authorities' work. So putting these recommendations into practice is not expected to cost more than is already spent in this area. An environment that encourages people to be more active will help prevent a range of chronic health conditions, leading to savings for the NHS, local authorities and society at large.\n\n## Evidence discussion\n\nThe outcomes that matter most\n\nPhysical activity is a broad concept that includes everyday activities such as housework, gardening and carrying shopping bags, as well as recreational or employment-related activities such as sports, manual work and active travel to work.\n\nThe committee were aware that various outcomes can be used to capture changes in physical activity levels. These include: total physical activity, total sedentary time and physical activity in daily life. These outcomes can be measured in different ways. For example, the proportion of participants meeting physical activity guidelines, the time spent in moderate to vigorous physical activity, or changes to 'metabolic equivalents' or METs per unit of time. However, the recommendations in this section are based on expert testimony rather than evidence from the reviews because little published evidence was identified in relation to these recommendations, meaning that expert testimony provided the best available evidence.\n\nThe committee agreed that when considering the population as a whole, the objective is to increase the amount of moderate to vigorous activity most people do. However, they noted that there is a continuum of benefits from being physically active. For people who are least active, moving from being inactive to having low levels of activity, or replacing sedentary behaviour with physical activity, would bring the greatest health benefits. (Matthews et al. 2015, Department of Health's Start active, stay active: a report on physical activity in the UK and Kyu et al. 2016).\n\nThe quality of the evidence\n\nA key limitation of the evidence from the reviews is that there was a dearth of information on changes to the environment to enable those with limited mobility to be more physically active. However, the committee heard expert testimony from a range of sources that supported these recommendations [Expert papers 2, 4, 6, 7]. Expert testimony is usually considered to be more susceptible to bias than the published evidence. But the committee thought that in this case the expert testimony gave valuable information about barriers or facilitators to physical activity among these groups, and they agreed with it. Likewise, the reviews did not provide any insight into identifying and addressing the needs of different groups, but expert testimony identified the importance of engaging with communities [Expert papers 1, 2, 6 and 9]. This is consistent with existing NICE guidance on community engagement.\n\nBenefits and harms of strategies, policies and plans to increase physical activity\n\nThe whole local population is considered in these recommendations. But to reduce health inequalities there is a particular focus on those who could gain most benefit from increasing their physical activity. This includes people who are currently inactive or have very low levels of physical activity, particularly those for whom environmental factors are barriers to physical activity.\n\nThe committee also recognised that if resources are limited it is best to target areas and groups of people who are likely to benefit most – such as those with limited mobility or low levels of physical activity.\n\nThe committee recognised that people may use different modes of transport at different times, potentially being a 'walker', a 'cyclist', a 'motorist' and a 'public transport user' at various points. They also recognised that the needs or preferences of people who are walking, cycling, using public transport, or driving may not always align. This can result in contested space, where one geographical space is used for different purposes, potentially causing conflict because of the different priorities for each type of user. They agreed that it is important to identify solutions that take account of the views of each of these groups, although solutions should aim to increase physical activity. Details about the road design user hierarchy can be found in the government's Manual for streets and Manual for streets 2.\n\nNo additional economic analysis was carried out for the review question underpinning this recommendation. However, the committee considered each of the case studies included in the economic analysis to be relevant to this recommendation.\n\nOverall the committee considered the use of strategies, plans and policies to increase levels of physical activity good value for money. This is an integral part of most local authorities' work so would not be expected to need significant extra resources. Costs related to the content of these strategies are not expected to be significant, and may be spread over time as they are rolled out.\n\nHowever, if the strategies, plans and policies lead to the creation of an environment that results in increased physical activity, then any additional investment would be expected to result in improved health outcomes in the longer term and potential future cost savings and benefits to the health and social care systems.\n\nThe committee agreed that examples of effective interventions in other parts of the world, such as those proven to increase cycling in parts of northern Europe, should be assessed to determine whether they are likely to be effective locally (Watts et al. 2011).\n\nThe committee were aware that local providers are encouraged to monitor and evaluate the impact of interventions using standard tools if possible.\n\nThe committee recognised that there is an overlap between interventions to create green infrastructure and this guideline. This is because this guideline focuses on green, blue and grey spaces which, in turn, can be conducive to physical activity. Green infrastructure interventions tend to focus on natural and ecological processes, which include urban drainage, climate change mitigation, biodiversity, air quality and other environmental factors. Although this guideline also focuses on open spaces it does so with the specific aim of encouraging physical activity.\n\nTherefore interventions that could be defined as green infrastructure are embedded in this guideline because of their effects on physical activity, but green infrastructure is not discussed further. More information can be found in Natural England's Green infrastructure guidance.\n\n## The evidence\n\nThe committee looked at evidence in:\n\nExpert testimony on active travel in London: Expert paper 1\n\nExpert testimony on disability and the built environment: Expert paper 2\n\nExpert testimony on environmental support for physical activity in older people, urban deprived populations and black and minority ethnic groups: Expert paper 4\n\nExpert testimony on improving the environment to encourage people to walk: Expert paper 6\n\nExpert testimony on learning from Paths for All: Expert paper 7\n\nExpert testimony on transport planning: Expert paper 9\n\nPhysical activity and the environment: Economic modelling report\n\n# Active travel\n\nRecommendations 1.2.1 to 1.2.9\n\n## Rationale and impact\n\nSome evidence suggested that there is more potential to increase active travel – and more benefit to be gained – in some areas than others. For example, interventions to increase active travel in areas where many short car journeys are made may be more effective than in areas where most destinations are much more easily reached by motor vehicle. The committee agreed that it was important to identify and prioritise these areas, along with ways to get more people using active modes of travel. The evidence was limited to expert opinion but the committee agreed that such an assessment was an important step towards a more active population.\n\nSome evidence suggested that if public transport is improved more people may use it, particularly if they live close to the improvements. This may encourage those who are inactive, or who usually drive, to be more active because they will be walking to and from bus stops and stations. The committee agreed with an expert that both spoken and visual announcements on public transport could encourage people who have visual or hearing impairments to use services. They also agreed that public transport should be accessible to everyone, including people with limited mobility.\n\nAn expert told the committee that it should be as easy as possible for people to get to parks and other open spaces from where they live, to encourage them to be active. They noted that some open spaces, particularly green or blue spaces, may not be within walking distance and agreed that public transport to these locations should be available. But they also agreed that more evidence is needed to see whether improvements to the public transport system lead to a sustained increase in physical activity levels and made a recommendation for research.\n\nEvidence suggested that if walking and cycling routes connect residential and commercial areas and other destinations, such as schools, then the number of people using them increases – as do their activity levels. The evidence also suggested that trails and footpaths that do not connect to transport links or a central hub were less likely to encourage people to walk or cycle. Regular points where people can get onto these routes are also important.\n\nExperts confirmed that it was important to make it as easy as possible for people to take a short walk from where they live to parks and other local amenities. The committee agreed that ensuring people can walk or cycle to a range of local destinations is important to encourage them to be physically active.\n\nThey also agreed that the focus should be on networks of routes rather than looking at each route in isolation. Additionally, improvements should be made when existing routes are refurbished, as well as being incorporated when planning new routes.\n\nSeveral experts highlighted the importance of ensuring footways and footpaths are well maintained to avoid falls and to ensure people feel safe when using them. They also highlighted the need for clear signs to help people find their way. Although the evidence was uncertain and focused on the needs of older people or those with limited mobility, the committee agreed that well-maintained footways and footpaths are important for everyone. They also agreed that these issues apply equally to cycle routes and that it was important to work with third sector organisations to ensure the recommendation is implemented.\n\nThis recommendation is from the 2008 guideline. Some new evidence for this update reinforced that introducing congestion charging increased the number of people using public transport and cycling. The committee heard that traffic-calming schemes had mixed effects on physical activity, and they agreed that some methods of traffic calming can affect air quality. However, the committee also agreed that carefully implemented traffic-calming measures and restricted vehicle access were important ways to encourage active travel.\n\nSome evidence suggested that improvements to cycling infrastructure do encourage more people to cycle regularly. If carefully implemented, they should also improve safety for cyclists and pedestrians.\n\nBut the committee were uncertain about how many people would benefit. They agreed that the needs of people who walk and drive in the local area need to be taken into account, as well as those of people who cycle. The views of people who do not cycle because of the current infrastructure and people with limited mobility also need to be taken into account. That is because there may be conflict when space is shared by people using different types of travel. An expert confirmed that it is important to do this when improving the local area for cycling. The committee were aware that there are various best practice guidelines that may be helpful when improving cycling infrastructure.\n\nSome experts suggested that people with limited mobility find it easier to move around their local area if, for example, footways include features such as tactile paving and even surfaces. Non-reflective, anti-glare paving surfaces can make it easier for people with visual impairments to interpret their surroundings. Seating could make it easier for people who need to rest regularly. The committee agreed that sometimes audible beeps at crossings may not be appropriate, for example if several crossings are close to each other audible beeps could cause confusion.\n\nThe committee agreed with experts that these actions should be recommended to encourage everyone, particularly people with limited mobility, to be physically active. But they also agreed that more evidence was needed on the effectiveness and cost effectiveness of environmental changes to increase physical activity among this group and made a recommendation for research.\n\nSome evidence suggested that improving routes for active travel to school could increase the number of children who walk and cycle to school. Evidence about the best ways to do this was mixed [1.2.9]. But the committee agreed that safety improvements near schools, including measures to reduce vehicle speed and more pedestrian crossings, could perhaps help. Some evidence suggested that parents, teachers and bus drivers approve of these safety measures. And other evidence showed that it also helps if routes are connected and accessible.\n\n## Why we need recommendations on this topic\n\nExperts told the committee that using public transport can help people build physical activity into their daily lives. But they also said that in some areas, particularly rural areas, public transport services may not be available or may be unreliable. Experts also said that some groups, especially those with limited mobility or with sensory impairments, may find it difficult to use services, particularly if they do not give spoken and visual announcements.\n\nThe environment can make it difficult for some groups to be active. For example, older people and others with limited mobility may find it difficult to cross the road in the time allowed. In addition, obstructions on footways can make it difficult to walk around an area and may cause injuries, particularly for those with visual impairments. For children, a lack of walking or cycling opportunities and fears of busy roads may stop them being physically active as part of their daily routine.\n\nPutting these recommendations into practice may involve additional costs for local authorities. Some changes – such as providing spoken and visual announcements about destinations and stops on public transport – may be more expensive than others. However, if these changes help to create an environment in which people are more active, it will help to prevent a range of chronic health conditions. This, in turn, will lead to savings for the NHS and local authorities as well as society at large. Also, costs may be spread over time as they are rolled out.\n\n## Evidence discussion\n\nThe outcomes that matter most\n\nRecommendations in this section aim to increase physical activity. Therefore, relevant outcomes include total physical activity, total sedentary time, physical activity in everyday life and active travel.\n\nA wide range of outcomes was used in the studies included in the reviews. In addition to physical activity being measured in several different ways (for example, proportion of participants meeting physical activity guidelines, time spent in moderate to vigorous physical activity, and change to 'metabolic equivalents' or METs per unit of time), time spent on specific activities such as walking and cycling were also used as outcomes. Some studies reported changes in 'mode' share, for example whether people changed from using cars to walking or cycling.\n\nPublic transport use was also reported as an outcome measure. Because using public transport can increase incidental physical activity when walking or cycling to or between stops and stations, the committee agreed it could be considered a proxy measure for physical activity.\n\nEach of the outcomes above were reported both as observed outcomes and as self-reported outcomes in the studies. Because of social desirability bias, recall bias and interpretation issues, the committee considered that observed outcomes were more reliable than self-reported measures.\n\nThe committee discussed which measure was most appropriate for considering the change to total physical activity. They agreed that when considering the population as a whole, the objective is to increase the amount of moderate to vigorous activity most people do. However, they noted that there is a continuum of benefits from being physically active and that for people who are least active, moving from being inactive to having low levels of activity, or replacing sedentary behaviour with physical activity would bring the greatest health benefits. (Matthews et al. 2015, Department of Health's Start active, stay active: a report on physical activity in the UK and Kyu et al. 2016).\n\nThe committee agreed that these small changes in physical activity are best captured by the use of METs. The economic modelling carried out to support this guidance also uses this approach.\n\nBecause the reviews used GRADE to assess the quality of the evidence, the committee identified which outcomes they considered to be critical or important. They considered all measures of physical activity, time spent in physical activity and public transport use to be critical outcomes. They also considered changes in transport mode share to be important.\n\nThe quality of the evidence\n\nThe certainty in the evidence base supporting this set of recommendations (29 evidence statements summarising evidence from 45 studies) was generally graded 'very low' or 'low', which means NICE has low confidence that the results would not change if more evidence became available.\n\nIn general the evidence showed that improvements to public transport may increase its use [ES1.3, ES1.5, ES1.7, ES1.9] particularly for those who live close-by [ES 1.2, ES 1.6, ES1.10]. Five studies suggested that public transport interventions increase participants' total physical activity. However, this increase depended on their existing travelling behaviour – new users of the intervention spent more time being moderately or vigorously active than existing or former users. But there was an exception. A small amount of evidence showed that those living near a new light rail line did not use it any more than anyone else and that it did not have an effect on moderate to vigorous physical activity [ES1.4]. However, this study may have used a control group that was located too close to the intervention and so its effect may have been underestimated.\n\nExpert paper 8 considered public transport services in rural areas and highlighted that buses are considered the most flexible service in meeting the needs of more rural communities. Expert papers 2 and 8 included a focus on the use of spoken announcements on public transport and their importance for people with visual impairments. Although these papers did not provide evidence that directly linked such announcements to physical activity levels, it was clear that a lack of them in some areas is a barrier to people with visual impairments feeling able to use public transport.\n\nExpert paper 3 noted that the incidental physical activity people accrue when using public transport can make a significant contribution to their overall physical activity levels. The committee felt that everyone should have an equal opportunity to increase their physical activity levels in this way and that such barriers should be addressed.\n\nSome evidence suggested that connectivity between areas can help increase physical activity. Two studies examined the effect of introducing greenways between residential and commercial areas. One found an increase in the number of people who walked or cycled and the other an increase in the proportion of people who were being moderately or vigorously active [ES2.12].\n\nAnother study considered the effect of 'Liveable Neighbourhoods', which included interconnected street networks, public transport stops and a range of different destinations within a 15-minute walk. It found that an increased number and diversity of destinations within walking distance was associated with increased active travel [ES3.6].\n\nTwo studies noted the importance of routes connecting to central transport hubs [ES3.8] and another the importance of connecting to feeder routes [ES2.14]. Expert testimony also supported these findings [Expert papers 5, 6 and 7].\n\nSome evidence suggested that congestion charging may increase use of public transport [ES1.1], although public transport services were also improved as part of the change. Some studies reported mixed evidence showing that traffic-calming measures along school routes may increase active travel to school [ES2.17] and that traffic-calming measures in neighbourhood areas may improve perceptions of street safety among older people [ES3.7]. The committee felt that design of traffic-calming measures, and parallel improvements to pedestrian and cycling infrastructure and public transport provision, should be carefully considered to ensure that active travel is not reduced.\n\nThe 2008 guideline included a recommendation on road-user charging schemes. The committee felt it was still relevant. The new evidence identified by this review and through expert testimony [Expert papers 1, 3, 4, 6 and 9] makes an additional contribution to the evidence base for that recommendation.\n\nThe evidence suggested that, in general, improvements to footways may increase walking [ES2.9, Expert papers 4, 6 and 7]. Some evidence showed no change in walking after extension of a greenway [ES2.8], but these studies used a threshold of 30\xa0minutes of walking per day so did not capture smaller changes in activity that may still be valuable.\n\nOne study considering the general population found that introducing wayfinding signs on a trail had no impact on the number of people who used it [ES2.11]. But several expert papers highlighted the importance of clear, inclusive signs in both urban and rural areas [Expert papers 4, 5, 6 and 7], particularly for people with disabilities. The committee considered the equity aspects of this intervention and agreed that poor signage was a potential barrier to physical activity and so made a recommendation in this area, so that increased equality in outcomes might be achieved.\n\nExperts also highlighted that lack of regular seating on streets could be a barrier to physical activity for older adults [Expert paper 4] and disabled people [Expert paper 6].\n\nAnother study found that lack of lighting was a concern for potential pedestrians and cyclists using an unlit footway and cycle path that ran parallel to a guided busway [ES1.10]. Expert paper 4 noted that lighting footways and ensuring they are not obscured by poorly-managed vegetation was important to ensure people feel secure when using them.\n\nEvidence from the reviews suggested that improvements to cycling infrastructure can increase bicycle trips [ES2.10; ES2.13]. This includes the number of people who commute by bicycle [ES2.3] and the number who cycle regularly [ES2.4]. Improvements can also increase the proportion of all journeys that are made by bicycle [ES2.6]. Improvements included off-street cycle routes, motor-vehicle-free bridges and the provision of bicycle racks in public places and on public transport. The committee were aware of tools such as the Propensity to Cycle tool to assess potential for increasing cycling.\n\nThe committee recognised that flexible seating arrangements could be used when adding cycle parking to public transport, to help ensure that enough seating is retained for those who need it.\n\nFour studies found that introducing on-street cycle lanes increased the number of cyclists counted each day. But the absolute numbers remained relatively small, with numbers at the beginning of the study ranging from 9 to 91 and at follow-up from 10 to 257 [ES2.15].\n\nFour studies suggested that Safe Routes to Schools have mixed effects on children walking and cycling to school [ES2.17]. Two studies found active commuting to school increased, but 1 of these studies (which reported on total physical activity) found no overall increase in activity levels. One study found no effect on the proportion of children who cycled to school whereas 2 others found an increase in the proportion walking and cycling [ES2.17]. One qualitative study found that parents, students, school staff and school bus operators approved of the improvements [ES2.18]. Interventions included improving footways and road crossings, speed reduction measures and drop-off zones.\n\nThe committee agreed that recommending drop-off zones may not be appropriate in the UK, because sometimes 'park and stride' or other drop-off methods are considered safer and may ease congestion. Some behavioural interventions were also included, which are beyond the scope of this guideline but it was not possible to separate the effects on outcomes [ES2.17].\n\nExpert paper 6 included improvements to footways and pedestrian crossings used as part of walking routes to school and some behavioural interventions. Improvements led to an increase in walking that was more or less sustained at 1- and 2-year follow-up (22% increase at year 1 and 19% increase at year 2).\n\nThe committee decided not to make a recommendation about extending motorways because only 1 study was identified. This looked at both the beneficial and adverse effects on local residents of extending a motorway that bisected the local area [ES1.8]. The committee also decided that there was insufficient certainty in the evidence to make recommendations on temporary road closures to allow events to promote physical activity (including Ciclovia interventions) [ES2.1, ES2.2].\n\nAs with recommendations in section 1.1, a key limitation for section 1.2 is the lack of evidence specifically considering interventions that allow those with limited mobility to increase their active travel. So the committee sought expert testimony to address these gaps in the evidence. Expert paper 2 focused in particular on the experience of people with visual impairments. Expert papers 4, 6 and 7 all included a focus on older people or people with limited mobility. These 4 expert papers all raised similar barriers or facilitators to mobility for these groups, including footway surfaces, tactile paving and pedestrian crossings.\n\nDespite generally low or very low quality evidence from the reviews, the committee noted that the evidence from reviews was consistent. Supplementary evidence from expert testimony was internally consistent. The committee considered that the available evidence combined with the fact that these recommendations address equity issues was sufficient to make some strong recommendations, so that increased equality in outcomes might be achieved.\n\nBenefits and harms of active travel\n\nThe committee were mindful that some groups may benefit more than others from incidental physical activity accrued through the regular use of public transport. They noted, for example, that people of working age, in employment and living in urban areas may be more likely to benefit than older people or those living in rural areas where transport stops are less available and services may be less frequent.\n\nThe committee were aware that increasing active travel may have some unintended consequences or adverse effects. The previously discussed concept of shared or contested space (see benefits and harms in the section on 'strategies, policies and plans to increase physical activity in the local environment') is also relevant here. The committee recognised that interventions benefiting some have the potential to deter others, if not well implemented. They noted the need for carefully designed interventions, for example cycle routes that minimise the risk of creating contested space.\n\nContested space may create conflict that could affect some groups, such as older people, disproportionately. For roads with possible conflicts, the WHO recommends a safe motor vehicle speed limit of 30\xa0km/h or 20\xa0mph.\n\nA second potential harm is around road traffic collisions. Improving cycle infrastructure may increase the number of cyclists. That, in turn, could result in an increase in the absolute number of cyclists being involved in road traffic collisions. However, the committee did note evidence that dedicated infrastructure for cyclists – in 1 case a tarmacked cycle route with regular junctions – may reduce cyclist collisions in the area around the cycle route [ES2.7].\n\nIn addition, the committee were aware that increasing the amount of active travel people do may increase their exposure to outdoor air pollution. They were aware that the physical activity benefits generally outweigh the risk of increased exposure to air pollution. (Cepeda et al. 2017 and Tainio et al. 2016). They also noted that a shift from motorised transport to walking and cycling could improve levels of air pollution. From a broader public health perspective, tackling outdoor air pollution is an important part of creating healthier environments in which people can be physically active. See NICE's guideline on air pollution: outdoor air quality and health.\n\nThe committee also noted that increased active travel may generally increase the numbers of people on the streets. This could, in turn, strengthen a feeling of security.\n\nSome cost effectiveness evidence about interventions relevant to these recommendations was identified from the reviews. Overall, the evidence showed that interventions could be cost effective if modest numbers of people increased their physical activity.\n\nOne study with high risk of bias, found the Department for Transport's Cycle Demonstration Towns cost effective, with a benefit–cost ratio of between £2.60 and £3.50 for every £1 spent [ES2.5]. Another study, with high risk of bias, found Living Streets' Fitter for Walking programmes cost effective in most locations, with benefit–cost ratios larger than £1. Benefit–cost ratios were higher if initial costs were lower [ES2.16]. One study, with low risk of bias, found the World Health Organization's Safe Routes to School programmes to be cost effective by both creating savings and gaining quality-adjusted life years (QALYs) [ES2.19].\n\nEconomic modelling was also undertaken. Economic analysis of case studies on Active living by Design, Cycle Demonstration Towns, the Paths for All Smarter Choices, Smarter Places and greenways found all 4 to be highly cost effective. The incremental cost effectiveness ratios (ICERs) were £1,397 for Active living by Design, £2,496 for Cycling Demonstration Towns, £4,423 for Paths for All Smarter Choices, Smarter Places and £7,652 for greenways. The analysis of Fitter for Walking found it could be cost effective up to a cost of £100 per person.\n\nThere may be additional resource implications for encouraging use of public transport by ensuring available services are reliable, providing information about public transport services, and ensuring footways, footpaths and off-road cycle routes are well maintained.\n\nThere are also resource implications for measures such as providing spoken and visual announcements about destinations and stops on bus services and at stops and stations. Guide Dogs for the Blind Association's Installing audio-visual equipment on buses – cost and practicality issues highlighted that installing audio-visual technology could cost £2,100 for a single-decker vehicle, or £2,550 for a double-decker. However, the committee noted that such technology need not be installed on all vehicles at once, but could be introduced as vehicles are replaced.\n\nIn addition, lower technology approaches such as spoken announcements by drivers were noted as being easily implementable with relatively small training costs. However, if such approaches create an environment that results in increased physical activity, then that will lead to improved health outcomes in the longer term and potential future cost savings to the healthcare and social care systems.\n\nThe committee did not make recommendations on car ownership or parking restrictions. They heard that, in London, car owners are 2 to 3 times less likely to do half an hour of active travel in a day than those who don't own cars [Expert paper 1]. They recognised the benefits of incidental physical activity accrued through using public transport [Expert paper 3; Beavis and Moodie 2014] and that some studies highlighted other potential benefits, for example drivers perceiving use of public transport as being less stressful than driving. [ES1.10].\n\nAlthough 2 studies highlighted a lack of parking at work as being associated with increased use of public transport or increased active travel [ES 1.9], the committee were conscious that these studies also included other aspects, such as providing a subsidised travel pass and access to a new transit link or providing workplace travel plans, and so did not make recommendations on this intervention.\n\nThe committee were conscious that not all areas have the same level of public transport access as London or other urban areas. They noted that the studies that included parking were done in workplaces and that the findings may not be transferable to other settings. They were also aware that for certain groups, such as some older people, having access to a car and being able to park outside their home was a key factor in determining whether people could get out of the house. This in turn resulted in opportunities to be physically active at destinations reached by car [Expert paper 4].\n\nThe committee noted that although using public transport may help people to build physical activity into their daily lives, it incurs a cost for most people. They noted that certain groups, such as older people and children and young people, have access to free or discounted travel on some public transport services (although the age of eligibility varies). However, fiscal measures such as ticket pricing were beyond the scope of this guidance, so the committee have not made recommendations in this area.\n\nThe committee noted that some guidance on increasing active travel already exists. But this is often restricted to walking and cycling as the most common methods of active travel (for example, the Chartered Institution of Highways and Transportation's guidance on Planning for walking and Planning for cycling).\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 1 on public transport interventions: ES1.1, ES1.2, ES1.3, ES1.4, ES1.5, ES1.6, ES1.7, ES1.8, ES1.9, ES1.10\n\nEvidence review 2 on Ciclovia, trails and safe routes to school interventions: ES2.3; ES2.4; ES2.6, ES2.7; ES 2.8; ES2.9; ES2.10; ES2.11; ES2.12, ES2.13, ES2.14, ES2.15, ES2.16; ES2.17, ES 2.18; ES2.19\n\nEvidence review 3 on parks, neighbourhood and multicomponent interventions: ES3.6, ES3.7, ES3.8\n\nExpert testimony on active travel in London: Expert paper 1\n\nExpert testimony on disability and the built environment: Expert paper 2\n\nExpert testimony on changes in scientific knowledge and transport practice since 2008: Expert paper 3\n\nExpert testimony on environmental support for physical activity in older people, urban deprived populations and black and minority ethnic groups: Expert paper 4\n\nExpert testimony on encouraging physical activity in the natural environment: Expert paper 5\n\nExpert testimony on improving the environment to encourage people to walk: Expert paper 6\n\nExpert testimony on learning from Paths for All: Expert paper 7\n\nExpert testimony on the Strathclyde Partnership for Transport: Expert paper 8\n\nExpert testimony on transport planning: Expert paper 9\n\nPhysical activity and the environment: Economic modelling report\n\n# Public open spaces\n\nRecommendations 1.3.1 to 1.3.3\n\n## Rationale and impact\n\nThe committee heard from an expert that the quality of green space is an important factor in encouraging people to use it, particularly in deprived urban areas. An expert told the committee that clear signs are important so that people know where they can walk, including where public access is allowed.\n\nSome evidence suggested that people, including those with limited mobility, might use outdoor open spaces if the facilities are improved. For example, improving park facilities like toilets and lighting, and better landscape design may encourage people to use parks, and increase the amount of physical activity they do there. Experts told the committee that facilities such as toilets, seating and footpath surfaces are particularly important for encouraging older people and those with limited mobility to use these spaces. Parking for blue badge holders is also important for these groups along with access on foot, by bike and using public transport.\n\nDespite little evidence on specific actions, the committee made suggestions based on their expertise. They also recommended research into how effective such changes are at creating and sustaining physical activity over the long term among the general population.\n\nRecommendation 1.3.2 is from the 2008 guideline. The committee reviewed this in the light of new evidence for this update, and decided it was still relevant. Experts also highlighted how community groups and volunteers can help design and manage public open spaces, footpaths and trails, as well as support the authorities responsible for maintaining them.\n\nGood quality local open green or blue space that is attractive, feels safe and welcoming and is easy to access may encourage a range of different groups and ages to be physically active.\n\nFor most older people walking is by far the most important activity. Getting out of the house at all, even by car or public transport, helps people to do some activity, even if it is a small amount. It may also bring about benefits through improved social connectedness. Pleasant and well-maintained destinations that provide facilities such as accessible toilets and appropriate seating can encourage them to use public open spaces.\n\nSome low income communities in the UK, including many black and minority ethnic communities, have less access to open green spaces than other groups, and the spaces available tend to be of poorer quality. People who don't have the use of a car may find green and blue spaces more difficult to access, particularly if there are no regular public transport services.\n\nUsing routine maintenance and refurbishment of facilities such as toilets in parks, to increase their accessibility, would be an efficient way of ensuring that existing facilities are of a high standard.\n\nProviding and maintaining facilities may cost money, but if they create an environment in which people are more active and their health improves as a result, this will lead to savings for the NHS and local authorities as well as society at large.\n\n## Evidence discussion\n\nThe outcomes that matter most\n\nThe studies supporting this recommendation used various different outcomes. These included total physical activity, which was measured in different ways (for example, proportion of participants meeting physical activity guidelines, time spent in moderate to vigorous physical activity, and change in 'metabolic equivalents' or METs per unit of time); sedentary behaviour; and use of, or visits to, parks and open spaces. Some studies reported the views on and perceptions of factors such as personal safety and security, antisocial behaviour, ease of getting around, maintenance and appearance of open spaces.\n\nBecause the reviews used GRADE to assess the quality of the evidence, the committee considered which outcomes were critical or important. They considered all of the outcomes listed above to be critical.\n\nThe committee noted that perceptions of personal safety and security and concerns about antisocial behaviour were often commented on in the studies [ES3.2; ES3.8]. These could be a strong deterrent to people who might use or visit an area. The committee recognised the importance of addressing these concerns but noted from their experience that in practice, if the area is attractive and the benefits outweigh the perceived risks, enthusiasm for an intervention may override such concerns.\n\nExpert paper 4 reported on studies of the impact of the quality of open spaces on physical activity levels. It reported on a survey that compared physical activity levels of different black and minority ethnic households with access to similar amounts, but varying quality, of open green space. Respondents were asked to rate: how satisfied they were with the quality of the green space nearest to their home; how attractive and pleasant it was to use; and how safe and secure they felt using the space. It found that satisfaction with green space was significantly associated with physical activity levels.\n\nThe committee recognised that there is no national definition of 'quality' or 'high standard' in relation to green space. The committee noted that other studies on the quality of green space have used measures such as the number of parks per urban authority awarded Green Flags and Best Value Performance Indicators (Commission for Architecture and the Built Environment's Urban green nation: building the evidence base).\n\nThe quality of the evidence\n\nThe certainty in the evidence base supporting this set of recommendations (6 evidence statements summarising evidence from 15 studies) was generally graded 'very low' or 'low', which means NICE has low confidence that the results would not change if more evidence became available.\n\nThree evidence statements summarised evidence from 12 studies on effectiveness of open space interventions [ES3.1, ES3.3, ES3.12]. Nine of these studies considered the effects of improvements to existing parks on total physical activity and physical activity in everyday life. They were graded 'very low' [ES3.1] but because there were a number of studies that generally showed similar effects, NICE can have a moderate level of confidence in the findings. Two studies graded low or very low, presented evidence about the creation of new parks [ES 3.3]. One study, graded very low, presented evidence from woodland projects [ES 3.12].\n\nFor existing parks, 9 studies showed that improvements had mixed effects on total physical activity. However, most showed either an increase or no effect. Of 9 studies, 6 reported an increase; 2 no effect; 1 a decrease in number or proportion of people engaging in moderate or vigorous physical activity. The 3 studies reporting change in MET hours showed an increase. The 2 studies reporting on meeting the recommended amounts of physical activity showed no effect for children or adults [ES3.1]. Likewise, although the evidence on the effect of interventions on using or visiting parks was mixed, most found either an increase or no effect. Of the 9 studies, 8 reported on park use. Six of these reported an increase, the other 2 reported either no difference or a decrease [ES 3.1].\n\nAfter creation of new parks, 1 study showed that reports by local survey participants of visiting any park once a week increased. A second study reported that after a new park was constructed on an undeveloped green space, visit frequency and energy expended during visits increased [ES 3.3].\n\nAfter interventions to improve 3 woodland areas by improving facilities, 1 study found that visitor numbers increased, but the proportion of visitors who had blue badges did not change. The proportion of visitors from black and minority ethnic groups also increased [ES 3.12].\n\nOne study considering the general population suggested that removing seating and picnic tables reduced the amount of time people spent sitting down [ES 3.5]. But several expert papers suggested that providing appropriate seating is an important way to encourage some groups to use outdoor spaces [Expert papers 2, 4, 6 and 7], particularly those with limited mobility.\n\nThe committee considered the equity aspects of removing seating and agreed that it could be a barrier to some groups using open spaces. They also drew on evidence that it is particularly important to help people who are least active to be more physically active, because their health and wellbeing will benefit the most. They therefore made a recommendation that adequate seating be provided to make open spaces accessible, so that increased equality in outcomes might be achieved.\n\nTwo evidence statements summarised evidence from 3 studies providing qualitative information on people's views of parks or Home Zone interventions [ES 3.2, ES 3.8]. Of these studies, 1 had high risk of bias, and the remaining 2 had low risk of bias. The study reporting people's views of parks that had undergone improvements had high risk of bias, and reported that antisocial behaviour was still a concern after the interventions [ES3.2]. The 2 studies reporting people's views of a Home Zone intervention reported that residents did not consider increased opportunity for physical activity to be important and were more concerned about security of the area. Perceptions of personal physical activity levels did not change, but participants mentioned increased outdoor play by children.\n\nThree evidence statements summarised evidence from 3 studies of multicomponent interventions [ES 3,9, ES 3.10, E3.11]. Two of these included renovating existing parks, or creating new ones [ES 3.9, ES3.10]. However, all 3 studies featured multiple changes to the local environment, for example improvements to public transport [ES3.11] and to paths and pedestrian crossings [ES 3.9] and 2 included a behavioural intervention [ES 3.9, ES 3.11]. Because both the nature and findings of these studies were mixed, the committee were unable to draw any clear conclusions from them and did not use them as a basis for their recommendations.\n\nMost evidence from the reviews focused on interventions in parks as opposed to open green spaces more broadly. One UK study focused on woodlands and none considered blue space. The committee therefore sought expert testimony to address these gaps.\n\nReferences cited in expert testimony [Expert paper 4] reported on associations between the quality of local green space and physical activity levels in deprived urban communities, which included a high proportion of people from black and minority ethnic groups. It also reported on a study of interventions in woodlands and their use for outdoor activity by deprived urban communities.\n\nExpert paper 4 also reported on factors that encourage older people to walk and to use open spaces. The quality of footways to open spaces, and facilities such as seating and toilets were important. Expert papers 2, 6 and 7 highlighted similar issues. Expert papers 5 and 7 highlighted the importance of wayfinding signs in rural areas and Expert papers 4, 6 and 7 noted the importance of these being clear and inclusive.\n\nExpert paper 5 provided a small amount of information about access to blue space, specifically coastal areas. Survey data showed that a third of the population would be more likely to visit the coast if access were improved. The paper noted that some areas of the coast are inaccessible to walkers and work is in progress to improve this with the construction of a coastal footpath around England.\n\nBenefits and harms of creating or improving public open spaces\n\nThe committee considered that the benefits of improving public open space considerably outweigh any potential harms. Benefits may include mental as well as physical health, and also potential benefits to the ecosystem. For example, urban green spaces are thought to affect not only physical activity but also mental wellbeing, and to provide opportunities for social interactions. The potential for these interventions to disproportionately benefit people in lower socioeconomic groups is important in terms of reducing health inequalities (World Health Organization's Urban green space interventions and health: A review of impacts and effectiveness).\n\nThe reviews identified some cost effectiveness evidence about interventions relevant to these recommendations. One US study with high risk of bias found that, when cost effectiveness was defined as less than $0.50 to $1.00 per MET-hour gained, refurbishing parks was cost effective in a large and busy park but not in a small one. A second study with high risk of bias, using the same definition of cost effectiveness, found that introduction of new, small parks was cost effective if parks were very busy but not if they were quiet.\n\nEconomic modelling was also undertaken. Economic analysis of case studies on Active living by Design and greenways found both to be highly cost effective, with ICERs of £1,397 and £7,652 respectively. The analysis of a new greenway extension and Fitter for Walking found both could be cost effective up to a cost of £950 per person for the former, £100 per person for the latter.\n\nA US-based park renovation intervention estimated to cost over £200 per person was not cost effective, with an ICER of £207,316 per QALY gained. The analysis reported that the intervention could be cost effective if the cost of the renovation could be reduced from £200 to £25 per person. The committee were aware that some interventions included both a physical and a social element, and some interventions may have combined these two elements without explicitly reporting it.\n\nIncreasing use of local public open spaces – especially green and blue spaces – by enhancing accessibility, quality and maintenance may have additional resource implications associated with providing, for example, clear signage, facilities, shelter and shade, or accessible toilets that are clean, well maintained and unlocked during daylight hours. However, if such approaches lead to the creation of an environment that results in increased physical activity, then that will lead to improved health outcomes in the longer term and potential future cost savings to the healthcare system.\n\nThe committee discussed the importance of attracting people of all ages and cultural backgrounds to open green spaces by providing a range of facilities to meet the needs of older people, and areas where children and their families can safely play.\n\nAlthough there was no evidence on effectiveness from the reviews, they noted from experience that providing points of interest such as nature trails and sculptures, and facilities such as picnic areas, may attract people to use open green spaces.\n\nThe committee also noted the importance of identifying where access to green space could be increased. One way of doing this is using the Accessible Natural Greenspace Standard, although the committee recognised its limitations (Natural England's Nature nearby: accessible natural greenspace guidance).\n\n## The evidence\n\nThe committee looked at evidence in:\n\nEvidence review 3 on parks, neighbourhood and multicomponent interventions: ES3.1, ES 3.2, ES3.3, ES 3.4, ES3.5, ES 3.8, ES 3.9, ES 3.10, ES 3.11, ES3.12\n\nExpert testimony on disability and the built environment: Expert paper 2\n\nExpert testimony on environmental support for physical activity in older people, urban deprived populations and black and minority ethnic groups: Expert paper 4\n\nExpert testimony on encouraging physical activity in the natural environment: Expert paper 5\n\nExpert testimony on improving the environment for people to walk in: Expert paper\xa06\n\nExpert testimony on learning from Paths for All: Expert paper 7\n\nPhysical activity and the environment: Economic modelling report\n\n# Buildings\n\nThe recommendations in the section on buildings are taken from the 2008 guideline and the evidence has not been reviewed for this update. For details of the evidence they were based on please see the evidence for PH8.\n\n# Schools\n\nThe recommendations in the section on schools are taken from the 2008 guideline and the evidence has not been reviewed for this update. For details of the evidence they were based on please see the evidence for PH8.\n\n# Issues beyond the scope of this guideline\n\nThe committee were aware that, in practice, if behaviour change is to be achieved some environmental interventions to encourage people to be more physically active may also need to be accompanied by social interventions to encourage the use of green, blue and grey spaces.\n\nSome studies included in the reviews reported that they included promotional activities and the committee were mindful that others may have done so but not specifically mentioned them. They were conscious that there is some evidence that environmental interventions alone may support existing physical activity behaviours, but not be sufficient to change behaviours (Sugiyama et al. 2013). Additionally, the same intervention may affect groups differently, changing behaviours in some but not others (Panter and Ogilvie 2017). But they noted for some groups, such as older people, maintaining existing activity levels is important.\n\nThe committee noted that an area for future research may be the relative effectiveness of interventions to change the environment alone, and interventions to change the environment that are supported by interventions to change people's behaviour. In the meantime they stressed the importance of these recommendations being implemented together with other NICE guidelines, for example those on physical activity: walking and cycling and behaviour change: individual approaches.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Public transport provision and ticketing\n\nHow effective and cost effective are changes to public transport provision and ticketing in creating and sustaining an increase in physical activity at a population level?\n\n## Why this is important\n\nIncreased use of public transport increases physical activity at a population level, and use can be increased by interventions to improve provision and facilities. But there is little information on how effective changes to public transport provision or ticketing policies (such as age of eligibility for passes and fare integration) are at sustaining an increase, and whether this is cost effective.\n\nLongitudinal research of public transport and ticketing interventions is needed, using objective measures of physical activity with a follow-up period of at least a year and preferably with a matched control group.\n\nResearch is also needed on the effects on physical activity of:\n\nlocation, such as rural or urban, and how easy it is for people to walk around the local area\n\nindividual characteristics, such as mobility, health, age, ethnicity\n\nservice characteristics, such as density and coverage, frequency, reliability, journey time\n\naccessibility of public transport, in terms of physical access, information, and affordability\n\nlinks with other forms of transport (cycling, walking, other modes of public transport)\n\noverall quality of service and infrastructure.\n\n# Changes to public open spaces\n\nHow effective and cost effective are environmental changes to public open spaces (including blue, green and grey spaces) in creating and sustaining an increase in physical activity at a population level?\n\n## Why this is important\n\nThere is evidence that open space that is accessible, well maintained, and engaging will be used more often by more people, and so could increase physical activity at a population level. But we found little information on how effective changes to public open spaces are at sustaining an increase, and whether this is cost effective.\n\nLongitudinal research of interventions to increase the use of public open spaces, with a follow-up period of at least a year and preferably with a matched control group, is needed to provide a better understanding of how investment in public open space can best enable increases in physical activity at a population level. Objective measures of physical activity are valuable even if increasing activity is not a focus of the intervention.\n\nResearch is also needed on the effects on physical activity of:\n\naccessibility by active travel\n\navailability and quality of public transport to open space\n\nfeatures and activities available\n\ninvolvement of local community in designing changes\n\nongoing 'ownership' by local community\n\nmanagement and maintenance.\n\n# Use of public open spaces by particular groups\n\nHow effective and cost effective are environmental changes to increase physical activity through use of public open spaces (including blue, green and grey spaces) by the following groups:\n\nblack and minority ethnic groups\n\ngroups with low socioeconomic status\n\ngroups experiencing other forms of disadvantage, for example carers, people with severe mental health conditions?\n\nAre effects maintained over time?\n\n## Why this is important\n\nSome groups, such as those listed above, use open spaces less than others even when these are publicly available. However, we found very little good quality evidence on environmental interventions that influence physical activity in these groups. We also found no cost effectiveness data for interventions among these population groups.\n\nLongitudinal research is needed of environmental interventions specifically targeting groups who use open spaces less than others, with a follow-up period of at least a year and preferably with a matched control group. This should provide a better understanding of how changes can best promote the use of public open spaces and so increase physical activity in these groups. Objective measures of physical activity are valuable even if increasing activity is not a focus of the intervention.\n\nResearch is also needed on the effects of cultural acceptability of environmental interventions to increase physical activity.\n\n# People with limited mobility\n\nHow effective and cost effective are environmental changes to increase physical activity among people with limited mobility because of either enduring or life-stage specific factors (for example, small children, parents with prams or buggies, disabled people including those with sensory impairments and learning disabilities, older people, people with dementia and their carers)? Are effects maintained over time?\n\n## Why this is important\n\nPeople who do little physical activity benefit most from becoming more active, and this may include people with limited mobility. But we found very little evidence on interventions specifically targeting them.\n\nLongitudinal research is needed on environmental interventions specifically targeting those with limited mobility, with a follow-up period of at least a year, and preferably with a matched control group. Objective measures of physical activity are valuable even if increasing activity is not a focus of the intervention.\n\nResearch is also needed to determine other factors affecting the observed results. This includes variation in the effectiveness of interventions among people with different needs, for example those with sensory impairments and learning disabilities. Interventions might include:\n\naudio-visual announcements on public transport services and at stops or stations\n\nchanges to the design of pedestrian crossings, for example increasing the length of time given for crossing\n\nsolutions to allow comfortable use of contested space by various groups, including those with limited mobility.\n\n# Reducing car ownership\n\nDoes reducing car use or ownership change physical activity levels? Are effects maintained over time?\n\n## Why this is important\n\nPeople who use more public transport can build physical activity into their daily lives through walking or cycling between stops and stations. There was some evidence from expert testimony that in London people who own cars are less likely to do half an hour of active travel in a day than those who don't own them. However, this evidence is limited and did not consider factors such as the effects on different groups, and in different areas. For example not all areas have ready access to public transport; and for some groups, such as some older people, having access to a car may provide an opportunity for incidental physical activity at destinations reached by car.\n\nLongitudinal research on interventions to reduce car ownership or use, with a follow-up period of at least a year and a matched control group, is needed to understand how it interacts with physical activity and, in the longer term, health status. An objective measure of physical activity is valuable even if that is not a focus of the intervention.\n\nResearch is needed on the effects of:\n\nthe location – for example, rural or urban, and how easy it is for people to walk around their local area; and availability of public transport\n\nindividual characteristics, such as baseline mobility, health, age, ethnicity.\n\n# Interaction between behavioural and environmental interventions\n\nWhat is the effectiveness and cost effectiveness of interventions to change the environment alone, compared with interventions to change the environment that are supported by interventions to change people's behaviour?\n\n## Why this is important\n\nBehavioural and environmental interventions are sometimes conducted in isolation. But there is some evidence that environmental interventions alone may support existing physical activity behaviours but may not be enough to change behaviour. Conversely, behavioural interventions implemented without any supporting environmental interventions may not be enough to change behaviours.\n\nLongitudinal research is needed on the relative effectiveness and cost effectiveness of environmental interventions – that include system changes such as congestion charging and street closures – in isolation compared with those supported by behavioural interventions. Research should have a follow-up period of at least a year because there is currently little evidence on whether changes are sustained in the longer term.", 'Glossary': "# Active travel\n\nGetting from place to place by a physically active means, such as walking or cycling, non-motorised scooters or rollerblades. This can be commuting, for example to work or school; a journey to other destinations, for example between home and shops and local amenities; or walking and cycling for leisure.\n\n# Blue spaces\n\nThese include the sea, rivers, lakes and canals.\n\n# Built environment\n\nThis includes roads (carriageways), pavements (footways), the external areas of buildings and open 'grey' space, such as urban squares and pedestrianised areas.\n\n# Connectivity\n\nThe extent to which routes connect with other routes and destinations to allow an unbroken journey.\n\n# Cycling\n\nUsing cycles for transport or leisure, including bikes, tricycles, tandems or hand cycles.\n\n# Footpaths\n\nPaths that are separate from a road, over which the public have a right of way on foot only (see section 329(1) of the Highways Act 1980).\n\n# Footways\n\nPaths that runs alongside a road, over which the public have a right of way on foot only (see section 329(1) of the Highways Act 1980). Commonly referred to as pavements.\n\n# Green spaces\n\nThese include urban parks, open green areas, woods and forests, coastland and countryside, and paths and routes connecting them.\n\n# Greenways\n\nSome studies examined greenway interventions. These studies were conducted in the USA and, in this context, greenways referred to strips of land that form open-space corridors, usually connecting urban areas. They tended to be reserved for recreational use or environmental conservation.\n\n# Grey spaces\n\nAreas of developed land, including urban squares and pedestrian areas.\n\n# Home Zones\n\nHome Zones aim to improve the quality of life in residential roads by making them places for people, instead of just being thoroughfares for vehicles. The key elements to a Home Zone are: community involvement to encourage a change in user behaviour; and for the road to be designed in such a way as to allow it to be used for a range of activities and to encourage very slow vehicle speeds (usually involving sensitively designed traffic calming. (The quiet lanes and home zones (England) regulations 2006).\n\n# Inactivity\n\nLow levels of physical activity, often quantified as less than 30\xa0minutes of moderate-intensity activity per week.\n\n# Land use mix\n\nThe variety of uses for land in an area, and the degree to which these are balanced. This can include residential, commercial, employment, recreational, and open space.\n\n# Metabolic equivalents or METs per unit of time\n\nMetabolic equivalents or METs per unit of time. METs are a measure used to estimate the energy expenditure of physical activity and can be used to categorise activities into different intensities – the higher the MET, the higher the intensity. The committee discussed which measure was most appropriate for considering the change to total physical activity.\n\n# Natural environment\n\nAll areas of land that would occur naturally and are not artificial. This includes areas of undeveloped land and water.\n\n# Pavement parking\n\nParking part, or the whole, of a motorised vehicle on a pavement.\n\n# Physical activity\n\nPhysical activity is: Any force exerted by skeletal muscle that results in energy expenditure above resting level (Caspersen et al. 1985). It includes the full range of human movement and can encompass everything from competitive sport and active hobbies to walking, cycling and the general activities involved in daily living (such as housework and gardening).\n\n# Physical activity measurements\n\nPhysical activity is measured in terms of:\n\nthe time it takes (duration)\n\nhow often it occurs (frequency)\n\nits intensity (the rate of energy expenditure – or rate at which calories are burnt).\n\nThe intensity of an activity is usually measured either in kcals per kg per minute or in METs (metabolic equivalents – multiples of resting metabolic rate). Depending on the intensity, the activity will be described as moderate intensity or vigorous intensity. Moderate-intensity activities increase the heart and breathing rates but, at the same time, allow someone to have a normal conversation. An example is brisk walking.\n\n# Public transport\n\nShared modes of transport that can be used by members of the public and are not owned by any individual member. They generally have fixed routes and schedules. This may include buses, coaches, trains, rapid transit systems, trams, and ferries.\n\n# Sedentary behaviour\n\n'Activities that do not increase energy expenditure much above resting levels. There is a difference between sedentary and light physical activities. Activities considered sedentary include sitting, lying down and sleeping because they do not require any muscle recruitment. Associated activities, such as watching TV and reading, are also in the sedentary category. (Department of Health's Start Active, Stay Active).\n\n# Street furniture\n\nPermanent or temporary items located on footways and pedestrianised areas. These may include chairs, hanging baskets and planters.\n\n# Translational research\n\nApplies the findings of scientific research to practice to improve people's health and wellbeing.\n\n# Vending boards\n\nPortable advertising boards placed on footways and in pedestrianised areas.\n\nFor other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster."}
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https://www.nice.org.uk/guidance/ng90
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This guideline covers how to improve the physical environment to encourage and support physical activity. The aim is to increase the general population’s physical activity levels.
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a56fe404f1d6217a7781c0e3a0a3a03352312f67
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nice
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Brodalumab for treating moderate to severe plaque psoriasis
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Brodalumab for treating moderate to severe plaque psoriasis
Evidence-based recommendations on brodalumab (Kyntheum) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Brodalumab is recommended as an option for treating plaque psoriasis in adults, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
the disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet A radiation), or these options are contraindicated or not tolerated and
the company provides the drug with the discount agreed in the patient access scheme.
Stop brodalumab at 12 weeks if the psoriasis has not responded adequately, defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with brodalumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trial results show that brodalumab improves severe psoriasis more than placebo and ustekinumab. When compared indirectly, it appears to be as effective as other anti-interleukin‑17 agents. Cost-effectiveness estimates for brodalumab compared with other biological treatments, and with apremilast and dimethyl fumarate, show that it is generally more cost effective (that is, depending on the comparator, it costs less but is more effective, or costs more but is considerably more effective). Brodalumab can be offered as an option to people with severe psoriasis that has not responded to other systemic non-biological therapies.# Information about brodalumab
Marketing authorisation
Brodalumab (Kyntheum, Leo Pharma) is indicated for the treatment of 'moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.
Dosage in the marketing authorisation
The recommended dose is 210 mg administered by subcutaneous injection at weeks 0, 1 and 2, followed by 210 mg every 2 weeks.
Price
£1,280 per pack of 2 syringes of 210 mg/1.5 ml solution (excluding VAT; British national formulary online ).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of brodalumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Leo Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Experience of people with psoriasis
## Psoriasis affects all aspects of a person's life
The committee understood that psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial). It noted that having treatments which are associated with few or manageable side effects, and which are effective on the face, hands, feet and genitals, is important to people with psoriasis, as is having a choice of treatments.
# Clinical management
## Psoriasis can be treated with topical therapies, phototherapy, systemic non-biological therapies and systemic biological therapies
People with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these treatments do not control the psoriasis, people may have systemic conventional non‑biological therapies third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological therapies (such as adalimumab, etanercept, ixekizumab, infliximab, secukinumab or ustekinumab), apremilast or dimethyl fumarate, which they continue as long as the drugs work. If the disease no longer responds to a biological therapy, people will be offered another biological therapy. This pattern is likely to be repeated over their lifetime. However, 1 clinical expert explained that switching treatments is likely to affect the effectiveness of subsequent drugs and, that in clinical practice, clinicians tend to avoid switching if possible. For people whose disease does not respond to multiple biological agents, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.
# Position of brodalumab in the treatment pathway
## Brodalumab is most likely to be used fourth line, as an alternative to systemic biological therapies, apremilast and dimethyl fumarate
The marketing authorisation for brodalumab is for 'adults who are candidates for systemic therapy'. However, the company positioned brodalumab fourth line, as an alternative to biological therapies, apremilast and dimethyl fumarate. One clinical expert confirmed that this is the stage in therapy at which NHS clinicians would most likely use brodalumab. The committee concluded that it would appraise brodalumab as a fourth-line therapy, which is when other biological therapies, apremilast and dimethyl fumarate are current treatment options.
# Clinical evidence
## The AMAGINE trials provide the key clinical evidence for brodalumab
The main evidence for brodalumab came from the 3 AMAGINE trials (1, 2 and 3). These were randomised double-blind trials that included a total of 4,373 patients with plaque psoriasis. They compared 2 doses of brodalumab (140 mg or 210 mg) with placebo (all trials) and ustekinumab (AMAGINE‑2 and -3 only). The company submission included data only for patients randomised to the licensed 210 mg dose of brodalumab (a total of 2,915 patients had brodalumab 210 mg, ustekinumab or placebo). The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the static Physician Global Assessment (sPGA). They were assessed at the end of the induction period (at 12 weeks) and differed depending on the treatment comparison:
Compared with placebo, the co-primary outcomes were:
a 75% reduction in the PASI score from when treatment started (PASI 75) and
a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the sPGA.
Compared with ustekinumab, the primary outcome was a 100% reduction in the PASI score from when treatment started (PASI 100), that is, complete clearance.Patients in all 3 trials were followed up in open-label extension studies.
## The population in AMAGINE is similar to patients in the NHS who may have brodalumab
The committee considered whether patients in AMAGINE were similar to those in NHS clinical practice with respect to:
Severity of disease: AMAGINE included patients with 'moderate to severe' psoriasis with a PASI score of 12 or more. No minimum Dermatology Life Quality Index (DLQI) score was included. Previous NICE technology appraisals defined 'severe' and 'very severe' psoriasis based on the PASI and DLQI, and the PASI threshold for 'severe' is 10 or more. One clinical expert explained that the AMAGINE population was generally aligned to NICE's technology appraisals definition of 'severe', and he did not expect that treatment response would differ depending on whether the PASI score was 10 or 12 at baseline.
Stability of disease: the committee noted that AMAGINE included people with 'stable' psoriasis for at least 6 months before randomisation. One clinical expert explained that, in trials, stable psoriasis usually means the absence of significant flares needing treatment in hospital. He advised that disease stability would be unlikely to change treatment effect.
Previous treatment: the committee noted that 17% to 35% of patients in AMAGINE did not have any previous systemic therapy or phototherapy, which is inconsistent with the proposed positioning of brodalumab as a fourth-line treatment in the NHS (see section 3.3). One clinical expert explained that international trials may include patients who have not had previous treatment because of different prescribing practices across countries. The company stated that, in the 3 AMAGINE trials, similar PASI 75 response rates were reported in subgroups of patients who had previously had systemic therapy or phototherapy compared with those who had not. The committee noted that these analyses were likely not powered to detect differences between subgroups. It recalled that previous treatment could change the effectiveness of subsequent therapy (see section 3.2).The committee concluded that, although the results from the overall AMAGINE population may have overestimated the clinical effectiveness of brodalumab because some patients in the trials had not had any previous systemic therapy or phototherapy, patients in the trials generally reflected those who would be treated with brodalumab in NHS clinical practice.
## Brodalumab is more clinically effective than placebo and ustekinumab
The committee noted that patients randomised to brodalumab were clinically and statistically significantly more likely to achieve PASI 75 and sPGA 0 or 1 response rates at week 12 compared with placebo and ustekinumab. The committee concluded that brodalumab was more clinically effective than placebo and ustekinumab.
## Brodalumab ranks high in the probability of achieving a PASI 75 response in the company's base case and sensitivity analyses
The company's base-case network meta-analysis indirectly compared brodalumab with adalimumab, apremilast, dimethyl fumarate, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab, using data from 59 trials (28,346 people). The base-case results showed that brodalumab had the second highest probability after ixekizumab of achieving a PASI 75 response. The company also included the results of 5 sensitivity analyses:
Sensitivity analysis 1: this included the licensed doses.
Sensitivity analysis 2: this used results at 16 weeks after starting treatment (rather than 12 weeks as in the base case) from 1 trial, 'CLEAR' (secukinumab compared with ustekinumab).
Sensitivity analysis 3: this excluded trials with fewer than 100 patients.
Sensitivity analysis 4: this excluded trials in which more than 30% of patients had had previous biological therapies.
Sensitivity analysis 5: this excluded trials with a mean baseline PASI score greater than 25.The ERG explained that the results from the sensitivity analyses compared with the base case were similar, but that it preferred the base case because it included more trials. The committee noted that sensitivity analysis 2 had the same number of trials and showed less statistical variation in the baseline risks for the populations across the trials compared with the base case (average between-study standard deviation was 131.9 in sensitivity analysis 2 versus 141.8 in the base case). However, it acknowledged that brodalumab was ranked consistently high in the base case and all the sensitivity analyses.
## The ERG's 'placebo-adjusted' model is the preferred model
The company identified differences in PASI response rates in the placebo groups of 49 trials included in its network meta-analysis. It explored the impact of adjusting for this variation but preferred an unadjusted model for its base case because it provided a better fit to the data; this was based on a marginally lower deviance information criterion. The ERG agreed that placebo PASI response varied markedly, noting that the PASI 50 response rates ranged from 5% to 33% across trials. It explained that the variation resulted from trials that differed in design, eligibility criteria, previous treatment and other characteristics at baseline, which may have influenced the relative efficacy of the intervention to placebo. Because of this, the ERG preferred the analysis that adjusted for the variation in response rates in the placebo groups across trials to the unadjusted analysis. It made minor revisions to the company's placebo-adjusted analysis, which resulted in the same treatment rankings as the company's unadjusted base-case analysis. One clinical expert confirmed that the treatment rankings from the company's and ERG's analyses appeared valid. The committee agreed that there was variation in the placebo response rates, and that adjusting for these differences could reduce unexplained variation between studies and improve the precision of the PASI response rate estimates. The committee preferred the adjusted model for decision-making and concluded that, with adjustment, brodalumab remained ranked among the top few treatments in terms of PASI response rate.
# Company's economic model
## The model has a Markov state transition structure
In its Markov state transition model used to assess the cost effectiveness of brodalumab, the company assumed that treatments improved quality of life but did not extend length of life. The model contained 4 health states: induction, maintenance, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence (see section 3.10). They moved from the induction state to the maintenance state if they had at least a PASI 75 response measured at the end of induction. From there, some patients could stop treatment for any reason and move onto the next treatment in the sequence. Patients who did not have a PASI 75 response moved onto the induction phase of the next treatment in the sequence. Patients moved into the best supportive care state between treatments in a sequence or if their psoriasis did not respond to the last active treatment in a sequence. All patients could move into the death state at any time.
## The company compared 9 treatment sequences in the model
The company's decision problem compared a sequence of treatments including brodalumab with 8 other treatment sequences excluding brodalumab. Each sequence comprised 4 treatments:
The first treatment was either brodalumab, another biological therapy (adalimumab, etanercept, infliximab, ixekizumab, secukinumab or ustekinumab), apremilast or dimethyl fumarate.
The second treatment was ustekinumab, except in the sequence in which ustekinumab was used as the first treatment; in that sequence, adalimumab was used as the second treatment.
The third treatment was secukinumab, except in the sequence in which secukinumab was used as the first treatment; in that sequence, adalimumab was used as the third treatment.
The fourth treatment in all sequences was best supportive care.The company chose these sequences based on expert advice and reported drug use in the British Association of Dermatologists registry. One clinical expert advised that these sequences generally reflected NHS practice and the NICE-accredited guidelines on biological therapy for psoriasis from the British Association of Dermatologists (2017). The committee was aware that additional factors should be considered when comparing treatment sequences rather than individual treatments, such as the optimal ordering of treatments and the impact of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal, and that the sequences chosen by the company broadly reflected NHS clinical practice.
# Assumptions in the economic model
## A general treatment stopping rate is acceptable for decision-making
The company assumed in its model that 18.7% of patients in the maintenance phase stop treatment every year for any reason and move onto the next treatment in the sequence. The clinical experts advised that the treatment stopping rate appeared reasonable. The committee preferred the company to use treatment-specific stopping rates, but understood that there were not enough data. It agreed that the company's assumption about the rate of stopping treatment was acceptable for decision-making.
## The impact of switching treatment on the effectiveness of a drug is uncertain
The company assumed in its model that a given treatment is equally effective regardless of its position in a sequence. One clinical expert explained that this is unlikely to be the case because a treatment given fourth in a sequence would likely be less effective than the same treatment given earlier on. However, he explained that there is currently no evidence to show the extent to which effectiveness of treatments changes when used at different stages in therapy. The company conducted subgroup analyses of patients previously treated and untreated (see section 3.5), but no evidence was presented that showed how treatment effects changed at different positions in a given sequence. The committee concluded that it is clinically plausible that the effectiveness of a drug would change depending on its position in a treatment sequence. However, without robust supporting evidence for this, it accepted the company's assumption of equal treatment effect at any point in a given sequence.
## Mortality rates adjusted for increased risk of death from psoriasis are appropriate
The company modelled the rate at which patients died in the model using age and sex-specific annual mortality rates from the general UK population, adjusted for the increased risk of death in patients with moderate to severe psoriasis relative to matched controls based on the UK GPRD study (hazard ratio 1.42, 95% confidence interval 1.25 to 1.62). The committee was aware that the increased risk was likely related to co-morbid conditions commonly associated with severe plaque psoriasis, and that treating psoriasis in itself would not extend life. The ERG explained that, because the risk of death was the same for all treatments, the mortality assumptions affected how long people lived in the model (that is, whether they lived long enough to have all 4 treatments in the sequence). The committee concluded that the company's approach to modelling mortality reflected the best available evidence.
# Utility values in the economic model
## Utility values adjusted for baseline EQ‑5D are preferable to those adjusted for baseline DLQI
To estimate how much brodalumab improves quality of life, the company used data from a subgroup of patients from AMAGINE‑1 who had a DLQI of greater than 10, stratified by PASI response levels and adjusted for baseline DLQI. It further adjusted the utility values for serious adverse events. The ERG preferred utility values adjusted for baseline EQ‑5D, rather than baseline DLQI, because the regression model adjusting for baseline EQ‑5D provided a better fit of the data. One clinical expert explained that the DLQI lacks sensitivity and tends to underestimate the quality of life of patients with chronic psoriasis. The committee concluded that utility values adjusted for baseline EQ‑5D were more appropriate than those adjusted for baseline DLQI.
# Costs in the economic model
## The ERG's cost estimates are preferable to the company's
The ERG made the following changes to the company's base case:
Brodalumab: the ERG costed 8 doses rather than the company's 7 doses because unit packs of 2 doses cannot be split.
For people whose disease does not respond to treatment and who have another treatment: the ERG applied a cost of £128 per 2‑week cycle in line with previous NICE technology appraisals; the company assumed that this cost is already included in the costs of 'best supportive care'.
Extra monitoring for dimethyl fumarate: the ERG included the cost for 2 additional outpatient visits and associated blood tests, applied as described in dimethyl fumarate's summary of product characteristics.The committee agreed that the ERG's adjustments to costs in the model were appropriate.
# Cost-effectiveness estimate
## Treatment sequences including drugs that are not cost effective may result in misleading cost-effectiveness estimates
The committee was aware that treatment sequences, although more likely to reflect clinical practice, may provide misleading cost-effectiveness estimates of brodalumab. This is because the company chose a limited number of treatment sequences and positions within these sequences. The cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding more expensive and potentially cost-ineffective subsequent treatments and best supportive care. Therefore, moving the position of the treatment within a sequence would affect which therapies patients have afterwards, and hence the cost effectiveness of treatment. Ideally, the committee would have liked to see all plausible sequences modelled in a fully incremental analysis taking into account different treatment positions and sequence lengths. Furthermore, the use of sequences may include treatments that are not cost effective. The committee was aware that, although previous NICE technology appraisals considered biological treatments, apremilast and dimethyl fumarate to be a cost-effective use of NHS resources, variation in model structure and inputs across appraisals may result in differences in cost-effectiveness estimates. The committee noted that the ERG compared individual treatments with best supportive care in its own base case, setting the second and third options in all sequences to best supportive care. The committee concluded that it would consider comparisons of individual treatments with best supportive care in its decision-making to account for potential bias from including non-cost-effective comparators in sequences.
## Brodalumab is cost effective compared with other biological treatments, apremilast and dimethyl fumarate for people with severe psoriasis
The committee considered whether brodalumab would be a cost-effective use of NHS resources for people with severe psoriasis for whom treatment with biological treatments, apremilast or dimethyl fumarate is an option, taking into account the patient access schemes associated with apremilast, ixekizumab and secukinumab. The committee considered the probabilistic results from the company's base case for pairwise comparisons of brodalumab in a sequence with other biological treatments, apremilast and dimethyl fumarate in a sequence. The results showed that the brodalumab sequence either dominated (was more effective and less costly) or had incremental cost-effectiveness ratios that were less than £25,000 per quality-adjusted life year (QALY) gained compared with other biological treatments, apremilast and dimethyl fumarate in a sequence. The committee then considered the results of the ERG's base case that compared individual treatments with best supportive care, given the potential for biased cost-effectiveness estimates in the company's model (see section 3.16). This analysis used the ERG's 'placebo-adjusted' network meta-analysis (see section 3.8), utility values adjusted for baseline EQ‑5D (see section 3.14), and revisions to cost assumptions in the model (see section 3.15), all which were modifications that the committee accepted. The ERG's analyses also showed that brodalumab was cost effective. The similarity between the company's and ERG's results reassured the committee that the model produced robust estimates. The committee concluded that it could recommend brodalumab as an option for treating severe chronic plaque psoriasis that has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet A radiation), or when these options are contraindicated or not tolerated.
## Brodalumab should be stopped if there is an inadequate response at 12 weeks
Previous NICE technology appraisals for treating psoriasis have recommended stopping treatment if there is an inadequate response; an adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that, if there was an inadequate response to brodalumab, the patient should stop treatment. It noted that PASI 75, assessed 12 weeks after starting treatment, was the primary outcome in the trial data used to model the cost effectiveness of brodalumab. The committee therefore concluded that brodalumab should be stopped if there is an inadequate response at 12 weeks, with an adequate response as defined in previous NICE technology appraisals.
# Other factors
## The company did not submit evidence for people with less severe psoriasis limited to the face, hands, feet and genitals
People with psoriasis at sites that particularly impact quality of life, such as the face, hands, feet and genitals, may not meet the PASI threshold used to define 'severe' in NICE technology appraisals, and so would not be eligible for fourth-line treatment (that is, their psoriasis may not cover a large enough part of their body to qualify for treatment). The committee agreed that this in itself was not an equality issue. It was also aware that the company submitted no evidence to enable it to make a separate recommendation for treating patients with psoriasis confined to these specific sites that has been defined as less severe (that is, a PASI lower than 10).
## The PASI and DLQI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.
## Innovation
The committee understood that brodalumab targets the same pathway as, but has a different mechanism of action from, other interleukin‑17 inhibitors; it targets a different part of the pathway. However, the committee concluded that, without evidence on the benefit of targeting a specific part of the pathway, there were no additional gains in health-related quality of life over those already included in the QALY calculations.
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{'Recommendations': 'Brodalumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nthe disease has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet\xa0A radiation), or these options are contraindicated or not tolerated and\n\nthe company provides the drug with the discount agreed in the patient access scheme.\n\nStop brodalumab at 12\xa0weeks if the psoriasis has not responded adequately, defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with brodalumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trial results show that brodalumab improves severe psoriasis more than placebo and ustekinumab. When compared indirectly, it appears to be as effective as other anti-interleukin‑17 agents. Cost-effectiveness estimates for brodalumab compared with other biological treatments, and with apremilast and dimethyl fumarate, show that it is generally more cost effective (that is, depending on the comparator, it costs less but is more effective, or costs more but is considerably more effective). Brodalumab can be offered as an option to people with severe psoriasis that has not responded to other systemic non-biological therapies.', 'Information about brodalumab': "Marketing authorisation\n\nBrodalumab (Kyntheum, Leo Pharma) is indicated for the treatment of 'moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.\n\nDosage in the marketing authorisation\n\nThe recommended dose is 210\xa0mg administered by subcutaneous injection at weeks\xa00, 1\xa0and\xa02, followed by 210\xa0mg every 2\xa0weeks.\n\nPrice\n\n£1,280 per pack of 2\xa0syringes of 210\xa0mg/1.5\xa0ml solution (excluding VAT; British national formulary [BNF] online [accessed January 2018]).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of brodalumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Leo Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Experience of people with psoriasis\n\n## Psoriasis affects all aspects of a person's life\n\nThe committee understood that psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial). It noted that having treatments which are associated with few or manageable side effects, and which are effective on the face, hands, feet and genitals, is important to people with psoriasis, as is having a choice of treatments.\n\n# Clinical management\n\n## Psoriasis can be treated with topical therapies, phototherapy, systemic non-biological therapies and systemic biological therapies\n\nPeople with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these treatments do not control the psoriasis, people may have systemic conventional non‑biological therapies third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological therapies (such as adalimumab, etanercept, ixekizumab, infliximab, secukinumab or ustekinumab), apremilast or dimethyl fumarate, which they continue as long as the drugs work. If the disease no longer responds to a biological therapy, people will be offered another biological therapy. This pattern is likely to be repeated over their lifetime. However, 1\xa0clinical expert explained that switching treatments is likely to affect the effectiveness of subsequent drugs and, that in clinical practice, clinicians tend to avoid switching if possible. For people whose disease does not respond to multiple biological agents, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.\n\n# Position of brodalumab in the treatment pathway\n\n## Brodalumab is most likely to be used fourth line, as an alternative to systemic biological therapies, apremilast and dimethyl fumarate\n\nThe marketing authorisation for brodalumab is for 'adults who are candidates for systemic therapy'. However, the company positioned brodalumab fourth line, as an alternative to biological therapies, apremilast and dimethyl fumarate. One clinical expert confirmed that this is the stage in therapy at which NHS clinicians would most likely use brodalumab. The committee concluded that it would appraise brodalumab as a fourth-line therapy, which is when other biological therapies, apremilast and dimethyl fumarate are current treatment options.\n\n# Clinical evidence\n\n## The AMAGINE trials provide the key clinical evidence for brodalumab\n\nThe main evidence for brodalumab came from the 3\xa0AMAGINE trials (1,\xa02 and\xa03). These were randomised double-blind trials that included a total of 4,373\xa0patients with plaque psoriasis. They compared 2\xa0doses of brodalumab (140\xa0mg [unlicensed] or 210\xa0mg) with placebo (all trials) and ustekinumab (AMAGINE‑2 and -3 only). The company submission included data only for patients randomised to the licensed 210\xa0mg\xa0dose of brodalumab (a total of 2,915 patients had brodalumab 210\xa0mg, ustekinumab or placebo). The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the static Physician Global Assessment (sPGA). They were assessed at the end of the induction period (at 12\xa0weeks) and differed depending on the treatment comparison:\n\nCompared with placebo, the co-primary outcomes were:\n\n\n\na 75% reduction in the PASI score from when treatment started (PASI\xa075) and\n\na rating of 'clear' (score of\xa00) or 'almost clear' (score of\xa01) on the sPGA.\n\n\n\nCompared with ustekinumab, the primary outcome was a 100% reduction in the PASI score from when treatment started (PASI\xa0100), that is, complete clearance.Patients in all 3\xa0trials were followed up in open-label extension studies.\n\n## The population in AMAGINE is similar to patients in the NHS who may have brodalumab\n\nThe committee considered whether patients in AMAGINE were similar to those in NHS clinical practice with respect to:\n\nSeverity of disease: AMAGINE included patients with 'moderate to severe' psoriasis with a PASI score of 12\xa0or more. No minimum Dermatology Life Quality Index (DLQI) score was included. Previous NICE technology appraisals defined 'severe' and 'very severe' psoriasis based on the PASI and DLQI, and the PASI threshold for 'severe' is 10 or more. One clinical expert explained that the AMAGINE population was generally aligned to NICE's technology appraisals definition of 'severe', and he did not expect that treatment response would differ depending on whether the PASI score was 10\xa0or\xa012 at baseline.\n\nStability of disease: the committee noted that AMAGINE included people with 'stable' psoriasis for at least 6\xa0months before randomisation. One clinical expert explained that, in trials, stable psoriasis usually means the absence of significant flares needing treatment in hospital. He advised that disease stability would be unlikely to change treatment effect.\n\nPrevious treatment: the committee noted that 17% to 35% of patients in AMAGINE did not have any previous systemic therapy or phototherapy, which is inconsistent with the proposed positioning of brodalumab as a fourth-line treatment in the NHS (see section 3.3). One clinical expert explained that international trials may include patients who have not had previous treatment because of different prescribing practices across countries. The company stated that, in the 3\xa0AMAGINE trials, similar PASI\xa075 response rates were reported in subgroups of patients who had previously had systemic therapy or phototherapy compared with those who had not. The committee noted that these analyses were likely not powered to detect differences between subgroups. It recalled that previous treatment could change the effectiveness of subsequent therapy (see section\xa03.2).The committee concluded that, although the results from the overall AMAGINE population may have overestimated the clinical effectiveness of brodalumab because some patients in the trials had not had any previous systemic therapy or phototherapy, patients in the trials generally reflected those who would be treated with brodalumab in NHS clinical practice.\n\n## Brodalumab is more clinically effective than placebo and ustekinumab\n\nThe committee noted that patients randomised to brodalumab were clinically and statistically significantly more likely to achieve PASI\xa075 and sPGA\xa00 or 1\xa0response rates at week\xa012 compared with placebo and ustekinumab. The committee concluded that brodalumab was more clinically effective than placebo and ustekinumab.\n\n## Brodalumab ranks high in the probability of achieving a PASI\xa075 response in the company's base case and sensitivity analyses\n\nThe company's base-case network meta-analysis indirectly compared brodalumab with adalimumab, apremilast, dimethyl fumarate, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab, using data from 59\xa0trials (28,346\xa0people). The base-case results showed that brodalumab had the second highest probability after ixekizumab of achieving a PASI\xa075 response. The company also included the results of 5\xa0sensitivity analyses:\n\nSensitivity analysis\xa01: this included the licensed doses.\n\nSensitivity analysis\xa02: this used results at 16\xa0weeks after starting treatment (rather than 12\xa0weeks as in the base case) from 1\xa0trial, 'CLEAR' (secukinumab compared with ustekinumab).\n\nSensitivity analysis\xa03: this excluded trials with fewer than 100\xa0patients.\n\nSensitivity analysis\xa04: this excluded trials in which more than 30% of patients had had previous biological therapies.\n\nSensitivity analysis\xa05: this excluded trials with a mean baseline PASI score greater than\xa025.The ERG explained that the results from the sensitivity analyses compared with the base case were similar, but that it preferred the base case because it included more trials. The committee noted that sensitivity analysis\xa02 had the same number of trials and showed less statistical variation in the baseline risks for the populations across the trials compared with the base case (average between-study standard deviation was\xa0131.9 in sensitivity analysis 2 versus 141.8 in the base case). However, it acknowledged that brodalumab was ranked consistently high in the base case and all the sensitivity analyses.\n\n## The ERG's 'placebo-adjusted' model is the preferred model\n\nThe company identified differences in PASI response rates in the placebo groups of 49\xa0trials included in its network meta-analysis. It explored the impact of adjusting for this variation but preferred an unadjusted model for its base case because it provided a better fit to the data; this was based on a marginally lower deviance information criterion. The ERG agreed that placebo PASI response varied markedly, noting that the PASI\xa050 response rates ranged from 5% to 33% across trials. It explained that the variation resulted from trials that differed in design, eligibility criteria, previous treatment and other characteristics at baseline, which may have influenced the relative efficacy of the intervention to placebo. Because of this, the ERG preferred the analysis that adjusted for the variation in response rates in the placebo groups across trials to the unadjusted analysis. It made minor revisions to the company's placebo-adjusted analysis, which resulted in the same treatment rankings as the company's unadjusted base-case analysis. One clinical expert confirmed that the treatment rankings from the company's and ERG's analyses appeared valid. The committee agreed that there was variation in the placebo response rates, and that adjusting for these differences could reduce unexplained variation between studies and improve the precision of the PASI response rate estimates. The committee preferred the adjusted model for decision-making and concluded that, with adjustment, brodalumab remained ranked among the top few treatments in terms of PASI response rate.\n\n# Company's economic model\n\n## The model has a Markov state transition structure\n\nIn its Markov state transition model used to assess the cost effectiveness of brodalumab, the company assumed that treatments improved quality of life but did not extend length of life. The model contained 4\xa0health states: induction, maintenance, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence (see section 3.10). They moved from the induction state to the maintenance state if they had at least a PASI\xa075 response measured at the end of induction. From there, some patients could stop treatment for any reason and move onto the next treatment in the sequence. Patients who did not have a PASI\xa075 response moved onto the induction phase of the next treatment in the sequence. Patients moved into the best supportive care state between treatments in a sequence or if their psoriasis did not respond to the last active treatment in a sequence. All patients could move into the death state at any time.\n\n## The company compared 9\xa0treatment sequences in the model\n\nThe company's decision problem compared a sequence of treatments including brodalumab with 8\xa0other treatment sequences excluding brodalumab. Each sequence comprised 4\xa0treatments:\n\nThe first treatment was either brodalumab, another biological therapy (adalimumab, etanercept, infliximab, ixekizumab, secukinumab or ustekinumab), apremilast or dimethyl fumarate.\n\nThe second treatment was ustekinumab, except in the sequence in which ustekinumab was used as the first treatment; in that sequence, adalimumab was used as the second treatment.\n\nThe third treatment was secukinumab, except in the sequence in which secukinumab was used as the first treatment; in that sequence, adalimumab was used as the third treatment.\n\nThe fourth treatment in all sequences was best supportive care.The company chose these sequences based on expert advice and reported drug use in the British Association of Dermatologists registry. One clinical expert advised that these sequences generally reflected NHS practice and the NICE-accredited guidelines on biological therapy for psoriasis from the British Association of Dermatologists (2017). The committee was aware that additional factors should be considered when comparing treatment sequences rather than individual treatments, such as the optimal ordering of treatments and the impact of including treatments that may not be cost effective. The committee agreed that, in principle, it was appropriate to compare treatment sequences in this appraisal, and that the sequences chosen by the company broadly reflected NHS clinical practice.\n\n# Assumptions in the economic model\n\n## A general treatment stopping rate is acceptable for decision-making\n\nThe company assumed in its model that 18.7% of patients in the maintenance phase stop treatment every year for any reason and move onto the next treatment in the sequence. The clinical experts advised that the treatment stopping rate appeared reasonable. The committee preferred the company to use treatment-specific stopping rates, but understood that there were not enough data. It agreed that the company's assumption about the rate of stopping treatment was acceptable for decision-making.\n\n## The impact of switching treatment on the effectiveness of a drug is uncertain\n\nThe company assumed in its model that a given treatment is equally effective regardless of its position in a sequence. One clinical expert explained that this is unlikely to be the case because a treatment given fourth in a sequence would likely be less effective than the same treatment given earlier on. However, he explained that there is currently no evidence to show the extent to which effectiveness of treatments changes when used at different stages in therapy. The company conducted subgroup analyses of patients previously treated and untreated (see section\xa03.5), but no evidence was presented that showed how treatment effects changed at different positions in a given sequence. The committee concluded that it is clinically plausible that the effectiveness of a drug would change depending on its position in a treatment sequence. However, without robust supporting evidence for this, it accepted the company's assumption of equal treatment effect at any point in a given sequence.\n\n## Mortality rates adjusted for increased risk of death from psoriasis are appropriate\n\nThe company modelled the rate at which patients died in the model using age and sex-specific annual mortality rates from the general UK population, adjusted for the increased risk of death in patients with moderate to severe psoriasis relative to matched controls based on the UK GPRD study (hazard ratio 1.42, 95% confidence interval 1.25 to 1.62). The committee was aware that the increased risk was likely related to co-morbid conditions commonly associated with severe plaque psoriasis, and that treating psoriasis in itself would not extend life. The ERG explained that, because the risk of death was the same for all treatments, the mortality assumptions affected how long people lived in the model (that is, whether they lived long enough to have all 4\xa0treatments in the sequence). The committee concluded that the company's approach to modelling mortality reflected the best available evidence.\n\n# Utility values in the economic model\n\n## Utility values adjusted for baseline EQ‑5D are preferable to those adjusted for baseline DLQI\n\nTo estimate how much brodalumab improves quality of life, the company used data from a subgroup of patients from AMAGINE‑1 who had a DLQI of greater than\xa010, stratified by PASI response levels and adjusted for baseline DLQI. It further adjusted the utility values for serious adverse events. The ERG preferred utility values adjusted for baseline EQ‑5D, rather than baseline DLQI, because the regression model adjusting for baseline EQ‑5D provided a better fit of the data. One clinical expert explained that the DLQI lacks sensitivity and tends to underestimate the quality of life of patients with chronic psoriasis. The committee concluded that utility values adjusted for baseline EQ‑5D were more appropriate than those adjusted for baseline DLQI.\n\n# Costs in the economic model\n\n## The ERG's cost estimates are preferable to the company's\n\nThe ERG made the following changes to the company's base case:\n\nBrodalumab: the ERG costed 8\xa0doses rather than the company's 7\xa0doses because unit packs of 2\xa0doses cannot be split.\n\nFor people whose disease does not respond to treatment and who have another treatment: the ERG applied a cost of £128 per 2‑week cycle in line with previous NICE technology appraisals; the company assumed that this cost is already included in the costs of 'best supportive care'.\n\nExtra monitoring for dimethyl fumarate: the ERG included the cost for 2\xa0additional outpatient visits and associated blood tests, applied as described in dimethyl fumarate's summary of product characteristics.The committee agreed that the ERG's adjustments to costs in the model were appropriate.\n\n# Cost-effectiveness estimate\n\n## Treatment sequences including drugs that are not cost effective may result in misleading cost-effectiveness estimates\n\nThe committee was aware that treatment sequences, although more likely to reflect clinical practice, may provide misleading cost-effectiveness estimates of brodalumab. This is because the company chose a limited number of treatment sequences and positions within these sequences. The cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding more expensive and potentially cost-ineffective subsequent treatments and best supportive care. Therefore, moving the position of the treatment within a sequence would affect which therapies patients have afterwards, and hence the cost effectiveness of treatment. Ideally, the committee would have liked to see all plausible sequences modelled in a fully incremental analysis taking into account different treatment positions and sequence lengths. Furthermore, the use of sequences may include treatments that are not cost effective. The committee was aware that, although previous NICE technology appraisals considered biological treatments, apremilast and dimethyl fumarate to be a cost-effective use of NHS resources, variation in model structure and inputs across appraisals may result in differences in cost-effectiveness estimates. The committee noted that the ERG compared individual treatments with best supportive care in its own base case, setting the second and third options in all sequences to best supportive care. The committee concluded that it would consider comparisons of individual treatments with best supportive care in its decision-making to account for potential bias from including non-cost-effective comparators in sequences.\n\n## Brodalumab is cost effective compared with other biological treatments, apremilast and dimethyl fumarate for people with severe psoriasis\n\nThe committee considered whether brodalumab would be a cost-effective use of NHS resources for people with severe psoriasis for whom treatment with biological treatments, apremilast or dimethyl fumarate is an option, taking into account the patient access schemes associated with apremilast, ixekizumab and secukinumab. The committee considered the probabilistic results from the company's base case for pairwise comparisons of brodalumab in a sequence with other biological treatments, apremilast and dimethyl fumarate in a sequence. The results showed that the brodalumab sequence either dominated (was more effective and less costly) or had incremental cost-effectiveness ratios that were less than £25,000 per quality-adjusted life year (QALY) gained compared with other biological treatments, apremilast and dimethyl fumarate in a sequence. The committee then considered the results of the ERG's base case that compared individual treatments with best supportive care, given the potential for biased cost-effectiveness estimates in the company's model (see section\xa03.16). This analysis used the ERG's 'placebo-adjusted' network meta-analysis (see section\xa03.8), utility values adjusted for baseline EQ‑5D (see section\xa03.14), and revisions to cost assumptions in the model (see section\xa03.15), all which were modifications that the committee accepted. The ERG's analyses also showed that brodalumab was cost effective. The similarity between the company's and ERG's results reassured the committee that the model produced robust estimates. The committee concluded that it could recommend brodalumab as an option for treating severe chronic plaque psoriasis that has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet\xa0A radiation), or when these options are contraindicated or not tolerated.\n\n## Brodalumab should be stopped if there is an inadequate response at 12\xa0weeks\n\nPrevious NICE technology appraisals for treating psoriasis have recommended stopping treatment if there is an inadequate response; an adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that, if there was an inadequate response to brodalumab, the patient should stop treatment. It noted that PASI\xa075, assessed 12\xa0weeks after starting treatment, was the primary outcome in the trial data used to model the cost effectiveness of brodalumab. The committee therefore concluded that brodalumab should be stopped if there is an inadequate response at 12\xa0weeks, with an adequate response as defined in previous NICE technology appraisals.\n\n# Other factors\n\n## The company did not submit evidence for people with less severe psoriasis limited to the face, hands, feet and genitals\n\nPeople with psoriasis at sites that particularly impact quality of life, such as the face, hands, feet and genitals, may not meet the PASI threshold used to define 'severe' in NICE technology appraisals, and so would not be eligible for fourth-line treatment (that is, their psoriasis may not cover a large enough part of their body to qualify for treatment). The committee agreed that this in itself was not an equality issue. It was also aware that the company submitted no evidence to enable it to make a separate recommendation for treating patients with psoriasis confined to these specific sites that has been defined as less severe (that is, a PASI lower than\xa010).\n\n## The PASI and DLQI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people, and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\n## Innovation\n\nThe committee understood that brodalumab targets the same pathway as, but has a different mechanism of action from, other interleukin‑17 inhibitors; it targets a different part of the pathway. However, the committee concluded that, without evidence on the benefit of targeting a specific part of the pathway, there were no additional gains in health-related quality of life over those already included in the QALY calculations."}
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https://www.nice.org.uk/guidance/ta511
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Evidence-based recommendations on brodalumab (Kyntheum) for treating moderate to severe plaque psoriasis in adults.
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c6c9e0f45abbc25ea2c3555cdcc232f98042fdb2
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nice
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Tivozanib for treating advanced renal cell carcinoma
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Tivozanib for treating advanced renal cell carcinoma
Evidence-based recommendations on tivozanib (Fotivda) for treating advanced renal cell carcinoma in adults.
# Recommendations
Tivozanib is recommended as an option for treating advanced renal cell carcinoma in adults, only if:
they have had no previous treatment and
the company provides tivozanib with the discount agreed in the patient access scheme.
This recommendation is not intended to affect treatment with tivozanib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made this recommendation
Current treatment in the NHS for untreated advanced renal cell carcinoma is usually sunitinib or pazopanib. There is no evidence to suggest that tivozanib is more effective than pazopanib and sunitinib in extending overall and progression-free survival. At best, tivozanib may have a similar effect to sunitinib or pazopanib. Also, the evidence does not clearly show that people tolerate the adverse effects of tivozanib better than those of sunitinib or pazopanib.
The cost of treating renal cell carcinoma with tivozanib is likely to be lower than the cost of treating it with sunitinib or pazopanib, but tivozanib is also likely to be less effective. The estimated cost savings are high enough to compensate for the estimated lower effectiveness. Also, there is a need to be able to offer tivozanib to people who do not tolerate existing treatments. Therefore, tivozanib is recommended as an option for treating advanced renal cell carcinoma in adults who have had no previous treatment.# Information about tivozanib
Marketing authorisation
Tivozanib (Fotivda, EUSA Pharma) is indicated for 'the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naive following disease progression after one prior treatment with cytokine therapy for advanced RCC'.
Dosage in the marketing authorisation
,340 micrograms taken orally once daily for 21 days, followed by a 7‑day rest period to make up 1 complete treatment cycle of 4 weeks. The treatment schedule should be continued until disease progression or unacceptable toxicity.
Price
A 21‑pack of 1,340 microgram hard capsules (that is, the pack size needed for 1 treatment cycle) costs £2,052 excluding VAT.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of tivozanib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by EUSA Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# New treatment option
## People with renal cell carcinoma would welcome a new treatment option
The patient and clinical experts explained that the adverse effects of current treatments for advanced renal cell carcinoma, such as extreme fatigue, hand and foot syndrome, and chronic diarrhoea, can significantly affect quality of life. So, some people would benefit from being able to switch to a different treatment, which they may tolerate better. The committee concluded that people with advanced renal cell carcinoma would welcome a new treatment option.
# Clinical management
## Tivozanib would be used only in untreated disease in the NHS
Tivozanib has a marketing authorisation for treating advanced renal cell carcinoma in adults who have had no previous treatment, or who have had 1 previous treatment with a cytokine (see section 2). The committee noted that the company had not submitted evidence for people who had been treated with cytokines. It heard from the clinical experts that cytokines are rarely used in the NHS for untreated renal cell carcinoma. The committee agreed that tivozanib would be used in the NHS only for people who have had no previous treatment.
## Sunitinib or pazopanib are the current treatments for untreated advanced renal cell carcinoma
The clinical experts confirmed that most people in the NHS with newly diagnosed untreated advanced renal cell carcinoma would be offered 1 of 2 tyrosine kinase inhibitors (TKIs), pazopanib or sunitinib, as recommended in NICE's technology appraisal guidance on pazopanib for the first-line treatment of advanced renal cell carcinoma and sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. Other treatments such as bevacizumab, sorafenib and temsirolimus have a marketing authorisation for previously untreated advanced renal cell carcinoma, but they are not recommended by NICE (see NICE's technology appraisal guidance on bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma) and are not used in the NHS. The committee concluded that pazopanib and sunitinib were the relevant comparators in this appraisal.
# Clinical evidence
## The comparator and location of the pivotal trial, TIVO‑1, has limited how generalisable the results are to clinical practice in England
The main clinical evidence for tivozanib came from TIVO‑1, an open-label randomised controlled trial that primarily investigated whether tivozanib (n=260) prolongs time to disease progression compared with sorafenib (n=257). At disease progression, patients in the sorafenib group could switch (cross over) to treatment with tivozanib. Patients in the tivozanib group could also have subsequent treatment if their disease progressed. The committee considered whether this trial was relevant to clinical practice in England:
Comparator: the comparator in TIVO‑1 was sorafenib, which is not used in the NHS and was not considered a comparator in this appraisal (see section 3.3).
Outcome: the primary outcome was progression-free survival, but the trial also measured overall survival and health-related quality of life.
Baseline characteristics: the clinical experts generally considered the baseline characteristics of patients in the trial to be similar to those of people who would be offered tivozanib in the NHS:
Most patients in the trial (88%) were enrolled in Central or Eastern Europe. The committee was concerned that these patients may have poorer access to second-, third- and fourth-line life-extending therapies. This would mean that the survival times in TIVO‑1 might be shorter than those in England.
Patients in the sorafenib group had a better average performance status than those in the tivozanib group. In the sorafenib group, 54% had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (meaning that they did not have any symptoms and were able to carry out usual activities unrestricted) compared with 45% in the tivozanib group. This means that the results may underestimate the effectiveness of tivozanib.The committee concluded that the comparator and location of TIVO‑1 limited the generalisability of the results.
## The most relevant subgroup is patients who have not had previous treatment
In TIVO‑1, 70% of patients had not had previous treatment and 30% had already had 1 systemic treatment. Because tivozanib would be used only for untreated disease in NHS clinical practice (see section 3.2), the committee considered that patients in the trial who had not been treated represented the most relevant population in this appraisal. It was concerned that focusing on a subgroup of patients in TIVO‑1 reduced the size of the population (n=362), and the statistical power of the study to detect differences between treatment groups. However, the committee concluded that, despite this, the group of patients not previously treated provided the most relevant evidence.
# Progression-free survival
## Tivozanib increases progression-free survival compared with sorafenib
The primary outcome in TIVO‑1 was progression-free survival (assessed by reviewers blinded to patients' treatments). Tivozanib increased median progression-free survival compared with sorafenib among patients who had not had previous treatment from 9.1 months to 12.7 months (hazard ratio 0.76, 95% confidence interval 0.58 to 0.99). The company used a Cox proportional hazards model to estimate the hazard ratio for progression-free survival. However, both the company and the ERG acknowledged that the proportional hazard assumptions underlying the Cox proportional hazards model may not hold. To address this, the company used a fractional polynomial method for the network meta-analysis (used to compare tivozanib with sunitinib and pazopanib, see section 3.8) and for cost-effectiveness modelling (see section 3.13).
# Overall survival
## Results for overall survival were confounded by treatment switching in TIVO‑1
Among the previously untreated population in TIVO‑1, patients randomised to tivozanib did not live as long as those randomised to sorafenib (HR 1.23, 95% CI 0.90 to 1.67). However, in TIVO‑1, patients could switch from sorafenib to tivozanib when their disease progressed and 62.6% of patients in the sorafenib group switched. The committee acknowledged that the amount of crossover confounded the results for overall survival. This was likely to make tivozanib appear less effective compared with sorafenib. The company carried out 2 analyses to adjust for the crossover:
The inverse probability of censoring weights (IPCW) method: the committee noted that the results from this method showed that tivozanib and sorafenib had a similar effect on overall survival (HR 1.02, 95% CI 0.67 to 1.55). It also noted that the company carried out the IPCW adjustment only for the full trial population, and that it was the company's preferred method of adjusting for crossover. The committee was aware of the limitations of this approach, including the weight the approach gave to the small number of patients who did not crossover to another treatment.
The rank preserving structural failure time (RPSFT) method: the committee noted that the results from this method showed the median overall survival for tivozanib (27.1 months) was lower than for sorafenib (32.3 months to 38.7 months depending on the type of analysis used). The committee noted that the company carried out this adjustment for patients in TIVO‑1 who had not had previous treatment, which the committee considered more appropriate than using the whole trial population (see section 3.5). It also noted that the RPSFT method was the ERG's preferred method of adjusting for crossover. However, it acknowledged that there were limitations with this approach, which assumes that the treatment benefit with tivozanib is the same whether patients take it instead of sorafenib or after sorafenib. The committee considered that patients who took tivozanib after sorafenib (in effect second line) may not respond as well as if had they had taken it earlier.The committee agreed that both methods of adjusting for crossover had limitations and that the adjusted results for overall survival were inconsistent. It concluded that the evidence presented by the company showed that, at best, tivozanib may be similar to sorafenib in extending overall survival. However, in the only analysis in the relevant population (that is, people who had not had previous treatment), patients randomised to tivozanib did not live as long as those randomised to sorafenib.
# Network meta-analysis
## The structure of the amended network used by the company and ERG and the trials included in it are appropriate
The company carried out a network meta-analysis to compare tivozanib with the comparators in the scope, pazopanib and sunitinib. The company submitted different approaches to the network meta-analysis, including a broad network of trials and several approaches to extrapolating beyond the end of the trials. However, the company's final network provided at the clarification stage of this appraisal was based on the ERG's suggested network of 4 trials: COMPARZ, which compared pazopanib with sunitinib; Cross‑J‑RCC, which compared sunitinib with sorafenib; SWITCH, which compared sorafenib with sunitinib; and TIVO‑1, which compared tivozanib with sorafenib. The committee understood that the baseline characteristics were broadly similar in the included trials, and that the ERG had also based its analyses on this network. In response to consultation, the company argued that the ERG should have excluded the Cross‑J‑RCC trial from the simplified network because it was small (n=124), it was carried out in a Japanese population, and its results were available only in poster form. However, the committee noted that the company had not provided the results based on the network without Cross‑J‑RCC. It concluded that the structure of the network provided by the company after clarification, and the trials included in it, were appropriate.
## The results of the network meta-analyses are uncertain because they are not adjusted for crossover
The company used fractional polynomial modelling, as described by Janssen et al. (2011), to fit overall and progression-free survival curves for tivozanib, pazopanib and sunitinib because the proportional hazards assumption did not hold for progression-free survival in TIVO‑1 (see section 3.6). The ERG corrected an error in the company's modelling of the fractional polynomial curves. It also presented its own preferred network meta-analysis (see table 1 for results) using fractional polynomial curves different to the ones chosen by the company, and taking into account clinical plausibility. In the ERG's network meta-analysis, median progression-free survival and overall survival were lower for tivozanib than for sunitinib and pazopanib. Neither the company nor the ERG adjusted for crossover in TIVO‑1, Cross‑J‑RCC and SWITCH, in which patients switched to other treatments when their disease progressed. The committee concluded that not adjusting for crossover meant that the results of the network meta-analysis were likely to be confounded with the direction of bias unknown.
Results
Median progression-free survival (months)
Median overall survival (months)
Trial results for tivozanib (TIVO‑1)
Not reported
Trial results for sunitinib (COMPARZ)
Trial results for pazopanib (COMPARZ)
Company results for tivozanib (error corrected)
Company results for sunitinib (error corrected)
Company results for pazopanib (error corrected)
Evidence review group results for tivozanib
Evidence review group results for sunitinib
Evidence review group results for pazopanib
## At best, tivozanib may have a similar effect to sunitinib or pazopanib
The committee had concerns about the company's and ERG's network meta-analyses. The clinical experts commented that some of the fractional polynomial curves in the company's network meta-analysis did not lead to clinically plausible results because the difference in overall survival between pazopanib and sunitinib (7.9 months in favour of sunitinib) contradicted the direct results from COMPARZ (0.9 months in favour of sunitinib). In the ERG's network meta-analysis, the results also contradicted the COMPARZ trial results, showing that pazopanib led to longer overall and progression-free survival than sunitinib. Moreover, the ERG estimated a median progression-free survival for tivozanib that was much lower than that seen in TIVO‑1 (6.1 months compared with 12.7 months), despite this outcome not being affected by crossover. The ERG explained that this was because sorafenib provided the link between tivozanib and the comparators, and because all curves were adjusted to this baseline. Nonetheless, the committee had reservations about using an analysis that estimated a median progression-free survival which was shorter than half the duration seen in the trial. The committee also noted that the choice of fractional polynomial model had a large effect on the estimates of progression-free and overall survival, and that the 95% credible intervals around the curves were wide, reflecting substantial uncertainty in the results. The committee considered that neither the company's nor the ERG's results were plausible or robust. This meant that the effectiveness of tivozanib compared with current treatments in the NHS (sunitinib and pazopanib) was unclear. The committee concluded that it had seen no evidence to suggest that tivozanib was more effective than sunitinib or pazopanib in extending overall and progression-free survival. What evidence there was suggested that, at best, tivozanib may have a similar effect to sunitinib or pazopanib.
# Adverse effects
## It is not clear if tivozanib is better tolerated than pazopanib or sunitinib
The clinical experts explained that different adverse effects affect a person's quality of life differently. For example, hypertension may not affect quality of life as much as skin problems, fatigue or diarrhoea. This makes it difficult to compare safety profiles between treatments. In response to consultation, the company provided data that it argued showed adverse events such as fatigue and diarrhoea to be less frequent with tivozanib than with sunitinib and pazopanib. The data came from a naive comparison of the incidence rates of all‑grade adverse events from the TIVO‑1 and COMPARZ trials including previously treated and untreated patients. The results of the ERG's network meta-analyses for grades 3 to 4 fatigue and diarrhoea in patients who had not had previous treatment favoured tivozanib, but the difference for fatigue were not statistically significant (p>0.05). The committee noted the company's comments about the limitations of the ERG's analysis, notably the small number of studies included, the perceived poor quality of the Cross‑J‑RCC study and the reliance on patient-reported adverse events from randomised controlled trials to synthesise the evidence. Nevertheless, the committee agreed that it was more appropriate to consider results from network meta-analyses than from naive comparisons of clinical trials to maintain the benefits of randomisation and reflect uncertainty in credible intervals. The committee agreed that tivozanib is reasonably well tolerated, but that it was not clear whether it is better tolerated than pazopanib or sunitinib.
# The company's economic model
## The company's model is appropriate for decision-making, although it does not capture the health effects of subsequent treatments
The company used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. The committee concluded that the model was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma. The model included either tivozanib, sunitinib or pazopanib as the first treatment, followed by axitinib or best supportive care. The committee was concerned that the model did not capture the clinical benefits of subsequent treatments, and that these benefits may extend overall survival beyond the 10‑year time horizon in the model.
# Treatment effects in the economic model
## Changing the fractional polynomial curve used in the model had a large impact on the cost-effectiveness results
The company based the treatment effects it used in the cost-effectiveness modelling on the network meta-analysis using fractional polynomials. The committee agreed that the uncertainties in clinical effectiveness (see section 3.10) carried over to the estimates of cost effectiveness. For example, changing the fractional polynomial curve used in the model had a large impact on the incremental cost-effectiveness ratios (ICERs). The committee concluded that the uncertainty in the clinical-effectiveness results meant that the ICERs were also uncertain.
# Utility values in the economic model
## Methods of modelling adverse effects had a limited effect on the cost-effectiveness results
The company derived utility values for the pre-progression and post-progression health states from data on health-related quality of life from EQ‑5D questionnaires given to patients in TIVO‑1. The company assumed the same utility values for each treatment. It adjusted the pre-progression utility values to incorporate decrements for adverse effects, which it derived from a published cost-effectiveness analysis of pazopanib. The committee understood that the ERG did not include the utility decrements for adverse effects in its base case because the values were estimated from a sample of the UK general population, rather than from people with renal cell carcinoma. Moreover, the ERG considered that, by including decrements, the company could have double-counted the impact of adverse effects on quality of life because the questionnaires in the trial were likely to have captured this. The committee noted that removing the decrements for adverse effects negligibly affected the ICER.
# Costs and resources in the company's economic model
## Disease management costs had a limited effect on the cost-effectiveness results
The company included costs for services and monitoring in its economic model, such as the costs of clinical appointments and CT scans. The ERG corrected an error in the company's calculation converting costs from monthly to weekly. The committee noted that, in its base-case model, the ERG included the costs of monthly blood tests and for managing adverse effects that differed from the company's, but that these had a limited effect on the ICER.
## Including actual doses compared with intended doses had a large effect on the cost-effectiveness results
The company assumed the relative dose intensity (the dose of the drug delivered as a proportion of the intended dose) for all treatments was 100% in its base-case model. The ERG included mean relative dose intensities of 94% for tivozanib, taken from TIVO‑1, and 86% for both pazopanib and sunitinib, taken from the pazopanib and sunitinib appraisals. The committee noted that including relative dose intensities made tivozanib substantially less cost effective compared with pazopanib and sunitinib. The clinical experts explained that doses which had been prescribed, but not taken by patients, were likely to be returned to the pharmacy to be destroyed and, as such, were unlikely to reduce costs in practice. The committee was aware that unused vials of injectable medicines would likely be returned to pharmacy to be destroyed but that it was unclear whether this would also happen with tablets and capsules. The committee concluded that the relative dose intensity was likely to be between 100% and the ERG's estimates of 86% for pazopanib and sunitinib and 94% for tivozanib, and was more likely to be closer to the ERG's estimates.
## The modelling reflects the impact on outcomes of differences in adherence to the intended treatment regimen
In its response to consultation, the company presented data showing that a lower proportion of people taking tivozanib interrupt or stop treatment, or reduce their dose, because of adverse events compared with people taking sunitinib or pazopanib. The company argued that this means tivozanib is better tolerated and leads to better outcomes and quality of life. The ERG stated that it was difficult to compare trials because of the differing definitions of dose interruptions and reductions. In addition, the results of the trials reflect the actual dose taken, which takes into account any variation in the scheduled dose. The committee concluded that the company's and ERG's modelling already captured any benefits from differences in adherence.
## The health benefits and costs of subsequent therapies assumed by the company were not realistic
The committee discussed the subsequent therapies (that is, second line and beyond) included in the economic model for patients whose disease progressed while taking tivozanib, sunitinib or pazopanib.
Company's model:
% had axitinib, 40% had best supportive care
patients on axitinib take it for the rest of their lives
costs were not discounted
benefits of subsequent therapy were not included.
ERG's model:
% had axitinib, 10% everolimus, 30% nivolumab, 10% best supportive care
mean treatment durations for axitinib, everolimus and nivolumab were from published literature
costs were discounted
benefits of subsequent therapy were not included.The committee agreed that the ERG's modelling of subsequent therapy costs better reflected the current treatment pathway (see section 3.3). However, the committee remained concerned that both the company and the ERG had included only the costs of subsequent therapies in the model, but not any benefits of subsequent therapies on progression-free or overall survival. It agreed that changing the modelling of subsequent therapies from the company's approach to the ERG's approach made tivozanib substantially less cost effective compared with pazopanib and sunitinib. The committee concluded that, although the ERG's assumptions were more appropriate than the company's assumptions, it would have preferred to have seen the ERG adjust for both the costs and benefits of subsequent treatments.
# End of life
## Tivozanib is not considered a life-extending treatment for people with a short life expectancy
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods, recognising that the company did not submit evidence to support tivozanib as an 'end of life' therapy. It noted that the company had not provided estimates for mean overall survival with tivozanib. It noted that the estimated median overall survival for people taking pazopanib or sunitinib in both the ERG's corrected company's network meta-analysis and the ERG's preferred network meta-analysis was more than 24 months. The committee noted that an average estimated survival was likely to be even longer, in part because means generally exceed medians, and because of the life-extending therapies now offered by the NHS that were unlikely to have been available to patients in the trials of pazopanib or sunitinib. It also noted that tivozanib did not increase median overall survival by 3 months or more compared with pazopanib or sunitinib in either analysis. The committee concluded that tivozanib did not meet the criteria for being considered as a life-extending treatment for people with a short life expectancy.
# Results of the cost-effectiveness analyses
## The main difference between the company and ERG base cases is the choice of progression-free and overall survival curves
The committee noted at its first meeting that the ERG's base-case model incorporated its preferred assumptions, including those about relative dose intensities (see section 3.16) and those modelling subsequent therapies (see section 3.18). In addition, the total quality-adjusted life years (QALYs) gained for pazopanib and sunitinib were more similar in the ERG's base-case results (2.35 and 2.24 respectively) than in the corrected company's base-case results (1.78 and 2.42 respectively). The committee agreed that the similar QALY gains in the ERG's base case better reflected the results of the direct comparison of pazopanib and sunitinib in the COMPARZ trial. In response to consultation, the company submitted a patient access scheme and updated its base case to reflect most of the above assumptions. The main difference between the company and ERG base cases was in the choice of the fractional polynomial curves used to model progression-free and overall survival.
## Tivozanib can be recommended as a cost-effective use of NHS resources
The company's revised results submitted in response to consultation and the ERG base-case results, including all patient access schemes for tivozanib and subsequent therapies, showed that tivozanib was cheaper and less effective than pazopanib and sunitinib. The company subsequently revised the patient access scheme for tivozanib, but did not provide updated results, agreeing that the ERG could provide them. The committee noted that, in situations in which an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. The ERG estimated ICERs greater than £30,000 saved per QALY lost for tivozanib compared with pazopanib, and greater than £50,000 saved per QALY lost compared with sunitinib. Because the subsequent therapies (axitinib, everolimus and nivolumab) included in the model are associated with confidential patient access schemes, the exact estimates of cost effectiveness cannot be reported here. The committee considered that, although the ICERs were within the range normally considered to represent cost-effective technologies, they were associated with a high degree of uncertainty. This was mainly because they did not account for the crossover in TIVO‑1 or any of the other trials in the network meta-analysis. The committee acknowledged comments from the Cancer Drugs Fund clinical lead suggesting that clinicians view tivozanib as being broadly similar in effectiveness as pazopanib and possibly having a better safety profile. This could benefit people that clinicians think would not be able to tolerate pazopanib. The committee agreed that extending treatment choices in this disease area would benefit both clinicians and patients. Taking into account the estimated cost effectiveness of tivozanib, the clinicians' views and unmet need, the committee recommended tivozanib as an option for treating advanced renal cell carcinoma in adults who have had no previous treatment.
# Other factors
## No other factors were identified that could affect the recommendation
The company did not provide evidence that tivozanib was an innovative treatment. However, the committee recognised that patient groups noted that tivozanib targets 3 vascular endothelial growth factor receptors. The committee was not presented with evidence about the extent to which these benefits were realised in practice. The committee concluded that it had not seen any additional evidence of benefits that were not captured in the measurement of QALYs.
|
{'Recommendations': 'Tivozanib is recommended as an option for treating advanced renal cell carcinoma in adults, only if:\n\nthey have had no previous treatment and\n\nthe company provides tivozanib with the discount agreed in the patient access scheme.\n\nThis recommendation is not intended to affect treatment with tivozanib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made this recommendation\n\nCurrent treatment in the NHS for untreated advanced renal cell carcinoma is usually sunitinib or pazopanib. There is no evidence to suggest that tivozanib is more effective than pazopanib and sunitinib in extending overall and progression-free survival. At best, tivozanib may have a similar effect to sunitinib or pazopanib. Also, the evidence does not clearly show that people tolerate the adverse effects of tivozanib better than those of sunitinib or pazopanib.\n\nThe cost of treating renal cell carcinoma with tivozanib is likely to be lower than the cost of treating it with sunitinib or pazopanib, but tivozanib is also likely to be less effective. The estimated cost savings are high enough to compensate for the estimated lower effectiveness. Also, there is a need to be able to offer tivozanib to people who do not tolerate existing treatments. Therefore, tivozanib is recommended as an option for treating advanced renal cell carcinoma in adults who have had no previous treatment.', 'Information about tivozanib': "Marketing authorisation\n\nTivozanib (Fotivda, EUSA Pharma) is indicated for 'the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naive following disease progression after one prior treatment with cytokine therapy for advanced RCC'.\n\nDosage in the marketing authorisation\n\n,340\xa0micrograms taken orally once daily for 21\xa0days, followed by a 7‑day rest period to make up 1\xa0complete treatment cycle of 4\xa0weeks. The treatment schedule should be continued until disease progression or unacceptable toxicity.\n\nPrice\n\nA 21‑pack of 1,340\xa0microgram hard capsules (that is, the pack size needed for 1\xa0treatment cycle) costs £2,052 excluding VAT.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of tivozanib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by EUSA Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with renal cell carcinoma would welcome a new treatment option\n\nThe patient and clinical experts explained that the adverse effects of current treatments for advanced renal cell carcinoma, such as extreme fatigue, hand and foot syndrome, and chronic diarrhoea, can significantly affect quality of life. So, some people would benefit from being able to switch to a different treatment, which they may tolerate better. The committee concluded that people with advanced renal cell carcinoma would welcome a new treatment option.\n\n# Clinical management\n\n## Tivozanib would be used only in untreated disease in the NHS\n\nTivozanib has a marketing authorisation for treating advanced renal cell carcinoma in adults who have had no previous treatment, or who have had 1\xa0previous treatment with a cytokine (see section\xa02). The committee noted that the company had not submitted evidence for people who had been treated with cytokines. It heard from the clinical experts that cytokines are rarely used in the NHS for untreated renal cell carcinoma. The committee agreed that tivozanib would be used in the NHS only for people who have had no previous treatment.\n\n## Sunitinib or pazopanib are the current treatments for untreated advanced renal cell carcinoma\n\nThe clinical experts confirmed that most people in the NHS with newly diagnosed untreated advanced renal cell carcinoma would be offered 1\xa0of\xa02 tyrosine kinase inhibitors (TKIs), pazopanib or sunitinib, as recommended in NICE's technology appraisal guidance on pazopanib for the first-line treatment of advanced renal cell carcinoma and sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. Other treatments such as bevacizumab, sorafenib and temsirolimus have a marketing authorisation for previously untreated advanced renal cell carcinoma, but they are not recommended by NICE (see NICE's technology appraisal guidance on bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma) and are not used in the NHS. The committee concluded that pazopanib and sunitinib were the relevant comparators in this appraisal.\n\n# Clinical evidence\n\n## The comparator and location of the pivotal trial, TIVO‑1, has limited how generalisable the results are to clinical practice in England\n\nThe main clinical evidence for tivozanib came from TIVO‑1, an open-label randomised controlled trial that primarily investigated whether tivozanib (n=260) prolongs time to disease progression compared with sorafenib (n=257). At disease progression, patients in the sorafenib group could switch (cross over) to treatment with tivozanib. Patients in the tivozanib group could also have subsequent treatment if their disease progressed. The committee considered whether this trial was relevant to clinical practice in England:\n\nComparator: the comparator in TIVO‑1 was sorafenib, which is not used in the NHS and was not considered a comparator in this appraisal (see section\xa03.3).\n\nOutcome: the primary outcome was progression-free survival, but the trial also measured overall survival and health-related quality of life.\n\nBaseline characteristics: the clinical experts generally considered the baseline characteristics of patients in the trial to be similar to those of people who would be offered tivozanib in the NHS:\n\n\n\nMost patients in the trial (88%) were enrolled in Central or Eastern Europe. The committee was concerned that these patients may have poorer access to second-, third- and fourth-line life-extending therapies. This would mean that the survival times in TIVO‑1 might be shorter than those in England.\n\nPatients in the sorafenib group had a better average performance status than those in the tivozanib group. In the sorafenib group, 54% had an Eastern Cooperative Oncology Group (ECOG) performance status score of\xa00 (meaning that they did not have any symptoms and were able to carry out usual activities unrestricted) compared with 45% in the tivozanib group. This means that the results may underestimate the effectiveness of tivozanib.The committee concluded that the comparator and location of TIVO‑1 limited the generalisability of the results.\n\n\n\n## The most relevant subgroup is patients who have not had previous treatment\n\nIn TIVO‑1, 70% of patients had not had previous treatment and 30% had already had 1\xa0systemic treatment. Because tivozanib would be used only for untreated disease in NHS clinical practice (see section\xa03.2), the committee considered that patients in the trial who had not been treated represented the most relevant population in this appraisal. It was concerned that focusing on a subgroup of patients in TIVO‑1 reduced the size of the population (n=362), and the statistical power of the study to detect differences between treatment groups. However, the committee concluded that, despite this, the group of patients not previously treated provided the most relevant evidence.\n\n# Progression-free survival\n\n## Tivozanib increases progression-free survival compared with sorafenib\n\nThe primary outcome in TIVO‑1 was progression-free survival (assessed by reviewers blinded to patients' treatments). Tivozanib increased median progression-free survival compared with sorafenib among patients who had not had previous treatment from 9.1\xa0months to 12.7\xa0months (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.58 to 0.99). The company used a Cox proportional hazards model to estimate the hazard ratio for progression-free survival. However, both the company and the ERG acknowledged that the proportional hazard assumptions underlying the Cox proportional hazards model may not hold. To address this, the company used a fractional polynomial method for the network meta-analysis (used to compare tivozanib with sunitinib and pazopanib, see section\xa03.8) and for cost-effectiveness modelling (see section\xa03.13).\n\n# Overall survival\n\n## Results for overall survival were confounded by treatment switching in TIVO‑1\n\nAmong the previously untreated population in TIVO‑1, patients randomised to tivozanib did not live as long as those randomised to sorafenib (HR\xa01.23, 95%\xa0CI 0.90 to 1.67). However, in TIVO‑1, patients could switch from sorafenib to tivozanib when their disease progressed and 62.6% of patients in the sorafenib group switched. The committee acknowledged that the amount of crossover confounded the results for overall survival. This was likely to make tivozanib appear less effective compared with sorafenib. The company carried out 2\xa0analyses to adjust for the crossover:\n\nThe inverse probability of censoring weights (IPCW) method: the committee noted that the results from this method showed that tivozanib and sorafenib had a similar effect on overall survival (HR\xa01.02, 95%\xa0CI 0.67 to 1.55). It also noted that the company carried out the IPCW adjustment only for the full trial population, and that it was the company's preferred method of adjusting for crossover. The committee was aware of the limitations of this approach, including the weight the approach gave to the small number of patients who did not crossover to another treatment.\n\nThe rank preserving structural failure time (RPSFT) method: the committee noted that the results from this method showed the median overall survival for tivozanib (27.1\xa0months) was lower than for sorafenib (32.3\xa0months to 38.7\xa0months depending on the type of analysis used). The committee noted that the company carried out this adjustment for patients in TIVO‑1 who had not had previous treatment, which the committee considered more appropriate than using the whole trial population (see section\xa03.5). It also noted that the RPSFT method was the ERG's preferred method of adjusting for crossover. However, it acknowledged that there were limitations with this approach, which assumes that the treatment benefit with tivozanib is the same whether patients take it instead of sorafenib or after sorafenib. The committee considered that patients who took tivozanib after sorafenib (in effect second line) may not respond as well as if had they had taken it earlier.The committee agreed that both methods of adjusting for crossover had limitations and that the adjusted results for overall survival were inconsistent. It concluded that the evidence presented by the company showed that, at best, tivozanib may be similar to sorafenib in extending overall survival. However, in the only analysis in the relevant population (that is, people who had not had previous treatment), patients randomised to tivozanib did not live as long as those randomised to sorafenib.\n\n# Network meta-analysis\n\n## The structure of the amended network used by the company and ERG and the trials included in it are appropriate\n\nThe company carried out a network meta-analysis to compare tivozanib with the comparators in the scope, pazopanib and sunitinib. The company submitted different approaches to the network meta-analysis, including a broad network of trials and several approaches to extrapolating beyond the end of the trials. However, the company's final network provided at the clarification stage of this appraisal was based on the ERG's suggested network of 4\xa0trials: COMPARZ, which compared pazopanib with sunitinib; Cross‑J‑RCC, which compared sunitinib with sorafenib; SWITCH, which compared sorafenib with sunitinib; and TIVO‑1, which compared tivozanib with sorafenib. The committee understood that the baseline characteristics were broadly similar in the included trials, and that the ERG had also based its analyses on this network. In response to consultation, the company argued that the ERG should have excluded the Cross‑J‑RCC trial from the simplified network because it was small (n=124), it was carried out in a Japanese population, and its results were available only in poster form. However, the committee noted that the company had not provided the results based on the network without Cross‑J‑RCC. It concluded that the structure of the network provided by the company after clarification, and the trials included in it, were appropriate.\n\n## The results of the network meta-analyses are uncertain because they are not adjusted for crossover\n\nThe company used fractional polynomial modelling, as described by Janssen et al. (2011), to fit overall and progression-free survival curves for tivozanib, pazopanib and sunitinib because the proportional hazards assumption did not hold for progression-free survival in TIVO‑1 (see section\xa03.6). The ERG corrected an error in the company's modelling of the fractional polynomial curves. It also presented its own preferred network meta-analysis (see table\xa01 for results) using fractional polynomial curves different to the ones chosen by the company, and taking into account clinical plausibility. In the ERG's network meta-analysis, median progression-free survival and overall survival were lower for tivozanib than for sunitinib and pazopanib. Neither the company nor the ERG adjusted for crossover in TIVO‑1, Cross‑J‑RCC and SWITCH, in which patients switched to other treatments when their disease progressed. The committee concluded that not adjusting for crossover meant that the results of the network meta-analysis were likely to be confounded with the direction of bias unknown.\n\nResults\n\nMedian progression-free survival (months)\n\nMedian overall survival (months)\n\nTrial results for tivozanib\xa0(TIVO‑1)\n\n\n\nNot reported\n\nTrial results for sunitinib\xa0(COMPARZ)\n\n\n\n\n\nTrial results for pazopanib\xa0(COMPARZ)\n\n\n\n\n\nCompany results for tivozanib (error corrected)\n\n\n\n\n\nCompany results for sunitinib (error corrected)\n\n\n\n\n\nCompany results for pazopanib (error corrected)\n\n\n\n\n\nEvidence review group results for tivozanib\n\n\n\n\n\nEvidence review group results for sunitinib\n\n\n\n\n\nEvidence review group results for pazopanib\n\n\n\n\n\n## At best, tivozanib may have a similar effect to sunitinib or pazopanib\n\nThe committee had concerns about the company's and ERG's network meta-analyses. The clinical experts commented that some of the fractional polynomial curves in the company's network meta-analysis did not lead to clinically plausible results because the difference in overall survival between pazopanib and sunitinib (7.9\xa0months in favour of sunitinib) contradicted the direct results from COMPARZ (0.9\xa0months in favour of sunitinib). In the ERG's network meta-analysis, the results also contradicted the COMPARZ trial results, showing that pazopanib led to longer overall and progression-free survival than sunitinib. Moreover, the ERG estimated a median progression-free survival for tivozanib that was much lower than that seen in TIVO‑1 (6.1\xa0months compared with 12.7\xa0months), despite this outcome not being affected by crossover. The ERG explained that this was because sorafenib provided the link between tivozanib and the comparators, and because all curves were adjusted to this baseline. Nonetheless, the committee had reservations about using an analysis that estimated a median progression-free survival which was shorter than half the duration seen in the trial. The committee also noted that the choice of fractional polynomial model had a large effect on the estimates of progression-free and overall survival, and that the 95% credible intervals around the curves were wide, reflecting substantial uncertainty in the results. The committee considered that neither the company's nor the ERG's results were plausible or robust. This meant that the effectiveness of tivozanib compared with current treatments in the NHS (sunitinib and pazopanib) was unclear. The committee concluded that it had seen no evidence to suggest that tivozanib was more effective than sunitinib or pazopanib in extending overall and progression-free survival. What evidence there was suggested that, at best, tivozanib may have a similar effect to sunitinib or pazopanib.\n\n# Adverse effects\n\n## It is not clear if tivozanib is better tolerated than pazopanib or sunitinib\n\nThe clinical experts explained that different adverse effects affect a person's quality of life differently. For example, hypertension may not affect quality of life as much as skin problems, fatigue or diarrhoea. This makes it difficult to compare safety profiles between treatments. In response to consultation, the company provided data that it argued showed adverse events such as fatigue and diarrhoea to be less frequent with tivozanib than with sunitinib and pazopanib. The data came from a naive comparison of the incidence rates of all‑grade adverse events from the TIVO‑1 and COMPARZ trials including previously treated and untreated patients. The results of the ERG's network meta-analyses for grades 3\xa0to\xa04 fatigue and diarrhoea in patients who had not had previous treatment favoured tivozanib, but the difference for fatigue were not statistically significant (p>0.05). The committee noted the company's comments about the limitations of the ERG's analysis, notably the small number of studies included, the perceived poor quality of the Cross‑J‑RCC study and the reliance on patient-reported adverse events from randomised controlled trials to synthesise the evidence. Nevertheless, the committee agreed that it was more appropriate to consider results from network meta-analyses than from naive comparisons of clinical trials to maintain the benefits of randomisation and reflect uncertainty in credible intervals. The committee agreed that tivozanib is reasonably well tolerated, but that it was not clear whether it is better tolerated than pazopanib or sunitinib.\n\n# The company's economic model\n\n## The company's model is appropriate for decision-making, although it does not capture the health effects of subsequent treatments\n\nThe company used a partitioned-survival economic model that included 3\xa0health states: pre-progression, post-progression and death. The committee concluded that the model was appropriate and consistent with the approach used in other appraisals for renal cell carcinoma. The model included either tivozanib, sunitinib or pazopanib as the first treatment, followed by axitinib or best supportive care. The committee was concerned that the model did not capture the clinical benefits of subsequent treatments, and that these benefits may extend overall survival beyond the 10‑year time horizon in the model.\n\n# Treatment effects in the economic model\n\n## Changing the fractional polynomial curve used in the model had a large impact on the cost-effectiveness results\n\nThe company based the treatment effects it used in the cost-effectiveness modelling on the network meta-analysis using fractional polynomials. The committee agreed that the uncertainties in clinical effectiveness (see section\xa03.10) carried over to the estimates of cost effectiveness. For example, changing the fractional polynomial curve used in the model had a large impact on the incremental cost-effectiveness ratios (ICERs). The committee concluded that the uncertainty in the clinical-effectiveness results meant that the ICERs were also uncertain.\n\n# Utility values in the economic model\n\n## Methods of modelling adverse effects had a limited effect on the cost-effectiveness results\n\nThe company derived utility values for the pre-progression and post-progression health states from data on health-related quality of life from EQ‑5D questionnaires given to patients in TIVO‑1. The company assumed the same utility values for each treatment. It adjusted the pre-progression utility values to incorporate decrements for adverse effects, which it derived from a published cost-effectiveness analysis of pazopanib. The committee understood that the ERG did not include the utility decrements for adverse effects in its base case because the values were estimated from a sample of the UK general population, rather than from people with renal cell carcinoma. Moreover, the ERG considered that, by including decrements, the company could have double-counted the impact of adverse effects on quality of life because the questionnaires in the trial were likely to have captured this. The committee noted that removing the decrements for adverse effects negligibly affected the ICER.\n\n# Costs and resources in the company's economic model\n\n## Disease management costs had a limited effect on the cost-effectiveness results\n\nThe company included costs for services and monitoring in its economic model, such as the costs of clinical appointments and CT scans. The ERG corrected an error in the company's calculation converting costs from monthly to weekly. The committee noted that, in its base-case model, the ERG included the costs of monthly blood tests and for managing adverse effects that differed from the company's, but that these had a limited effect on the ICER.\n\n## Including actual doses compared with intended doses had a large effect on the cost-effectiveness results\n\nThe company assumed the relative dose intensity (the dose of the drug delivered as a proportion of the intended dose) for all treatments was 100% in its base-case model. The ERG included mean relative dose intensities of 94% for tivozanib, taken from TIVO‑1, and 86% for both pazopanib and sunitinib, taken from the pazopanib and sunitinib appraisals. The committee noted that including relative dose intensities made tivozanib substantially less cost effective compared with pazopanib and sunitinib. The clinical experts explained that doses which had been prescribed, but not taken by patients, were likely to be returned to the pharmacy to be destroyed and, as such, were unlikely to reduce costs in practice. The committee was aware that unused vials of injectable medicines would likely be returned to pharmacy to be destroyed but that it was unclear whether this would also happen with tablets and capsules. The committee concluded that the relative dose intensity was likely to be between 100% and the ERG's estimates of 86% for pazopanib and sunitinib and 94% for tivozanib, and was more likely to be closer to the ERG's estimates.\n\n## The modelling reflects the impact on outcomes of differences in adherence to the intended treatment regimen\n\nIn its response to consultation, the company presented data showing that a lower proportion of people taking tivozanib interrupt or stop treatment, or reduce their dose, because of adverse events compared with people taking sunitinib or pazopanib. The company argued that this means tivozanib is better tolerated and leads to better outcomes and quality of life. The ERG stated that it was difficult to compare trials because of the differing definitions of dose interruptions and reductions. In addition, the results of the trials reflect the actual dose taken, which takes into account any variation in the scheduled dose. The committee concluded that the company's and ERG's modelling already captured any benefits from differences in adherence.\n\n## The health benefits and costs of subsequent therapies assumed by the company were not realistic\n\nThe committee discussed the subsequent therapies (that is, second line and beyond) included in the economic model for patients whose disease progressed while taking tivozanib, sunitinib or pazopanib.\n\nCompany's model:\n\n\n\n% had axitinib, 40% had best supportive care\n\npatients on axitinib take it for the rest of their lives\n\ncosts were not discounted\n\nbenefits of subsequent therapy were not included.\n\n\n\nERG's model:\n\n\n\n% had axitinib, 10% everolimus, 30% nivolumab, 10% best supportive care\n\nmean treatment durations for axitinib, everolimus and nivolumab were from published literature\n\ncosts were discounted\n\nbenefits of subsequent therapy were not included.The committee agreed that the ERG's modelling of subsequent therapy costs better reflected the current treatment pathway (see section\xa03.3). However, the committee remained concerned that both the company and the ERG had included only the costs of subsequent therapies in the model, but not any benefits of subsequent therapies on progression-free or overall survival. It agreed that changing the modelling of subsequent therapies from the company's approach to the ERG's approach made tivozanib substantially less cost effective compared with pazopanib and sunitinib. The committee concluded that, although the ERG's assumptions were more appropriate than the company's assumptions, it would have preferred to have seen the ERG adjust for both the costs and benefits of subsequent treatments.\n\n\n\n# End of life\n\n## Tivozanib is not considered a life-extending treatment for people with a short life expectancy\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods, recognising that the company did not submit evidence to support tivozanib as an 'end of life' therapy. It noted that the company had not provided estimates for mean overall survival with tivozanib. It noted that the estimated median overall survival for people taking pazopanib or sunitinib in both the ERG's corrected company's network meta-analysis and the ERG's preferred network meta-analysis was more than 24\xa0months. The committee noted that an average estimated survival was likely to be even longer, in part because means generally exceed medians, and because of the life-extending therapies now offered by the NHS that were unlikely to have been available to patients in the trials of pazopanib or sunitinib. It also noted that tivozanib did not increase median overall survival by 3\xa0months or more compared with pazopanib or sunitinib in either analysis. The committee concluded that tivozanib did not meet the criteria for being considered as a life-extending treatment for people with a short life expectancy.\n\n# Results of the cost-effectiveness analyses\n\n## The main difference between the company and ERG base cases is the choice of progression-free and overall survival curves\n\nThe committee noted at its first meeting that the ERG's base-case model incorporated its preferred assumptions, including those about relative dose intensities (see section\xa03.16) and those modelling subsequent therapies (see section\xa03.18). In addition, the total quality-adjusted life years (QALYs) gained for pazopanib and sunitinib were more similar in the ERG's base-case results (2.35 and 2.24 respectively) than in the corrected company's base-case results (1.78 and 2.42 respectively). The committee agreed that the similar QALY gains in the ERG's base case better reflected the results of the direct comparison of pazopanib and sunitinib in the COMPARZ trial. In response to consultation, the company submitted a patient access scheme and updated its base case to reflect most of the above assumptions. The main difference between the company and ERG base cases was in the choice of the fractional polynomial curves used to model progression-free and overall survival.\n\n## Tivozanib can be recommended as a cost-effective use of NHS resources\n\nThe company's revised results submitted in response to consultation and the ERG base-case results, including all patient access schemes for tivozanib and subsequent therapies, showed that tivozanib was cheaper and less effective than pazopanib and sunitinib. The company subsequently revised the patient access scheme for tivozanib, but did not provide updated results, agreeing that the ERG could provide them. The committee noted that, in situations in which an ICER is estimated for a technology that is less effective and less costly than its comparator, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed. The ERG estimated ICERs greater than £30,000 saved per QALY lost for tivozanib compared with pazopanib, and greater than £50,000 saved per QALY lost compared with sunitinib. Because the subsequent therapies (axitinib, everolimus and nivolumab) included in the model are associated with confidential patient access schemes, the exact estimates of cost effectiveness cannot be reported here. The committee considered that, although the ICERs were within the range normally considered to represent cost-effective technologies, they were associated with a high degree of uncertainty. This was mainly because they did not account for the crossover in TIVO‑1 or any of the other trials in the network meta-analysis. The committee acknowledged comments from the Cancer Drugs Fund clinical lead suggesting that clinicians view tivozanib as being broadly similar in effectiveness as pazopanib and possibly having a better safety profile. This could benefit people that clinicians think would not be able to tolerate pazopanib. The committee agreed that extending treatment choices in this disease area would benefit both clinicians and patients. Taking into account the estimated cost effectiveness of tivozanib, the clinicians' views and unmet need, the committee recommended tivozanib as an option for treating advanced renal cell carcinoma in adults who have had no previous treatment.\n\n# Other factors\n\n## No other factors were identified that could affect the recommendation\n\nThe company did not provide evidence that tivozanib was an innovative treatment. However, the committee recognised that patient groups noted that tivozanib targets 3\xa0vascular endothelial growth factor receptors. The committee was not presented with evidence about the extent to which these benefits were realised in practice. The committee concluded that it had not seen any additional evidence of benefits that were not captured in the measurement of QALYs."}
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https://www.nice.org.uk/guidance/ta512
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Evidence-based recommendations on tivozanib (Fotivda) for treating advanced renal cell carcinoma in adults.
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3a0b64d872b66e9127037710d88c03857af480e5
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nice
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Obinutuzumab for untreated advanced follicular lymphoma
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Obinutuzumab for untreated advanced follicular lymphoma
Evidence-based recommendations on obinutuzumab (Gazyvaro) for untreated advanced follicular lymphoma in adults.
# Recommendations
Obinutuzumab is recommended as an option for untreated advanced follicular lymphoma in adults (that is, first as induction treatment with chemotherapy, then alone as maintenance therapy), only if:
the person has a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 or more
the company provides obinutuzumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with obinutuzumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current first-line treatment for symptomatic advanced follicular lymphoma is induction therapy with rituximab plus chemotherapy, followed by maintenance treatment with rituximab when there has been a response to induction therapy.
The main evidence on the effectiveness and safety of obinutuzumab is from an ongoing clinical trial. It shows that obinutuzumab plus chemotherapy followed by obinutuzumab maintenance treatment delays disease progression more than current treatment. However, it also shows that undesirable side effects are more common with obinutuzumab than with rituximab. There are not enough data to know with certainty whether obinutuzumab increases life expectancy.
The company's revised economic analyses focuses on higher-risk subgroups. Obinutuzumab costs more than branded rituximab and even more than the biosimilar versions of rituximab. However, using the preferred assumptions and the discounted prices for obinutuzumab and rituximab, the cost-effectiveness estimate for obinutuzumab plus chemotherapy followed by obinutuzumab maintenance treatment, compared with rituximab plus chemotherapy followed by rituximab maintenance treatment, is lower than £30,000 per quality-adjusted life year gained. Therefore, obinutuzumab is recommended as an option for untreated advanced follicular lymphoma in patients at higher risk.# Information about obinutuzumab
# Marketing authorisation indication
Obinutuzumab (Gazyvaro, Roche) 'in combination with chemotherapy, followed by maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma'.
# Dosage in the marketing authorisation
Obinutuzumab is given by intravenous infusion. Induction consists of obinutuzumab plus chemotherapy dosage:
with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or cyclophosphamide, vincristine and prednisolone (CVP):
cycle 1: 1,000 mg on days 1, 8 and 15 of the first 21‑day treatment cycle
cycles 2 to 8: 1,000 mg on day 1 of each 21‑day treatment cycle (with the CHOP regimen, obinutuzumab is given alone for the last 2 cycles), or
with bendamustine:
cycle 1: 1,000 mg on days 1, 8 and 15 of the first 28‑day treatment cycle
cycles 2 to 6: 1,000 mg on day 1 of each 28‑day treatment cycle and
maintenance dosage of 1,000 mg every 2 months for 2 years or until disease progression (whichever occurs first).
# Price
£3,312 per 1,000‑mg vial (excluding VAT; BNF online, August 2017). The company has a commercial arrangement. This makes obinutuzumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need in advanced follicular lymphoma
## People with follicular lymphoma want further options for treatment
Follicular lymphoma progresses slowly over many years, often without symptoms. The patient experts noted that, despite this, knowing that the disease will eventually progress can cause considerable distress. People also realise that they will need further treatment when the disease progresses, which adds to the physical and psychological burden, and increases their wish to have more treatment options. The committee agreed that delaying disease progression and having treatment options would benefit people with untreated follicular lymphoma.
# Treatment pathway
## People with symptomatic disease are the relevant population
The clinical experts advised that they do not routinely offer active treatment to people with asymptomatic disease, and instead use 'watchful waiting'. Although the NICE guideline on non-Hodgkin's lymphoma also recommends rituximab induction therapy for people with advanced-stage (stages 3 and 4) asymptomatic follicular lymphoma, the clinical experts stated that this does not reflect clinical practice. They explained that active treatment is normally reserved for people with symptomatic disease who have bulky disease at multiple sites, especially if lymph nodes cause problems because of their location, or if people have fever, night sweats or unintentional weight loss. The committee concluded that people with symptomatic disease reflect the relevant population to consider in this appraisal.
## Rituximab plus chemotherapy is the main treatment for untreated follicular lymphoma
The clinical experts explained that rituximab plus chemotherapy is the main 'induction treatment' for untreated advanced follicular lymphoma. Other potential options for induction therapy include:
Rituximab alone: the clinical experts advised that this is rarely used to treat symptomatic disease; they may use it when chemotherapy is not indicated, or if the person would prefer starting treatment rather than 'watchful waiting'.
Bendamustine alone: this does not have a marketing authorisation for the first-line treatment of follicular lymphoma, but is funded for this indication through the Cancer Drugs Fund. The clinical experts expressed that, in NHS clinical practice, bendamustine alone (rather than with an immunotherapy such as rituximab or obinutuzumab) is hardly ever used as first-line treatment.The committee concluded that rituximab plus chemotherapy is the most commonly used first-line induction treatment for symptomatic advanced follicular lymphoma.
## The chemotherapies most commonly used with rituximab are CVP, bendamustine and CHOP
NICE technology appraisal guidance on rituximab for the first-line treatment of stage 3 to 4 follicular lymphoma recommends rituximab plus 1 of the following chemotherapy regimens:
cyclophosphamide, vincristine and prednisolone (CVP)
cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine and prednisolone (CHOP)
mitoxantrone, chlorambucil and prednisolone (MCP)
cyclophosphamide, doxorubicin, etoposide (VP‑16), prednisolone and interferon alfa (CHVPi) and
chlorambucil.Rituximab plus bendamustine is also available through the Cancer Drugs Fund. The clinical experts stated that most people in the NHS have either rituximab plus CVP or rituximab plus bendamustine or, to a lesser extent, rituximab plus CHOP as induction treatment. CHOP is associated with more adverse effects than the other 2 regimens. Therefore, bendamustine and CVP are more commonly used. CHOP is more likely to be reserved for high-grade follicular lymphoma at risk of transformation to a more aggressive form (large diffuse B‑cell lymphoma) and also for younger, fitter people who can better tolerate the potential cardiotoxicity of doxorubicin. The clinical experts noted that bendamustine use has declined since the Medicines and Healthcare products Regulatory Agency issued a safety alert about off-label use of bendamustine as a first-line treatment for follicular lymphoma plus an immunotherapy (such as rituximab or obinutuzumab). The committee concluded that, in clinical practice, CVP, CHOP and bendamustine are the main chemotherapies used with induction therapy, and that the adverse effects of each chemotherapy largely drive treatment choice.
## Rituximab maintenance therapy is recommended when there has been a response to induction therapy
If the disease goes into complete or partial remission with induction therapy, rituximab monotherapy is generally given as 'maintenance treatment' for up to 2 years. The scope for this appraisal included rituximab-based chemotherapy without rituximab maintenance treatment as a comparator. The committee noted that, in its technology appraisal guidance on rituximab, NICE recommended rituximab maintenance treatment for follicular lymphoma that has responded to first-line induction therapy with rituximab plus chemotherapy. The clinical experts explained that using rituximab maintenance therapy is increasingly controversial, citing the PRIMA study. In this, patients were randomised to rituximab maintenance treatment or observation only. The results of the PRIMA study showed: no survival benefit; a modest benefit with respect to progression-free survival and time to next treatment; an increased risk of infections including reactivation of hepatitis B; and long-term safety concerns. Nevertheless, the clinical experts stated that, in clinical practice, most people (around 80% to 90%) whose disease responds to induction therapy have rituximab maintenance therapy. The NHS England's Cancer Drugs Fund clinical lead explained that maintenance treatment is available in routine commissioning, and should be considered for all people whose disease has responded to induction treatment. The committee concluded that rituximab maintenance therapy, following response to induction therapy, reflects routine clinical practice in the NHS, and that induction not followed by rituximab monotherapy was not a relevant comparator for this appraisal.
## Rituximab plus chemotherapy followed by rituximab maintenance is the appropriate comparator
Based on information from the clinical experts and NHS England, the committee did not consider the following 3 comparators specified in the final scope to be relevant:
rituximab monotherapy
rituximab-based chemotherapy without rituximab maintenance treatment
bendamustine monotherapy.Referring to its discussion on the treatment pathway (see sections 3.2 to 3.5), the committee concluded that the appropriate comparison should be between obinutuzumab plus either CHOP, CVP or bendamustine followed by obinutuzumab maintenance treatment, and rituximab plus either CHOP, CVP or bendamustine followed by rituximab maintenance treatment, in line with the company's decision problem.
# Clinical evidence
## The main evidence is from GALLIUM, an open-label randomised controlled trial
The main clinical evidence for this appraisal came from an ongoing, open-label phase 3 randomised controlled trial (GALLIUM). GALLIUM compared the efficacy and safety of induction therapy with obinutuzumab plus chemotherapy followed by obinutuzumab maintenance treatment (n=601) with rituximab plus chemotherapy induction therapy followed by rituximab maintenance treatment (n=601) in adults with advanced follicular lymphoma (grades 1 to 3a). The primary outcome was progression-free survival assessed by the investigator, defined as the time from day of randomisation until first symptomatic deterioration, disease transformation or death from any cause, whichever occurred first. Progression-free survival assessed through a radiological and oncological review of patient responses by an independent review committee was a secondary outcome. Patients were treated across 177 trial sites in 18 countries, including the UK (n=293 patients). Each site chose 1 of the 3 chemotherapeutic regimens (CHOP, CVP or bendamustine) to accompany obinutuzumab or rituximab (that is, all patients at a given site had the same concomitant chemotherapy, whether with obinutuzumab or rituximab). Two of the prespecified subgroups in GALLIUM were patients at intermediate or high risk of mortality, categorised by Follicular Lymphoma International Prognostic Index (FLIPI) scores (n=474). In response to consultation, the company suggested that patients in these subgroups were the most relevant population (see section 3.9). The company based its analysis on these higher-risk subgroups.
## The whole population in GALLIUM reasonably reflects the NHS population
The committee discussed whether the population in GALLIUM reflected people who would be offered treatment in the NHS with respect to:
Age: the median age of patients in GALLIUM was 59.0 years. The committee heard from the clinical experts and the ERG that this reflected a younger population than would be seen in clinical practice. In response to consultation, the company changed the median age used in its economic model to 62.2 years.
Ethnicity: the committee heard that some ethnic groups were under-represented in GALLIUM (for example, black people of African or Caribbean family origin).
Chemotherapeutic regimen used with obinutuzumab or rituximab: the committee noted the discrepancy between the distribution of concomitant chemotherapies used in GALLIUM and clinical practice. In particular, patients in GALLIUM were more likely to have bendamustine than in the NHS. The committee was not presented with evidence on the differential effectiveness of the chemotherapies given with obinutuzumab or rituximab. However, it took the view that any differences in the proportions of treatments used between the trial and NHS practice would be unlikely to affect the generalisability of the trial's results.The committee was satisfied that the overall trial population reasonably reflected people with advanced follicular lymphoma having treatment in the NHS.
## Patients who are at intermediate or high risk from GALLIUM are a clinically relevant population
The summary of product characteristics states that obinutuzumab's efficacy in patients at low risk of premature mortality (that is, people with FLIPI score of 0 to 1) is 'inconclusive'. Because of this, and in response to consultation, the company changed the population in its analysis from all people with advanced follicular lymphoma to people with an intermediate or high FLIPI score (collectively called patients at higher risk because they are at higher risk of dying than patients with lower scores). The committee questioned whether clinicians use FLIPI scores to categorise severity of disease. The Cancer Drugs Fund clinical lead explained that FLIPI scores are not routinely used to inform treatment, but they are used to assess prognosis. This was confirmed by comments submitted by the clinical experts who attended the first meeting. The committee understood that the factors used to determine FLIPI scores (such as stage of Ann Arbor classification system, haemoglobin, serum lactate dehydrogenase and number of nodal sites affected) are already routinely measured, and that using FLIPI scores to inform treatment would not be a large extra burden for the NHS. Overall, the committee was satisfied that the higher-risk subgroup (based on FLIPI scores) was the clinically relevant population to consider in this appraisal.
# Efficacy results
## Obinutuzumab delays disease progression in the short term, but its longer-term effect on progression-free survival is unknown
The company had done several analyses in the higher-risk subgroup, including the prespecified 'primary analysis' for progression-free survival on 31 January 2016 and the post-hoc 'updated analysis' on 10 September 2016. The committee noted that, as of September 2016, 81.7% of patients at higher risk randomised to obinutuzumab compared with 72.5% of those randomised to rituximab were alive and free of disease progression (as assessed by investigators). For progression-free survival assessed by the independent review committee, the respective proportions were 83.2% and 76.0%. Obinutuzumab reduced the risk of disease progression in patients at higher risk by 38% (hazard ratio 0.62, 95% confidence interval 0.47 to 0.80) according to investigator assessment, and by 33% (HR 0.67, 95% CI 0.51 to 0.88) according to the independent review committee. Because there were few events, median progression-free survival could not be estimated in either assessment. The committee recognised that there was no trial evidence on the effect of obinutuzumab on progression-free survival after 5 years. Therefore, the committee concluded that obinutuzumab delays disease progression in the short term, but that there is uncertainty about its long-term effect on progression-free survival.
## There is merit in determining progression by both investigator and independent committee
The committee discussed whether the investigator or the independent review committee assessment of progression-free survival was more appropriate for inferring the effectiveness of obinutuzumab. The committee recalled that it usually prefers outcomes assessed by an independent review committee from trials in which both investigators and patients knew the treatment allocation. This is because the risk of bias introduced by an open-label design is minimised when subjective outcomes are assessed independently. The clinical experts stated that, in clinical practice, disease progression is usually determined by radiographic evidence and usually occurs before symptomatic deterioration. They considered that the discrepancy in the results was because of strict adherence to the protocol-defined progression criteria by the independent committee. The company explained that it had chosen investigator-assessed progression-free survival as the primary outcome to produce 'quicker results' and to avoid inconsistent assessments in people followed up for long periods. The committee noted that, in its response to consultation, the company based its new analyses on outcomes assessed by an independent review committee; the committee agreed that this was appropriate.
## GALLIUM does not provide robust information on whether obinutuzumab-based treatments prolong survival compared with rituximab-based treatments
GALLIUM was not designed to estimate the difference in overall survival between the 2 treatments. At the time of the analysis, 7.8% of patients at higher risk had died, at which point there was no statistically significant difference between obinutuzumab and rituximab (HR 0.76; 95% CI 0.49 to 1.16). The clinical experts stated that the lack of an overall survival benefit with obinutuzumab despite a progression-free survival benefit was possible, and that there is often a discrepancy between the 2 outcomes in slowly growing lymphomas such as follicular lymphoma. The committee recognised that, in addition to the trial being underpowered to show a difference in overall survival, the data were highly immature. The committee also recognised that it had not been presented with evidence supporting the association between progression-free and overall survival in follicular lymphoma. The committee could not conclude that obinutuzumab prolongs overall survival compared with rituximab based on the evidence from GALLIUM.
## Time to next treatment may be more meaningful to patients than progression-free survival
The committee heard from clinical experts and the NHS England Cancer Drugs Fund clinical lead, who explained that time to next treatment is more relevant to patients than progression-free survival. The disease may progress slightly on radiographic scans, but with little or no impact on the patient's wellbeing and symptoms. As a result, people with follicular lymphoma may have a gap between disease progression and time to next treatment. So, ultimately what matters to patients is when they need a subsequent treatment. The committee noted the clinical experts' comment that time to next treatment would be longer in clinical practice than in clinical trials because clinicians assess patients less frequently in practice. The committee concluded that time to next treatment may be more meaningful to patients than progression-free survival. However, in response to consultation, the company noted that independently assessed progression-free survival is a more conservative measure than time to next treatment. The committee acknowledged this and used the company's modelled progression-free survival to make its decision, but considered that time to next treatment was a more meaningful outcome for patients.
## There is no difference in health-related quality of life for people having obinutuzumab or rituximab
In GALLIUM, data were collected on health-related quality of life using 2 tools: a lymphoma specific tool, the Functional Assessment of Cancer Therapy for Lymphoma (FACT‑Lym) questionnaire, and a generic tool, EQ‑5D‑3L. Patients were asked to fill in FACT‑Lym at baseline, on completing induction, on completing maintenance and at 36‑month follow up. The committee noted that the differences in the EQ‑5D scores between arms were not statistically significant.
# Safety results
## Obinutuzumab-based therapy is associated with a higher rate of adverse events than rituximab-based therapy
In the overall follicular lymphoma population of GALLIUM, more patients in the obinutuzumab arm than in the rituximab arm had adverse events of grade 3 or more (76.6% compared with 70.0%), serious adverse events (46.6% compared with 40.0%), adverse events leading to stopping any treatment (16.0% compared with 14.4%) and fatal adverse events (4.0% compared with 3.4%). The committee concluded that obinutuzumab is associated with a higher burden of adverse events than rituximab, and that it was important to adequately capture this in the economic model.
# Cost effectiveness
## Different modelled states for early- and late-progressing disease are acceptable
To estimate cost effectiveness, the company used a state-transition Markov model with 4 states:
progression-free state (which the company further divided into 2 sub-states: on and off treatment)
early progressed-disease state (progression within 2 years after starting treatment)
late progressed-disease state (progression 2 or more years after starting treatment)
death.The committee questioned the rationale for separating early and late disease progression. The clinical experts explained that the people whose disease progresses early have a worse prognosis than people whose disease progresses late. The committee accepted the separate modelling of early- and late-progressing disease and the 2‑year cut-off to differentiate them.
## It is preferable to model treatment effects independently
When the company first modelled progression-free survival, it assumed proportional hazards during the first 9 years (that is, the effect of obinutuzumab relative to rituximab remains the same over time). The company based this assumption on log-cumulative hazard plots for progression-free survival from GALLIUM, which it interpreted to be parallel. However, the committee considered that the plots converged, suggesting that the proportional hazards assumption did not hold. Responding to this, the company revised its model to assume non-proportional hazards, and modelled treatment effects independently.
## The revised extrapolation of progression-free survival is appropriate
The company initially used an exponential function (assuming proportional hazards) to extrapolate and explore the likely progression-free survival benefit of obinutuzumab beyond the follow-up period of GALLIUM. At the first committee meeting, the ERG suggested that a Weibull extrapolation model assuming non-proportional hazards was more appropriate, which the committee accepted. The company argued that the Weibull function was inappropriate because it implied that the risk of progression increased with time spent in the progression-free state. After consultation, it submitted a revised model using a log-logistic extrapolation and assuming non-proportional hazards. The committee accepted that, in the full population, risk of progression may not increase with time spent in the progression-free state. It recognised that the patients who are progression free for a long time could plausibly be the patients who started with a lower baseline risk, and that their risk of progression may remain low over time. However, the committee decided that this assumption would not hold for the higher-risk subgroup because it would not include patients whose risk starts and remains low. Because of this, the committee concluded that the Weibull distribution remained a potential extrapolation option. The committee compared various functions to see whether the modelled extrapolated outcomes were clinically plausible. The company's clinical experts had originally estimated that 30% to 40% of patients in the overall population having rituximab would remain progression free at 10 years. The committee understood that fewer patients at higher risk may remain progression free at 10 years compared with the overall follicular lymphoma population, but decided that the experts' estimates of progression-free survival for patients using rituximab were appropriate for estimating progression-free survival for patients using obinutuzumab. The log-logistic model predicted that 41.3% of patients at higher risk having rituximab would remain progression free for 10 years. Because this prediction fell outside the clinically plausible range estimated by experts, the committee considered that the log-logistic model overestimated progression-free survival. The Gompertz, Weibull and exponential distributions provided estimates within the experts' range for 10‑year progression-free survival using rituximab (36.7%, 34.3% and 36.7% respectively). The committee decided that the Gompertz distribution was too pessimistic because the number of people remaining progression free declined at a much higher rate after 10 years in the obinutuzumab arm than the rituximab arm. The committee concluded that estimates based on the Weibull or exponential functions estimated progression-free survival more realistically. After the second committee meeting, the company submitted a revised model and provided incremental cost-effectiveness ratios (ICERs) based only on Weibull and exponential extrapolations, in line with the committee's preference.
## The treatment effect duration is more than 5 years but much less than 20 years
When extrapolating progression-free survival, the company initially assumed that the benefit of obinutuzumab over rituximab would last for 9 years after starting treatment (6.5 years after the 2.5 years of maximum treatment duration with obinutuzumab) and then stop. This was because the company had interpreted the results from PRIMA to show that the effect of rituximab maintenance treatment compared with 'observation only' did not decrease during the 9‑year follow up. However, the committee did not consider that generalising evidence from 1 population who had rituximab (PRIMA) to a different population who had obinutuzumab (GALLIUM) necessarily reflected the course of patients having obinutuzumab-based therapy. The committee preferred to see analyses assuming no effect beyond the GALLIUM trial follow up of 5 years. In response to consultation, the company provided evidence of a treatment effect for obinutuzumab in a different setting (obinutuzumab compared with rituximab in chronic lymphocytic leukaemia; median progression-free survival of 2.4 years compared with 1.3 years). The company also provided additional evidence for the duration of rituximab's treatment effect, and argued that obinutuzumab would have a similar effect because it has a similar mechanism of action to rituximab (2 studies of rituximab plus chemotherapy compared with chemotherapy alone reported treatment effects of 8.4 years and 8.7 years). The company revised its economic model to assume non-proportional hazards between obinutuzumab and rituximab (see section 3.17), which lowered the treatment effect of obinutuzumab compared with rituximab. The company argued that this removed the need to limit the duration of the treatment effect. The committee noted that the company's model (which used a log-logistic progression-free survival extrapolation) implied a treatment effect of obinutuzumab compared with rituximab of approximately 20 years. The committee was also aware that using a Weibull extrapolation without limiting the treatment effect duration implied a treatment effect of approximately 33 years, and using an exponential extrapolation without limiting the treatment effect duration implied an indefinite treatment effect. The committee acknowledged that treatment effect duration was uncertain, but recalled that it had not seen any clinical evidence of a 20‑year treatment effect. Based on the clinical evidence presented by the company, the committee concluded that the treatment effect duration was longer than 5 years but much less than 20 years. After the second committee meeting, the company provided ICER estimates based on treatment effect durations of 5 years and 9 years, which the committee used to make its decision.
## There is uncertainty about the size of the overall survival benefit of obinutuzumab
The company estimated overall survival as the estimated time spent in the progression-free state plus the estimated time spent in the post-progression state. This meant that the increase in progression-free survival with obinutuzumab-based therapy translated into an overall survival gain. The committee recalled that overall survival data from GALLIUM were highly immature, and that the relationship between progression-free and overall survival was not well established in follicular lymphoma (see section 3.12). Because of this, the committee considered the company's approach to modelling overall survival represented an optimistic scenario and concluded that the evidence did not support the company's original modelling of overall survival. In response to consultation, the company argued that the overall survival benefit modelled was similar to the benefit of obinutuzumab in the rituximab-refractory follicular lymphoma setting and the benefit of rituximab in the first-line induction setting. The Cancer Drugs Fund clinical lead suggested that a progression-free survival benefit was likely to translate to overall survival benefit, but that this would be hard to quantify given the different lines of treatment patients had. The Cancer Drugs Fund clinical lead advised that there was evidence of a benefit in prognosis from rituximab, and that it would be reasonable to assume a similar benefit in obinutuzumab. The committee agreed that there was a likely overall survival benefit, but that there was uncertainty about the size of this benefit because of the lack of evidence from the GALLIUM trial.
# Health-related quality of life
## The utility value for the progressed-disease state is acceptable
The company used utility values derived from EQ‑5D measures from GALLIUM for the progression-free state (for both on- and off-treatment states), but used values from the literature for the progressed-disease state (Wild et al. 2006; Wild et al. 2005). The company used utility values of 0.62 (Wild et al. 2006) and 0.77 (Wild et al. 2005) to reflect the early and late-progressing disease states (because people whose disease progresses early have a worse prognosis than people whose disease progresses late). According to the company's submission, Wild et al. collected data from 222 patients with follicular lymphoma in 8 UK centres using the EQ‑5D questionnaire. The company chose not to use values derived from GALLIUM to populate the progressed-disease states because, in its opinion, data from GALLIUM were collected only once after progression and so did not capture advanced stages of progression. The committee was concerned that these values lacked face validity because they were lower than expected for a patient population with the prospect of a long life expectancy after disease progression. However, it acknowledged that the quality of life of patients with progressed disease was uncertain and concluded that the company's approach was acceptable.
# Resource use
## Vial sharing is a realistic assumption for intravenous rituximab
In the company's analysis, the acquisition costs of obinutuzumab and rituximab were confidential because of nationally available confidential discounts. In its base case, the company initially assumed vial sharing for both obinutuzumab and rituximab. The committee heard from the NHS England representative that obinutuzumab is given as a fixed dose, so there would be no vial sharing. For rituximab, however, it heard from the NHS England representative that the NHS uses a Commissioning for Quality and Innovation (CQUIN) for 'hospital medicines optimisation' to promote fully optimising medicines commissioned by specialised services. This includes vial sharing for rituximab because of its many indications across oncology, dermatology, rheumatology and nephrology. The committee concluded that the model should allow for some vial sharing for intravenous rituximab, but not for obinutuzumab. After the second committee meeting, the company updated its model to reflect this.
## Subcutaneous rituximab would incur a lower administration cost than intravenous administration
The committee was aware that rituximab can be given intravenously or subcutaneously, and that subcutaneous rituximab is cheaper to administer. In the model, the company assumed that rituximab would only be given intravenously during induction but that, based on its market research, a proportion of patients would have rituximab subcutaneously during the maintenance phase, which would incur a lower administration cost. The committee heard from the representative from NHS England that the proportion used by the company was reasonable.
## The modelled administration costs are acceptable for decision making
The company initially assumed the same administration costs for intravenous rituximab and obinutuzumab during induction (£407 for the first infusion, which takes longer, and £361 for subsequent infusions) and during maintenance (£337). However, the committee understood that administration costs were likely to be higher for obinutuzumab because obinutuzumab infusions take longer than rituximab infusions. In response to consultation, the company revised the administration costs to reflect this. However, the Cancer Drugs Fund clinical lead noted that the administration costs were not correct because of differences in the number of appointments needed for each accompanying chemotherapy treatment; for example, obinutuzumab with bendamustine costs more to administer than obinutuzumab with CVP or CHOP (£1,352 compared with £1,047 respectively). The company updated its model using administration costs based on national reference costs specific to each chemotherapy treatment, plus pharmacy and transport costs. The ERG agreed with the company's chosen source for administration costs. The committee acknowledged that, although the tariff costs suggested by the Cancer Drugs Fund clinical lead were more recent than the national reference costs, the effect on the ICER was likely to be modest. The committee concluded that the administration costs modelled by the company were acceptable for decision making.
## The availability of cheaper rituximab biosimilars should be taken into account
The company's model assumed that a proportion of patients have rituximab maintenance treatment subcutaneously, and that the remaining patients have rituximab intravenously. The committee was aware that 2 biosimilar versions of intravenous rituximab have a marketing authorisation. NHS England encourages use of biosimilars through a CQUIN for 'hospital medicines optimisation' because biosimilars are similarly effective to branded medications and less expensive. The manufacturers of rituximab biosimilars have discounted price agreements with NHS England, which they shared with NICE in confidence. The ERG used the price for biosimilar rituximab in the company's base case and scenario analyses, and in its own exploratory analyses. The committee initially decided that analyses using the acquisition costs of biosimilar rituximab would be the basis of its recommendation. However, in response to consultation, the company argued that the uptake of biosimilars would not be 100%, referencing uptake of etanercept and infliximab biosimilars described in the commissioning framework for biological medicines. Following this, the committee heard from the Cancer Drugs Fund clinical lead that uptake of biosimilar rituximab was around 40% in October 2017 and 65% in November 2017, and is increasing rapidly. The company modelled 40% biosimilar uptake in its final model. The committee agreed to use the most recent biosimilar uptake estimate (65%) for decision making.
## The company did not incorporate the subsequent treatment costs properly in the model
The company modelled the costs of subsequent lines of treatment taken after obinutuzumab or rituximab by applying a single cost at disease progression. It assumed that next-line treatment would be the same between both treatment arms and for early or late disease progression, and that costs and outcomes would be similar. The committee understood that, in clinical practice, subsequent treatment costs would be likely to increase with time spent in the progressed-disease state. It was unsure about whether obinutuzumab's effect in delaying progression would result in a decrease in time spent in the progressed-disease state because of the uncertainty about whether obinutuzumab prolonged survival (see section 3.20). The committee decided that the subsequent treatment costs could be better captured in the model, although it was uncertain about how this would affect the ICER.
# Cost-effectiveness results
## The company modelled most of the committee's preferred assumptions
The company's final model assumed:
vial sharing for rituximab only
that administration costs could be based on NHS reference costs, accounting for differences between any accompanying chemotherapy treatment.The company presented scenario analyses that considered Weibull and exponential extrapolations for progression-free survival and varied the treatment effect duration between 5 years and 9 years. Although the committee agreed that the company's model could have better captured subsequent treatment costs, it concluded that the model captured most of its preferred assumptions and was appropriate for decision making.
## The most plausible ICER comparing obinutuzumab with rituximab is less than £30,000 per QALY gained
The company presented ICER estimates for Weibull and exponential extrapolations for progression-free survival and for treatment effect durations of 5 years and 9 years. The ERG recalculated the ICERs from these analyses to include the confidential discounted biosimilar prices and a 65% uptake of biosimilar rituximab. The recalculated ICERs were less than £30,000 per quality-adjusted life year (QALY) gained for obinutuzumab-based therapy compared with rituximab-based therapy. The committee acknowledged that there was substantial uncertainty in the evidence base and ICER in terms of the treatment effect duration and immaturity of the clinical data. However, the committee concluded that obinutuzumab, provided with the discount agreed in the patient access scheme, is a cost-effective use of NHS resources for adults with untreated follicular lymphoma with a FLIPI score of 2 or more.
# End of life
## Obinutuzumab is not a life-extending treatment
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee heard from the company that life expectancy for people with treated follicular lymphoma exceeds 2 years, and concluded that obinutuzumab for first-line treatment of advanced follicular lymphoma did not meet the end-of-life criteria.
# Innovation
## Obinutuzumab is not innovative
The company explained that it considered obinutuzumab to be innovative. However, the committee heard from the clinical experts that obinutuzumab's mechanism was similar to that of rituximab, so it did not reflect a 'step change' in treatment. The committee did not identify health benefits excluded from the modelling. It concluded that obinutuzumab was new, but not innovative.
|
{'Recommendations': "Obinutuzumab is recommended as an option for untreated advanced follicular lymphoma in adults (that is, first as induction treatment with chemotherapy, then alone as maintenance therapy), only if:\n\nthe person has a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2\xa0or more\n\nthe company provides obinutuzumab according to the\xa0commercial arrangement.\n\nThis recommendation is not intended to affect treatment with obinutuzumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent first-line treatment for symptomatic advanced follicular lymphoma is induction therapy with rituximab plus chemotherapy, followed by maintenance treatment with rituximab when there has been a response to induction therapy.\n\nThe main evidence on the effectiveness and safety of obinutuzumab is from an ongoing clinical trial. It shows that obinutuzumab plus chemotherapy followed by obinutuzumab maintenance treatment delays disease progression more than current treatment. However, it also shows that undesirable side effects are more common with obinutuzumab than with rituximab. There are not enough data to know with certainty whether obinutuzumab increases life expectancy.\n\nThe company's revised economic analyses focuses on higher-risk subgroups. Obinutuzumab costs more than branded rituximab and even more than the biosimilar versions of rituximab. However, using the preferred assumptions and the discounted prices for obinutuzumab and rituximab, the cost-effectiveness estimate for obinutuzumab plus chemotherapy followed by obinutuzumab maintenance treatment, compared with rituximab plus chemotherapy followed by rituximab maintenance treatment, is lower than £30,000 per quality-adjusted life year gained. Therefore, obinutuzumab is recommended as an option for untreated advanced follicular lymphoma in patients at higher risk.", 'Information about obinutuzumab': "# Marketing authorisation indication\n\nObinutuzumab (Gazyvaro, Roche) 'in combination with chemotherapy, followed by [obinutuzumab] maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma'.\n\n# Dosage in the marketing authorisation\n\nObinutuzumab is given by intravenous infusion. Induction consists of obinutuzumab plus chemotherapy dosage:\n\nwith cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or cyclophosphamide, vincristine and prednisolone (CVP):\n\n\n\ncycle 1: 1,000 mg on days 1, 8 and 15 of the first 21‑day treatment cycle\n\ncycles 2 to 8: 1,000 mg on day 1 of each 21‑day treatment cycle (with the CHOP regimen, obinutuzumab is given alone for the last 2 cycles), or\n\n\n\nwith bendamustine:\n\n\n\ncycle 1: 1,000 mg on days 1, 8 and 15 of the first 28‑day treatment cycle\n\ncycles 2 to 6: 1,000 mg on day 1 of each 28‑day treatment cycle and\n\n\n\nmaintenance dosage of 1,000\xa0mg every 2\xa0months for 2\xa0years or until disease progression (whichever occurs first).\n\n# Price\n\n£3,312 per 1,000‑mg vial (excluding VAT; BNF online, August 2017). The company has a commercial arrangement. This makes obinutuzumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need in advanced follicular lymphoma\n\n## People with follicular lymphoma want further options for treatment\n\nFollicular lymphoma progresses slowly over many years, often without symptoms. The patient experts noted that, despite this, knowing that the disease will eventually progress can cause considerable distress. People also realise that they will need further treatment when the disease progresses, which adds to the physical and psychological burden, and increases their wish to have more treatment options. The committee agreed that delaying disease progression and having treatment options would benefit people with untreated follicular lymphoma.\n\n# Treatment pathway\n\n## People with symptomatic disease are the relevant population\n\nThe clinical experts advised that they do not routinely offer active treatment to people with asymptomatic disease, and instead use 'watchful waiting'. Although the NICE guideline on non-Hodgkin's lymphoma also recommends rituximab induction therapy for people with advanced-stage (stages\xa03 and\xa04) asymptomatic follicular lymphoma, the clinical experts stated that this does not reflect clinical practice. They explained that active treatment is normally reserved for people with symptomatic disease who have bulky disease at multiple sites, especially if lymph nodes cause problems because of their location, or if people have fever, night sweats or unintentional weight loss. The committee concluded that people with symptomatic disease reflect the relevant population to consider in this appraisal.\n\n## Rituximab plus chemotherapy is the main treatment for untreated follicular lymphoma\n\nThe clinical experts explained that rituximab plus chemotherapy is the main 'induction treatment' for untreated advanced follicular lymphoma. Other potential options for induction therapy include:\n\nRituximab alone: the clinical experts advised that this is rarely used to treat symptomatic disease; they may use it when chemotherapy is not indicated, or if the person would prefer starting treatment rather than 'watchful waiting'.\n\nBendamustine alone: this does not have a marketing authorisation for the first-line treatment of follicular lymphoma, but is funded for this indication through the Cancer Drugs Fund. The clinical experts expressed that, in NHS clinical practice, bendamustine alone (rather than with an immunotherapy such as rituximab or obinutuzumab) is hardly ever used as first-line treatment.The committee concluded that rituximab plus chemotherapy is the most commonly used first-line induction treatment for symptomatic advanced follicular lymphoma.\n\n## The chemotherapies most commonly used with rituximab are CVP, bendamustine and CHOP\n\nNICE technology appraisal guidance on rituximab for the first-line treatment of stage\xa03 to\xa04 follicular lymphoma recommends rituximab plus 1\xa0of the following chemotherapy regimens:\n\ncyclophosphamide, vincristine and prednisolone (CVP)\n\ncyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine and prednisolone (CHOP)\n\nmitoxantrone, chlorambucil and prednisolone (MCP)\n\ncyclophosphamide, doxorubicin, etoposide (VP‑16), prednisolone and interferon alfa (CHVPi) and\n\nchlorambucil.Rituximab plus bendamustine is also available through the Cancer Drugs Fund. The clinical experts stated that most people in the NHS have either rituximab plus CVP or rituximab plus bendamustine or, to a lesser extent, rituximab plus CHOP as induction treatment. CHOP is associated with more adverse effects than the other 2\xa0regimens. Therefore, bendamustine and CVP are more commonly used. CHOP is more likely to be reserved for high-grade follicular lymphoma at risk of transformation to a more aggressive form (large diffuse B‑cell lymphoma) and also for younger, fitter people who can better tolerate the potential cardiotoxicity of doxorubicin. The clinical experts noted that bendamustine use has declined since the Medicines and Healthcare products Regulatory Agency issued a safety alert about off-label use of bendamustine as a first-line treatment for follicular lymphoma plus an immunotherapy (such as rituximab or obinutuzumab). The committee concluded that, in clinical practice, CVP, CHOP and bendamustine are the main chemotherapies used with induction therapy, and that the adverse effects of each chemotherapy largely drive treatment choice.\n\n## Rituximab maintenance therapy is recommended when there has been a response to induction therapy\n\nIf the disease goes into complete or partial remission with induction therapy, rituximab monotherapy is generally given as 'maintenance treatment' for up to 2\xa0years. The scope for this appraisal included rituximab-based chemotherapy without rituximab maintenance treatment as a comparator. The committee noted that, in its technology appraisal guidance on rituximab, NICE recommended rituximab maintenance treatment for follicular lymphoma that has responded to first-line induction therapy with rituximab plus chemotherapy. The clinical experts explained that using rituximab maintenance therapy is increasingly controversial, citing the PRIMA study. In this, patients were randomised to rituximab maintenance treatment or observation only. The results of the PRIMA study showed: no survival benefit; a modest benefit with respect to progression-free survival and time to next treatment; an increased risk of infections including reactivation of hepatitis\xa0B; and long-term safety concerns. Nevertheless, the clinical experts stated that, in clinical practice, most people (around 80% to 90%) whose disease responds to induction therapy have rituximab maintenance therapy. The NHS England's Cancer Drugs Fund clinical lead explained that maintenance treatment is available in routine commissioning, and should be considered for all people whose disease has responded to induction treatment. The committee concluded that rituximab maintenance therapy, following response to induction therapy, reflects routine clinical practice in the NHS, and that induction not followed by rituximab monotherapy was not a relevant comparator for this appraisal.\n\n## Rituximab plus chemotherapy followed by rituximab maintenance is the appropriate comparator\n\nBased on information from the clinical experts and NHS England, the committee did not consider the following 3\xa0comparators specified in the final scope to be relevant:\n\nrituximab monotherapy\n\nrituximab-based chemotherapy without rituximab maintenance treatment\n\nbendamustine monotherapy.Referring to its discussion on the treatment pathway (see sections\xa03.2 to\xa03.5), the committee concluded that the appropriate comparison should be between obinutuzumab plus either CHOP, CVP or bendamustine followed by obinutuzumab maintenance treatment, and rituximab plus either CHOP, CVP or bendamustine followed by rituximab maintenance treatment, in line with the company's decision problem.\n\n# Clinical evidence\n\n## The main evidence is from GALLIUM, an open-label randomised controlled trial\n\nThe main clinical evidence for this appraisal came from an ongoing, open-label phase\xa03 randomised controlled trial (GALLIUM). GALLIUM compared the efficacy and safety of induction therapy with obinutuzumab plus chemotherapy followed by obinutuzumab maintenance treatment (n=601) with rituximab plus chemotherapy induction therapy followed by rituximab maintenance treatment (n=601) in adults with advanced follicular lymphoma (grades\xa01 to\xa03a). The primary outcome was progression-free survival assessed by the investigator, defined as the time from day of randomisation until first symptomatic deterioration, disease transformation or death from any cause, whichever occurred first. Progression-free survival assessed through a radiological and oncological review of patient responses by an independent review committee was a secondary outcome. Patients were treated across 177\xa0trial sites in 18\xa0countries, including the UK (n=293 patients). Each site chose 1\xa0of the 3\xa0chemotherapeutic regimens (CHOP, CVP or bendamustine) to accompany obinutuzumab or rituximab (that is, all patients at a given site had the same concomitant chemotherapy, whether with obinutuzumab or rituximab). Two of the prespecified subgroups in GALLIUM were patients at intermediate or high risk of mortality, categorised by Follicular Lymphoma International Prognostic Index (FLIPI) scores (n=474). In response to consultation, the company suggested that patients in these subgroups were the most relevant population (see section\xa03.9). The company based its analysis on these higher-risk subgroups.\n\n## The whole population in GALLIUM reasonably reflects the NHS population\n\nThe committee discussed whether the population in GALLIUM reflected people who would be offered treatment in the NHS with respect to:\n\nAge: the median age of patients in GALLIUM was 59.0\xa0years. The committee heard from the clinical experts and the ERG that this reflected a younger population than would be seen in clinical practice. In response to consultation, the company changed the median age used in its economic model to 62.2\xa0years.\n\nEthnicity: the committee heard that some ethnic groups were under-represented in GALLIUM (for example, black people of African or Caribbean family origin).\n\nChemotherapeutic regimen used with obinutuzumab or rituximab: the committee noted the discrepancy between the distribution of concomitant chemotherapies used in GALLIUM and clinical practice. In particular, patients in GALLIUM were more likely to have bendamustine than in the NHS. The committee was not presented with evidence on the differential effectiveness of the chemotherapies given with obinutuzumab or rituximab. However, it took the view that any differences in the proportions of treatments used between the trial and NHS practice would be unlikely to affect the generalisability of the trial's results.The committee was satisfied that the overall trial population reasonably reflected people with advanced follicular lymphoma having treatment in the NHS.\n\n## Patients who are at intermediate or high risk from GALLIUM are a clinically relevant population\n\nThe summary of product characteristics states that obinutuzumab's efficacy in patients at low risk of premature mortality (that is, people with FLIPI score of 0\xa0to\xa01) is 'inconclusive'. Because of this, and in response to consultation, the company changed the population in its analysis from all people with advanced follicular lymphoma to people with an intermediate or high FLIPI score (collectively called patients at higher risk because they are at higher risk of dying than patients with lower scores). The committee questioned whether clinicians use FLIPI scores to categorise severity of disease. The Cancer Drugs Fund clinical lead explained that FLIPI scores are not routinely used to inform treatment, but they are used to assess prognosis. This was confirmed by comments submitted by the clinical experts who attended the first meeting. The committee understood that the factors used to determine FLIPI scores (such as stage of Ann Arbor classification system, haemoglobin, serum lactate dehydrogenase and number of nodal sites affected) are already routinely measured, and that using FLIPI scores to inform treatment would not be a large extra burden for the NHS. Overall, the committee was satisfied that the higher-risk subgroup (based on FLIPI scores) was the clinically relevant population to consider in this appraisal.\n\n# Efficacy results\n\n## Obinutuzumab delays disease progression in the short term, but its longer-term effect on progression-free survival is unknown\n\nThe company had done several analyses in the higher-risk subgroup, including the prespecified 'primary analysis' for progression-free survival on 31\xa0January 2016 and the post-hoc 'updated analysis' on 10\xa0September 2016. The committee noted that, as of September 2016, 81.7% of patients at higher risk randomised to obinutuzumab compared with 72.5% of those randomised to rituximab were alive and free of disease progression (as assessed by investigators). For progression-free survival assessed by the independent review committee, the respective proportions were 83.2% and 76.0%. Obinutuzumab reduced the risk of disease progression in patients at higher risk by 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.47 to 0.80) according to investigator assessment, and by 33% (HR\xa00.67, 95%\xa0CI 0.51 to 0.88) according to the independent review committee. Because there were few events, median progression-free survival could not be estimated in either assessment. The committee recognised that there was no trial evidence on the effect of obinutuzumab on progression-free survival after 5\xa0years. Therefore, the committee concluded that obinutuzumab delays disease progression in the short term, but that there is uncertainty about its long-term effect on progression-free survival.\n\n## There is merit in determining progression by both investigator and independent committee\n\nThe committee discussed whether the investigator or the independent review committee assessment of progression-free survival was more appropriate for inferring the effectiveness of obinutuzumab. The committee recalled that it usually prefers outcomes assessed by an independent review committee from trials in which both investigators and patients knew the treatment allocation. This is because the risk of bias introduced by an open-label design is minimised when subjective outcomes are assessed independently. The clinical experts stated that, in clinical practice, disease progression is usually determined by radiographic evidence and usually occurs before symptomatic deterioration. They considered that the discrepancy in the results was because of strict adherence to the protocol-defined progression criteria by the independent committee. The company explained that it had chosen investigator-assessed progression-free survival as the primary outcome to produce 'quicker results' and to avoid inconsistent assessments in people followed up for long periods. The committee noted that, in its response to consultation, the company based its new analyses on outcomes assessed by an independent review committee; the committee agreed that this was appropriate.\n\n## GALLIUM does not provide robust information on whether obinutuzumab-based treatments prolong survival compared with rituximab-based treatments\n\nGALLIUM was not designed to estimate the difference in overall survival between the 2\xa0treatments. At the time of the analysis, 7.8% of patients at higher risk had died, at which point there was no statistically significant difference between obinutuzumab and rituximab (HR\xa00.76; 95%\xa0CI 0.49 to 1.16). The clinical experts stated that the lack of an overall survival benefit with obinutuzumab despite a progression-free survival benefit was possible, and that there is often a discrepancy between the 2\xa0outcomes in slowly growing lymphomas such as follicular lymphoma. The committee recognised that, in addition to the trial being underpowered to show a difference in overall survival, the data were highly immature. The committee also recognised that it had not been presented with evidence supporting the association between progression-free and overall survival in follicular lymphoma. The committee could not conclude that obinutuzumab prolongs overall survival compared with rituximab based on the evidence from GALLIUM.\n\n## Time to next treatment may be more meaningful to patients than progression-free survival\n\nThe committee heard from clinical experts and the NHS England Cancer Drugs Fund clinical lead, who explained that time to next treatment is more relevant to patients than progression-free survival. The disease may progress slightly on radiographic scans, but with little or no impact on the patient's wellbeing and symptoms. As a result, people with follicular lymphoma may have a gap between disease progression and time to next treatment. So, ultimately what matters to patients is when they need a subsequent treatment. The committee noted the clinical experts' comment that time to next treatment would be longer in clinical practice than in clinical trials because clinicians assess patients less frequently in practice. The committee concluded that time to next treatment may be more meaningful to patients than progression-free survival. However, in response to consultation, the company noted that independently assessed progression-free survival is a more conservative measure than time to next treatment. The committee acknowledged this and used the company's modelled progression-free survival to make its decision, but considered that time to next treatment was a more meaningful outcome for patients.\n\n## There is no difference in health-related quality of life for people having obinutuzumab or rituximab\n\nIn GALLIUM, data were collected on health-related quality of life using 2\xa0tools: a lymphoma specific tool, the Functional Assessment of Cancer Therapy for Lymphoma (FACT‑Lym) questionnaire, and a generic tool, EQ‑5D‑3L. Patients were asked to fill in FACT‑Lym at baseline, on completing induction, on completing maintenance and at 36‑month follow\xa0up. The committee noted that the differences in the EQ‑5D scores between arms were not statistically significant.\n\n# Safety results\n\n## Obinutuzumab-based therapy is associated with a higher rate of adverse events than rituximab-based therapy\n\nIn the overall follicular lymphoma population of GALLIUM, more patients in the obinutuzumab arm than in the rituximab arm had adverse events of grade\xa03 or more (76.6% compared with 70.0%), serious adverse events (46.6% compared with 40.0%), adverse events leading to stopping any treatment (16.0% compared with 14.4%) and fatal adverse events (4.0% compared with 3.4%). The committee concluded that obinutuzumab is associated with a higher burden of adverse events than rituximab, and that it was important to adequately capture this in the economic model.\n\n# Cost effectiveness\n\n## Different modelled states for early- and late-progressing disease are acceptable\n\nTo estimate cost effectiveness, the company used a state-transition Markov model with 4\xa0states:\n\nprogression-free state (which the company further divided into 2\xa0sub-states: on and off treatment)\n\nearly progressed-disease state (progression within 2\xa0years after starting treatment)\n\nlate progressed-disease state (progression 2\xa0or more years after starting treatment)\n\ndeath.The committee questioned the rationale for separating early and late disease progression. The clinical experts explained that the people whose disease progresses early have a worse prognosis than people whose disease progresses late. The committee accepted the separate modelling of early- and late-progressing disease and the 2‑year cut-off to differentiate them.\n\n## It is preferable to model treatment effects independently\n\nWhen the company first modelled progression-free survival, it assumed proportional hazards during the first 9\xa0years (that is, the effect of obinutuzumab relative to rituximab remains the same over time). The company based this assumption on log-cumulative hazard plots for progression-free survival from GALLIUM, which it interpreted to be parallel. However, the committee considered that the plots converged, suggesting that the proportional hazards assumption did not hold. Responding to this, the company revised its model to assume non-proportional hazards, and modelled treatment effects independently.\n\n## The revised extrapolation of progression-free survival is appropriate\n\nThe company initially used an exponential function (assuming proportional hazards) to extrapolate and explore the likely progression-free survival benefit of obinutuzumab beyond the follow-up period of GALLIUM. At the first committee meeting, the ERG suggested that a Weibull extrapolation model assuming non-proportional hazards was more appropriate, which the committee accepted. The company argued that the Weibull function was inappropriate because it implied that the risk of progression increased with time spent in the progression-free state. After consultation, it submitted a revised model using a log-logistic extrapolation and assuming non-proportional hazards. The committee accepted that, in the full population, risk of progression may not increase with time spent in the progression-free state. It recognised that the patients who are progression free for a long time could plausibly be the patients who started with a lower baseline risk, and that their risk of progression may remain low over time. However, the committee decided that this assumption would not hold for the higher-risk subgroup because it would not include patients whose risk starts and remains low. Because of this, the committee concluded that the Weibull distribution remained a potential extrapolation option. The committee compared various functions to see whether the modelled extrapolated outcomes were clinically plausible. The company's clinical experts had originally estimated that 30% to 40% of patients in the overall population having rituximab would remain progression free at 10\xa0years. The committee understood that fewer patients at higher risk may remain progression free at 10\xa0years compared with the overall follicular lymphoma population, but decided that the experts' estimates of progression-free survival for patients using rituximab were appropriate for estimating progression-free survival for patients using obinutuzumab. The log-logistic model predicted that 41.3% of patients at higher risk having rituximab would remain progression free for 10\xa0years. Because this prediction fell outside the clinically plausible range estimated by experts, the committee considered that the log-logistic model overestimated progression-free survival. The Gompertz, Weibull and exponential distributions provided estimates within the experts' range for 10‑year progression-free survival using rituximab (36.7%, 34.3% and 36.7% respectively). The committee decided that the Gompertz distribution was too pessimistic because the number of people remaining progression free declined at a much higher rate after 10\xa0years in the obinutuzumab arm than the rituximab arm. The committee concluded that estimates based on the Weibull or exponential functions estimated progression-free survival more realistically. After the second committee meeting, the company submitted a revised model and provided incremental cost-effectiveness ratios (ICERs) based only on Weibull and exponential extrapolations, in line with the committee's preference.\n\n## The treatment effect duration is more than 5\xa0years but much less than 20\xa0years\n\nWhen extrapolating progression-free survival, the company initially assumed that the benefit of obinutuzumab over rituximab would last for 9\xa0years after starting treatment (6.5\xa0years after the 2.5\xa0years of maximum treatment duration with obinutuzumab) and then stop. This was because the company had interpreted the results from PRIMA to show that the effect of rituximab maintenance treatment compared with 'observation only' did not decrease during the 9‑year follow\xa0up. However, the committee did not consider that generalising evidence from 1\xa0population who had rituximab (PRIMA) to a different population who had obinutuzumab (GALLIUM) necessarily reflected the course of patients having obinutuzumab-based therapy. The committee preferred to see analyses assuming no effect beyond the GALLIUM trial follow\xa0up of 5\xa0years. In response to consultation, the company provided evidence of a treatment effect for obinutuzumab in a different setting (obinutuzumab compared with rituximab in chronic lymphocytic leukaemia; median progression-free survival of 2.4\xa0years compared with 1.3\xa0years). The company also provided additional evidence for the duration of rituximab's treatment effect, and argued that obinutuzumab would have a similar effect because it has a similar mechanism of action to rituximab (2\xa0studies of rituximab plus chemotherapy compared with chemotherapy alone reported treatment effects of 8.4\xa0years and 8.7\xa0years). The company revised its economic model to assume non-proportional hazards between obinutuzumab and rituximab (see section\xa03.17), which lowered the treatment effect of obinutuzumab compared with rituximab. The company argued that this removed the need to limit the duration of the treatment effect. The committee noted that the company's model (which used a log-logistic progression-free survival extrapolation) implied a treatment effect of obinutuzumab compared with rituximab of approximately 20\xa0years. The committee was also aware that using a Weibull extrapolation without limiting the treatment effect duration implied a treatment effect of approximately 33\xa0years, and using an exponential extrapolation without limiting the treatment effect duration implied an indefinite treatment effect. The committee acknowledged that treatment effect duration was uncertain, but recalled that it had not seen any clinical evidence of a 20‑year treatment effect. Based on the clinical evidence presented by the company, the committee concluded that the treatment effect duration was longer than 5\xa0years but much less than 20\xa0years. After the second committee meeting, the company provided ICER estimates based on treatment effect durations of 5\xa0years and 9\xa0years, which the committee used to make its decision.\n\n## There is uncertainty about the size of the overall survival benefit of obinutuzumab\n\nThe company estimated overall survival as the estimated time spent in the progression-free state plus the estimated time spent in the post-progression state. This meant that the increase in progression-free survival with obinutuzumab-based therapy translated into an overall survival gain. The committee recalled that overall survival data from GALLIUM were highly immature, and that the relationship between progression-free and overall survival was not well established in follicular lymphoma (see section\xa03.12). Because of this, the committee considered the company's approach to modelling overall survival represented an optimistic scenario and concluded that the evidence did not support the company's original modelling of overall survival. In response to consultation, the company argued that the overall survival benefit modelled was similar to the benefit of obinutuzumab in the rituximab-refractory follicular lymphoma setting and the benefit of rituximab in the first-line induction setting. The Cancer Drugs Fund clinical lead suggested that a progression-free survival benefit was likely to translate to overall survival benefit, but that this would be hard to quantify given the different lines of treatment patients had. The Cancer Drugs Fund clinical lead advised that there was evidence of a benefit in prognosis from rituximab, and that it would be reasonable to assume a similar benefit in obinutuzumab. The committee agreed that there was a likely overall survival benefit, but that there was uncertainty about the size of this benefit because of the lack of evidence from the GALLIUM trial.\n\n# Health-related quality of life\n\n## The utility value for the progressed-disease state is acceptable\n\nThe company used utility values derived from EQ‑5D measures from GALLIUM for the progression-free state (for both on- and off-treatment states), but used values from the literature for the progressed-disease state (Wild et al. 2006; Wild et al. 2005). The company used utility values of\xa00.62 (Wild et al. 2006) and 0.77 (Wild et al. 2005) to reflect the early and late-progressing disease states (because people whose disease progresses early have a worse prognosis than people whose disease progresses late). According to the company's submission, Wild et al. collected data from 222\xa0patients with follicular lymphoma in 8\xa0UK centres using the EQ‑5D questionnaire. The company chose not to use values derived from GALLIUM to populate the progressed-disease states because, in its opinion, data from GALLIUM were collected only once after progression and so did not capture advanced stages of progression. The committee was concerned that these values lacked face validity because they were lower than expected for a patient population with the prospect of a long life expectancy after disease progression. However, it acknowledged that the quality of life of patients with progressed disease was uncertain and concluded that the company's approach was acceptable.\n\n# Resource use\n\n## Vial sharing is a realistic assumption for intravenous rituximab\n\nIn the company's analysis, the acquisition costs of obinutuzumab and rituximab were confidential because of nationally available confidential discounts. In its base case, the company initially assumed vial sharing for both obinutuzumab and rituximab. The committee heard from the NHS England representative that obinutuzumab is given as a fixed dose, so there would be no vial sharing. For rituximab, however, it heard from the NHS England representative that the NHS uses a Commissioning for Quality and Innovation (CQUIN) for 'hospital medicines optimisation' to promote fully optimising medicines commissioned by specialised services. This includes vial sharing for rituximab because of its many indications across oncology, dermatology, rheumatology and nephrology. The committee concluded that the model should allow for some vial sharing for intravenous rituximab, but not for obinutuzumab. After the second committee meeting, the company updated its model to reflect this.\n\n## Subcutaneous rituximab would incur a lower administration cost than intravenous administration\n\nThe committee was aware that rituximab can be given intravenously or subcutaneously, and that subcutaneous rituximab is cheaper to administer. In the model, the company assumed that rituximab would only be given intravenously during induction but that, based on its market research, a proportion of patients would have rituximab subcutaneously during the maintenance phase, which would incur a lower administration cost. The committee heard from the representative from NHS England that the proportion used by the company was reasonable.\n\n## The modelled administration costs are acceptable for decision making\n\nThe company initially assumed the same administration costs for intravenous rituximab and obinutuzumab during induction (£407 for the first infusion, which takes longer, and £361 for subsequent infusions) and during maintenance (£337). However, the committee understood that administration costs were likely to be higher for obinutuzumab because obinutuzumab infusions take longer than rituximab infusions. In response to consultation, the company revised the administration costs to reflect this. However, the Cancer Drugs Fund clinical lead noted that the administration costs were not correct because of differences in the number of appointments needed for each accompanying chemotherapy treatment; for example, obinutuzumab with bendamustine costs more to administer than obinutuzumab with CVP or CHOP (£1,352 compared with £1,047 respectively). The company updated its model using administration costs based on national reference costs specific to each chemotherapy treatment, plus pharmacy and transport costs. The ERG agreed with the company's chosen source for administration costs. The committee acknowledged that, although the tariff costs suggested by the Cancer Drugs Fund clinical lead were more recent than the national reference costs, the effect on the ICER was likely to be modest. The committee concluded that the administration costs modelled by the company were acceptable for decision making.\n\n## The availability of cheaper rituximab biosimilars should be taken into account\n\nThe company's model assumed that a proportion of patients have rituximab maintenance treatment subcutaneously, and that the remaining patients have rituximab intravenously. The committee was aware that 2\xa0biosimilar versions of intravenous rituximab have a marketing authorisation. NHS England encourages use of biosimilars through a CQUIN for 'hospital medicines optimisation' because biosimilars are similarly effective to branded medications and less expensive. The manufacturers of rituximab biosimilars have discounted price agreements with NHS England, which they shared with NICE in confidence. The ERG used the price for biosimilar rituximab in the company's base case and scenario analyses, and in its own exploratory analyses. The committee initially decided that analyses using the acquisition costs of biosimilar rituximab would be the basis of its recommendation. However, in response to consultation, the company argued that the uptake of biosimilars would not be 100%, referencing uptake of etanercept and infliximab biosimilars described in the commissioning framework for biological medicines. Following this, the committee heard from the Cancer Drugs Fund clinical lead that uptake of biosimilar rituximab was around 40% in October 2017 and 65% in November 2017, and is increasing rapidly. The company modelled 40% biosimilar uptake in its final model. The committee agreed to use the most recent biosimilar uptake estimate (65%) for decision making.\n\n## The company did not incorporate the subsequent treatment costs properly in the model\n\nThe company modelled the costs of subsequent lines of treatment taken after obinutuzumab or rituximab by applying a single cost at disease progression. It assumed that next-line treatment would be the same between both treatment arms and for early or late disease progression, and that costs and outcomes would be similar. The committee understood that, in clinical practice, subsequent treatment costs would be likely to increase with time spent in the progressed-disease state. It was unsure about whether obinutuzumab's effect in delaying progression would result in a decrease in time spent in the progressed-disease state because of the uncertainty about whether obinutuzumab prolonged survival (see section\xa03.20). The committee decided that the subsequent treatment costs could be better captured in the model, although it was uncertain about how this would affect the ICER.\n\n# Cost-effectiveness results\n\n## The company modelled most of the committee's preferred assumptions\n\nThe company's final model assumed:\n\nvial sharing for rituximab only\n\nthat administration costs could be based on NHS reference costs, accounting for differences between any accompanying chemotherapy treatment.The company presented scenario analyses that considered Weibull and exponential extrapolations for progression-free survival and varied the treatment effect duration between 5\xa0years and 9\xa0years. Although the committee agreed that the company's model could have better captured subsequent treatment costs, it concluded that the model captured most of its preferred assumptions and was appropriate for decision making.\n\n## The most plausible ICER comparing obinutuzumab with rituximab is less than £30,000 per QALY gained\n\nThe company presented ICER estimates for Weibull and exponential extrapolations for progression-free survival and for treatment effect durations of 5\xa0years and 9\xa0years. The ERG recalculated the ICERs from these analyses to include the confidential discounted biosimilar prices and a 65% uptake of biosimilar rituximab. The recalculated ICERs were less than £30,000 per quality-adjusted life year (QALY) gained for obinutuzumab-based therapy compared with rituximab-based therapy. The committee acknowledged that there was substantial uncertainty in the evidence base and ICER in terms of the treatment effect duration and immaturity of the clinical data. However, the committee concluded that obinutuzumab, provided with the discount agreed in the patient access scheme, is a cost-effective use of NHS resources for adults with untreated follicular lymphoma with a FLIPI score of 2\xa0or more.\n\n# End of life\n\n## Obinutuzumab is not a life-extending treatment\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. The committee heard from the company that life expectancy for people with treated follicular lymphoma exceeds 2\xa0years, and concluded that obinutuzumab for first-line treatment of advanced follicular lymphoma did not meet the end-of-life criteria.\n\n# Innovation\n\n## Obinutuzumab is not innovative\n\nThe company explained that it considered obinutuzumab to be innovative. However, the committee heard from the clinical experts that obinutuzumab's mechanism was similar to that of rituximab, so it did not reflect a 'step change' in treatment. The committee did not identify health benefits excluded from the modelling. It concluded that obinutuzumab was new, but not innovative."}
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https://www.nice.org.uk/guidance/ta513
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Evidence-based recommendations on obinutuzumab (Gazyvaro) for untreated advanced follicular lymphoma in adults.
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99ea73f4aa362b70337a3ccabadd3fe93cac4b49
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nice
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Mosaicplasty for symptomatic articular cartilage defects of the knee
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Mosaicplasty for symptomatic articular cartilage defects of the knee
Evidence-based recommendations on mosaicplasty in people with symptomatic articular cartilage defects of the knee. This involves taking healthy cartilage from the edge .of the joint and inserting it into drilled tunnels in the damaged site.
# Recommendations
Current evidence on the safety and efficacy of mosaicplasty for knee cartilage defects is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
The procedure should only be done by surgeons experienced in cartilage surgery and with specific training in mosaicplasty for knee cartilage defects.
Clinicians should enter data from all patients having the procedure onto the International Cartilage Regeneration and Joint Preservation Society (ICRS) Patient Registry.# The condition, current treatments and procedure
# The condition
Chondral damage (that is, localised damage to the articular cartilage) in the knee can be caused by injury or arthritis, or it can occur spontaneously (a condition called osteochondritis dissecans). It can also occur because of knee instability, muscle weakness or abnormal unbalanced pressures, for example, after an injury to a ligament or meniscal cartilage. In young people, the most common cause of cartilage damage is sporting injuries. Symptoms associated with cartilage loss include pain, swelling, instability, and joint catching and locking, and may lead to degenerative changes in the joint (osteoarthritis).
# Current treatments
There is no uniform approach to managing cartilage defects in the knee. Treatment options depend on the size of the defect and its location. There are 2 main categories of procedure: those intended primarily for symptom relief and those that also try to re-establish the articular surface. Interventions that aim to re-establish the articular surface include marrow stimulation techniques (such as abrasion arthroplasty, Pridie drilling and microfracture), mosaicplasty (also known as osteochondral transplantation) and autologous chondrocyte implantation (in which chondrocytes harvested from the knee are cultured and implanted into the damaged cartilage). Interventions that aim to relieve symptoms include knee washout (lavage) with or without debridement, osteotomy and knee replacement.
# The procedure
Mosaicplasty (also called osteochondral autologous transfer mosaicplasty) is a technique for creating an osteochondral autograft. Small cylindrical osteochondral plugs are harvested from the periphery of the patellofemoral area (because it bears less weight) and inserted into drilled tunnels in the affected weight-bearing part of the knee joint. The procedure is done in a single sitting, commonly by open surgery but sometimes arthroscopically when perpendicular access to the harvesting and implantation sites is feasible. The harvesting and implantation process is repeated until about 70% of the defective area is filled, with minimal spacing between plugs. The number and size of plugs used may vary depending on lesion size and mosaicplasty technique. A drain may be needed postoperatively, and the patient is advised not to weight bear for 4 to 8 weeks depending on the size and location of the treated defect. Passive mobilisation after surgery is done for 2 to 4 weeks, progressing to active mobilisation and physiotherapy that is continued for several months.
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{'Recommendations': 'Current evidence on the safety and efficacy of mosaicplasty for knee cartilage defects is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nThe procedure should only be done by surgeons experienced in cartilage surgery and with specific training in mosaicplasty for knee cartilage defects.\n\nClinicians should enter data from all patients having the procedure onto the International Cartilage Regeneration and Joint Preservation Society (ICRS) Patient Registry.', 'The condition, current treatments and procedure': '# The condition\n\nChondral damage (that is, localised damage to the articular cartilage) in the knee can be caused by injury or arthritis, or it can occur spontaneously (a condition called osteochondritis dissecans). It can also occur because of knee instability, muscle weakness or abnormal unbalanced pressures, for example, after an injury to a ligament or meniscal cartilage. In young people, the most common cause of cartilage damage is sporting injuries. Symptoms associated with cartilage loss include pain, swelling, instability, and joint catching and locking, and may lead to degenerative changes in the joint (osteoarthritis).\n\n# Current treatments\n\nThere is no uniform approach to managing cartilage defects in the knee. Treatment options depend on the size of the defect and its location. There are 2\xa0main categories of procedure: those intended primarily for symptom relief and those that also try to re-establish the articular surface. Interventions that aim to re-establish the articular surface include marrow stimulation techniques (such as abrasion arthroplasty, Pridie drilling and microfracture), mosaicplasty (also known as osteochondral transplantation) and autologous chondrocyte implantation (in which chondrocytes harvested from the knee are cultured and implanted into the damaged cartilage). Interventions that aim to relieve symptoms include knee washout (lavage) with or without debridement, osteotomy and knee replacement.\n\n# The procedure\n\nMosaicplasty (also called osteochondral autologous transfer mosaicplasty) is a technique for creating an osteochondral autograft. Small cylindrical osteochondral plugs are harvested from the periphery of the patellofemoral area (because it bears less weight) and inserted into drilled tunnels in the affected weight-bearing part of the knee joint. The procedure is done in a single sitting, commonly by open surgery but sometimes arthroscopically when perpendicular access to the harvesting and implantation sites is feasible. The harvesting and implantation process is repeated until about 70% of the defective area is filled, with minimal spacing between plugs. The number and size of plugs used may vary depending on lesion size and mosaicplasty technique. A drain may be needed postoperatively, and the patient is advised not to weight bear for 4\xa0to 8\xa0weeks depending on the size and location of the treated defect. Passive mobilisation after surgery is done for 2\xa0to 4\xa0weeks, progressing to active mobilisation and physiotherapy that is continued for several months.'}
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https://www.nice.org.uk/guidance/ipg607
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Evidence-based recommendations on mosaicplasty in people with symptomatic articular cartilage defects of the knee. This involves taking healthy cartilage from the edge .of the joint and inserting it into drilled tunnels in the damaged site.
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e018a975528e3fe3bcc9fe06a3a1ae0838e4efd4
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nice
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Laparoscopic mesh pectopexy for apical prolapse of the uterus or vagina
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Laparoscopic mesh pectopexy for apical prolapse of the uterus or vagina
Evidence-based recommendations on laparoscopic mesh pectopexy for apical prolapse of the uterus or vagina. This involves inserting mesh to hold the uterus or the top of the vagina in place.
# Recommendations
Current evidence on the safety and efficacy of laparoscopic mesh pectopexy for apical prolapse of the uterus or vagina is insufficient in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
The procedure should only be done by surgeons experienced and trained in laparoscopic urogynaecological surgery.
All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.
Further research should include details of patient selection and long-term outcomes.# The condition, current treatments and procedure
# The condition
Apical prolapse is the descent of the uterus, cervix, or vaginal vault. Vaginal vault prolapse is when the upper part of the vagina descends from its usual position, sometimes out through the vaginal opening. It is common after hysterectomy. Apical prolapse can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function.
# Current treatments
Treatment is rarely indicated if there are no symptoms. Mild-to-moderate prolapse may be treated with conservative measures such as pelvic floor muscle training, electrical stimulation and biofeedback. Topical oestrogens and mechanical measures such as pessaries may also be used. Surgery may be needed when the prolapse is severe. Several surgical procedures are available including hysterectomy, mesh sacrocolpopexy, uterine suspension sling (including sacrohysteropexy) and uterine or vault suspension (without sling). Some procedures involve using mesh to provide additional support.
# The procedure
Laparoscopic mesh pectopexy is done with the patient under general anaesthesia. Using a laparoscopic approach, a polyvinylidene fluoride (PVDF) monofilament mesh is inserted into the abdominal cavity. The ends of the mesh are attached to the iliopectineal ligaments on each side of the pelvis, using nonabsorbable suture material. The cervical stump or vaginal apex is elevated to the intended tension-free position and sutured to the central part of the mesh. The mesh is then completely covered with peritoneum, secured using absorbable suture material, so that no mesh is visible in the abdominal cavity.
This procedure may offer an alternative to laparoscopic sacrohysteropexy when access to the sacral promontory is limited, for example because of abnormal anatomy, obesity, adhesions, or previous surgery.
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{'Recommendations': 'Current evidence on the safety and efficacy of laparoscopic mesh pectopexy for apical prolapse of the uterus or vagina is insufficient in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nThe procedure should only be done by surgeons experienced and trained in laparoscopic urogynaecological surgery.\n\nAll adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nFurther research should include details of patient selection and long-term outcomes.', 'The condition, current treatments and procedure': '# The condition\n\nApical prolapse is the descent of the uterus, cervix, or vaginal vault. Vaginal vault prolapse is when the upper part of the vagina descends from its usual position, sometimes out through the vaginal opening. It is common after hysterectomy. Apical prolapse can affect quality of life by causing pressure and discomfort, and by its effect on urinary, bowel and sexual function.\n\n# Current treatments\n\nTreatment is rarely indicated if there are no symptoms. Mild-to-moderate prolapse may be treated with conservative measures such as pelvic floor muscle training, electrical stimulation and biofeedback. Topical oestrogens and mechanical measures such as pessaries may also be used. Surgery may be needed when the prolapse is severe. Several surgical procedures are available including hysterectomy, mesh sacrocolpopexy, uterine suspension sling (including sacrohysteropexy) and uterine or vault suspension (without sling). Some procedures involve using mesh to provide additional support.\n\n# The procedure\n\nLaparoscopic mesh pectopexy is done with the patient under general anaesthesia. Using a laparoscopic approach, a polyvinylidene fluoride (PVDF) monofilament mesh is inserted into the abdominal cavity. The ends of the mesh are attached to the iliopectineal ligaments on each side of the pelvis, using nonabsorbable suture material. The cervical stump or vaginal apex is elevated to the intended tension-free position and sutured to the central part of the mesh. The mesh is then completely covered with peritoneum, secured using absorbable suture material, so that no mesh is visible in the abdominal cavity.\n\nThis procedure may offer an alternative to laparoscopic sacrohysteropexy when access to the sacral promontory is limited, for example because of abnormal anatomy, obesity, adhesions, or previous surgery.'}
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https://www.nice.org.uk/guidance/ipg608
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Evidence-based recommendations on laparoscopic mesh pectopexy for apical prolapse of the uterus or vagina. This involves inserting mesh to hold the uterus or the top of the vagina in place.
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29d30d7e2a70e2398adbdea2b3dc3c476fa2c790
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nice
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Autologous chondrocyte implantation using chondrosphere for treating symptomatic articular cartilage defects of the knee
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Autologous chondrocyte implantation using chondrosphere for treating symptomatic articular cartilage defects of the knee
Evidence-based recommendations on autologous chondrocyte implantation using chondrosphere (Spherox) for treating symptomatic articular cartilage defects of the knee in adults.
# Recommendations
Autologous chondrocyte implantation (ACI) using chondrosphere is recommended as an option for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee (International Cartilage Repair Society grade III or IV) in adults, only if:
the person has not had previous surgery to repair articular cartilage defects
there is minimal osteoarthritic damage to the knee (as assessed by clinicians experienced in investigating knee cartilage damage using a validated measure for knee osteoarthritis) and
the defect is over 2 cm2.
Why the committee made these recommendations
Current surgical treatments for symptomatic articular cartilage defects of the knee include microfracture, ACI and mosaicplasty.
Clinical trial results show that ACI using chondrosphere is as effective in the short term as microfracture, which is the most commonly used surgical option. But it is unclear how well chondrosphere works in the longer term compared with microfracture, because there are little data available beyond 2 years. Chondrosphere has greater benefit in articular cartilage defects larger than 2 cm2.
The most plausible cost-effectiveness estimate for chondrosphere compared with microfracture is £4,360 per quality-adjusted life year (QALY) gained. However, this is likely to be an underestimate because it does not accurately consider the long-term effects of microfracture, which are uncertain. Defects larger than 2 cm2 are often treated by best supportive care. The cost-effectiveness estimate for chondrosphere compared with best supportive care is likely to be lower than £20,000 per QALY gained, for defects larger than 2 cm2.# Information about chondrosphere
Marketing authorisation
Chondrosphere (Spherox, Co.don) is indicated for the 'repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee (International Cartilage Repair Society grade III or IV) with defect sizes up to 10 cm2 in adults'.
Dosage in the marketing authorisation
to 70 spheroids are applied per square centimetre of defect.
Price
£10,000 per culture per patient, including cell costs and transportation. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 6) considered evidence submitted by Co.don and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## Treatments for articular cartilage defects of the knee include best supportive care and surgery
The clinical expert explained that the aims of treating symptomatic articular cartilage defects of the knee are to reduce symptoms, restore function and prevent osteoarthritis. The clinical expert confirmed that people with defects will first be offered physiotherapy, corticosteroid injection, pain management and weight loss. If symptoms persist, people will be considered for surgery including knee lavage with or without debridement, microfracture, autologous chondrocyte implantation (ACI) and mosaicplasty. The choice of surgery depends on the size of the defect, condition of the cartilage and other patient-related factors including previous articular cartilage knee repair surgery, age and BMI. The committee understood that in current clinical practice, the preferred surgery for defects larger than 2 cm2 would be ACI, provided that the person has minimal osteoarthritis (if any) and no history of previous cartilage repair surgery for the affected knee (see NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee), but that ACI is not widely available (see section 3.3). If symptoms persist after microfracture or ACI, people could have mosaicplasty or further ACI. When all other options have been exhausted, osteotomy, partial and total knee replacement are considered later in the treatment pathway.
# Autologous chondrocyte implantation using chondrosphere
## Chondrosphere would provide a surgical option for articular cartilage defects larger than 2 cm2
The committee noted that no submissions or expert nominations were received from any patient or professional organisations invited to participate in this appraisal. The clinical expert highlighted that microfracture is commonly used, including for salvage procedures, because it is inexpensive and minimally invasive. However, the expert noted a growing trend of limiting microfracture to smaller defects, with thresholds ranging from 2 cm2 to 4 cm2. Although NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee recommends ACI for defects larger than 2 cm2, the committee noted that there is currently no good surgical alternative to microfracture (see section 3.3). It concluded that there are limited options available for managing articular cartilage defects, particularly those larger than 2 cm2.
# Comparators
## The most relevant comparators are microfracture (for defects up to 2 cm2) and best supportive care (for defects larger than 2 cm2)
The final scope issued by NICE listed a number of comparators, depending on defect size. The committee appreciated that there is variation in the use of these procedures in clinical practice, because of the experience and preference of the treating clinician and the availability of treatment. However, it concluded that the most relevant comparators for this appraisal are microfracture and best supportive care:
Microfracture – the committee heard from the clinical expert that this option is used only for small defects, usually up to 2 cm2. It agreed that microfracture is a relevant comparator for defects up to 2 cm2, in line with current clinical best practice (see section 3.1).
ACI – the ERG highlighted that ACI is not widely available in the NHS. 'Traditional' ACI is currently available at 1 centre in England, under hospital exemption on a non-routine basis. The committee was aware that 2 other ACI technologies were appraised in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee (ChondroCelect and MACI) but both of these no longer have marketing authorisation in the UK. The committee agreed that 'traditional' ACI cannot be considered standard care because of its limited availability in the NHS, and therefore concluded that it is not a relevant comparator.
Knee debridement – the company noted that this option is used before or after ACI or microfracture. The committee agreed that knee debridement is not a relevant comparator.
Mosaicplasty – the ERG noted that mosaicplasty is rarely used in NHS clinical practice. The committee agreed that this option is rarely used in NHS clinical practice and therefore is not a relevant comparator.
Best supportive care (non-surgical options) – the committee agreed that there are limited surgical options available for defects larger than 2 cm2 (see section 3.2). Therefore, it concluded that the most relevant comparator for defects larger than 2 cm2 is best supportive care.
# Clinical evidence
## The clinical evidence for chondrosphere came from 2 trials
Two trials on chondrosphere used the primary outcome of a 10‑point improvement in overall Knee injury and Osteoarthritis Outcome Score (KOOS) from the day of the surgical procedure:
A dose-finding study: a phase 2, randomised, open-label, multi-centre, parallel arm trial in 75 adults (18 years to 50 years) with a single International Cartilage Repair Society (ICRS) Grade III or IV knee defect (37% femur, 63% patella) ranging in size from 4 cm2 to 10 cm2. It compared low, medium and high doses of chondrosphere (3 to 7 spheroids/cm2, 10 to 30 spheroids/cm2 and 40 to 70 spheroids/cm2).
COWISI: a phase 3, randomised, open-label, multi-centre, parallel arm, non-inferiority (non-inferiority margin of 8.5% in overall KOOS) trial of 102 adults (18 years to 50 years) with a single ICRS Grade III or IV knee defect (99% femur, 1% patella) ranging in size from 1 cm2 to 4 cm2. It compared chondrosphere (mean dose 25±16, range 7 to 70 spheroids/cm2) with microfracture.The committee noted that the trials were different at baseline in defect size and location. The clinical expert explained that the average defect size on a German registry is 3.7 cm2, with a large proportion of defects ranging in size from 4 cm2 to 5.5 cm2. The committee considered it likely that the population having treatment in Germany is broadly similar to patients seen in the NHS in England. The expert explained that femoral defects are the most common, followed by patella defects, and recent evidence suggests that patella defects do not have worse outcomes after ACI than femoral defects. The committee considered the baseline proportion of people with traumatic knee defects (42% in COWISI) and proportion of smokers (33% in COWISI). The clinical expert stated that the imbalance between the 2 trials in traumatic knee defects and smokers does not represent an important clinical difference. The committee agreed that the trial populations are generalisable to patients likely to be seen in the NHS.
## Indirect clinical evidence from a network meta-analysis is not relevant because the ACI comparators are not licensed in the UK
Indirect clinical evidence came from a network meta-analysis on the response and failure rates from 3 ACI trials (chondrosphere and 2 other ACI technologies, ChondroCelect and MACI) with microfracture as a common comparator. The ERG was concerned that the 3 trials were severely imbalanced at baseline in several factors that are likely to affect treatment outcomes: defect size, previous articular cartilage knee repair surgery and level of disease burden assessed by KOOS. The committee agreed that it is not appropriate to combine the trials in a network meta-analysis because of these differences. It noted that the ACI comparators (ChondroCelect and MACI) are not relevant to this appraisal because they do not have current marketing authorisation in the UK (see section 3.3). The committee recalled that 'traditional' ACI is available at 1 centre in England, under hospital exemption on a non-routine basis (see section 3.3), but had not been included because there are currently no published data available that enables a network meta-analysis to be done. Therefore, the committee concluded that the most relevant clinical evidence is from COWISI, which provides direct evidence of chondrosphere compared with microfracture.
## Chondrosphere is at least as effective as microfracture at 2 years for defects of 1 cm2 to 4 cm2, with a greater difference in defects over 2 cm2 up to 4 cm2
The clinical expert confirmed that the minimal clinically important difference in overall KOOS of 8.5 points in COWISI is consistent with clinical practice. The committee noted that chondrosphere is non-inferior to microfracture for all defect sizes (1 cm2 to 4 cm2). However, it noted that the improvement from baseline in overall KOOS at 2‑year follow-up was numerically greater in patients who had chondrosphere compared with microfracture. The committee also noted that the difference in overall KOOS between chondrosphere and microfracture was greater for larger defect sizes (2 cm2 to 4 cm2) compared with smaller defect sizes (1 cm2 to less than 2 cm2). It noted that the proportions of 'responders' (defined as those achieving a 10‑point improvement in overall KOOS) were similar for chondrosphere and microfracture at 2 years. The committee concluded that chondrosphere is at least as effective as microfracture.
## Chondrosphere improves outcomes at 4 years for larger defects ranging in size from 4 cm2 to 10 cm2
The committee noted that there are little long-term data available on chondrosphere compared with microfracture. It agreed that the phase 2 study (see section 3.4) provides non-comparative evidence of the longer-term effect of chondrosphere at 4 years and in larger defects. It noted that there was continual improvement in overall KOOS from baseline at 1 year and up to 4 years, and the differences were clinically significant. The ERG stated that the benefit of ACI is likely to be seen over the longer term based on observational studies included in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee. The committee agreed that the long-term benefit of chondrosphere is uncertain. However, it concluded that chondrosphere improves outcomes at 4 years and for larger defects.
# Company's economic model
## Model structure
The company used a Markov model to assess the cost effectiveness of chondrosphere compared with microfracture and other ACI technologies. It modelled 2 possible treatments in sequence. The model used a lifetime horizon of 100 years, a cycle length of 1 year and transitions between each health state at the end of each cycle. The model population included 60% men and had a starting average age of 33 years. The model was divided into 2 parts, up to and after 55 years:
Up to 55 years, patients could have knee repair surgery and be in the following health states: primary repair, successful primary repair, second repair, successful second repair and no further repair. The model allowed 2 outcomes after primary or second repair; permanent success (staying in the successful primary or second repair health states) or temporary success (repair fails after being symptom free for years; patients can decide to have a second repair or no further repair). Patients could also move into the 'death' state at any time.
After 55 years, patients could have knee replacement and be in the following health states: first knee replacement, successful first knee replacement, further knee replacement, successful further knee replacement and no further knee replacement. The model allowed 2 outcomes after first or further knee replacement; permanent success (no further replacement or staying in the successful further knee replacement health state) or temporary success (further knee replacement or no further knee replacement). Patients could also move into the 'death' state at any time.The committee noted that the company's model was broadly similar to the model in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee. The main difference is that the model did not allow movement from successful primary repair to no further repair, only to a second repair. The ERG explained that the company's model would therefore likely overstate the treatment benefits for ACI (including chondrosphere) because patients in the 'successful primary repair' health state have a higher utility value than those in the 'no further repair' health state. However, the committee noted that the probability of a second repair in the model is very small and has little effect on the cost-effectiveness estimates. The committee concluded that although it would prefer a model that allows movement from successful primary repair to no further repair, the company's approach is acceptable.
## The most relevant treatment sequences are microfracture only, chondrosphere only and chondrosphere followed by chondrosphere
The company modelled the same treatment sequences included in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee:
microfracture followed by microfracture
microfracture followed by ACI
ACI followed by microfracture
ACI followed by ACI.In the company's model, ACI could be chondrosphere, ChondroCelect or MACI and the primary and second ACI are assumed to be the same. The committee noted that the probability of second repairs is very low in the company's model and heard from the clinical expert that ACI followed by microfracture is an unlikely treatment sequence in clinical practice. The committee was aware that NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee recommends ACI only for people with no previous articular cartilage knee repair surgery. The clinical expert suggested that microfracture followed by ACI is sometimes used in clinical practice. However, the committee noted that ACI is not recommended in people with previous articular cartilage knee repair surgery, including microfracture. Therefore, the committee agreed that microfracture followed by ACI is not a relevant treatment sequence. The committee considered that the only relevant comparator is microfracture (see section 3.3) and concluded that the only relevant treatment sequences are:
microfracture only
ACI followed by microfracture
ACI followed by ACI.
# Assumptions in the economic model
## Assuming that the utility value of a successful microfracture returns to baseline level after 5 years is arbitrary and may favour ACI
The committee noted that, like the model in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee, the company's model assumed that after successful microfracture the utility value returns to the baseline value after 5 years (that is, from 0.82 to 0.65). In that appraisal, the committee considered that this was equivalent to assuming that microfracture had failed in all people at year 5. In this appraisal, the clinical expert explained that decline in knee function would likely start at 1.5 years after microfracture. The committee agreed that reducing the utility value for microfracture after 5 years was arbitrary and may have biased the results in favour of ACI. It noted that the company had done a sensitivity analysis in which the utility value of a successful microfracture at 5 years and beyond was maintained at 0.82. The committee understood that removing the assumption that utility decreased over time following a successful microfracture would likely increase the company's base-case incremental cost-effectiveness ratio (ICER). The committee would have preferred the model to adjust for the rate of loss of benefit following microfracture more explicitly, by changing the transition probabilities instead of the utility value of the successful repair health state. In the absence of such analysis, the committee accepted the assumption that there is no further benefit of microfracture after 5 years, but agreed it underestimated the ICER.
# Clinical effectiveness inputs and transition probabilities
## Concerns about the modelled clinical effectiveness and transition probabilities mainly relate to other ACI technologies
The committee noted the concerns from the ERG about how the company had derived its clinical effectiveness inputs from the network meta-analysis results, which subsequently informed the transition probabilities in the model. The committee noted that these concerns largely affect the other ACI technologies, ChondroCelect and MACI. It noted that a network meta-analysis is not appropriate and that the data from COWISI, which provide direct evidence of chondrosphere compared with microfracture, are preferred (see section 3.5). The committee noted the ERG's scenario analyses using direct evidence from COWISI, and it concluded that these analyses are most appropriate for decision making.
# Costs in the economic model
## The committee preferred the ERG's cost inputs
The ERG explained that it had applied the committee's preferred procedure costs from NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee in this appraisal:
£870 (Health Resource Group code HB25F) for cell harvesting, compared with £734 in the company's model, and
£2,396 (Health Resource Group code HB25F) for cell implantation, compared with £1,065 in the company's model.The ERG also explained that it had corrected the company's outpatient visit costs from £121 (paediatric trauma/orthopaedics) to £110 (trauma/orthopaedics). The committee accepted the ERG's changes to these costs.
# Cost-effectiveness estimate
## The committee preferred the ERG's scenario analyses using only COWISI data
The committee concluded that the most relevant comparators for this appraisal are microfracture for defects up to 2 cm2 and best supportive care for defects larger than 2 cm2 (see section 3.3). Therefore, it preferred the following assumptions:
direct evidence from COWISI data rather than the network meta-analysis (see section 3.4 and section 3.11)
treatment sequences of microfracture only, chondrosphere only and chondrosphere followed by chondrosphere (see section 3.9)
no further benefit of microfracture after 5 years (see section 3.10), although it noted that this is likely to underestimate the ICER
the ERG's cost inputs (see section 3.12).The ERG included all of these assumptions and inputs in its scenario analyses. The committee concluded that the ERG's scenario analyses are most relevant for decision making.
## Chondrosphere is likely to be a cost-effective option for treating articular cartilage defects of the knee larger than 2 cm2
When microfracture is assumed to return to baseline utility values after 5 years, the ICERs are £4,360 per quality-adjusted life year (QALY) gained for chondrosphere only compared with microfracture only, and £5,294 per QALY gained for chondrosphere followed by chondrosphere compared with microfracture only. The committee noted that there is considerable uncertainty surrounding the ICERs because the long-term benefit of chondrosphere is yet to be established (see section 3.7). It also noted that the low ICERs are largely due to the decline in the utility value for microfracture after 5 years, which underestimates the ICERs (see section 3.4 and section 3.10). The committee was aware that most patients with larger defects are likely to have best supportive care in clinical practice (see section 3.3), and the clinical benefit of chondrosphere compared with best supportive care is likely to be greater than when compared with microfracture. The committee had decided that other forms of ACI are not relevant comparators in this appraisal, because they are not widely available in the NHS (see section 3.3). However, it noted that chondrosphere is cheaper than many of the other ACI technologies appraised in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee (£10,000 for chondrosphere cell costs, compared with £9,300 to £18,300 for the technologies in that appraisal). The committee recalled that the population in COWISI did not have previous knee surgery to repair articular cartilage defects, and agreed that it would be appropriate to only recommend chondrosphere in the same population. Because of the uncertainties related to the comparison with microfracture, the committee agreed that it would be appropriate to recommend chondrosphere only for defects larger than 2 cm2. Therefore, the committee applied similar conditions as in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee and concluded that chondrosphere is a cost-effective use of NHS resources for defects larger than 2 cm2, in people with no previous surgery to repair articular cartilage defects and minimal osteoarthritic damage to the knee. The committee noted that the recommendation in the technology appraisal on ACI specifies that ACI is only done in a tertiary referral centre. This is because the laboratory that makes the only licensed ACI technology available at the time of that appraisal is affiliated with a tertiary referral NHS orthopaedic hospital. However, the committee agreed that this caveat is not relevant for this appraisal because there is no such constraint on the use of chondrosphere and that removing it would avoid restricting access to treatment. The company stated that although it had not specifically made a case for chondrosphere in the population for which ACI is recommended in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee, it would be satisfied with a similar recommendation.
# Other factors
## There is an unmet need for the treatment of articular cartilage defects in the NHS
The committee agreed that there is an unmet need because currently ACI is not widely available in the NHS, and there are no good alternative surgical options for people with defects larger than 2 cm2.
## Chondrosphere is innovative but the health benefits are already captured within the economic modelling
The company explained that it considers chondrosphere to be innovative. The committee noted that chondrosphere is an improved ACI technology that does not need fibrin glue or a cover flap, and does not include any animal derivatives. The committee considered chondrosphere to be innovative but did not identify any additional health benefits not already included in the economic modelling.
## The recommendation does not exclude access to chondrosphere for people who are eligible to have it
The committee considered its recommendation in the context of the equality legislation. It was aware that 1 of its criteria for treatment (that is, minimal osteoarthritic damage to the knee) excludes people with advanced or severe osteoarthritis, which can be disabling. However, one of the contraindications in the marketing authorisation for the technology is advanced osteoarthritis. The committee did not stipulate any specific threshold for the level of osteoarthritis, but instead states in the recommendations that it is appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for chondrosphere using a validated measure for osteoarthritis of the knee. The committee was therefore satisfied that it has mitigated, as far as it can, any potential unfairness.# Recommendations for data collection
The committee noted that there are little long-term data available on chondrosphere and agreed that data should be entered into a register, including defect size and location in relation to outcomes.
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{'Recommendations': 'Autologous chondrocyte implantation (ACI) using chondrosphere is recommended as an option for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee (International Cartilage Repair Society grade\xa0III or\xa0IV) in adults, only if:\n\nthe person has not had previous surgery to repair articular cartilage defects\n\nthere is minimal osteoarthritic damage to the knee (as assessed by clinicians experienced in investigating knee cartilage damage using a validated measure for knee osteoarthritis) and\n\nthe defect is over 2\xa0cm2.\n\nWhy the committee made these recommendations\n\nCurrent surgical treatments for symptomatic articular cartilage defects of the knee include microfracture, ACI and mosaicplasty.\n\nClinical trial results show that ACI using chondrosphere is as effective in the short term as microfracture, which is the most commonly used surgical option. But it is unclear how well chondrosphere works in the longer term compared with microfracture, because there are little data available beyond 2\xa0years. Chondrosphere has greater benefit in articular cartilage defects larger than 2\xa0cm2.\n\nThe most plausible cost-effectiveness estimate for chondrosphere compared with microfracture is £4,360 per quality-adjusted life year (QALY) gained. However, this is likely to be an underestimate because it does not accurately consider the long-term effects of microfracture, which are uncertain. Defects larger than 2\xa0cm2 are often treated by best supportive care. The cost-effectiveness estimate for chondrosphere compared with best supportive care is likely to be lower than £20,000 per QALY gained, for defects larger than 2\xa0cm2.', 'Information about chondrosphere': "Marketing authorisation\n\nChondrosphere (Spherox, Co.don) is indicated for the 'repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee (International Cartilage Repair Society [ICRS] grade III or IV) with defect sizes up to 10\xa0cm2 in adults'.\n\nDosage in the marketing authorisation\n\nto 70\xa0spheroids are applied per square centimetre of defect.\n\nPrice\n\n£10,000 per culture per patient, including cell costs and transportation. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence submitted by Co.don and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Treatments for articular cartilage defects of the knee include best supportive care and surgery\n\nThe clinical expert explained that the aims of treating symptomatic articular cartilage defects of the knee are to reduce symptoms, restore function and prevent osteoarthritis. The clinical expert confirmed that people with defects will first be offered physiotherapy, corticosteroid injection, pain management and weight loss. If symptoms persist, people will be considered for surgery including knee lavage with or without debridement, microfracture, autologous chondrocyte implantation (ACI) and mosaicplasty. The choice of surgery depends on the size of the defect, condition of the cartilage and other patient-related factors including previous articular cartilage knee repair surgery, age and BMI. The committee understood that in current clinical practice, the preferred surgery for defects larger than 2\xa0cm2 would be ACI, provided that the person has minimal osteoarthritis (if any) and no history of previous cartilage repair surgery for the affected knee (see NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee), but that ACI is not widely available (see section\xa03.3). If symptoms persist after microfracture or ACI, people could have mosaicplasty or further ACI. When all other options have been exhausted, osteotomy, partial and total knee replacement are considered later in the treatment pathway.\n\n# Autologous chondrocyte implantation using chondrosphere\n\n## Chondrosphere would provide a surgical option for articular cartilage defects larger than 2\xa0cm2\n\nThe committee noted that no submissions or expert nominations were received from any patient or professional organisations invited to participate in this appraisal. The clinical expert highlighted that microfracture is commonly used, including for salvage procedures, because it is inexpensive and minimally invasive. However, the expert noted a growing trend of limiting microfracture to smaller defects, with thresholds ranging from 2\xa0cm2 to 4\xa0cm2. Although NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee recommends ACI for defects larger than 2\xa0cm2, the committee noted that there is currently no good surgical alternative to microfracture (see section\xa03.3). It concluded that there are limited options available for managing articular cartilage defects, particularly those larger than 2\xa0cm2.\n\n# Comparators\n\n## The most relevant comparators are microfracture (for defects up to 2\xa0cm2) and best supportive care (for defects larger than 2\xa0cm2)\n\nThe final scope issued by NICE listed a number of comparators, depending on defect size. The committee appreciated that there is variation in the use of these procedures in clinical practice, because of the experience and preference of the treating clinician and the availability of treatment. However, it concluded that the most relevant comparators for this appraisal are microfracture and best supportive care:\n\nMicrofracture – the committee heard from the clinical expert that this option is used only for small defects, usually up to 2\xa0cm2. It agreed that microfracture is a relevant comparator for defects up to 2\xa0cm2, in line with current clinical best practice (see section\xa03.1).\n\nACI – the ERG highlighted that ACI is not widely available in the NHS. 'Traditional' ACI is currently available at 1\xa0centre in England, under hospital exemption on a non-routine basis. The committee was aware that 2 other ACI technologies were appraised in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee (ChondroCelect and MACI) but both of these no longer have marketing authorisation in the UK. The committee agreed that 'traditional' ACI cannot be considered standard care because of its limited availability in the NHS, and therefore concluded that it is not a relevant comparator.\n\nKnee debridement – the company noted that this option is used before or after ACI or microfracture. The committee agreed that knee debridement is not a relevant comparator.\n\nMosaicplasty – the ERG noted that mosaicplasty is rarely used in NHS clinical practice. The committee agreed that this option is rarely used in NHS clinical practice and therefore is not a relevant comparator.\n\nBest supportive care (non-surgical options) – the committee agreed that there are limited surgical options available for defects larger than 2\xa0cm2 (see section\xa03.2). Therefore, it concluded that the most relevant comparator for defects larger than 2\xa0cm2 is best supportive care.\n\n# Clinical evidence\n\n## The clinical evidence for chondrosphere came from 2\xa0trials\n\nTwo trials on chondrosphere used the primary outcome of a 10‑point improvement in overall Knee injury and Osteoarthritis Outcome Score (KOOS) from the day of the surgical procedure:\n\nA dose-finding study: a phase\xa02, randomised, open-label, multi-centre, parallel arm trial in 75\xa0adults (18\xa0years to 50\xa0years) with a single International Cartilage Repair Society (ICRS) Grade\xa0III or\xa0IV knee defect (37% femur, 63% patella) ranging in size from 4\xa0cm2 to 10\xa0cm2. It compared low, medium and high doses of chondrosphere (3\xa0to\xa07 spheroids/cm2, 10\xa0to\xa030 spheroids/cm2 and 40\xa0to\xa070 spheroids/cm2).\n\nCOWISI: a phase\xa03, randomised, open-label, multi-centre, parallel arm, non-inferiority (non-inferiority margin of 8.5% in overall KOOS) trial of 102\xa0adults (18\xa0years to 50\xa0years) with a single ICRS Grade\xa0III or\xa0IV knee defect (99% femur, 1% patella) ranging in size from 1\xa0cm2 to 4\xa0cm2. It compared chondrosphere (mean dose 25±16, range 7\xa0to 70\xa0spheroids/cm2) with microfracture.The committee noted that the trials were different at baseline in defect size and location. The clinical expert explained that the average defect size on a German registry is 3.7\xa0cm2, with a large proportion of defects ranging in size from 4\xa0cm2 to 5.5\xa0cm2. The committee considered it likely that the population having treatment in Germany is broadly similar to patients seen in the NHS in England. The expert explained that femoral defects are the most common, followed by patella defects, and recent evidence suggests that patella defects do not have worse outcomes after ACI than femoral defects. The committee considered the baseline proportion of people with traumatic knee defects (42% in COWISI) and proportion of smokers (33% in COWISI). The clinical expert stated that the imbalance between the 2\xa0trials in traumatic knee defects and smokers does not represent an important clinical difference. The committee agreed that the trial populations are generalisable to patients likely to be seen in the NHS.\n\n## Indirect clinical evidence from a network meta-analysis is not relevant because the ACI comparators are not licensed in the UK\n\nIndirect clinical evidence came from a network meta-analysis on the response and failure rates from 3\xa0ACI trials (chondrosphere and 2\xa0other ACI technologies, ChondroCelect and MACI) with microfracture as a common comparator. The ERG was concerned that the 3\xa0trials were severely imbalanced at baseline in several factors that are likely to affect treatment outcomes: defect size, previous articular cartilage knee repair surgery and level of disease burden assessed by KOOS. The committee agreed that it is not appropriate to combine the trials in a network meta-analysis because of these differences. It noted that the ACI comparators (ChondroCelect and MACI) are not relevant to this appraisal because they do not have current marketing authorisation in the UK (see section\xa03.3). The committee recalled that 'traditional' ACI is available at 1\xa0centre in England, under hospital exemption on a non-routine basis (see section\xa03.3), but had not been included because there are currently no published data available that enables a network meta-analysis to be done. Therefore, the committee concluded that the most relevant clinical evidence is from COWISI, which provides direct evidence of chondrosphere compared with microfracture.\n\n## Chondrosphere is at least as effective as microfracture at 2\xa0years for defects of 1\xa0cm2 to 4\xa0cm2, with a greater difference in defects over 2\xa0cm2 up to 4\xa0cm2\n\nThe clinical expert confirmed that the minimal clinically important difference in overall KOOS of 8.5\xa0points in COWISI is consistent with clinical practice. The committee noted that chondrosphere is non-inferior to microfracture for all defect sizes (1\xa0cm2 to\xa04\xa0cm2). However, it noted that the improvement from baseline in overall KOOS at 2‑year follow-up was numerically greater in patients who had chondrosphere compared with microfracture. The committee also noted that the difference in overall KOOS between chondrosphere and microfracture was greater for larger defect sizes (2\xa0cm2 to 4\xa0cm2) compared with smaller defect sizes (1\xa0cm2 to less than 2\xa0cm2). It noted that the proportions of 'responders' (defined as those achieving a 10‑point improvement in overall KOOS) were similar for chondrosphere and microfracture at 2\xa0years. The committee concluded that chondrosphere is at least as effective as microfracture.\n\n## Chondrosphere improves outcomes at 4\xa0years for larger defects ranging in size from 4\xa0cm2 to 10\xa0cm2\n\nThe committee noted that there are little long-term data available on chondrosphere compared with microfracture. It agreed that the phase\xa02 study (see section\xa03.4) provides non-comparative evidence of the longer-term effect of chondrosphere at 4\xa0years and in larger defects. It noted that there was continual improvement in overall KOOS from baseline at 1\xa0year and up to 4\xa0years, and the differences were clinically significant. The ERG stated that the benefit of ACI is likely to be seen over the longer term based on observational studies included in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee. The committee agreed that the long-term benefit of chondrosphere is uncertain. However, it concluded that chondrosphere improves outcomes at 4\xa0years and for larger defects.\n\n# Company's economic model\n\n## Model structure\n\nThe company used a Markov model to assess the cost effectiveness of chondrosphere compared with microfracture and other ACI technologies. It modelled 2\xa0possible treatments in sequence. The model used a lifetime horizon of 100\xa0years, a cycle length of 1\xa0year and transitions between each health state at the end of each cycle. The model population included 60% men and had a starting average age of 33\xa0years. The model was divided into 2\xa0parts, up to and after 55\xa0years:\n\nUp to 55\xa0years, patients could have knee repair surgery and be in the following health states: primary repair, successful primary repair, second repair, successful second repair and no further repair. The model allowed 2\xa0outcomes after primary or second repair; permanent success (staying in the successful primary or second repair health states) or temporary success (repair fails after being symptom free for years; patients can decide to have a second repair or no further repair). Patients could also move into the 'death' state at any time.\n\nAfter 55\xa0years, patients could have knee replacement and be in the following health states: first knee replacement, successful first knee replacement, further knee replacement, successful further knee replacement and no further knee replacement. The model allowed 2\xa0outcomes after first or further knee replacement; permanent success (no further replacement or staying in the successful further knee replacement health state) or temporary success (further knee replacement or no further knee replacement). Patients could also move into the 'death' state at any time.The committee noted that the company's model was broadly similar to the model in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee. The main difference is that the model did not allow movement from successful primary repair to no further repair, only to a second repair. The ERG explained that the company's model would therefore likely overstate the treatment benefits for ACI (including chondrosphere) because patients in the 'successful primary repair' health state have a higher utility value than those in the 'no further repair' health state. However, the committee noted that the probability of a second repair in the model is very small and has little effect on the cost-effectiveness estimates. The committee concluded that although it would prefer a model that allows movement from successful primary repair to no further repair, the company's approach is acceptable.\n\n## The most relevant treatment sequences are microfracture only, chondrosphere only and chondrosphere followed by chondrosphere\n\nThe company modelled the same treatment sequences included in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee:\n\nmicrofracture followed by microfracture\n\nmicrofracture followed by ACI\n\nACI followed by microfracture\n\nACI followed by ACI.In the company's model, ACI could be chondrosphere, ChondroCelect or MACI and the primary and second ACI are assumed to be the same. The committee noted that the probability of second repairs is very low in the company's model and heard from the clinical expert that ACI followed by microfracture is an unlikely treatment sequence in clinical practice. The committee was aware that NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee recommends ACI only for people with no previous articular cartilage knee repair surgery. The clinical expert suggested that microfracture followed by ACI is sometimes used in clinical practice. However, the committee noted that ACI is not recommended in people with previous articular cartilage knee repair surgery, including microfracture. Therefore, the committee agreed that microfracture followed by ACI is not a relevant treatment sequence. The committee considered that the only relevant comparator is microfracture (see section\xa03.3) and concluded that the only relevant treatment sequences are:\n\nmicrofracture only\n\nACI followed by microfracture\n\nACI followed by ACI.\n\n# Assumptions in the economic model\n\n## Assuming that the utility value of a successful microfracture returns to baseline level after 5\xa0years is arbitrary and may favour ACI\n\nThe committee noted that, like the model in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee, the company's model assumed that after successful microfracture the utility value returns to the baseline value after 5\xa0years (that is, from 0.82 to 0.65). In that appraisal, the committee considered that this was equivalent to assuming that microfracture had failed in all people at year\xa05. In this appraisal, the clinical expert explained that decline in knee function would likely start at 1.5\xa0years after microfracture. The committee agreed that reducing the utility value for microfracture after 5\xa0years was arbitrary and may have biased the results in favour of ACI. It noted that the company had done a sensitivity analysis in which the utility value of a successful microfracture at 5\xa0years and beyond was maintained at\xa00.82. The committee understood that removing the assumption that utility decreased over time following a successful microfracture would likely increase the company's base-case incremental cost-effectiveness ratio (ICER). The committee would have preferred the model to adjust for the rate of loss of benefit following microfracture more explicitly, by changing the transition probabilities instead of the utility value of the successful repair health state. In the absence of such analysis, the committee accepted the assumption that there is no further benefit of microfracture after 5\xa0years, but agreed it underestimated the ICER.\n\n# Clinical effectiveness inputs and transition probabilities\n\n## Concerns about the modelled clinical effectiveness and transition probabilities mainly relate to other ACI technologies\n\nThe committee noted the concerns from the ERG about how the company had derived its clinical effectiveness inputs from the network meta-analysis results, which subsequently informed the transition probabilities in the model. The committee noted that these concerns largely affect the other ACI technologies, ChondroCelect and MACI. It noted that a network meta-analysis is not appropriate and that the data from COWISI, which provide direct evidence of chondrosphere compared with microfracture, are preferred (see section\xa03.5). The committee noted the ERG's scenario analyses using direct evidence from COWISI, and it concluded that these analyses are most appropriate for decision making.\n\n# Costs in the economic model\n\n## The committee preferred the ERG's cost inputs\n\nThe ERG explained that it had applied the committee's preferred procedure costs from NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee in this appraisal:\n\n£870 (Health Resource Group code HB25F) for cell harvesting, compared with £734 in the company's model, and\n\n£2,396 (Health Resource Group code HB25F) for cell implantation, compared with £1,065 in the company's model.The ERG also explained that it had corrected the company's outpatient visit costs from £121 (paediatric trauma/orthopaedics) to £110 (trauma/orthopaedics). The committee accepted the ERG's changes to these costs.\n\n# Cost-effectiveness estimate\n\n## The committee preferred the ERG's scenario analyses using only COWISI data\n\nThe committee concluded that the most relevant comparators for this appraisal are microfracture for defects up to 2\xa0cm2 and best supportive care for defects larger than 2\xa0cm2 (see section\xa03.3). Therefore, it preferred the following assumptions:\n\ndirect evidence from COWISI data rather than the network meta-analysis (see section\xa03.4 and section 3.11)\n\ntreatment sequences of microfracture only, chondrosphere only and chondrosphere followed by chondrosphere (see section\xa03.9)\n\nno further benefit of microfracture after 5\xa0years (see section\xa03.10), although it noted that this is likely to underestimate the ICER\n\nthe ERG's cost inputs (see section\xa03.12).The ERG included all of these assumptions and inputs in its scenario analyses. The committee concluded that the ERG's scenario analyses are most relevant for decision making.\n\n## Chondrosphere is likely to be a cost-effective option for treating articular cartilage defects of the knee larger than 2\xa0cm2\n\nWhen microfracture is assumed to return to baseline utility values after 5\xa0years, the ICERs are £4,360 per quality-adjusted life year (QALY) gained for chondrosphere only compared with microfracture only, and £5,294 per QALY gained for chondrosphere followed by chondrosphere compared with microfracture only. The committee noted that there is considerable uncertainty surrounding the ICERs because the long-term benefit of chondrosphere is yet to be established (see section\xa03.7). It also noted that the low ICERs are largely due to the decline in the utility value for microfracture after 5\xa0years, which underestimates the ICERs (see section\xa03.4 and section\xa03.10). The committee was aware that most patients with larger defects are likely to have best supportive care in clinical practice (see section\xa03.3), and the clinical benefit of chondrosphere compared with best supportive care is likely to be greater than when compared with microfracture. The committee had decided that other forms of ACI are not relevant comparators in this appraisal, because they are not widely available in the NHS (see section\xa03.3). However, it noted that chondrosphere is cheaper than many of the other ACI technologies appraised in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee (£10,000 for chondrosphere cell costs, compared with £9,300 to £18,300 for the technologies in that appraisal). The committee recalled that the population in COWISI did not have previous knee surgery to repair articular cartilage defects, and agreed that it would be appropriate to only recommend chondrosphere in the same population. Because of the uncertainties related to the comparison with microfracture, the committee agreed that it would be appropriate to recommend chondrosphere only for defects larger than 2\xa0cm2. Therefore, the committee applied similar conditions as in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee and concluded that chondrosphere is a cost-effective use of NHS resources for defects larger than 2\xa0cm2, in people with no previous surgery to repair articular cartilage defects and minimal osteoarthritic damage to the knee. The committee noted that the recommendation in the technology appraisal on ACI specifies that ACI is only done in a tertiary referral centre. This is because the laboratory that makes the only licensed ACI technology available at the time of that appraisal is affiliated with a tertiary referral NHS orthopaedic hospital. However, the committee agreed that this caveat is not relevant for this appraisal because there is no such constraint on the use of chondrosphere and that removing it would avoid restricting access to treatment. The company stated that although it had not specifically made a case for chondrosphere in the population for which ACI is recommended in NICE's technology appraisal guidance on ACI for treating symptomatic articular cartilage defects of the knee, it would be satisfied with a similar recommendation.\n\n# Other factors\n\n## There is an unmet need for the treatment of articular cartilage defects in the NHS\n\nThe committee agreed that there is an unmet need because currently ACI is not widely available in the NHS, and there are no good alternative surgical options for people with defects larger than 2\xa0cm2.\n\n## Chondrosphere is innovative but the health benefits are already captured within the economic modelling\n\nThe company explained that it considers chondrosphere to be innovative. The committee noted that chondrosphere is an improved ACI technology that does not need fibrin glue or a cover flap, and does not include any animal derivatives. The committee considered chondrosphere to be innovative but did not identify any additional health benefits not already included in the economic modelling.\n\n## The recommendation does not exclude access to chondrosphere for people who are eligible to have it\n\nThe committee considered its recommendation in the context of the equality legislation. It was aware that 1\xa0of its criteria for treatment (that is, minimal osteoarthritic damage to the knee) excludes people with advanced or severe osteoarthritis, which can be disabling. However, one of the contraindications in the marketing authorisation for the technology is advanced osteoarthritis. The committee did not stipulate any specific threshold for the level of osteoarthritis, but instead states in the recommendations that it is appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for chondrosphere using a validated measure for osteoarthritis of the knee. The committee was therefore satisfied that it has mitigated, as far as it can, any potential unfairness.", 'Recommendations for data collection': 'The committee noted that there are little long-term data available on chondrosphere and agreed that data should be entered into a register, including defect size and location in relation to outcomes.'}
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https://www.nice.org.uk/guidance/ta508
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Evidence-based recommendations on autologous chondrocyte implantation using chondrosphere (Spherox) for treating symptomatic articular cartilage defects of the knee in adults.
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1120f4c3c25c031809eaf4dad4b4a06778f7b9e1
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nice
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Pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer
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Pertuzumab with trastuzumab and docetaxel for treating HER2-positive breast cancer
Evidence-based recommendations on pertuzumab (Perjeta) for treating HER2‑positive, locally recurrent or metastatic (secondary) breast cancer that has not been treated with chemotherapy or targeted HER‑2 therapy before, in adults.
# Recommendations
Pertuzumab, in combination with trastuzumab and docetaxel, is recommended, within its marketing authorisation, for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer, in adults who have not had previous anti‑HER2 therapy or chemotherapy for their metastatic disease, only if the company provides pertuzumab within the agreed commercial access arrangement.
Why the committee made these recommendations
This recommendation is for a drug that has been available on the Cancer Drugs Fund for several years and the committee recognised this as an exceptional circumstance. In this context, the committee considered it reasonable to apply flexibility in its interpretation of the criteria for special consideration as a life-extending treatment for people with a short life expectancy, but noted that the weight applied to the quality-adjusted life years gained would not be at the maximum allocated in other, more regular, circumstances where the end of life criteria have been applied. With this in mind, the committee accepted that the incremental cost-effectiveness ratio, taking into account the commercial access arrangement, provides for an acceptable use of NHS resources.# The technology
Description of the technology
Pertuzumab (Perjeta, Roche Products) is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Pertuzumab binds to the HER2 receptor and inhibits intracellular signalling. It is administered by intravenous infusion.
Marketing authorisation
Pertuzumab has a UK marketing authorisation for use 'in combination with trastuzumab and docetaxel in adult patients with HER2 positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti HER2 therapy or chemotherapy for their metastatic disease'.
Adverse reactions
The summary of product characteristics lists the following adverse reactions for pertuzumab in combination with trastuzumab and docetaxel: left ventricular dysfunction (including congestive heart failure), infusion reactions, hypersensitivity reactions (including anaphylaxis), neutropenia, febrile neutropenia, leukopenia, diarrhoea, alopecia and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
The recommended dose of pertuzumab is an initial loading dose of 840 mg followed every 3 weeks by a maintenance dose of 420 mg in combination with trastuzumab and docetaxel. Treatment with pertuzumab should be continued until disease progression or unmanageable toxicity.
Price
Pertuzumab is £2,395 per 420‑mg vial (BNF 17). Therefore the cost of pertuzumab (excluding VAT) is estimated to be £4,790 for the initial dose and £2,395 for subsequent doses.
The company has agreed a commercial access arrangement for pertuzumab with NHS England. The commercial access arrangement replaces the patient access scheme agreed with the Department of Health for pertuzumab. The details of this commercial access arrangement are commercial in confidence.# Evidence
The appraisal committee (section 6) considered evidence submitted by Roche and a review of this submission by the evidence review group. The appraisal was paused in 2014 to allow NICE's decision support unit to provide a discussion paper and then later reconsidered as part of the transition to the new Cancer Drugs Fund system. The reconsideration focussed on the final analysis of the CLEOPATRA trial and an updated economic model that incorporated a confidential commercial access arrangement. See the committee papers for full details of the evidence.
The company included 1 randomised controlled trial in its original submission (CLEOPATRA). This was a double-blind, randomised, placebo-controlled trial assessing the efficacy and safety of pertuzumab plus trastuzumab and docetaxel in 808 adults with human epidermal growth factor receptor 2 (HER2)‑positive metastatic breast cancer in 25 countries including the UK. Randomisation was stratified by geographic region (Asia, Europe, North America and South America) and prior treatment status (de novo and prior adjuvant or neoadjuvant chemotherapy). Investigators randomised patients in a 1:1 ratio to either pertuzumab plus trastuzumab and docetaxel (n=402), or placebo plus trastuzumab and docetaxel (n=406). Patients had either pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks or by placebo every 3 weeks, until disease progression or unacceptable toxicity occurred. All patients had trastuzumab at a loading dose of 8 mg/kg body weight followed by 6 mg/kg body weight every 3 weeks, and docetaxel 75 to 100 mg/m2 (at investigator discretion) every 3 weeks for at least 6 cycles.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of pertuzumab plus trastuzumab and docetaxel, having considered evidence on the nature of human epidermal growth factor receptor 2 (HER2)‑positive metastatic or locally recurrent unresectable breast cancer and the value placed on the benefits of pertuzumab plus trastuzumab and docetaxel by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee discussed the management of HER2‑positive metastatic or locally recurrent unresectable breast cancer. It noted comments received from professional groups that over 90% of people in the UK with HER2‑positive breast cancer have trastuzumab, usually in combination with docetaxel, in the neoadjuvant or adjuvant setting. The committee noted a comment received in consultation suggesting that 90% could be an overestimate because some people would have metastatic disease at first diagnosis and would not have adjuvant therapy, or they would have had treatment for primary breast cancer before adjuvant therapy with trastuzumab became standard practice. The clinical expert highlighted that the introduction of neoadjuvant or adjuvant trastuzumab for early breast cancer had dramatically changed the disease course and prognosis of people with HER2‑positive breast cancer. The committee concluded that in clinical practice pertuzumab would be used in combination with trastuzumab and docetaxel or paclitaxel for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer in people who have not had previous anti‑HER2 therapy or chemotherapy for their metastatic disease, and that the majority of people would have had trastuzumab before this as adjuvant or neoadjuvant therapy.
The committee was aware that people with metastatic breast cancer understand that they have a life-limiting incurable disease that will eventually progress. It heard from the patient experts that although extension to life is important to patients, the benefits of progression-free survival should not be underestimated because it allows them to maintain a good quality of life during this period. The patient experts also stated that treatments that extend life, even for a few weeks or months, are important to people, and that they may be willing to accept the side effects associated with such treatments. The committee also heard from the patient experts that they consider pertuzumab to be an innovative technology because of the benefits shown in terms of progression‑free survival and overall survival. The committee concluded that the availability of new treatments such as pertuzumab is important to people with HER2‑positive metastatic or locally recurrent unresectable breast cancer.
When it reconsidered the evidence after pertuzumab had been available on the Cancer Drugs Fund for nearly 4 years, the committee heard from the clinical and patient experts that pertuzumab was now considered standard of care for all patients with metastatic or locally recurrent unresectable breast cancer who meet the criteria. The committee heard from the NHS England representative that although pertuzumab may be perceived by patients and clinicians to be standard of care, the Cancer Drugs Fund was always intended to be a temporary mechanism for access to treatments that have not been recommended by NICE. For this reason, pertuzumab with trastuzumab and docetaxel cannot be strictly considered as standard of care, because it has a different status to treatments that are recommended for baseline commissioning.
The committee heard from the clinical experts that pertuzumab with trastuzumab and docetaxel is a very effective treatment, and has been shown to improve overall survival by approximately 16 months compared with trastuzumab plus docetaxel. The patient expert noted that pertuzumab represents one of the most important advances in the treatment of HER2-positive metastatic breast cancer in recent years. It is generally well tolerated, giving patients good quality of life while they are taking it. This enables many patients to return to normal activities including work and family life, which is highly valued by patients and their families. Furthermore, in a disease with no cure, the availability of such an effective treatment gives patients hope and a more positive outlook on their treatment regimen and course of disease. The committee also heard that because pertuzumab with trastuzumab and docetaxel had become standard of care through its availability in the Cancer Drugs Fund, patients have an expectation that this treatment will continue to be available as a treatment option. If it were no longer available that would be a devastating blow. The committee appreciated the importance placed on the availability of effective treatments for breast cancer.
# Clinical effectiveness
The committee noted that the main source of evidence for the clinical effectiveness of pertuzumab plus trastuzumab and docetaxel was the CLEOPATRA trial. It agreed with the evidence review group (ERG's) comments that overall this was a well-designed double-blind randomised, placebo-controlled trial and that the prevention of crossover between arms before the May 2012 data cut-off minimised the risk of bias. However, the committee heard from the clinical expert that the CLEOPATRA protocol and inclusion criteria do not reflect current clinical practice in the UK. The clinical expert highlighted that only 11% of the randomised population in CLEOPATRA had previously had trastuzumab in the adjuvant setting. This is a different population compared with patients in clinical practice in the UK, where trastuzumab is standard treatment in the neoadjuvant or adjuvant setting. The committee heard from the company that although trastuzumab was available in the UK from 2006, it was not a standard adjuvant therapy in all 25 different countries where the CLEOPATRA trial was conducted. The committee was aware that the results of the additional subgroup analysis on the clinical effectiveness of pertuzumab in patients who had received previous treatment with trastuzumab in the adjuvant setting (requested by the Committee for Medicinal Products for Human Use) were consistent with the results found for the whole trial population. It noted, however, the clinical expert's comment about the small number of patients in this subgroup. The committee also considered comments received from professional groups that the inclusion criteria of the CLEOPATRA trial specified disease progression occurring at least 12 months after neoadjuvant or adjuvant therapy. It heard from the clinical expert that people who had experienced a 12‑month disease‑free interval might be expected to have a better prognosis than the whole population with HER2‑positive metastatic breast cancer. The committee considered that there were differences between the population in the CLEOPATRA trial and people currently having treatment for HER2‑positive metastatic breast cancer in the NHS, and expressed some reservations about the applicability and generalisability of the CLEOPATRA trial to UK clinical practice. However, there was no way for the committee to resolve this issue. It concluded that there remained uncertainty as to whether the clinical effectiveness of pertuzumab in clinical practice in the UK would be the same as demonstrated in the CLEOPATRA trial because of the inclusion of patients who might have a better prognosis, and the inclusion of only small numbers of people previously treated with HER2‑targeted therapies, which might affect their subsequent response.
The committee discussed the end points in the CLEOPATRA trial. It noted that pertuzumab plus trastuzumab and docetaxel was associated with a statistically significant gain in median progression‑free survival of 6.1 months at the first data cut-off. In the final analysis of the CLEOPATRA data (February 2014) in which patients had been followed up for a median of 49.5 months in the pertuzumab group and 50.6 months in the control group, pertuzumab was associated with an additional 6.3 months progression-free survival compared with the control group. The committee noted that the final analysis of overall survival (which was not adjusted for crossover from the control to the pertuzumab arm) showed a 15.7 month median overall survival benefit with the addition of pertuzumab, compared with trastuzumab and docetaxel. The committee heard from clinical experts that this magnitude of overall survival benefit is unprecedented in the treatment and palliation of advanced breast cancer and represents a step change in the treatment of patients with HER2-positive advanced breast cancer. The committee concluded that the addition of pertuzumab to trastuzumab and docetaxel results in substantial benefits for patients in improved progression-free and overall survival.
# Cost effectiveness
The committee considered the structure, assumptions and results of the company's economic model, which was based on data from CLEOPATRA. It noted that the ERG considered the company's model structure to be appropriate to describe the decision problem, easy to understand and correctly implemented. The committee was aware that the model structure had been used in other appraisals of metastatic breast cancer. It concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pertuzumab plus trastuzumab and docetaxel for treating HER2‑positive metastatic breast cancer.
The committee considered the way in which progression‑free survival and overall survival data had been extrapolated in the company's model. It noted that the company's base-case cost-effectiveness estimate for pertuzumab in combination with trastuzumab and docetaxel is associated with a 0% probability of being cost effective at £30,000 per quality-adjusted life year (QALY) gained. The committee further considered the deterministic sensitivity analysis and the ERG's exploratory analysis, which demonstrated that the model was sensitive to the long-term projection of overall survival.
At its first committee meeting, the committee considered the most plausible incremental cost-effectiveness ratio (ICER) for pertuzumab plus trastuzumab and docetaxel compared with trastuzumab and docetaxel presented by the company and by the ERG in its exploratory analyses. These were based on list prices for the technologies concerned. The committee noted that the company's base-case ICER was well outside the range normally considered to be a cost-effective use of NHS resources. It noted that the ERG's preferred ICER was based on an assumption of no benefit from pertuzumab in the post‑progression state and this reflected the worst case scenario. At that stage, the committee noted the considerable uncertainty around the presence or magnitude of benefit from pertuzumab in the post‑progression state when treatment has been stopped. However, even if the company's base-case ICER was accepted as plausible, there was a 0% probability that pertuzumab plus trastuzumab and docetaxel could be considered cost effective at a maximum acceptable ICER of £30,000 per QALY gained. The committee concluded that pertuzumab plus trastuzumab and docetaxel would not be a cost-effective use of NHS resources for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer compared with trastuzumab and docetaxel alone.
In its revised submission for the Cancer Drugs Fund reconsideration, the company included:
an additional 2 years follow-up data from CLEOPATRA, used to model progression-free and overall survival
a commercial access arrangement between Roche and NHS England
an updated model incorporating new data and using some of the ERG's preferred assumptions:
including subcutaneous trastuzumab in the comparator arm only
using the commercial medicines unit price for docetaxel
updating the pharmacy, administration and health-state costs
correcting the utility values for progression-free and progression health states in response to errors identified by the ERG
evidence on the uptake of pertuzumab with trastuzumab and docetaxel through the Cancer Drugs Fund since April 2013
a request for flexibility in the application of the life expectancy criteria in this appraisal.
The committee considered the company's updated economic model and the ERG's critique and exploratory analyses. The committee considered several amendments made by the ERG to the updated company model to explore the impact on the company ICER. The ERG used digitalised values for the Swain et al. paper (based on the final analysis of the CLEOPATRA data) to validate the company's long-term extrapolation of progression-free and overall survival. The committee noted that although the ERG preferred an exponential projection of the Kaplan–Meier data (compared with a log-logistic extrapolation in the updated company model) and an exponential extrapolation of the overall survival data (compared with gamma function in the updated company model) the method of extrapolation had little effect on the ICER. The ERG also corrected an error in the mean age of participants who estimated utility, which should have been 47 years for consistency with the participants in the original EQ-5D calibration panel (but was 38.2 years in the company model). This also had little effect on the ICER. The committee was reassured that although the combined effect of the ERG's changes slightly increased the ICER it remained similar to the company's base-case ICER. The ICER is commercial in confidence to protect the confidentiality of the commercial access agreement. The committee accepted that the commercial access arrangement reduced the ICER from the original submission, but that it still remained in excess of what is considered to be a cost-effective use of NHS resources for technologies that are not given special consideration as life-extending treatments for people with a short life expectancy.
# Innovation
The committee discussed whether pertuzumab should be considered an innovative treatment. It noted that the clinical expert emphasised the benefits of HER2 therapies in changing the prognosis of people with this disease and the significant progression‑free survival benefit observed with this new HER2‑targeted therapy. Patient experts regard it as an innovative treatment because it significantly increases the duration of progression‑free survival, thereby maintaining a good quality of life for patients. The committee considered that the innovative nature of pertuzumab had been demonstrated in the statistically significant progression‑free survival gain in CLEOPATRA and had been incorporated in the economic model. The committee concluded that all relevant health-related benefits of pertuzumab had been captured in the QALY calculation.
# End‑of‑life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee also noted the request from the company that the committee exercise 'flexibility' around the interpretation of the extension-to-life criteria (which specifies that life expectancy of patients would be normally less than 24 months) because of the substantial extension in overall survival of adding pertuzumab to trastuzumab and docetaxel. The committee acknowledged that the wording referring to the end-of-life criteria is deliberately expressed to provide committees with discretion required when they consider it reasonable to apply a weight to the QALYs gained in circumstances where one of the criteria does meet the exact level described in the policy.
The committee noted that the survival benefit with pertuzumab met, and far exceeded the 3 month extension to life criteria, and it had heard from the clinical experts that a 15.7 month median survival gain was unprecedented in the treatment of metastatic HER2‑positive breast cancer and represented a step-change in the treatment of this condition. The committee noted that the life expectancy of patients on chemotherapy alone based on the unadjusted median overall survival in the control arm of CLEOPATRA was 40.8 months, which exceeds the 24 months stated in the end-of-life criteria. However, people in the CLEOPATRA trial may have a better prognosis than people in UK clinical practice (see section 4.6). The committee also noted the company's estimates for overall survival with a trastuzumab and chemotherapy containing regimen, which were between approximately 2 and 3 years. The committee agreed that although life expectancy in the trial was greater than 24 months, the exceptional proportional gain in survival with pertuzumab in people with a relatively modest life expectancy should be taken into account. The committee concluded that it was fair and reasonable to accept that pertuzumab fulfilled the criteria for special consideration on this basis.
The committee recognised the exceptional nature of this decision, which it found reasonable in the context of ensuring continued access to a highly effective treatment option for people with advanced breast cancer. In this context, the committee considered it reasonable to expect that the weight that needs to be applied to the QALYs gained in order to allow continued access would not have to be at the very maximum allocated in other, more regular, circumstances where the end of life criteria have been applied. With this in mind, the committee accepted that the ICER, taking into account the commercial access arrangement, provides for an acceptable use of NHS resources.
# Conclusions
The committee considered that the updated clinical-effectiveness evidence clearly demonstrates that the addition of pertuzumab to trastuzumab leads to a substantial improvement in progression-free and overall survival, which is unprecedented in the treatment of advanced breast cancer. When considering the clinical and cost effectiveness of pertuzumab the committee thought it relevant that pertuzumab in combination with trastuzumab and docetaxel for metastatic HER2‑positive breast cancer is currently a Cancer Drugs Fund transition topic and will remain on the Cancer Drugs Fund until guidance is issued by NICE. It considered the appraisal of pertuzumab to be a special case because it has been available for this indication for 4 years in the NHS. When considering the evidence it was mindful that it was deliberating whether pertuzumab should continue to be funded by the NHS or removing funding for an effective treatment which has become, in the minds of patients and clinicians, standard of care for treating metastatic breast cancer. The committee appreciated the different impact of disinvestment compared with investment decisions on opportunity cost. The committee noted that there is no specific guidance in the methods for technology appraisal for disinvestment decisions.
The committee acknowledged the flexibilities in the application of the end-of-life criteria. The committee considered that the unprecedented survival benefit with the addition of pertuzumab should be considered in the light of modest life expectancy of these patients and concluded that it was fair and reasonable to accept that pertuzumab fulfils the end-of-life criteria. The committee further accepted that in the context of the exceptional circumstance this case presents, it would be reasonable not to be asked to have to apply the maximum weight to the QALYs gained by pertuzumab. The committee accepted that the ICER, taking into account the commercial access arrangement, provides for an acceptable use of NHS resources.
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{'Recommendations': 'Pertuzumab, in combination with trastuzumab and docetaxel, is recommended, within its marketing authorisation, for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer, in adults who have not had previous anti‑HER2 therapy or chemotherapy for their metastatic disease, only if the company provides pertuzumab within the agreed commercial access arrangement.\n\nWhy the committee made these recommendations\n\nThis recommendation is for a drug that has been available on the Cancer Drugs Fund for several years and the committee recognised this as an exceptional circumstance. In this context, the committee considered it reasonable to apply flexibility in its interpretation of the criteria for special consideration as a life-extending treatment for people with a short life expectancy, but noted that the weight applied to the quality-adjusted life years gained would not be at the maximum allocated in other, more regular, circumstances where the end of life criteria have been applied. With this in mind, the committee accepted that the incremental cost-effectiveness ratio, taking into account the commercial access arrangement, provides for an acceptable use of NHS resources.', 'The technology': "Description of the technology\n\nPertuzumab (Perjeta, Roche Products) is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Pertuzumab binds to the HER2 receptor and inhibits intracellular signalling. It is administered by intravenous infusion.\n\nMarketing authorisation\n\nPertuzumab has a UK marketing authorisation for use 'in combination with trastuzumab and docetaxel in adult patients with HER2 positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti HER2 therapy or chemotherapy for their metastatic disease'.\n\nAdverse reactions\n\nThe summary of product characteristics lists the following adverse reactions for pertuzumab in combination with trastuzumab and docetaxel: left ventricular dysfunction (including congestive heart failure), infusion reactions, hypersensitivity reactions (including anaphylaxis), neutropenia, febrile neutropenia, leukopenia, diarrhoea, alopecia and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dose of pertuzumab is an initial loading dose of 840\xa0mg followed every 3\xa0weeks by a maintenance dose of 420\xa0mg in combination with trastuzumab and docetaxel. Treatment with pertuzumab should be continued until disease progression or unmanageable toxicity.\n\nPrice\n\nPertuzumab is £2,395 per 420‑mg vial (BNF\xa017). Therefore the cost of pertuzumab (excluding VAT) is estimated to be £4,790 for the initial dose and £2,395 for subsequent doses.\n\nThe company has agreed a commercial access arrangement for pertuzumab with NHS England. The commercial access arrangement replaces the patient access scheme agreed with the Department of Health for pertuzumab. The details of this commercial access arrangement are commercial in confidence.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Roche and a review of this submission by the evidence review group. The appraisal was paused in 2014 to allow NICE's decision support unit to provide a discussion paper and then later reconsidered as part of the transition to the new Cancer Drugs Fund system. The reconsideration focussed on the final analysis of the CLEOPATRA trial and an updated economic model that incorporated a confidential commercial access arrangement. See the committee papers for full details of the evidence.\n\nThe company included 1\xa0randomised controlled trial in its original submission (CLEOPATRA). This was a double-blind, randomised, placebo-controlled trial assessing the efficacy and safety of pertuzumab plus trastuzumab and docetaxel in 808\xa0adults with human epidermal growth factor receptor 2 (HER2)‑positive metastatic breast cancer in 25 countries including the UK. Randomisation was stratified by geographic region (Asia, Europe, North America and South America) and prior treatment status (de novo and prior adjuvant or neoadjuvant chemotherapy). Investigators randomised patients in a 1:1\xa0ratio to either pertuzumab plus trastuzumab and docetaxel (n=402), or placebo plus trastuzumab and docetaxel (n=406). Patients had either pertuzumab at a loading dose of 840\xa0mg followed by 420\xa0mg every 3\xa0weeks or by placebo every 3\xa0weeks, until disease progression or unacceptable toxicity occurred. All patients had trastuzumab at a loading dose of 8\xa0mg/kg body weight followed by 6\xa0mg/kg body weight every 3\xa0weeks, and docetaxel 75\xa0to\xa0100\xa0mg/m2 (at investigator discretion) every 3\xa0weeks for at least 6\xa0cycles.", 'Committee discussion ': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of pertuzumab plus trastuzumab and docetaxel, having considered evidence on the nature of human epidermal growth factor receptor 2 (HER2)‑positive metastatic or locally recurrent unresectable breast cancer and the value placed on the benefits of pertuzumab plus trastuzumab and docetaxel by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee discussed the management of HER2‑positive metastatic or locally recurrent unresectable breast cancer. It noted comments received from professional groups that over 90% of people in the UK with HER2‑positive breast cancer have trastuzumab, usually in combination with docetaxel, in the neoadjuvant or adjuvant setting. The committee noted a comment received in consultation suggesting that 90% could be an overestimate because some people would have metastatic disease at first diagnosis and would not have adjuvant therapy, or they would have had treatment for primary breast cancer before adjuvant therapy with trastuzumab became standard practice. The clinical expert highlighted that the introduction of neoadjuvant or adjuvant trastuzumab for early breast cancer had dramatically changed the disease course and prognosis of people with HER2‑positive breast cancer. The committee concluded that in clinical practice pertuzumab would be used in combination with trastuzumab and docetaxel or paclitaxel for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer in people who have not had previous anti‑HER2 therapy or chemotherapy for their metastatic disease, and that the majority of people would have had trastuzumab before this as adjuvant or neoadjuvant therapy.\n\nThe committee was aware that people with metastatic breast cancer understand that they have a life-limiting incurable disease that will eventually progress. It heard from the patient experts that although extension to life is important to patients, the benefits of progression-free survival should not be underestimated because it allows them to maintain a good quality of life during this period. The patient experts also stated that treatments that extend life, even for a few weeks or months, are important to people, and that they may be willing to accept the side effects associated with such treatments. The committee also heard from the patient experts that they consider pertuzumab to be an innovative technology because of the benefits shown in terms of progression‑free survival and overall survival. The committee concluded that the availability of new treatments such as pertuzumab is important to people with HER2‑positive metastatic or locally recurrent unresectable breast cancer.\n\nWhen it reconsidered the evidence after pertuzumab had been available on the Cancer Drugs Fund for nearly 4\xa0years, the committee heard from the clinical and patient experts that pertuzumab was now considered standard of care for all patients with metastatic or locally recurrent unresectable breast cancer who meet the criteria. The committee heard from the NHS England representative that although pertuzumab may be perceived by patients and clinicians to be standard of care, the Cancer Drugs Fund was always intended to be a temporary mechanism for access to treatments that have not been recommended by NICE. For this reason, pertuzumab with trastuzumab and docetaxel cannot be strictly considered as standard of care, because it has a different status to treatments that are recommended for baseline commissioning.\n\nThe committee heard from the clinical experts that pertuzumab with trastuzumab and docetaxel is a very effective treatment, and has been shown to improve overall survival by approximately 16\xa0months compared with trastuzumab plus docetaxel. The patient expert noted that pertuzumab represents one of the most important advances in the treatment of HER2-positive metastatic breast cancer in recent years. It is generally well tolerated, giving patients good quality of life while they are taking it. This enables many patients to return to normal activities including work and family life, which is highly valued by patients and their families. Furthermore, in a disease with no cure, the availability of such an effective treatment gives patients hope and a more positive outlook on their treatment regimen and course of disease. The committee also heard that because pertuzumab with trastuzumab and docetaxel had become standard of care through its availability in the Cancer Drugs Fund, patients have an expectation that this treatment will continue to be available as a treatment option. If it were no longer available that would be a devastating blow. The committee appreciated the importance placed on the availability of effective treatments for breast cancer.\n\n# Clinical effectiveness\n\nThe committee noted that the main source of evidence for the clinical effectiveness of pertuzumab plus trastuzumab and docetaxel was the CLEOPATRA trial. It agreed with the evidence review group (ERG's) comments that overall this was a well-designed double-blind randomised, placebo-controlled trial and that the prevention of crossover between arms before the May\xa02012 data cut-off minimised the risk of bias. However, the committee heard from the clinical expert that the CLEOPATRA protocol and inclusion criteria do not reflect current clinical practice in the UK. The clinical expert highlighted that only 11% of the randomised population in CLEOPATRA had previously had trastuzumab in the adjuvant setting. This is a different population compared with patients in clinical practice in the UK, where trastuzumab is standard treatment in the neoadjuvant or adjuvant setting. The committee heard from the company that although trastuzumab was available in the UK from 2006, it was not a standard adjuvant therapy in all 25\xa0different countries where the CLEOPATRA trial was conducted. The committee was aware that the results of the additional subgroup analysis on the clinical effectiveness of pertuzumab in patients who had received previous treatment with trastuzumab in the adjuvant setting (requested by the Committee for Medicinal Products for Human Use) were consistent with the results found for the whole trial population. It noted, however, the clinical expert's comment about the small number of patients in this subgroup. The committee also considered comments received from professional groups that the inclusion criteria of the CLEOPATRA trial specified disease progression occurring at least 12\xa0months after neoadjuvant or adjuvant therapy. It heard from the clinical expert that people who had experienced a 12‑month disease‑free interval might be expected to have a better prognosis than the whole population with HER2‑positive metastatic breast cancer. The committee considered that there were differences between the population in the CLEOPATRA trial and people currently having treatment for HER2‑positive metastatic breast cancer in the NHS, and expressed some reservations about the applicability and generalisability of the CLEOPATRA trial to UK clinical practice. However, there was no way for the committee to resolve this issue. It concluded that there remained uncertainty as to whether the clinical effectiveness of pertuzumab in clinical practice in the UK would be the same as demonstrated in the CLEOPATRA trial because of the inclusion of patients who might have a better prognosis, and the inclusion of only small numbers of people previously treated with HER2‑targeted therapies, which might affect their subsequent response.\n\nThe committee discussed the end points in the CLEOPATRA trial. It noted that pertuzumab plus trastuzumab and docetaxel was associated with a statistically significant gain in median progression‑free survival of 6.1\xa0months at the first data cut-off. In the final analysis of the CLEOPATRA data (February 2014) in which patients had been followed up for a median of 49.5\xa0months in the pertuzumab group and 50.6\xa0months in the control group, pertuzumab was associated with an additional 6.3\xa0months progression-free survival compared with the control group. The committee noted that the final analysis of overall survival (which was not adjusted for crossover from the control to the pertuzumab arm) showed a 15.7\xa0month median overall survival benefit with the addition of pertuzumab, compared with trastuzumab and docetaxel. The committee heard from clinical experts that this magnitude of overall survival benefit is unprecedented in the treatment and palliation of advanced breast cancer and represents a step change in the treatment of patients with HER2-positive advanced breast cancer. The committee concluded that the addition of pertuzumab to trastuzumab and docetaxel results in substantial benefits for patients in improved progression-free and overall survival.\n\n# Cost effectiveness\n\nThe committee considered the structure, assumptions and results of the company's economic model, which was based on data from CLEOPATRA. It noted that the ERG considered the company's model structure to be appropriate to describe the decision problem, easy to understand and correctly implemented. The committee was aware that the model structure had been used in other appraisals of metastatic breast cancer. It concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pertuzumab plus trastuzumab and docetaxel for treating HER2‑positive metastatic breast cancer.\n\nThe committee considered the way in which progression‑free survival and overall survival data had been extrapolated in the company's model. It noted that the company's base-case cost-effectiveness estimate for pertuzumab in combination with trastuzumab and docetaxel is associated with a 0% probability of being cost effective at £30,000 per quality-adjusted life year (QALY) gained. The committee further considered the deterministic sensitivity analysis and the ERG's exploratory analysis, which demonstrated that the model was sensitive to the long-term projection of overall survival.\n\nAt its first committee meeting, the committee considered the most plausible incremental cost-effectiveness ratio (ICER) for pertuzumab plus trastuzumab and docetaxel compared with trastuzumab and docetaxel presented by the company and by the ERG in its exploratory analyses. These were based on list prices for the technologies concerned. The committee noted that the company's base-case ICER was well outside the range normally considered to be a cost-effective use of NHS resources. It noted that the ERG's preferred ICER was based on an assumption of no benefit from pertuzumab in the post‑progression state and this reflected the worst case scenario. At that stage, the committee noted the considerable uncertainty around the presence or magnitude of benefit from pertuzumab in the post‑progression state when treatment has been stopped. However, even if the company's base-case ICER was accepted as plausible, there was a 0% probability that pertuzumab plus trastuzumab and docetaxel could be considered cost effective at a maximum acceptable ICER of £30,000 per QALY gained. The committee concluded that pertuzumab plus trastuzumab and docetaxel would not be a cost-effective use of NHS resources for treating HER2‑positive metastatic or locally recurrent unresectable breast cancer compared with trastuzumab and docetaxel alone.\n\nIn its revised submission for the Cancer Drugs Fund reconsideration, the company included:\n\nan additional 2\xa0years follow-up data from CLEOPATRA, used to model progression-free and overall survival\n\na commercial access arrangement between Roche and NHS England\n\nan updated model incorporating new data and using some of the ERG's preferred assumptions:\n\n\n\nincluding subcutaneous trastuzumab in the comparator arm only\n\nusing the commercial medicines unit price for docetaxel\n\nupdating the pharmacy, administration and health-state costs\n\ncorrecting the utility values for progression-free and progression health states in response to errors identified by the ERG\n\n\n\nevidence on the uptake of pertuzumab with trastuzumab and docetaxel through the Cancer Drugs Fund since April 2013\n\na request for flexibility in the application of the life expectancy criteria in this appraisal.\n\nThe committee considered the company's updated economic model and the ERG's critique and exploratory analyses. The committee considered several amendments made by the ERG to the updated company model to explore the impact on the company ICER. The ERG used digitalised values for the Swain et al. paper (based on the final analysis of the CLEOPATRA data) to validate the company's long-term extrapolation of progression-free and overall survival. The committee noted that although the ERG preferred an exponential projection of the Kaplan–Meier data (compared with a log-logistic extrapolation in the updated company model) and an exponential extrapolation of the overall survival data (compared with gamma function in the updated company model) the method of extrapolation had little effect on the ICER. The ERG also corrected an error in the mean age of participants who estimated utility, which should have been 47 years for consistency with the participants in the original EQ-5D calibration panel (but was 38.2 years in the company model). This also had little effect on the ICER. The committee was reassured that although the combined effect of the ERG's changes slightly increased the ICER it remained similar to the company's base-case ICER. The ICER is commercial in confidence to protect the confidentiality of the commercial access agreement. The committee accepted that the commercial access arrangement reduced the ICER from the original submission, but that it still remained in excess of what is considered to be a cost-effective use of NHS resources for technologies that are not given special consideration as life-extending treatments for people with a short life expectancy.\n\n# Innovation\n\nThe committee discussed whether pertuzumab should be considered an innovative treatment. It noted that the clinical expert emphasised the benefits of HER2 therapies in changing the prognosis of people with this disease and the significant progression‑free survival benefit observed with this new HER2‑targeted therapy. Patient experts regard it as an innovative treatment because it significantly increases the duration of progression‑free survival, thereby maintaining a good quality of life for patients. The committee considered that the innovative nature of pertuzumab had been demonstrated in the statistically significant progression‑free survival gain in CLEOPATRA and had been incorporated in the economic model. The committee concluded that all relevant health-related benefits of pertuzumab had been captured in the QALY calculation.\n\n# End‑of‑life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee also noted the request from the company that the committee exercise 'flexibility' around the interpretation of the extension-to-life criteria (which specifies that life expectancy of patients would be normally less than 24 months) because of the substantial extension in overall survival of adding pertuzumab to trastuzumab and docetaxel. The committee acknowledged that the wording referring to the end-of-life criteria is deliberately expressed to provide committees with discretion required when they consider it reasonable to apply a weight to the QALYs gained in circumstances where one of the criteria does meet the exact level described in the policy.\n\nThe committee noted that the survival benefit with pertuzumab met, and far exceeded the 3\xa0month extension to life criteria, and it had heard from the clinical experts that a 15.7\xa0month median survival gain was unprecedented in the treatment of metastatic HER2‑positive breast cancer and represented a step-change in the treatment of this condition. The committee noted that the life expectancy of patients on chemotherapy alone based on the unadjusted median overall survival in the control arm of CLEOPATRA was 40.8\xa0months, which exceeds the 24\xa0months stated in the end-of-life criteria. However, people in the CLEOPATRA trial may have a better prognosis than people in UK clinical practice (see section 4.6). The committee also noted the company's estimates for overall survival with a trastuzumab and chemotherapy containing regimen, which were between approximately 2\xa0and 3\xa0years. The committee agreed that although life expectancy in the trial was greater than 24\xa0months, the exceptional proportional gain in survival with pertuzumab in people with a relatively modest life expectancy should be taken into account. The committee concluded that it was fair and reasonable to accept that pertuzumab fulfilled the criteria for special consideration on this basis.\n\nThe committee recognised the exceptional nature of this decision, which it found reasonable in the context of ensuring continued access to a highly effective treatment option for people with advanced breast cancer. In this context, the committee considered it reasonable to expect that the weight that needs to be applied to the QALYs gained in order to allow continued access would not have to be at the very maximum allocated in other, more regular, circumstances where the end of life criteria have been applied. With this in mind, the committee accepted that the ICER, taking into account the commercial access arrangement, provides for an acceptable use of NHS resources.\n\n# Conclusions\n\nThe committee considered that the updated clinical-effectiveness evidence clearly demonstrates that the addition of pertuzumab to trastuzumab leads to a substantial improvement in progression-free and overall survival, which is unprecedented in the treatment of advanced breast cancer. When considering the clinical and cost effectiveness of pertuzumab the committee thought it relevant that pertuzumab in combination with trastuzumab and docetaxel for metastatic HER2‑positive breast cancer is currently a Cancer Drugs Fund transition topic and will remain on the Cancer Drugs Fund until guidance is issued by NICE. It considered the appraisal of pertuzumab to be a special case because it has been available for this indication for 4\xa0years in the NHS. When considering the evidence it was mindful that it was deliberating whether pertuzumab should continue to be funded by the NHS or removing funding for an effective treatment which has become, in the minds of patients and clinicians, standard of care for treating metastatic breast cancer. The committee appreciated the different impact of disinvestment compared with investment decisions on opportunity cost. The committee noted that there is no specific guidance in the methods for technology appraisal for disinvestment decisions.\n\nThe committee acknowledged the flexibilities in the application of the end-of-life criteria. The committee considered that the unprecedented survival benefit with the addition of pertuzumab should be considered in the light of modest life expectancy of these patients and concluded that it was fair and reasonable to accept that pertuzumab fulfils the end-of-life criteria. The committee further accepted that in the context of the exceptional circumstance this case presents, it would be reasonable not to be asked to have to apply the maximum weight to the QALYs gained by pertuzumab. The committee accepted that the ICER, taking into account the commercial access arrangement, provides for an acceptable use of NHS resources."}
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https://www.nice.org.uk/guidance/ta509
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Evidence-based recommendations on pertuzumab (Perjeta) for treating HER2‑positive, locally recurrent or metastatic (secondary) breast cancer that has not been treated with chemotherapy or targeted HER‑2 therapy before, in adults.
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ca8e1408d6280df21c528b22542cf998f068cb8e
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nice
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Unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson's disease
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Unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson's disease
Evidence-based recommendations on unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson’s disease in adults. This involves applying ultrasound to a specific area on 1 side of the brain (thalamus).
# Recommendations
Current evidence on the safety and efficacy of unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson's disease is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research, which could include randomised controlled trials, should address patient selection and report on long-term follow-up.# The condition, current treatments and procedure
# The condition
Parkinson's disease is a progressive neurodegenerative disease characterised by gradually worsening tremor, muscle rigidity, and difficulties with starting and stopping movements. The tremor in Parkinson's disease occurs at rest and becomes less prominent with voluntary movement. It typically occurs first in the distal upper extremities then moves proximally and spreads to affect other parts of the body over time.
# Current treatments
Treatment for Parkinson's disease includes supportive therapies and medications such as levodopa, dopamine agonists and monoamine oxidase B inhibitors.
Surgery may be considered in people whose condition has not responded adequately to best medical therapy. Surgical treatments include deep brain stimulation and radiofrequency thalamotomy.
# The procedure
This procedure is carried out with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are kept awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low-power (sub-lethal) ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate target tissue. Chilled water is circulated around the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3 hours and symptom relief should be immediate.
The potential benefits of unilateral MRI-guided focused ultrasound thalamotomy are that it: is less invasive than the other existing procedures; results in a faster recovery time; and allows for testing of the effects of sub-lethal doses before ablation. However, unlike deep brain stimulation it can only be done on 1 side.
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{'Recommendations': "Current evidence on the safety and efficacy of unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson's disease is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research, which could include randomised controlled trials, should address patient selection and report on long-term follow-up.", 'The condition, current treatments and procedure': "# The condition\n\nParkinson's disease is a progressive neurodegenerative disease characterised by gradually worsening tremor, muscle rigidity, and difficulties with starting and stopping movements. The tremor in Parkinson's disease occurs at rest and becomes less prominent with voluntary movement. It typically occurs first in the distal upper extremities then moves proximally and spreads to affect other parts of the body over time.\n\n# Current treatments\n\nTreatment for Parkinson's disease includes supportive therapies and medications such as levodopa, dopamine agonists and monoamine oxidase\xa0B inhibitors.\n\nSurgery may be considered in people whose condition has not responded adequately to best medical therapy. Surgical treatments include deep brain stimulation and radiofrequency thalamotomy.\n\n# The procedure\n\nThis procedure is carried out with the patient lying supine inside an MRI scanner. The patient's head is shaved and a stereotactic head frame is attached. Patients are kept awake so they can report any improvement or adverse events to the operator during the procedure. However, they may be offered light sedation. Continuous MRI and thermal mapping are used to identify the target area of the brain and monitor treatment. Low-power (sub-lethal) ultrasound is delivered to confirm the chosen location. Then, high-power focused ultrasound pulses are administered to irreversibly ablate target tissue. Chilled water is circulated around the head during the treatment to prevent thermal damage to the scalp caused by the increase in bone temperature. The procedure takes about 3\xa0hours and symptom relief should be immediate.\n\nThe potential benefits of unilateral MRI-guided focused ultrasound thalamotomy are that it: is less invasive than the other existing procedures; results in a faster recovery time; and allows for testing of the effects of sub-lethal doses before ablation. However, unlike deep brain stimulation it can only be done on 1\xa0side."}
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https://www.nice.org.uk/guidance/ipg606
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Evidence-based recommendations on unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson’s disease in adults. This involves applying ultrasound to a specific area on 1 side of the brain (thalamus).
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4daa7e53c387e839457742c213376042907a7dc0
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nice
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Sofosbuvir–velpatasvir–voxilaprevir for treating chronic hepatitis C
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Sofosbuvir–velpatasvir–voxilaprevir for treating chronic hepatitis C
Evidence-based recommendations on sofosbuvir–velpatasvir–voxilaprevir (Vosevi) for treating chronic hepatitis C in adults.
# Recommendations
Sofosbuvir–velpatasvir–voxilaprevir is recommended as an option for treating chronic hepatitis C in adults, only if it is used as specified in table 1 and the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit.
Treatment history
Hepatitis C virus genotype
Liver disease stage
Recommendation
Previous direct-acting antivirals
With or without compensated cirrhosis
Recommended for 12 weeks
No direct-acting antivirals
With or without compensated cirrhosis
Recommended for 8 weeks
It is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.
These recommendations are not intended to affect treatment with sofosbuvir–velpatasvir–voxilaprevir that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment options for chronic hepatitis C depend on the genotype of the virus and the person's cirrhosis status and treatment history. They include direct-acting antivirals (DAA) and interferon-containing treatments. There are currently no treatments with a marketing authorisation available for people who have had unsuccessful treatment with DAA.
Clinical trials show that sofosbuvir–velpatasvir–voxilaprevir is effective for treating all genotypes of chronic hepatitis C, irrespective of the person's cirrhosis status and treatment history.
The company's economic evidence is limited to people who have had DAA (genotypes 1–6) and people with genotype 3 hepatitis C who have not had DAA before. This reflects the groups with the highest unmet clinical need. Cost-effectiveness estimates for sofosbuvir–velpatasvir–voxilaprevir are within what NICE usually considers acceptable. Therefore sofosbuvir–velpatasvir–voxilaprevir can be recommended for these groups for treating chronic hepatitis C, as specified in table 1.# Information about sofosbuvir–velpatasvir–voxilaprevir
Marketing authorisation indication
Sofosbuvir–velpatasvir–voxilaprevir (Vosevi, Gilead Sciences) has a marketing authorisation in the UK for 'the treatment of chronic hepatitis C virus infection in adults'.
This includes genotypes 1–6, with or without compensated cirrhosis, and includes people who have had previous treatment with direct-acting antivirals.
Dosage in the marketing authorisation
The recommended dose is 1 tablet taken orally once daily. Each tablet contains 400 mg sofosbuvir, 100 mg velpatasvir and 100 mg voxilaprevir.
Treatment duration is 8 or 12 weeks depending on cirrhosis status and whether the person has had previous treatment with direct-acting antivirals. Please see the summary of product characteristics for more details.
Price
Sofosbuvir–velpatasvir–voxilaprevir costs £14,942.33 per 28‑day pack. The total costs are £29,884.66 for an 8-week course and £44,826.99 for a 12-week course (company submission).
The company agreed a nationally available price reduction for sofosbuvir–velpatasvir–voxilaprevir with the Commercial Medicines Unit. The contract prices agreed through the framework are commercial in confidence.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Gilead Sciences and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## A suitable treatment option is needed when direct-acting antivirals are unsuccessful
The use of interferon-containing treatments has reduced substantially in clinical practice because of the introduction of newer direct-acting antivirals (DAA) for hepatitis C. Clinical and patient experts stated that sofosbuvir–velpatasvir–voxilaprevir is effective when DAA have been unsuccessful. This is particularly important because there are no NICE-recommended treatments available in this situation. The committee agreed with the clinical and patient experts that there is an unmet need when treatment with DAA is unsuccessful and sofosbuvir–velpatasvir–voxilaprevir is effective for genotypes 1–6 of hepatitis C in people who have had DAA before. Also, sofosbuvir–velpatasvir–voxilaprevir offers a short treatment duration for people who haven't had DAA before. The committee recognised that patients and clinicians would welcome an effective and tolerable treatment, especially for people who have had unsuccessful treatment with DAA before. It concluded that sofosbuvir–velpatasvir–voxilaprevir is a valuable treatment option.
# Clinical effectiveness
## Sofosbuvir–velpatasvir–voxilaprevir is effective for treating chronic hepatitis C
The key clinical evidence for sofosbuvir–velpatasvir–voxilaprevir came from 4 randomised controlled phase 3 clinical trials (POLARIS-1, -2, -3 and -4).
Two trials recruited people who had previous DAA treatment (genotypes 1–6, with or without compensated cirrhosis) and compared 12-week sofosbuvir–velpatasvir–voxilaprevir treatment with placebo (POLARIS-1) or sofosbuvir–velpatasvir (POLARIS-4).
Two trials recruited people who had no previous DAA treatment and compared 8-week sofosbuvir–velpatasvir–voxilaprevir treatment with sofosbuvir–velpatasvir in people with genotypes 1–6, with or without compensated cirrhosis (POLARIS-2) or in people with genotype 3 and compensated cirrhosis (POLARIS-3).The ERG considered that the trials were generally well conducted, although there was a higher risk of bias in POLARIS-2, -3 and -4 because they were open-label studies, and because only POLARIS-1 randomised all patients. The trial results showed high sustained virological response at 12 weeks, ranging from 80% to 100%, irrespective of hepatitis C virus genotype, cirrhosis stage or treatment history. The committee concluded that sofosbuvir–velpatasvir–voxilaprevir is effective for treating chronic hepatitis C across all subgroups and for genotypes 1–6.
## Sofosbuvir–velpatasvir–voxilaprevir is generally well tolerated
The most commonly reported adverse events with sofosbuvir–velpatasvir–voxilaprevir were headache and fatigue. The patient expert noted that sofosbuvir–velpatasvir–voxilaprevir is a 3-agent treatment and therefore may result in more adverse events than a 2-agent treatment, but it is still generally tolerable. The committee agreed that sofosbuvir–velpatasvir–voxilaprevir has a relatively favourable safety and tolerability profile (irrespective of cirrhosis stage or treatment history) and concluded that the adverse events associated with sofosbuvir–velpatasvir–voxilaprevir were generally tolerable.
# Cost-effectiveness analysis
## The company's model structure is acceptable for decision-making
The structure of the model and its assumptions about the natural history of the disease are similar to models submitted for other NICE technology appraisals for chronic hepatitis C. The ERG noted that treatment-related mortality and background mortality are related to treatment duration and can lead to counterintuitive results when comparing treatments of unequal durations. This is because the mortality in the model starts earlier for the shorter treatment. The company explained that this is a conservative assumption for sofosbuvir–velpatasvir–voxilaprevir because of the short treatment duration of 8 to 12 weeks. The committee was aware that the company had grouped people with mild and moderate fibrosis into a single health state (non-cirrhotic), and agreed that this was consistent with how people are diagnosed in current practice. The committee concluded that the structure of the model was acceptable for decision-making.
## The population in the company's model is different to the population in the marketing authorisation
Although the marketing authorisation for sofosbuvir–velpatasvir–voxilaprevir includes treatment for people with hepatitis C genotypes 1–6 regardless of cirrhosis status and treatment history, the company included only 3 subgroups in its model:
people who have had DAA (DAA-experienced; genotypes 1–6 with or without cirrhosis)
people who have not had DAA (DAA-naive; genotype 3) without cirrhosis and
people who have not had DAA (DAA-naive; genotype 3) with compensated cirrhosis.The company explained that it focused on populations with high unmet clinical need. It emphasised that there are currently no other licensed treatments for disease previously treated with DAA, and that people with genotype 3 who have not had DAA are at highest risk of cirrhosis progression. The clinical experts and the representatives from NHS England agreed that there is an unmet need for people who have had DAA. They noted that other effective DAA treatments are available for people who have not had DAA (including for genotype 3). They confirmed that sofosbuvir–velpatasvir–voxilaprevir would mostly be used in clinical practice when previous DAA treatment has been unsuccessful. The committee was satisfied that the company's model reflected how the treatment would likely be used in clinical practice in England. Also, the comparators included by the company were those used in clinical practice for the included populations. Therefore it concluded that the company's approach was acceptable, and that subsequent discussions and recommendations would cover only the populations presented.
## Reinfection and future transmission of hepatitis C is modelled as a scenario analysis for people with genotype 3 who have not had DAA
The company did a separate scenario analysis using dynamic transition modelling, which investigated the impact of onward transmission and reinfection for people with genotype 3 who have not had DAA. In the analysis, the company assumed that only people who inject drugs transmit hepatitis C or become reinfected after being cured. The results were similar to the results of the company's base case. The ERG explained that the scenario analysis made simplifying assumptions and was done only for people with genotype 3 who have not had DAA, with no results by cirrhosis status provided. In previous NICE chronic hepatitis C appraisals, the committee stated that it would have preferred to see a model including both reinfection and transmission. Having seen that the company's results were similar when both types of model structures were used, the committee concluded that the company's base-case model (excluding reinfection and transmission) was acceptable for decision-making.
## The company's naive indirect comparison of sustained virological response rates leads to uncertainty in the model results
The company used a naive indirect comparison to compare sofosbuvir–velpatasvir–voxilaprevir with the relevant comparators in people with genotype 3 who have not had DAA. Because of the lack of comparative trial data for some of the comparators, an indirect treatment comparison was not feasible. The rates of sustained virological response for the comparators in the company's model were selected from individual arms of randomised controlled trials. The company used some of the same rates of sustained virological response for comparator technologies as those used in NICE's technology appraisal guidance on sofosbuvir–velpatasvir. The committee noted that this approach meant that the results were at risk of the kind of bias normally associated with observational studies. The ERG noted that the company combined the rates for people who had, and people who did not have, a previous treatment for the sofosbuvir plus ribavirin treatment. But for the sofosbuvir plus peginterferon alfa and ribavirin treatment, it used only the rates for people who did not have a treatment before. The ERG combined the rates for people who had, and people who did not have, a previous treatment for sofosbuvir plus peginterferon alfa and ribavirin in its exploratory analyses; this had only marginal impact on the company's results. The committee agreed that for consistency, it preferred the ERG's approach to estimating the rates for sofosbuvir plus peginterferon alfa and ribavirin. It concluded that overall, the company's method of estimating efficacy in the model introduced some uncertainty in the results.
## The company's transition probabilities with the ERG's amendment are appropriate for decision-making
The company used the same sources for non-treatment-specific transition probabilities as those used in NICE's technology appraisal guidance on sofosbuvir–velpatasvir. This included Kanwal et al. (2014) for genotype-specific fibrosis progression and Cardoso et al. (2010) for non-fibrosis progression (not genotype-specific). In its revision to the company's base case, the ERG applied a transition probability from a more recent source (Hepatitis C Trust, 2017) for progression from liver transplant to death. Also, the ERG explored using transition probabilities for compensated cirrhosis (to decompensated cirrhosis and hepatocellular carcinoma), decompensated cirrhosis (to hepatocellular carcinoma and death), and hepatocellular carcinoma (to death) from Fattovich et al. (1997) instead of Cardoso et al. in a scenario analysis, as recommended in the sofosbuvir–velpatasvir guidance. The ERG's analyses had only marginal impact on the company's results. The committee was generally satisfied with the company's approach, but preferred the ERG's approach of using more recent data sources to estimate transition probabilities for progression from liver transplant to death.
## The committee prefers utility values from clinical trials, but it accepted the company's utility values
In its base-case analyses, the company used utility data from the literature (Wright et al. 2006 and Vera-Llonch et al. 2013) in line with NICE's previous technology appraisal guidance on hepatitis C. This was to inform the difference in utility of a health state with or without sustained virological response. The ERG stated that although EQ-5D was not an outcome in the POLARIS trials, health-related quality-of-life data were collected (for example, SF-36 data) and a review of utilities (especially for severe heath states) is needed. The committee noted that in the sofosbuvir–velpatasvir guidance it emphasised that, when available, utility values from the clinical trials are preferred. The committee accepted the company's base-case utility estimates, but stressed that in future hepatitis C appraisals, utility values from the literature will no longer be considered acceptable if there are utility values collected in clinical trials.
## Treatment for 8 weeks is appropriate for people with genotype 3 and compensated cirrhosis who have not had direct-acting antivirals
For disease not previously treated with DAA, the marketing authorisation for sofosbuvir–velpatasvir–voxilaprevir recommends 12 weeks of treatment for people with compensated cirrhosis and suggests 8 weeks for people with genotype 3. The company modelled 8-week treatment in its base case, in line with the clinical trials for genotype 3 hepatitis C in this population, but presented a scenario analysis using 12-week treatment. The analyses suggested that extending treatment to 12 weeks in this population increased the incremental cost-effectiveness ratio (ICER) significantly. The clinical experts acknowledged that people with compensated cirrhosis normally have treatment for 12 weeks using the new DAA treatments. However, they stated that 8-week treatment with sofosbuvir–velpatasvir–voxilaprevir is effective for genotype 3 and could possibly be implemented in clinical practice in line with the clinical trials. They further noted that DAA treatments are already available for this population. The committee agreed that 8-week treatment is appropriate for people with genotype 3 and compensated cirrhosis. It will consider both the 8-week and 12-week treatments for people with genotype 3 and compensated cirrhosis who have not had DAA in its decision-making.
# Cost-effectiveness results
## Sofosbuvir–velpatasvir–voxilaprevir is cost effective
The committee's preferred assumptions were based on the ERG's revisions to the company's base case, including:
the more consistent estimation of sustained virological response for sofosbuvir plus peginterferon alfa and ribavirin in people with genotype 3 who have not had DAA (95.1% and 87.9% for non-cirrhotic and cirrhotic disease respectively; see section 3.7)
the more recent transition probability from liver transplant to death (16% and 5.2% in year 1 and subsequent years respectively; see section 3.8)
increasing the proportion of mild compared with moderate fibrosis in the non-cirrhotic state (from a 83:17 split to a 50:50 split) to better reflect clinical experience and
decreasing the length of follow-up for people without cirrhosis who had a sustained virological response from 2 years to 1 year to better reflect clinical practice.Using the committee's preferred assumptions and the confidential price discounts for sofosbuvir–velpatasvir–voxilaprevir and its comparators, the ICERs for sofosbuvir–velpatasvir–voxilaprevir were below £20,000 per quality-adjusted life year (QALY) gained, except for the scenario with 12-week treatment for sofosbuvir–velpatasvir–voxilaprevir for people with genotype 3 and compensated cirrhosis who have not had DAA. In this scenario, the ICER was considerably above the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained). So 12-week treatment for sofosbuvir–velpatasvir–voxilaprevir in this subgroup could not be recommended. The committee concluded that sofosbuvir–velpatasvir–voxilaprevir was cost effective for the populations in the company's base-case analysis. It can be recommended for treating chronic hepatitis C:
as a 12-week treatment for people with genotypes 1–6 (with or without compensated cirrhosis) who have had DAA and
as an 8-week treatment for people with genotype 3 (with or without compensated cirrhosis) who have not had DAA before.
# Other factors
## Treatment and prescribing decisions
Previous NICE technology appraisal guidance on hepatitis C included recommendations on treatment and prescribing decisions because of capacity constraints within the NHS. The clinical experts stated that many people eligible for treatment, particularly people with cirrhosis, have now had treatment creating additional capacity to treat more. The clinical experts also stated that having more affordable drugs with shorter treatment durations also creates additional capacity. However, NHS England commented that there is considerable value in the existing NICE recommendation for multidisciplinary teams in the operational delivery networks to prioritise treatment for people with the highest unmet clinical need and the need for its continuation. NHS England considers that removing this wording would create major challenges and that the capacity constraints within the NHS have not changed sufficiently for the recommendation to be removed at this present time. On balance, after considering arguments both for and against, the committee accepted it was appropriate to continue to include the recommendation on this aspect (see section 1.2) as in previous NICE guidance for the oral hepatitis C treatments.
## Innovation
The committee considered whether sofosbuvir–velpatasvir–voxilaprevir could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee agreed with the company that there is an unmet need for people who have had unsuccessful treatment with DAA. However, the committee concluded that it had taken these potential benefits into account when considering the cost effectiveness of sofosbuvir–velpatasvir–voxilaprevir.
## Equality
The committee noted potential equality issues raised during the NICE scoping process. Chronic hepatitis C disproportionately affects some populations such as certain immigrant populations, prison populations, and drug users, in terms of accessing the healthcare system and having access to innovative new treatments. In addition, the Haemophilia Society suggested that this treatment should be a priority for people with a bleeding disorder. Having decided that sofosbuvir–velpatasvir–voxilaprevir should be recommended for all the groups for whom there was evidence presented, the committee agreed that its recommendations were fair. It concluded that no further consideration of potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment.
|
{'Recommendations': "Sofosbuvir–velpatasvir–voxilaprevir is recommended as an option for treating chronic hepatitis\xa0C in adults, only if it is used as specified in table\xa01 and the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit.\n\nTreatment history\n\nHepatitis\xa0C virus genotype\n\nLiver disease stage\n\nRecommendation\n\nPrevious direct-acting antivirals\n\n–6\n\nWith or without compensated cirrhosis\n\nRecommended for 12\xa0weeks\n\nNo direct-acting antivirals\n\n\n\nWith or without compensated cirrhosis\n\nRecommended for 8\xa0weeks\n\nIt is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.\n\nThese recommendations are not intended to affect treatment with sofosbuvir–velpatasvir–voxilaprevir that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment options for chronic hepatitis\xa0C depend on the genotype of the virus and the person's cirrhosis status and treatment history. They include direct-acting antivirals (DAA) and interferon-containing treatments. There are currently no treatments with a marketing authorisation available for people who have had unsuccessful treatment with DAA.\n\nClinical trials show that sofosbuvir–velpatasvir–voxilaprevir is effective for treating all genotypes of chronic hepatitis\xa0C, irrespective of the person's cirrhosis status and treatment history.\n\nThe company's economic evidence is limited to people who have had DAA (genotypes\xa01–6) and people with genotype\xa03 hepatitis\xa0C who have not had DAA before. This reflects the groups with the highest unmet clinical need. Cost-effectiveness estimates for sofosbuvir–velpatasvir–voxilaprevir are within what NICE usually considers acceptable. Therefore sofosbuvir–velpatasvir–voxilaprevir can be recommended for these groups for treating chronic hepatitis\xa0C, as specified in table\xa01.", 'Information about sofosbuvir–velpatasvir–voxilaprevir': "Marketing authorisation indication\n\nSofosbuvir–velpatasvir–voxilaprevir (Vosevi, Gilead Sciences) has a marketing authorisation in the UK for 'the treatment of chronic hepatitis\xa0C virus infection in adults'.\n\nThis includes genotypes\xa01–6, with or without compensated cirrhosis, and includes people who have had previous treatment with direct-acting antivirals.\n\nDosage in the marketing authorisation\n\nThe recommended dose is 1\xa0tablet taken orally once daily. Each tablet contains 400\xa0mg sofosbuvir, 100\xa0mg velpatasvir and 100\xa0mg voxilaprevir.\n\nTreatment duration is 8\xa0or\xa012 weeks depending on cirrhosis status and whether the person has had previous treatment with direct-acting antivirals. Please see the summary of product characteristics for more details.\n\nPrice\n\nSofosbuvir–velpatasvir–voxilaprevir costs £14,942.33 per 28‑day pack. The total costs are £29,884.66 for an 8-week course and £44,826.99 for a 12-week course (company submission).\n\nThe company agreed a nationally available price reduction for sofosbuvir–velpatasvir–voxilaprevir with the Commercial Medicines Unit. The contract prices agreed through the framework are commercial in confidence.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Gilead Sciences and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## A suitable treatment option is needed when direct-acting antivirals are unsuccessful\n\nThe use of interferon-containing treatments has reduced substantially in clinical practice because of the introduction of newer direct-acting antivirals (DAA) for hepatitis\xa0C. Clinical and patient experts stated that sofosbuvir–velpatasvir–voxilaprevir is effective when DAA have been unsuccessful. This is particularly important because there are no NICE-recommended treatments available in this situation. The committee agreed with the clinical and patient experts that there is an unmet need when treatment with DAA is unsuccessful and sofosbuvir–velpatasvir–voxilaprevir is effective for genotypes\xa01–6 of hepatitis\xa0C in people who have had DAA before. Also, sofosbuvir–velpatasvir–voxilaprevir offers a short treatment duration for people who haven't had DAA before. The committee recognised that patients and clinicians would welcome an effective and tolerable treatment, especially for people who have had unsuccessful treatment with DAA before. It concluded that sofosbuvir–velpatasvir–voxilaprevir is a valuable treatment option.\n\n# Clinical effectiveness\n\n## Sofosbuvir–velpatasvir–voxilaprevir is effective for treating chronic hepatitis\xa0C\n\nThe key clinical evidence for sofosbuvir–velpatasvir–voxilaprevir came from 4\xa0randomised controlled phase\xa03 clinical trials (POLARIS-1, -2, -3 and -4).\n\nTwo trials recruited people who had previous DAA treatment (genotypes\xa01–6, with or without compensated cirrhosis) and compared 12-week sofosbuvir–velpatasvir–voxilaprevir treatment with placebo (POLARIS-1) or sofosbuvir–velpatasvir (POLARIS-4).\n\nTwo trials recruited people who had no previous DAA treatment and compared 8-week sofosbuvir–velpatasvir–voxilaprevir treatment with sofosbuvir–velpatasvir in people with genotypes\xa01–6, with or without compensated cirrhosis (POLARIS-2) or in people with genotype\xa03 and compensated cirrhosis (POLARIS-3).The ERG considered that the trials were generally well conducted, although there was a higher risk of bias in POLARIS-2, -3 and -4 because they were open-label studies, and because only POLARIS-1 randomised all patients. The trial results showed high sustained virological response at 12\xa0weeks, ranging from 80% to 100%, irrespective of hepatitis\xa0C virus genotype, cirrhosis stage or treatment history. The committee concluded that sofosbuvir–velpatasvir–voxilaprevir is effective for treating chronic hepatitis\xa0C across all subgroups and for genotypes\xa01–6.\n\n## Sofosbuvir–velpatasvir–voxilaprevir is generally well tolerated\n\nThe most commonly reported adverse events with sofosbuvir–velpatasvir–voxilaprevir were headache and fatigue. The patient expert noted that sofosbuvir–velpatasvir–voxilaprevir is a 3-agent treatment and therefore may result in more adverse events than a 2-agent treatment, but it is still generally tolerable. The committee agreed that sofosbuvir–velpatasvir–voxilaprevir has a relatively favourable safety and tolerability profile (irrespective of cirrhosis stage or treatment history) and concluded that the adverse events associated with sofosbuvir–velpatasvir–voxilaprevir were generally tolerable.\n\n# Cost-effectiveness analysis\n\n## The company's model structure is acceptable for decision-making\n\nThe structure of the model and its assumptions about the natural history of the disease are similar to models submitted for other NICE technology appraisals for chronic hepatitis\xa0C. The ERG noted that treatment-related mortality and background mortality are related to treatment duration and can lead to counterintuitive results when comparing treatments of unequal durations. This is because the mortality in the model starts earlier for the shorter treatment. The company explained that this is a conservative assumption for sofosbuvir–velpatasvir–voxilaprevir because of the short treatment duration of 8\xa0to\xa012 weeks. The committee was aware that the company had grouped people with mild and moderate fibrosis into a single health state (non-cirrhotic), and agreed that this was consistent with how people are diagnosed in current practice. The committee concluded that the structure of the model was acceptable for decision-making.\n\n## The population in the company's model is different to the population in the marketing authorisation\n\nAlthough the marketing authorisation for sofosbuvir–velpatasvir–voxilaprevir includes treatment for people with hepatitis\xa0C genotypes\xa01–6 regardless of cirrhosis status and treatment history, the company included only 3\xa0subgroups in its model:\n\npeople who have had DAA (DAA-experienced; genotypes\xa01–6 with or without cirrhosis)\n\npeople who have not had DAA (DAA-naive; genotype\xa03) without cirrhosis and\n\npeople who have not had DAA (DAA-naive; genotype\xa03) with compensated cirrhosis.The company explained that it focused on populations with high unmet clinical need. It emphasised that there are currently no other licensed treatments for disease previously treated with DAA, and that people with genotype\xa03 who have not had DAA are at highest risk of cirrhosis progression. The clinical experts and the representatives from NHS England agreed that there is an unmet need for people who have had DAA. They noted that other effective DAA treatments are available for people who have not had DAA (including for genotype\xa03). They confirmed that sofosbuvir–velpatasvir–voxilaprevir would mostly be used in clinical practice when previous DAA treatment has been unsuccessful. The committee was satisfied that the company's model reflected how the treatment would likely be used in clinical practice in England. Also, the comparators included by the company were those used in clinical practice for the included populations. Therefore it concluded that the company's approach was acceptable, and that subsequent discussions and recommendations would cover only the populations presented.\n\n## Reinfection and future transmission of hepatitis\xa0C is modelled as a scenario analysis for people with genotype\xa03 who have not had DAA\n\nThe company did a separate scenario analysis using dynamic transition modelling, which investigated the impact of onward transmission and reinfection for people with genotype\xa03 who have not had DAA. In the analysis, the company assumed that only people who inject drugs transmit hepatitis\xa0C or become reinfected after being cured. The results were similar to the results of the company's base case. The ERG explained that the scenario analysis made simplifying assumptions and was done only for people with genotype\xa03 who have not had DAA, with no results by cirrhosis status provided. In previous NICE chronic hepatitis\xa0C appraisals, the committee stated that it would have preferred to see a model including both reinfection and transmission. Having seen that the company's results were similar when both types of model structures were used, the committee concluded that the company's base-case model (excluding reinfection and transmission) was acceptable for decision-making.\n\n## The company's naive indirect comparison of sustained virological response rates leads to uncertainty in the model results\n\nThe company used a naive indirect comparison to compare sofosbuvir–velpatasvir–voxilaprevir with the relevant comparators in people with genotype\xa03 who have not had DAA. Because of the lack of comparative trial data for some of the comparators, an indirect treatment comparison was not feasible. The rates of sustained virological response for the comparators in the company's model were selected from individual arms of randomised controlled trials. The company used some of the same rates of sustained virological response for comparator technologies as those used in NICE's technology appraisal guidance on sofosbuvir–velpatasvir. The committee noted that this approach meant that the results were at risk of the kind of bias normally associated with observational studies. The ERG noted that the company combined the rates for people who had, and people who did not have, a previous treatment for the sofosbuvir plus ribavirin treatment. But for the sofosbuvir plus peginterferon alfa and ribavirin treatment, it used only the rates for people who did not have a treatment before. The ERG combined the rates for people who had, and people who did not have, a previous treatment for sofosbuvir plus peginterferon alfa and ribavirin in its exploratory analyses; this had only marginal impact on the company's results. The committee agreed that for consistency, it preferred the ERG's approach to estimating the rates for sofosbuvir plus peginterferon alfa and ribavirin. It concluded that overall, the company's method of estimating efficacy in the model introduced some uncertainty in the results.\n\n## The company's transition probabilities with the ERG's amendment are appropriate for decision-making\n\nThe company used the same sources for non-treatment-specific transition probabilities as those used in NICE's technology appraisal guidance on sofosbuvir–velpatasvir. This included Kanwal et al. (2014) for genotype-specific fibrosis progression and Cardoso et al. (2010) for non-fibrosis progression (not genotype-specific). In its revision to the company's base case, the ERG applied a transition probability from a more recent source (Hepatitis\xa0C Trust, 2017) for progression from liver transplant to death. Also, the ERG explored using transition probabilities for compensated cirrhosis (to decompensated cirrhosis and hepatocellular carcinoma), decompensated cirrhosis (to hepatocellular carcinoma and death), and hepatocellular carcinoma (to death) from Fattovich et al. (1997) instead of Cardoso et al. in a scenario analysis, as recommended in the sofosbuvir–velpatasvir guidance. The ERG's analyses had only marginal impact on the company's results. The committee was generally satisfied with the company's approach, but preferred the ERG's approach of using more recent data sources to estimate transition probabilities for progression from liver transplant to death.\n\n## The committee prefers utility values from clinical trials, but it accepted the company's utility values\n\nIn its base-case analyses, the company used utility data from the literature (Wright et al. 2006 and Vera-Llonch et al. 2013) in line with NICE's previous technology appraisal guidance on hepatitis\xa0C. This was to inform the difference in utility of a health state with or without sustained virological response. The ERG stated that although EQ-5D was not an outcome in the POLARIS trials, health-related quality-of-life data were collected (for example, SF-36 data) and a review of utilities (especially for severe heath states) is needed. The committee noted that in the sofosbuvir–velpatasvir guidance it emphasised that, when available, utility values from the clinical trials are preferred. The committee accepted the company's base-case utility estimates, but stressed that in future hepatitis\xa0C appraisals, utility values from the literature will no longer be considered acceptable if there are utility values collected in clinical trials.\n\n## Treatment for 8\xa0weeks is appropriate for people with genotype\xa03 and compensated cirrhosis who have not had direct-acting antivirals\n\nFor disease not previously treated with DAA, the marketing authorisation for sofosbuvir–velpatasvir–voxilaprevir recommends 12\xa0weeks of treatment for people with compensated cirrhosis and suggests 8\xa0weeks for people with genotype\xa03. The company modelled 8-week treatment in its base case, in line with the clinical trials for genotype\xa03 hepatitis\xa0C in this population, but presented a scenario analysis using 12-week treatment. The analyses suggested that extending treatment to 12\xa0weeks in this population increased the incremental cost-effectiveness ratio (ICER) significantly. The clinical experts acknowledged that people with compensated cirrhosis normally have treatment for 12\xa0weeks using the new DAA treatments. However, they stated that 8-week treatment with sofosbuvir–velpatasvir–voxilaprevir is effective for genotype\xa03 and could possibly be implemented in clinical practice in line with the clinical trials. They further noted that DAA treatments are already available for this population. The committee agreed that 8-week treatment is appropriate for people with genotype\xa03 and compensated cirrhosis. It will consider both the 8-week and 12-week treatments for people with genotype\xa03 and compensated cirrhosis who have not had DAA in its decision-making.\n\n# Cost-effectiveness results\n\n## Sofosbuvir–velpatasvir–voxilaprevir is cost effective\n\nThe committee's preferred assumptions were based on the ERG's revisions to the company's base case, including:\n\nthe more consistent estimation of sustained virological response for sofosbuvir plus peginterferon alfa and ribavirin in people with genotype\xa03 who have not had DAA (95.1% and 87.9% for non-cirrhotic and cirrhotic disease respectively; see section\xa03.7)\n\nthe more recent transition probability from liver transplant to death (16% and 5.2% in year\xa01 and subsequent years respectively; see section\xa03.8)\n\nincreasing the proportion of mild compared with moderate fibrosis in the non-cirrhotic state (from a 83:17 split to a 50:50 split) to better reflect clinical experience and\n\ndecreasing the length of follow-up for people without cirrhosis who had a sustained virological response from 2\xa0years to 1\xa0year to better reflect clinical practice.Using the committee's preferred assumptions and the confidential price discounts for sofosbuvir–velpatasvir–voxilaprevir and its comparators, the ICERs for sofosbuvir–velpatasvir–voxilaprevir were below £20,000 per quality-adjusted life year (QALY) gained, except for the scenario with 12-week treatment for sofosbuvir–velpatasvir–voxilaprevir for people with genotype\xa03 and compensated cirrhosis who have not had DAA. In this scenario, the ICER was considerably above the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained). So 12-week treatment for sofosbuvir–velpatasvir–voxilaprevir in this subgroup could not be recommended. The committee concluded that sofosbuvir–velpatasvir–voxilaprevir was cost effective for the populations in the company's base-case analysis. It can be recommended for treating chronic hepatitis\xa0C:\n\nas a 12-week treatment for people with genotypes\xa01–6 (with or without compensated cirrhosis) who have had DAA and\n\nas an 8-week treatment for people with genotype\xa03 (with or without compensated cirrhosis) who have not had DAA before.\n\n# Other factors\n\n## Treatment and prescribing decisions\n\nPrevious NICE technology appraisal guidance on hepatitis\xa0C included recommendations on treatment and prescribing decisions because of capacity constraints within the NHS. The clinical experts stated that many people eligible for treatment, particularly people with cirrhosis, have now had treatment creating additional capacity to treat more. The clinical experts also stated that having more affordable drugs with shorter treatment durations also creates additional capacity. However, NHS England commented that there is considerable value in the existing NICE recommendation for multidisciplinary teams in the operational delivery networks to prioritise treatment for people with the highest unmet clinical need and the need for its continuation. NHS England considers that removing this wording would create major challenges and that the capacity constraints within the NHS have not changed sufficiently for the recommendation to be removed at this present time. On balance, after considering arguments both for and against, the committee accepted it was appropriate to continue to include the recommendation on this aspect (see section\xa01.2) as in previous NICE guidance for the oral hepatitis\xa0C treatments.\n\n## Innovation\n\nThe committee considered whether sofosbuvir–velpatasvir–voxilaprevir could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee agreed with the company that there is an unmet need for people who have had unsuccessful treatment with DAA. However, the committee concluded that it had taken these potential benefits into account when considering the cost effectiveness of sofosbuvir–velpatasvir–voxilaprevir.\n\n## Equality\n\nThe committee noted potential equality issues raised during the NICE scoping process. Chronic hepatitis\xa0C disproportionately affects some populations such as certain immigrant populations, prison populations, and drug users, in terms of accessing the healthcare system and having access to innovative new treatments. In addition, the Haemophilia Society suggested that this treatment should be a priority for people with a bleeding disorder. Having decided that sofosbuvir–velpatasvir–voxilaprevir should be recommended for all the groups for whom there was evidence presented, the committee agreed that its recommendations were fair. It concluded that no further consideration of potential equality issues was needed to meet NICE's obligation to promote equality of access to treatment."}
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https://www.nice.org.uk/guidance/ta507
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Evidence-based recommendations on sofosbuvir–velpatasvir–voxilaprevir (Vosevi) for treating chronic hepatitis C in adults.
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9a217f246ead61f38e1e30502e23bbd7b22c408f
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nice
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People's experience in adult social care services: improving the experience of care and support for people using adult social care services
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People's experience in adult social care services: improving the experience of care and support for people using adult social care services
This guideline covers the care and support of adults receiving social care in their own homes, residential care and community settings. It aims to help people understand what care they can expect and to improve their experience by supporting them to make decisions about their care.
# Context
In 2015 to 2016, there were over 800,000 people receiving long-term care and support (more than 12 months) from adult social care. Services also responded to a further 1.8 million new requests for care and support (including short-term support; NHS Digital Community care statistics: social services activity, England - 2015 to 2016 report). The core purpose of adult care and support is to help people achieve the outcomes that matter to them in their life. People's experiences of care and support, and the extent to which they feel supported to live their life as they want to, are therefore of key importance.
In 2016, 64% of respondents to the annual personal social services adult social care survey said they were either extremely or very satisfied with the care and support they received. However, only 33% said that they had as much control as they wanted over their daily life; 18% said they had some, but not enough, control and 6% had no control at all.
This guideline is developed in a context of working towards better integration of health and social care, and complements NICE's guidelines on patient experience in adult NHS services and service user experience in adult mental health. For people who use services, integrated care means joined up, coordinated health and social care that is planned and organised around the needs and preferences of the individual, their carer and family (see Think Local Act Personal's care and support jargon buster). Relevant to this is the Care Act 2014 that places a statutory duty on local authorities to integrate health and social care and related services where this promotes wellbeing, and prevent, reduce or delay needs.
This guideline covers good practice in the care and support of adults, including people with learning disabilities, physical disabilities, sensory impairment, and mental health or physical conditions. It aims to improve peoples' experiences of care and support services. It is based on evidence about the views of people who use services on what is important to them in their care and support.
The application of the recommendations in this guideline is not mandatory. Different types of NICE guidance have a different status within the NHS, public health and social care. Although there is no legal obligation to implement our health and social care guidance, health and social care practitioners are actively encouraged to follow our recommendations to help them deliver the highest quality care and support. Our recommendations are not intended to replace the professional expertise and judgement of practitioners, as they discuss care and support options with people.
The guideline has been developed by a committee of people who use services, and carers and professionals. It has used information from a review of research evidence about people's experiences of care and support, and from expert witnesses. The committee also gave careful consideration to the potential resource impact of the recommendations. The included recommendations are considered to be aspirational but achievable.
This guideline does not replace statutory duties and good practice as set out in relevant legislation and guidance, including:
Care Act 2014 and associated guidance
Equality Act 2010
Mental Capacity Act 2005
Accessible Information Standard
UN Convention on the rights of persons with disabilities
Human Rights Act 1998.
This guideline aims to complement legislation and guidance by providing evidence-based recommendations about how to improve people's experiences of care and support. Actions already required by law, or recommended in guidance, are not replicated here unless there was evidence to suggest that these were not happening in practice, or were of particular importance to people's experiences.
You can see everything NICE says on this topic in the NICE Pathway on people's experience in adult social care services.
To find NICE guidance on related topics, including guidance in development, see the NICE webpage on adult's social care.
For full details of the evidence and the guideline committee's discussions, see the full guideline and appendices. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice.# Recommendations
People have the right to be involved in discussions and make decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Overarching principles
Recognise that each person who uses services is an individual. Use each person's self-defined strengths, preferences, aspirations and needs as the basis on which to provide care and support to live an independent life.
Support people to maintain their independence. This means finding out what people want from their life, and providing the support and assistance they need to do this
## Co-production and enabling people to make decisions
Respect people's right to make their own decisions, and do not make assumptions about people's capacity to be in control of their own care and support (for example, if the person is severely disabled).
Actively involve the person in all decisions that affect them.
Provide support to people, if they need it, to express their views, preferences and aspirations in relation to their care and support. Identify and record how the person wishes to communicate and if they have any communication needs (in line with the Accessible Information Standard). This could include:
advocacy support
an independent interpreter (that is, someone who does not have a relationship with the person or the services they are using) to enable people to communicate in a language they can readily converse in, including sign language
a carer, if that is what the person wants
communication aids (such as pictures, videos, symbols, large print, Braille, hearing loops)
evidence-based techniques for communication
additional time to understand and process information
environmental conditions that support communication, such as clear lighting, and minimal noise interference.
If a person lacks the capacity to make a decision, the provisions of the Mental Capacity Act 2005 must be followed.
Use plain language and personalise the communication approach to encourage and enable people to be actively involved in their care and support. If technical language or jargon has to be used, or complicated ideas are being discussed, take time to check that the person, or a carer who knows them well, understands what is being said.
If a third party or advocate is supporting someone to give their views, ensure that enough time has been allowed for them to do it.
Local authorities and service providers should work with people who use adult social care services and their carers as far as possible to co-produce:
the information they provide
-rganisational policies and procedures
staff training.
## Access to care
Ensure that everyone with social care needs has access to services based on their needs, taking account of age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race, religion and belief, sex and sexual orientation, and socio-economic status or other aspects of their identity.
Service providers should be aware of the cultural and religious needs of people who use services, and provide care and support that meets these needs. Examples include treatment choices, food choice and preparation, enabling people to dress in accordance with their culture or religion, personal grooming, or changes in timing of services around religious festivals – for example, during Ramadan.
Commissioners and service providers should consider seeking advice from voluntary and community sector organisations such as disabled people's organisations and user-led organisations with expertise in equality and diversity issues to ensure that they can deliver services that meet the needs and preferences arising from:
gender, including transgender
sexual orientation and sexuality
disability
ethnicity
religious and cultural practices.
Ensure that people who use services and have caring responsibilities (for another adult or a child) receive support to access social care services, including information about childcare, or respite care
## Involving carers, families and friends
Ask the person at the first point of contact whether and how they would like their carers, family, friends and advocates or other people of their choosing (for example, personal assistants) to be involved in discussions and decisions about their care and support, and follow their wishes. Review this regularly (at least every 6 to 12 months), or when requested.
If the person would like their carers, family, friends and advocates involved:
explain the principles of confidentiality, and how these are applied in the best interests of the person
discuss with the person and their carers, family, friends and advocates what this would mean for them
share information with carers, family, friends and advocates as agreed.
If a person lacks the capacity to make a decision about whether they wish their carers, family, friends and advocates to be involved, the provisions of the Mental Capacity Act 2005 must be followed.
# Information
In line with the Care Act 2014, local authorities must provide information about care and support services for people and their carers, including:
the types of care and support available
how to access care and support, including eligibility criteria
how to get financial advice about care and support
local safeguarding procedures and how to raise safeguarding concerns or make a complaint
rights and entitlements to assessments and care and support services
personal budgets and all the options for taking a personal budget – for example, local authority managed, Individual Service Fund or direct payment.
Local authorities should ensure that information about care and support services is widely and publicly promoted – for example, in GP surgeries and community spaces, as well as in specialist services such as homeless health centres.
Local authorities should provide information about the circumstances in which independent advocacy is available, in line with the Accessible Information Standard, and how to access it.
Local authorities should provide comprehensive information about community resources and support, including voluntary organisations, user-led organisations and disabled people's organisations, and about available housing options.
# Care and support needs assessment and care planning
Local authorities must, in line with the Care Act 2014, provide independent advocacy to enable people to participate in:
care and support needs assessment
and
care planning and
the implementation process and review where they would otherwise have substantial difficulty in doing so.
People who are supported by an independent advocate during care and support needs assessment and care planning should have enough time with their advocate:
for preparation before the assessment or care planning session
to ensure they have understood the outcome afterwards.
## Needs assessment
Local authorities must ensure that care and support needs assessment under the Care Act 2014 focuses on the person's needs and how they impact on their wellbeing, and the outcomes they want to achieve in their day-to-day life.
Care and support needs assessment should:
involve the person and their carers in discussions and decisions about their care and support
take into account the person's personal history and life story
take a whole family approach
take into account the needs of carers
take into account the person's housing status, and where and who they want to live with
be aimed at promoting their interests and independence
be respectful of their dignity
be transparent in terms of letting people and their families and carers know how, when and why decisions are made
take into account the potential negative effect of social isolation on people's health and wellbeing.
Local authorities should consider the person's preferences in terms of the time, date and location of the care and support needs assessment, and conduct the assessment face-to-face unless the person prefers a different method of assessment.
Local authorities should ensure that:
the person is given details of the care and support needs assessment process and timescale at the start
the person is given details of the nature and purpose of the assessment
the person can have someone they choose to be present at the assessment
the assessment uses up-to-date information and documentation about the person
the person does not have to provide the same information in subsequent assessments.
See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of people using services who have caring responsibilities.
Ensure that care and support needs assessment documentation about the person is accurate, up to date and well maintained and clarifies what assessed needs will be met and how.
Offer the person a copy of any or all of the care and support needs assessment documentation. It should be shared with the person's carer if that is what they want.
## Care and support plans
As part of care planning, consider identifying a named coordinator who is competent to:
act as the first point of contact for any questions or problems
contribute to the assessment process
liaise and work with the person, their families, carers and advocates
liaise and work with all health, social care and housing services involved with the person, including those provided by the voluntary and community sector
ensure that any referrals needed are made and are actioned.
Build in flexibility to the care and support plan to accommodate changes to a person's priorities, needs and preferences – for example, by using direct payments (see recommendations 1.3.20 and 1.3.21) and agreeing a rolling 3‑monthly budget so that people can use their money differently each week.
Local authorities and providers should ensure that the person's care and support plan includes clear information about what involvement from others (carers, family, friends and advocates) they want in their care and support, in line with the Care Act 2014. (See also recommendation 1.1.14.)
Ensure there is a transparent process for 'matching' care workers to people, taking into account:
the person's care and support needs and
the care workers' knowledge, skills and experience and
if possible and appropriate, both parties' interests and preferences.
Ensure care workers are able to deliver care and support in a way that respects the person's cultural, religious and communication needs (see recommendation 1.1.11) .
Care and support plans should record and address the specific needs of people in relation to equality and diversity issues.
Care and support plans should be regularly reviewed, and include information on how and when these reviews should be carried out.
Care and support plans should include contingency planning and what to do in a crisis.
## Personal budgets and direct payments
The local authority must include the person's personal budget in their care and support plan, in line with the Care Act 2014.
Local authorities should:
inform people that they have the option to control their own funding to buy different sorts of care and support that meets their needs and chosen outcomes
provide information, advice and support so that the person can choose which option suits them best
give people the opportunity to exercise as much control as possible over the way they use any allocated funds to purchase a care package
inform people of the different options for managing their budget.
Local authorities should ensure that the direct payment process is:
transparent about how the level of funding is decided
straightforward
accessible to all adults who receive social care and are eligible for local authority funding
reviewed periodically to make sure that it is meeting the objectives of the care and support plan
able to meet the legal obligations of the person receiving that direct payment if they employ personal assistants.
Local authorities should provide accessible information about direct payments, and peer support for people to use them. For example, this could be provided through user-led Centres for Independent Living.
In line with the Care Act statutory guidance, local authorities should support local services that provide peer support. Their contribution could include:
financial support for local peer support services
providing physical space for people who give peer support to hold meetings with people who use services
helping peer support services with applying for grants for funding.
## Personal assistants
If people have eligible needs that could be met by employing a personal assistant, the local authority should ensure that this option is discussed with the person and understood by them at the care and support planning stage.
In line with the Care Act statutory guidance, local authorities should ensure that support is available for people employing personal assistants, and that they are told about where to get support with:
recruitment and retention of staff
their role and responsibilities as an employer (for example, payroll, terms and conditions, redundancy and contingency planning).
Local authorities should consider the following to deliver support for people who employ personal assistants:
user-led Centres for Independent Living
-ther peer-support arrangements.
In line with the market shaping duty in the Care Act 2014, local authorities should work with people who use social care services and their carers to enable access to personal assistants. For example, this could be done by providing training opportunities for people who are interested in becoming personal assistants.
# Providing care and support
## Care and support in all settings
The following recommendations refer to care and support in all settings. For further detail about home care, please see the NICE guideline on home care for older people.
Service providers should foster a culture that enables practitioners to respect people's individual choices and preferences, in all settings where care and support is delivered, by:
co-producing policies and protocols with people who use services and their carers (see recommendation 1.1.9)
ensuring that there are open channels of communication between practitioners and people who use services
using the communication methods that suit the person, in line with the Accessible Information Standard
supporting people to take managed risks to achieve their goals – for example, taking part in hobbies or sports
ensuring that there are systems in place for reporting concerns or abuse
ensuring that practitioners have the time to build relationships with people
training and supporting practitioners to work in this way, and checking they are doing so.
Practitioners working in all settings where care and support is delivered should ask the person using services, their carers, family, friends and advocates what name they prefer to be called, and use their preferred name.
Practitioners working in all settings where care and support is delivered should take time to build rapport with the people they support.
Practitioners working in all settings where care and support is delivered should respond flexibly to the priorities a person might identify each day. For example, a person might ask a home care worker to spend more time helping them get dressed and less time on other tasks if they have a special event to attend.
Day care and residential care providers should offer a choice of activities that are led by the person's needs, preferences and interests. Encourage people to take part by including activities that motivate them, support them to learn new skills and increase their level of independence. Recognise that preferences are not fixed and may change.
## Continuity and consistency
Service providers in all settings, with oversight by commissioners, should review staffing numbers and skill mix regularly to ensure that staffing and skill levels are sufficient.
Commissioners and managers in all settings should ensure that there is continuity in care and support for people, including:
ensuring that all practitioners involved with the person's care and support are familiar with how that person likes support to be given
where possible, the same people are supporting the person
if the same staff are not available, ensuring there are good handover arrangements
ensuring that all staff supporting the person have similar levels of skills and competency
using the same independent advocate where possible.
Providers and managers in all settings should ensure that:
people are informed in advance if staff will be changed and
any changes to care and support – for example, when visits will be made, are negotiated with the person.
Support people to make decisions about entering a new care setting or moving to a different setting. For guidance on transitions between particular settings, see the NICE guidelines on:
transition from children's to adults' services for young people using health or social care services
transition between inpatient hospital settings and community or care home settings for adults with social care needs
transition between inpatient mental health settings and community or care home settings.
To support collaborative working between services, commissioners and managers should consider putting the following in place:
a local policy for sharing information relevant to people's care within and between services in line with the Caldicott principles and the Health and Social Care (Safety and Quality) Act 2015
joined-up policies, processes and systems.
## Personal care
All practitioners providing personal care should ensure that personal care needs are responded to in a timely, appropriate and dignified manner in line with the person's wishes and their support plan – for example, making sure that people can go to the toilet when and how they want.
## Promoting positive relationships between people who use services
Service managers and practitioners in day care and residential settings should promote a sense of community and mutual support – for example, by facilitating interactions and building social connections between residents through activities such as social events.
## Residential settings
Practitioners and managers in residential settings should:
ensure that the environment allows for people's preferences, self-expression and choice – for example, enabling people to have their own furniture and pictures
support people to have control over their own medicines where possible (see the NICE guideline on managing medicines in care homes)
deliver care and support in a personalised and friendly way
give people privacy, especially when delivering personal care
treat people with dignity and respect.
When designing residential services, providers should ensure that environments:
create space where practitioners and residents can have positive interactions
are welcoming to visits from family, friends, carers and advocates
are stimulating, while not creating additional challenges for residents, including those with sensory impairments or dementia (for example, if the layout is frequently changed or there is poor lighting)
enable positive risk taking (for example, being able to use outside spaces)
support residents' autonomy (for example, by adapting kitchen facilities for people with physical disability).
Ensure that support in residential care is based on a good understanding of people's needs, including:
providing practical and emotional support
accommodating speech and communication needs
helping people to maintain the personal relationships and friendships that are important to them
supporting people to take part in activities and social groups that they want to be involved in, both in the residential setting and in the community
viewing behaviour that challenges as communication
providing access to community health teams and specialist support.
Practitioners should support people to participate fully in tasks and activities by ensuring that:
the environment is conducive to their needs
they have access to the equipment they need (for example, hoists or recliner chairs).
Managers should ensure that practitioners are trained to support residents to use any equipment they need.
## End-of-life support in residential settings
For more information on end-of-life care, see NICE's guideline on care of the dying adult.
Managers in residential settings should co‑produce a policy on end-of-life care with people who use services and their carers. This should include information about:
documenting treatment and care preferences at the earliest opportunity (including formal ways of documenting preferences such as Lasting Power of Attorney for health and care decisions, advance statements of wishes and care preferences or advance decisions to refuse treatment)
a named lead in the residential setting
training on supporting people and their carers at the end of their lives, tailored to different staff groups and updated regularly
-ngoing support to enable practitioners to support people near the end of their lives, including creative ways of engaging people in discussions (for example, opportunities to discuss end-of-life care with peers).
Managers in residential settings should consider making someone available who is independent and not part of the usual staff team to discuss end-of-life issues, for people who want to do this – for example, from an advocacy organisation.
# Staff skills and experience
Have a transparent and fair recruitment and selection process that:
uses values-based interviews and approaches to identify the personal attributes and attitudes essential for a caring and compassionate workforce and
ensures that staff have the necessary language, literacy and numeracy skills to do the job.
Local authorities should ensure that people undertaking needs and eligibility assessments have the knowledge and skills to carry out assessments as described in recommendations 1.3.3 to 1.3.9.
Service providers should consider involving people who use services and their carers ('experts by experience') in the recruitment and training of staff. For example:
being on interview panels
contributing to development and delivery training
helping to develop job descriptions
supporting and training others to be experts by experience.
Consider providing opportunities for practitioners to learn from the personal experiences of all people who use services, in all settings where care and support is provided. This could be through:
forums within residential and day care services
audit, planning and evaluation of services
practitioners being mentored by people who use services.
Service providers should ensure that practitioners are aware of the local arrangements for, and understand the function of, other services that they may need to work with, such as other health and social care service providers and services provided by the voluntary sector.
Service providers should provide opportunities for practitioners to take part in interprofessional learning and development.
Service providers should ensure that practitioners are able to use any equipment or devices people need – for example, hearing aid loops.
Service providers should ensure that practitioners are aware of issues relating to information sharing and confidentiality.
# Involving people in service design and improvement
Local authorities must provide opportunities for people who use services to be involved if they want to in strategic decision-making about services, not just their own care and support, in line with the Local Government and Public Involvement in Health Act 2007. This should include involving people in:
decisions about the way services are commissioned, run and are governed and
checking that the service is delivering quality care and support.
## Using people's views to improve services
All research into the views of people using care and support and their carers should be co‑produced at all stages, including the research design, how it is carried out, and any resulting actions (for example, developing or refining quality indicators, developing monitoring tools or identifying gaps in services).
Commissioners and service providers should communicate clearly the outcome that any exercise to collect people's views is aiming to achieve and what will be done as a result.
Commissioners and service providers should consider using a range of approaches to gather views and experiences (for example, focus groups, interviews or observation in addition to surveys), and use evidence from a range of sources. This could include:
the lived experiences of people who use services
information from voluntary organisations that represent people who use social care services – for example, Healthwatch
existing sources of information, such as complaints.
Local authorities should consider gathering and analysing evidence on people's experience of services in collaboration with other health and social care organisations serving the same populations to reduce duplication and ensure economies of scale.
Organisations conducting research should consider from the outset how to ensure that all groups are able to participate, including people who may lack capacity and people with different communication needs. This may involve adapting different research methods (see recommendation 1.6.4) or providing materials in a range of formats. If the participation or response rate for a particular group is low, the organisations should take action to improve it. This could include investigating what specific communication or cultural reasons may account for the low response and adapting materials or response formats to better suit that group.
Service providers should seek the views of people who use services about the extent to which the things that are important to them are being addressed. This should be done in such a way that the person feels safe to express their views, even if these are critical (for example, a care home resident may not want to give feedback directly to the manager).
Organisations or individuals conducting research or seeking feedback from people who use services should ensure that independent advocacy is available and offered when:
this would help someone to take part or
the person expresses a preference to use advocacy.
Service providers should consider employing people who use services to monitor people's experience of health and social care services, including conducting research. This could be done by:
-ffering training to 'experts by experience' on how to conduct interviews with people who use services, including supporting them in applying ethical principles such as informed consent and confidentiality
paying them to undertake exit interviews with people who have recently left a service or moved to another service.
Commissioners and providers should ensure that the results of research with people are used to inform improvements to services.
Commissioners and service providers should make available the results of research with people who use services, using approaches developed with people who use services. This should include:
publishing the results
giving feedback directly to people who took part
making public how they have responded to people's feedback – for example, by using 'you said, we did' tables or case studies.
## Survey research
Consider using existing validated surveys before deciding to develop a new survey.
Local authorities should analyse the characteristics of people who did not or could not respond to surveys and:
report on any under-represented groups in their published report of the survey and seek to understand the reasons for this
develop ways to address these gaps in the future – for example, by considering alternative modes of response, such as a telephone response line
ensure that information about under-represented groups is fed back to the survey designers.
Local authorities should ensure that people in their organisations who are responsible for interpreting and implementing survey findings have the necessary skills and capacity.
# Terms used in this guideline
## Care and support needs assessment
Under the Care Act 2014, local authorities must carry out an assessment of anyone who appears to require care and support. The aim of assessment is to understand the person's needs and goals. After carrying out the assessment, the local authority consider whether any of the needs identified are eligible for support.
## Care and support plan
A written plan after a person has had an assessment, setting out what their care and support needs are, how they will be met (including what they or anyone who cares for them will do) and what services they will receive.
## Carer
A person who provides unpaid support to a partner, family member, friend or neighbour who is ill, struggling or disabled and could not manage without this help. This is distinct from a care worker, who is paid to support people.
## Centre for Independent Living
A local organisation run by people with disabilities, that supports disabled people in their area to make choices about how and where they live their lives, with the assistance and support they need to live as independently as possible.
## Commissioner
A person or organisation that plans the services that are needed by the people who live in the area the organisation covers, and ensures that services are available. Sometimes the commissioner will pay for services, but not always. The local council is the commissioner for adult social care. NHS care is commissioned separately by local clinical commissioning groups. In many areas, health and social care commissioners work together to make sure that the right services are in place for the local population.
## Communication aid
A communication aid helps a person to communicate more effectively with those around them. This could range from a simple letter board to a more sophisticated piece of electronic equipment.
## Co-production
When a person who uses services is involved as an equal partner in designing the support and services they receive. Co‑production recognises that people who use social care services (and their families) have knowledge and experience that can be used to help make services better, not only for themselves but for other people who need social care.
The Think Local Act Personal's 6 principles of co-production are:
recognising people as assets
building on people's capabilities
developing 2‑way, reciprocal relationships
encouraging peer support
blurring boundaries between delivering and receiving services
facilitating rather than delivering.
## Day care services
Opportunities for people to do things during the day, while living in their own home. These may include social activities, education, or the opportunity to learn new skills. What the local council offers will vary, depending on what a person needs and what is available in that area. People who use services may have to pay something towards the cost.
## Home care
Care provided in a person's own home by paid care workers to help them with their daily life. It is also known as domiciliary care. Home care workers are usually employed by an independent agency, and the service may be arranged by the local council or by the person that needs care (or someone acting on their behalf).
## Information sharing
Information sharing refers to the sharing of information about people who use services within and between organisations. Personal information can be shared within or between organisations with the person's consent, or if it is believed to be in the public interest. See the 7 golden rules of information sharing.
## Joint commissioning
When 2 or more organisations in a local area – usually the NHS and local council – work together to plan services to meet the needs of people who live in the area. Together the commissioners plan what kind of services should be available, who should provide them and how they should be paid for.
## Named care coordinator
The person in an organisation who is responsible for coordinating support for the person and their family if needed – for example, a named social worker or a nurse. The coordinator role refers to a function and not a post.
## Peer support
The practical and emotional help and support that people who have personal experience of a particular health condition or disability can give each other, based on their shared experience. People support each other as equals, one-to-one or in groups, either face-to-face, online or on the telephone.
## Person who uses services
A person who receives services from a care and support provider. It is often preferred to the term 'service user'.
## Personal assistant
Someone the person using services chooses to employ to provide the support they need, in the way that suits them best. This may include cooking, cleaning, help with personal care such as washing and dressing, and other things such as getting out and about in the community. A personal assistant can be paid through a direct payment.
## Personalised care
An approach that puts the person receiving care and support at the centre of the way care is planned and delivered. It is based around the person and their own needs, preferences and priorities. It treats the person receiving services as an equal partner, and puts into practice the principle of 'no decision about me without me'.
## Practitioner
Any worker who provides support to the person and their family and carers. Practitioners include people working in all settings and in different roles – for example, social workers, health professionals and care home staff. Practitioners could also include those with designated roles, such as care coordinators or key workers.
## Residential settings
Accommodation where care and support are provided by staff. These settings can be run by the private sector, voluntary sector or local authority. Residential settings can include residential care homes and nursing homes and also include supported living.
## Supported living
Accommodation and support that enables adults with disabilities to live in their own home, with the help they need to be independent. It allows people to choose where they want to live, who they want to live with, how they want to be supported, and what happens in their home.
## Voluntary sector
Also referred to as 'voluntary and community social enterprise sector' (VCSE). It refers to organisations that are independent of the government and local councils. Their role is to benefit the people they serve, not to make a profit. Social care services are often provided by VCSEs, by arrangement with the council or with the individual. Some are user-led organisations, which means they are run by and for the people the organisation is designed to benefit – for example, disabled people.
The source of some of these definitions is the Think Local, Act Personal's care and support jargon buster. Also see the jargon buster for other social care terms.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Supporting people who use services to maintain their independence is a key requirement for wellbeing and is an achievable expectation, but it will require a significant change in practice for some services.
Working with people who use social care to ensure that there is a well-developed 'market' for personal assistants (PAs) will lead to better outcomes for people who employ PAs and better use of resources. However, for some authorities this will involve a new focus on market development and a change of practice that will require staff to be re‑trained.
Making sure that people are supported in a residential setting that is appropriate to their needs and building a culture that enables staff to respect people's individual choices and preferences are essential factors in promoting a good quality of life for people who live in a residential setting. Services may find it challenging to implement these changes because they will involve a major rethink in their approach to service delivery.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Methods and approaches for gathering the experiences of people who use adult social care services
When conducting research for the purposes of service improvement, what research methods are acceptable, appropriate and effective in meaningfully gathering the views and experiences of people who use services?
## Why this is important
Current research methods for gathering the views and experiences of people who use services commonly include standardised surveys and measures (for example, patient-reported outcome measures ; NHS and social care: public perceptions surveys; The National Adult Social Care User Experience Survey). However, the evidence reviewed for this guideline suggests that measures of this kind may have limitations in terms of how comprehensive and representative these people are who are typically willing and able to respond to these kinds of self-completion postal surveys. This means that some people's views and experiences of social care may not be included in surveys designed to support service improvement. Further research is needed to:
Determine the extent to which frequently used research methods meaningfully engage people and provide an accurate picture of their views and experiences.
Develop and test new or innovative methods for gathering views and experiences. This could include narrative methods and the use of technology such as apps. The methods would be compared in relation to how well they were able to provide accurate and detailed information on people's views and experiences of care and support.
# Co-producing research into the views and experiences of people who use services
What approaches have been shown to work in supporting the co‑production of research for the purposes of service improvement with people who use services?
## Why this is important
Co-production is a key concept in the development of public services (Co-production in social care: what it is and how to do it, Social Care Institute for Excellence ), and there are many examples in practice that highlight how individuals and communities can positively shape the way that services are designed, commissioned and delivered (Co-production in commissioning, Think Local Act Personal 2015). Co‑produced research on the views and experiences of people who use services is a potential means of improving services. Co‑producing all stages of the research process with people who use services is an important principle, which may signpost pertinent issues and questions that would have otherwise been neglected. However, there is little published evidence about how to put the principle of co‑production into practice in research, although it appears that there may be good practice occurring within the sector.
# Identifying barriers and enablers to using the views and experiences of people who use services to improve services
What are the barriers and enablers to gathering, synthesising and applying data on the views and experiences of people who use services for the purposes of service improvement?
## Why this is important
There are several examples of data-gathering processes designed with the purpose of improving services – for example, annual mandatory local authority surveys, audit, and small-scale consultation at the individual organisation level. However, little is known about how the data from these exercises are translated into change and improvement in services, including:
What capacity is needed within organisations to gather data and make use of it, and whether this is present?
What factors determine whether the findings of research are implemented in practice?
# Use of technology in providing care
What are the views and experiences of people who use adult social care services on assistive technologies?
## Why this is important
Assistive technology is one means by which social care services can help people to maintain independence. These technologies include a wide range of devices, ranging from simple, low-cost devices such as pendant alarms, to more intricate home monitoring systems using electronic information and communication technology – for example, integrated systems of sensors, alarms and remote monitoring. Across all population groups, there is a paucity of evidence about how acceptable assistive technology is to people who use services, and the impact of the technology on their satisfaction with services. Issues that could be explored include the extent to which the technology is and can be personalised, anxiety that it may be used to scale back services and reduce human contact, loss of confidentiality where personal information is shared, and ethical questions around privacy and surveillance.
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{'Context': "In 2015 to 2016, there were over 800,000\xa0people receiving long-term care and support (more than 12\xa0months) from adult social care. Services also responded to a further 1.8\xa0million new requests for care and support (including short-term support; NHS Digital Community care statistics: social services activity, England - 2015 to 2016 report). The core purpose of adult care and support is to help people achieve the outcomes that matter to them in their life. People's experiences of care and support, and the extent to which they feel supported to live their life as they want to, are therefore of key importance.\n\nIn 2016, 64% of respondents to the annual personal social services adult social care survey said they were either extremely or very satisfied with the care and support they received. However, only 33% said that they had as much control as they wanted over their daily life; 18% said they had some, but not enough, control and 6% had no control at all.\n\nThis guideline is developed in a context of working towards better integration of health and social care, and complements NICE's guidelines on patient experience in adult NHS services and service user experience in adult mental health. For people who use services, integrated care means joined up, coordinated health and social care that is planned and organised around the needs and preferences of the individual, their carer and family (see Think Local Act Personal's care and support jargon buster). Relevant to this is the Care Act\xa02014 that places a statutory duty on local authorities to integrate health and social care and related services where this promotes wellbeing, and prevent, reduce or delay needs.\n\nThis guideline covers good practice in the care and support of adults, including people with learning disabilities, physical disabilities, sensory impairment, and mental health or physical conditions. It aims to improve peoples' experiences of care and support services. It is based on evidence about the views of people who use services on what is important to them in their care and support.\n\nThe application of the recommendations in this guideline is not mandatory. Different types of NICE guidance have a different status within the NHS, public health and social care. Although there is no legal obligation to implement our health and social care guidance, health and social care practitioners are actively encouraged to follow our recommendations to help them deliver the highest quality care and support. Our recommendations are not intended to replace the professional expertise and judgement of practitioners, as they discuss care and support options with people.\n\nThe guideline has been developed by a committee of people who use services, and carers and professionals. It has used information from a review of research evidence about people's experiences of care and support, and from expert witnesses. The committee also gave careful consideration to the potential resource impact of the recommendations. The included recommendations are considered to be aspirational but achievable.\n\nThis guideline does not replace statutory duties and good practice as set out in relevant legislation and guidance, including:\n\nCare Act\xa02014 and associated guidance\n\nEquality Act\xa02010\n\nMental Capacity Act\xa02005\n\nAccessible Information Standard\n\nUN Convention on the rights of persons with disabilities\n\nHuman Rights Act\xa01998.\n\nThis guideline aims to complement legislation and guidance by providing evidence-based recommendations about how to improve people's experiences of care and support. Actions already required by law, or recommended in guidance, are not replicated here unless there was evidence to suggest that these were not happening in practice, or were of particular importance to people's experiences.\n\nYou can see everything NICE says on this topic in the\xa0NICE Pathway on people's experience in adult social care services.\n\nTo find NICE guidance on related topics, including guidance in development, see the\xa0NICE webpage on adult's social care.\n\nFor full details of the evidence and the guideline committee's discussions, see the\xa0full guideline and appendices. You can also find information about\xa0how the guideline was developed, including details of the committee.\n\nNICE has produced\xa0tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see\xa0resources to help you put NICE guidance into practice.", 'Recommendations': "People have the right to be involved in discussions and make decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Overarching principles\n\nRecognise that each person who uses services is an individual. Use each person's self-defined strengths, preferences, aspirations and needs as the basis on which to provide care and support to live an independent life.\n\nSupport people to maintain their independence. This means finding out what people want from their life, and providing the support and assistance they need to do this\n\n## Co-production and enabling people to make decisions\n\nRespect people's right to make their own decisions, and do not make assumptions about people's capacity to be in control of their own care and support (for example, if the person is severely disabled).\n\nActively involve the person in all decisions that affect them.\n\nProvide support to people, if they need it, to express their views, preferences and aspirations in relation to their care and support. Identify and record how the person wishes to communicate and if they have any communication needs (in line with the Accessible Information Standard). This could include:\n\nadvocacy support\n\nan independent interpreter (that is, someone who does not have a relationship with the person or the services they are using) to enable people to communicate in a language they can readily converse in, including sign language\n\na carer, if that is what the person wants\n\ncommunication aids (such as pictures, videos, symbols, large print, Braille, hearing loops)\n\nevidence-based techniques for communication\n\nadditional time to understand and process information\n\nenvironmental conditions that support communication, such as clear lighting, and minimal noise interference.\n\nIf a person lacks the capacity to make a decision, the provisions of the Mental Capacity Act\xa02005 must be followed.\n\nUse plain language and personalise the communication approach to encourage and enable people to be actively involved in their care and support. If technical language or jargon has to be used, or complicated ideas are being discussed, take time to check that the person, or a carer who knows them well, understands what is being said.\n\nIf a third party or advocate is supporting someone to give their views, ensure that enough time has been allowed for them to do it.\n\nLocal authorities and service providers should work with people who use adult social care services and their carers as far as possible to co-produce:\n\nthe information they provide\n\norganisational policies and procedures\n\nstaff training.\n\n## Access to care\n\nEnsure that everyone with social care needs has access to services based on their needs, taking account of age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race, religion and belief, sex and sexual orientation, and socio-economic status or other aspects of their identity.\n\nService providers should be aware of the cultural and religious needs of people who use services, and provide care and support that meets these needs. Examples include treatment choices, food choice and preparation, enabling people to dress in accordance with their culture or religion, personal grooming, or changes in timing of services around religious festivals – for example, during Ramadan.\n\nCommissioners and service providers should consider seeking advice from voluntary and community sector organisations such as disabled people's organisations and user-led organisations with expertise in equality and diversity issues to ensure that they can deliver services that meet the needs and preferences arising from:\n\ngender, including transgender\n\nsexual orientation and sexuality\n\ndisability\n\nethnicity\n\nreligious and cultural practices.\n\nEnsure that people who use services and have caring responsibilities (for another adult or a child) receive support to access social care services, including information about childcare, or respite care\n\n## Involving carers, families and friends\n\nAsk the person at the first point of contact whether and how they would like their carers, family, friends and advocates or other people of their choosing (for example, personal assistants) to be involved in discussions and decisions about their care and support, and follow their wishes. Review this regularly (at least every 6\xa0to 12\xa0months), or when requested.\n\nIf the person would like their carers, family, friends and advocates involved:\n\nexplain the principles of confidentiality, and how these are applied in the best interests of the person\n\ndiscuss with the person and their carers, family, friends and advocates what this would mean for them\n\nshare information with carers, family, friends and advocates as agreed.\n\nIf a person lacks the capacity to make a decision about whether they wish their carers, family, friends and advocates to be involved, the provisions of the Mental Capacity Act\xa02005 must be followed.\n\n# Information\n\nIn line with the Care Act\xa02014, local authorities must provide information about care and support services for people and their carers, including:\n\nthe types of care and support available\n\nhow to access care and support, including eligibility criteria\n\nhow to get financial advice about care and support\n\nlocal safeguarding procedures and how to raise safeguarding concerns or make a complaint\n\nrights and entitlements to assessments and care and support services\n\npersonal budgets and all the options for taking a personal budget – for example, local authority managed, Individual Service Fund or direct payment.\n\nLocal authorities should ensure that information about care and support services is widely and publicly promoted – for example, in GP surgeries and community spaces, as well as in specialist services such as homeless health centres.\n\nLocal authorities should provide information about the circumstances in which independent advocacy is available, in line with the Accessible Information Standard, and how to access it.\n\nLocal authorities should provide comprehensive information about community resources and support, including voluntary organisations, user-led organisations and disabled people's organisations, and about available housing options.\n\n# Care and support needs assessment and care planning\n\nLocal authorities must, in line with the Care Act\xa02014, provide independent advocacy to enable people to participate in:\n\ncare and support needs assessment\n and\n\ncare planning and\n\nthe implementation process and review where they would otherwise have substantial difficulty in doing so.\n\nPeople who are supported by an independent advocate during care and support needs assessment and care planning should have enough time with their advocate:\n\nfor preparation before the assessment or care planning session\n\nto ensure they have understood the outcome afterwards.\n\n## Needs assessment\n\nLocal authorities must ensure that care and support needs assessment under the Care Act\xa02014 focuses on the person's needs and how they impact on their wellbeing, and the outcomes they want to achieve in their day-to-day life.\n\nCare and support needs assessment should:\n\ninvolve the person and their carers in discussions and decisions about their care and support\n\ntake into account the person's personal history and life story\n\ntake a whole family approach\n\ntake into account the needs of carers\n\ntake into account the person's housing status, and where and who they want to live with\n\nbe aimed at promoting their interests and independence\n\nbe respectful of their dignity\n\nbe transparent in terms of letting people and their families and carers know how, when and why decisions are made\n\ntake into account the potential negative effect of social isolation on people's health and wellbeing.\n\nLocal authorities should consider the person's preferences in terms of the time, date and location of the care and support needs assessment, and conduct the assessment face-to-face unless the person prefers a different method of assessment.\n\nLocal authorities should ensure that:\n\nthe person is given details of the care and support needs assessment process and timescale at the start\n\nthe person is given details of the nature and purpose of the assessment\n\nthe person can have someone they choose to be present at the assessment\n\nthe assessment uses up-to-date information and documentation about the person\n\nthe person does not have to provide the same information in subsequent assessments.\n\nSee the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of people using services who have caring responsibilities.\n\nEnsure that care and support needs assessment documentation about the person is accurate, up to date and well maintained and clarifies what assessed needs will be met and how.\n\nOffer the person a copy of any or all of the care and support needs assessment documentation. It should be shared with the person's carer if that is what they want.\n\n## Care and support plans\n\nAs part of care planning, consider identifying a named coordinator who is competent to:\n\nact as the first point of contact for any questions or problems\n\ncontribute to the assessment process\n\nliaise and work with the person, their families, carers and advocates\n\nliaise and work with all health, social care and housing services involved with the person, including those provided by the voluntary and community sector\n\nensure that any referrals needed are made and are actioned.\n\nBuild in flexibility to the care and support plan to accommodate changes to a person's priorities, needs and preferences – for example, by using direct payments (see recommendations\xa01.3.20 and\xa01.3.21) and agreeing a rolling 3‑monthly budget so that people can use their money differently each week.\n\nLocal authorities and providers should ensure that the person's care and support plan includes clear information about what involvement from others (carers, family, friends and advocates) they want in their care and support, in line with the Care Act\xa02014. (See also recommendation\xa01.1.14.)\n\nEnsure there is a transparent process for 'matching' care workers to people, taking into account:\n\nthe person's care and support needs and\n\nthe care workers' knowledge, skills and experience and\n\nif possible and appropriate, both parties' interests and preferences.\n\nEnsure care workers are able to deliver care and support in a way that respects the person's cultural, religious and communication needs (see recommendation\xa01.1.11) .\n\nCare and support plans should record and address the specific needs of people in relation to equality and diversity issues.\n\nCare and support plans should be regularly reviewed, and include information on how and when these reviews should be carried out.\n\nCare and support plans should include contingency planning and what to do in a crisis.\n\n## Personal budgets and direct payments\n\nThe local authority must include the person's personal budget in their care and support plan, in line with the Care Act\xa02014.\n\nLocal authorities should:\n\ninform people that they have the option to control their own funding to buy different sorts of care and support that meets their needs and chosen outcomes\n\nprovide information, advice and support so that the person can choose which option suits them best\n\ngive people the opportunity to exercise as much control as possible over the way they use any allocated funds to purchase a care package\n\ninform people of the different options for managing their budget.\n\nLocal authorities should ensure that the direct payment process is:\n\ntransparent about how the level of funding is decided\n\nstraightforward\n\naccessible to all adults who receive social care and are eligible for local authority funding\n\nreviewed periodically to make sure that it is meeting the objectives of the care and support plan\n\nable to meet the legal obligations of the person receiving that direct payment if they employ personal assistants.\n\nLocal authorities should provide accessible information about direct payments, and peer support for people to use them. For example, this could be provided through user-led Centres for Independent Living.\n\nIn line with the Care Act statutory guidance, local authorities should support local services that provide peer support. Their contribution could include:\n\nfinancial support for local peer support services\n\nproviding physical space for people who give peer support to hold meetings with people who use services\n\nhelping peer support services with applying for grants for funding.\n\n## Personal assistants\n\nIf people have eligible needs that could be met by employing a personal assistant, the local authority should ensure that this option is discussed with the person and understood by them at the care and support planning stage.\n\nIn line with the Care Act statutory guidance, local authorities should ensure that support is available for people employing personal assistants, and that they are told about where to get support with:\n\nrecruitment and retention of staff\n\ntheir role and responsibilities as an employer (for example, payroll, terms and conditions, redundancy and contingency planning).\n\nLocal authorities should consider the following to deliver support for people who employ personal assistants:\n\nuser-led Centres for Independent Living\n\nother peer-support arrangements.\n\nIn line with the market shaping duty in the Care Act\xa02014, local authorities should work with people who use social care services and their carers to enable access to personal assistants. For example, this could be done by providing training opportunities for people who are interested in becoming personal assistants.\n\n# Providing care and support\n\n## Care and support in all settings\n\nThe following recommendations refer to care and support in all settings. For further detail about home care, please see the NICE guideline on home care for older people.\n\nService providers should foster a culture that enables practitioners to respect people's individual choices and preferences, in all settings where care and support is delivered, by:\n\nco-producing policies and protocols with people who use services and their carers (see recommendation\xa01.1.9)\n\nensuring that there are open channels of communication between practitioners and people who use services\n\nusing the communication methods that suit the person, in line with the Accessible Information Standard\n\nsupporting people to take managed risks to achieve their goals – for example, taking part in hobbies or sports\n\nensuring that there are systems in place for reporting concerns or abuse\n\nensuring that practitioners have the time to build relationships with people\n\ntraining and supporting practitioners to work in this way, and checking they are doing so.\n\nPractitioners working in all settings where care and support is delivered should ask the person using services, their carers, family, friends and advocates what name they prefer to be called, and use their preferred name.\n\nPractitioners working in all settings where care and support is delivered should take time to build rapport with the people they support.\n\nPractitioners working in all settings where care and support is delivered should respond flexibly to the priorities a person might identify each day. For example, a person might ask a home care worker to spend more time helping them get dressed and less time on other tasks if they have a special event to attend.\n\nDay care and residential care providers should offer a choice of activities that are led by the person's needs, preferences and interests. Encourage people to take part by including activities that motivate them, support them to learn new skills and increase their level of independence. Recognise that preferences are not fixed and may change.\n\n## Continuity and consistency\n\nService providers in all settings, with oversight by commissioners, should review staffing numbers and skill mix regularly to ensure that staffing and skill levels are sufficient.\n\nCommissioners and managers in all settings should ensure that there is continuity in care and support for people, including:\n\nensuring that all practitioners involved with the person's care and support are familiar with how that person likes support to be given\n\nwhere possible, the same people are supporting the person\n\nif the same staff are not available, ensuring there are good handover arrangements\n\nensuring that all staff supporting the person have similar levels of skills and competency\n\nusing the same independent advocate where possible.\n\nProviders and managers in all settings should ensure that:\n\npeople are informed in advance if staff will be changed and\n\nany changes to care and support – for example, when visits will be made, are negotiated with the person.\n\nSupport people to make decisions about entering a new care setting or moving to a different setting. For guidance on transitions between particular settings, see the NICE guidelines on:\n\ntransition from children's to adults' services for young people using health or social care services\n\ntransition between inpatient hospital settings and community or care home settings for adults with social care needs\n\ntransition between inpatient mental health settings and community or care home settings.\n\nTo support collaborative working between services, commissioners and managers should consider putting the following in place:\n\na local policy for sharing information relevant to people's care within and between services in line with the Caldicott principles and the Health and Social Care (Safety and Quality) Act\xa02015\n\njoined-up policies, processes and systems.\n\n## Personal care\n\nAll practitioners providing personal care should ensure that personal care needs are responded to in a timely, appropriate and dignified manner in line with the person's wishes and their support plan – for example, making sure that people can go to the toilet when and how they want.\n\n## Promoting positive relationships between people who use services\n\nService managers and practitioners in day care and residential settings should promote a sense of community and mutual support – for example, by facilitating interactions and building social connections between residents through activities such as social events.\n\n## Residential settings\n\nPractitioners and managers in residential settings should:\n\nensure that the environment allows for people's preferences, self-expression and choice – for example, enabling people to have their own furniture and pictures\n\nsupport people to have control over their own medicines where possible (see the NICE guideline on managing medicines in care homes)\n\ndeliver care and support in a personalised and friendly way\n\ngive people privacy, especially when delivering personal care\n\ntreat people with dignity and respect.\n\nWhen designing residential services, providers should ensure that environments:\n\ncreate space where practitioners and residents can have positive interactions\n\nare welcoming to visits from family, friends, carers and advocates\n\nare stimulating, while not creating additional challenges for residents, including those with sensory impairments or dementia (for example, if the layout is frequently changed or there is poor lighting)\n\nenable positive risk taking (for example, being able to use outside spaces)\n\nsupport residents' autonomy (for example, by adapting kitchen facilities for people with physical disability).\n\nEnsure that support in residential care is based on a good understanding of people's needs, including:\n\nproviding practical and emotional support\n\naccommodating speech and communication needs\n\nhelping people to maintain the personal relationships and friendships that are important to them\n\nsupporting people to take part in activities and social groups that they want to be involved in, both in the residential setting and in the community\n\nviewing behaviour that challenges as communication\n\nproviding access to community health teams and specialist support.\n\nPractitioners should support people to participate fully in tasks and activities by ensuring that:\n\nthe environment is conducive to their needs\n\nthey have access to the equipment they need (for example, hoists or recliner chairs).\n\nManagers should ensure that practitioners are trained to support residents to use any equipment they need.\n\n## End-of-life support in residential settings\n\nFor more information on end-of-life care, see NICE's guideline on care of the dying adult.\n\nManagers in residential settings should co‑produce a policy on end-of-life care with people who use services and their carers. This should include information about:\n\ndocumenting treatment and care preferences at the earliest opportunity (including formal ways of documenting preferences such as Lasting Power of Attorney for health and care decisions, advance statements of wishes and care preferences or advance decisions to refuse treatment)\n\na named lead in the residential setting\n\ntraining on supporting people and their carers at the end of their lives, tailored to different staff groups and updated regularly\n\nongoing support to enable practitioners to support people near the end of their lives, including creative ways of engaging people in discussions (for example, opportunities to discuss end-of-life care with peers).\n\nManagers in residential settings should consider making someone available who is independent and not part of the usual staff team to discuss end-of-life issues, for people who want to do this – for example, from an advocacy organisation.\n\n# Staff skills and experience\n\nHave a transparent and fair recruitment and selection process that:\n\nuses values-based interviews and approaches to identify the personal attributes and attitudes essential for a caring and compassionate workforce and\n\nensures that staff have the necessary language, literacy and numeracy skills to do the job.\n\nLocal authorities should ensure that people undertaking needs and eligibility assessments have the knowledge and skills to carry out assessments as described in recommendations\xa01.3.3 to\xa01.3.9.\n\nService providers should consider involving people who use services and their carers ('experts by experience') in the recruitment and training of staff. For example:\n\nbeing on interview panels\n\ncontributing to development and delivery training\n\nhelping to develop job descriptions\n\nsupporting and training others to be experts by experience.\n\nConsider providing opportunities for practitioners to learn from the personal experiences of all people who use services, in all settings where care and support is provided. This could be through:\n\nforums within residential and day care services\n\naudit, planning and evaluation of services\n\npractitioners being mentored by people who use services.\n\nService providers should ensure that practitioners are aware of the local arrangements for, and understand the function of, other services that they may need to work with, such as other health and social care service providers and services provided by the voluntary sector.\n\nService providers should provide opportunities for practitioners to take part in interprofessional learning and development.\n\nService providers should ensure that practitioners are able to use any equipment or devices people need – for example, hearing aid loops.\n\nService providers should ensure that practitioners are aware of issues relating to information sharing and confidentiality.\n\n# Involving people in service design and improvement\n\nLocal authorities must provide opportunities for people who use services to be involved if they want to in strategic decision-making about services, not just their own care and support, in line with the Local Government and Public Involvement in Health Act\xa02007. This should include involving people in:\n\ndecisions about the way services are commissioned, run and are governed and\n\nchecking that the service is delivering quality care and support.\n\n## Using people's views to improve services\n\nAll research into the views of people using care and support and their carers should be co‑produced at all stages, including the research design, how it is carried out, and any resulting actions (for example, developing or refining quality indicators, developing monitoring tools or identifying gaps in services).\n\nCommissioners and service providers should communicate clearly the outcome that any exercise to collect people's views is aiming to achieve and what will be done as a result.\n\nCommissioners and service providers should consider using a range of approaches to gather views and experiences (for example, focus groups, interviews or observation in addition to surveys), and use evidence from a range of sources. This could include:\n\nthe lived experiences of people who use services\n\ninformation from voluntary organisations that represent people who use social care services – for example, Healthwatch\n\nexisting sources of information, such as complaints.\n\nLocal authorities should consider gathering and analysing evidence on people's experience of services in collaboration with other health and social care organisations serving the same populations to reduce duplication and ensure economies of scale.\n\nOrganisations conducting research should consider from the outset how to ensure that all groups are able to participate, including people who may lack capacity and people with different communication needs. This may involve adapting different research methods (see recommendation\xa01.6.4) or providing materials in a range of formats. If the participation or response rate for a particular group is low, the organisations should take action to improve it. This could include investigating what specific communication or cultural reasons may account for the low response and adapting materials or response formats to better suit that group.\n\nService providers should seek the views of people who use services about the extent to which the things that are important to them are being addressed. This should be done in such a way that the person feels safe to express their views, even if these are critical (for example, a care home resident may not want to give feedback directly to the manager).\n\nOrganisations or individuals conducting research or seeking feedback from people who use services should ensure that independent advocacy is available and offered when:\n\nthis would help someone to take part or\n\nthe person expresses a preference to use advocacy.\n\nService providers should consider employing people who use services to monitor people's experience of health and social care services, including conducting research. This could be done by:\n\noffering training to 'experts by experience' on how to conduct interviews with people who use services, including supporting them in applying ethical principles such as informed consent and confidentiality\n\npaying them to undertake exit interviews with people who have recently left a service or moved to another service.\n\nCommissioners and providers should ensure that the results of research with people are used to inform improvements to services.\n\nCommissioners and service providers should make available the results of research with people who use services, using approaches developed with people who use services. This should include:\n\npublishing the results\n\ngiving feedback directly to people who took part\n\nmaking public how they have responded to people's feedback – for example, by using 'you said, we did' tables or case studies.\n\n## Survey research\n\nConsider using existing validated surveys before deciding to develop a new survey.\n\nLocal authorities should analyse the characteristics of people who did not or could not respond to surveys and:\n\nreport on any under-represented groups in their published report of the survey and seek to understand the reasons for this\n\ndevelop ways to address these gaps in the future – for example, by considering alternative modes of response, such as a telephone response line\n\nensure that information about under-represented groups is fed back to the survey designers.\n\nLocal authorities should ensure that people in their organisations who are responsible for interpreting and implementing survey findings have the necessary skills and capacity.\n\n# Terms used in this guideline\n\n## Care and support needs assessment\n\nUnder the Care Act\xa02014, local authorities must carry out an assessment of anyone who appears to require care and support. The aim of assessment is to understand the person's needs and goals. After carrying out the assessment, the local authority consider whether any of the needs identified are eligible for support.\n\n## Care and support plan\n\nA written plan after a person has had an assessment, setting out what their care and support needs are, how they will be met (including what they or anyone who cares for them will do) and what services they will receive.\n\n## Carer\n\nA person who provides unpaid support to a partner, family member, friend or neighbour who is ill, struggling or disabled and could not manage without this help. This is distinct from a care worker, who is paid to support people.\n\n## Centre for Independent Living\n\nA local organisation run by people with disabilities, that supports disabled people in their area to make choices about how and where they live their lives, with the assistance and support they need to live as independently as possible.\n\n## Commissioner\n\nA person or organisation that plans the services that are needed by the people who live in the area the organisation covers, and ensures that services are available. Sometimes the commissioner will pay for services, but not always. The local council is the commissioner for adult social care. NHS care is commissioned separately by local clinical commissioning groups. In many areas, health and social care commissioners work together to make sure that the right services are in place for the local population.\n\n## Communication aid\n\nA communication aid helps a person to communicate more effectively with those around them. This could range from a simple letter board to a more sophisticated piece of electronic equipment.\n\n## Co-production\n\nWhen a person who uses services is involved as an equal partner in designing the support and services they receive. Co‑production recognises that people who use social care services (and their families) have knowledge and experience that can be used to help make services better, not only for themselves but for other people who need social care.\n\nThe Think Local Act Personal's 6\xa0principles of co-production are:\n\nrecognising people as assets\n\nbuilding on people's capabilities\n\ndeveloping 2‑way, reciprocal relationships\n\nencouraging peer support\n\nblurring boundaries between delivering and receiving services\n\nfacilitating rather than delivering.\n\n## Day care services\n\nOpportunities for people to do things during the day, while living in their own home. These may include social activities, education, or the opportunity to learn new skills. What the local council offers will vary, depending on what a person needs and what is available in that area. People who use services may have to pay something towards the cost.\n\n## Home care\n\nCare provided in a person's own home by paid care workers to help them with their daily life. It is also known as domiciliary care. Home care workers are usually employed by an independent agency, and the service may be arranged by the local council or by the person that needs care (or someone acting on their behalf).\n\n## Information sharing\n\nInformation sharing refers to the sharing of information about people who use services within and between organisations. Personal information can be shared within or between organisations with the person's consent, or if it is believed to be in the public interest. See the 7\xa0golden rules of information sharing.\n\n## Joint commissioning\n\nWhen 2\xa0or more organisations in a local area – usually the NHS and local council – work together to plan services to meet the needs of people who live in the area. Together the commissioners plan what kind of services should be available, who should provide them and how they should be paid for.\n\n## Named care coordinator\n\nThe person in an organisation who is responsible for coordinating support for the person and their family if needed – for example, a named social worker or a nurse. The coordinator role refers to a function and not a post.\n\n## Peer support\n\nThe practical and emotional help and support that people who have personal experience of a particular health condition or disability can give each other, based on their shared experience. People support each other as equals, one-to-one or in groups, either face-to-face, online or on the telephone.\n\n## Person who uses services\n\nA person who receives services from a care and support provider. It is often preferred to the term 'service user'.\n\n## Personal assistant\n\nSomeone the person using services chooses to employ to provide the support they need, in the way that suits them best. This may include cooking, cleaning, help with personal care such as washing and dressing, and other things such as getting out and about in the community. A personal assistant can be paid through a direct payment.\n\n## Personalised care\n\nAn approach that puts the person receiving care and support at the centre of the way care is planned and delivered. It is based around the person and their own needs, preferences and priorities. It treats the person receiving services as an equal partner, and puts into practice the principle of 'no decision about me without me'.\n\n## Practitioner\n\nAny worker who provides support to the person and their family and carers. Practitioners include people working in all settings and in different roles – for example, social workers, health professionals and care home staff. Practitioners could also include those with designated roles, such as care coordinators or key workers.\n\n## Residential settings\n\nAccommodation where care and support are provided by staff. These settings can be run by the private sector, voluntary sector or local authority. Residential settings can include residential care homes and nursing homes and also include supported living.\n\n## Supported living\n\nAccommodation and support that enables adults with disabilities to live in their own home, with the help they need to be independent. It allows people to choose where they want to live, who they want to live with, how they want to be supported, and what happens in their home.\n\n## Voluntary sector\n\nAlso referred to as 'voluntary and community social enterprise sector' (VCSE). It refers to organisations that are independent of the government and local councils. Their role is to benefit the people they serve, not to make a profit. Social care services are often provided by VCSEs, by arrangement with the council or with the individual. Some are user-led organisations, which means they are run by and for the people the organisation is designed to benefit – for example, disabled people.\n\nThe source of some of these definitions is the Think Local, Act Personal's care and support jargon buster. Also see the jargon buster for other social care terms.", 'Putting this guideline into practice ': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nSupporting people who use services to maintain their independence is a key requirement for wellbeing and is an achievable expectation, but it will require a significant change in practice for some services.\n\nWorking with people who use social care to ensure that there is a well-developed 'market' for personal assistants (PAs) will lead to better outcomes for people who employ PAs and better use of resources. However, for some authorities this will involve a new focus on market development and a change of practice that will require staff to be re‑trained.\n\nMaking sure that people are supported in a residential setting that is appropriate to their needs and building a culture that enables staff to respect people's individual choices and preferences are essential factors in promoting a good quality of life for people who live in a residential setting. Services may find it challenging to implement these changes because they will involve a major rethink in their approach to service delivery.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Recommendations for research ': "The guideline committee has made the following recommendations for research.\n\n# Methods and approaches for gathering the experiences of people who use adult social care services\n\nWhen conducting research for the purposes of service improvement, what research methods are acceptable, appropriate and effective in meaningfully gathering the views and experiences of people who use services?\n\n## Why this is important\n\nCurrent research methods for gathering the views and experiences of people who use services commonly include standardised surveys and measures (for example, patient-reported outcome measures [PROMs]; NHS and social care: public perceptions surveys; The National Adult Social Care User Experience Survey). However, the evidence reviewed for this guideline suggests that measures of this kind may have limitations in terms of how comprehensive and representative these people are who are typically willing and able to respond to these kinds of self-completion postal surveys. This means that some people's views and experiences of social care may not be included in surveys designed to support service improvement. Further research is needed to:\n\nDetermine the extent to which frequently used research methods meaningfully engage people and provide an accurate picture of their views and experiences.\n\nDevelop and test new or innovative methods for gathering views and experiences. This could include narrative methods and the use of technology such as apps. The methods would be compared in relation to how well they were able to provide accurate and detailed information on people's views and experiences of care and support.\n\n# Co-producing research into the views and experiences of people who use services\n\nWhat approaches have been shown to work in supporting the co‑production of research for the purposes of service improvement with people who use services?\n\n## Why this is important\n\nCo-production is a key concept in the development of public services (Co-production in social care: what it is and how to do it, Social Care Institute for Excellence [SCIE]), and there are many examples in practice that highlight how individuals and communities can positively shape the way that services are designed, commissioned and delivered (Co-production in commissioning, Think Local Act Personal\xa02015). Co‑produced research on the views and experiences of people who use services is a potential means of improving services. Co‑producing all stages of the research process with people who use services is an important principle, which may signpost pertinent issues and questions that would have otherwise been neglected. However, there is little published evidence about how to put the principle of co‑production into practice in research, although it appears that there may be good practice occurring within the sector.\n\n# Identifying barriers and enablers to using the views and experiences of people who use services to improve services\n\nWhat are the barriers and enablers to gathering, synthesising and applying data on the views and experiences of people who use services for the purposes of service improvement?\n\n## Why this is important\n\nThere are several examples of data-gathering processes designed with the purpose of improving services – for example, annual mandatory local authority surveys, audit, and small-scale consultation at the individual organisation level. However, little is known about how the data from these exercises are translated into change and improvement in services, including:\n\nWhat capacity is needed within organisations to gather data and make use of it, and whether this is present?\n\nWhat factors determine whether the findings of research are implemented in practice?\n\n# Use of technology in providing care\n\nWhat are the views and experiences of people who use adult social care services on assistive technologies?\n\n## Why this is important\n\nAssistive technology is one means by which social care services can help people to maintain independence. These technologies include a wide range of devices, ranging from simple, low-cost devices such as pendant alarms, to more intricate home monitoring systems using electronic information and communication technology – for example, integrated systems of sensors, alarms and remote monitoring. Across all population groups, there is a paucity of evidence about how acceptable assistive technology is to people who use services, and the impact of the technology on their satisfaction with services. Issues that could be explored include the extent to which the technology is and can be personalised, anxiety that it may be used to scale back services and reduce human contact, loss of confidentiality where personal information is shared, and ethical questions around privacy and surveillance."}
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https://www.nice.org.uk/guidance/ng86
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This guideline covers the care and support of adults receiving social care in their own homes, residential care and community settings. It aims to help people understand what care they can expect and to improve their experience by supporting them to make decisions about their care.
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60a34350c3d05bf03efa2cb716b2fb4e6e075e53
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nice
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Aortic valve reconstruction with processed bovine pericardium
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Aortic valve reconstruction with processed bovine pericardium
Evidence-based recommendations on aortic valve reconstruction with processed bovine pericardium. This involves replacing a damaged aortic valve with a new valve made from chemically treated cow pericardium.
# Recommendations
Current evidence on the safety and efficacy of aortic valve reconstruction with processed bovine pericardium is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should address patient selection and report long-term outcomes, particularly the durability of the valve.# The condition, current treatments and procedure
# The condition
Aortic valve disease (stenosis or regurgitation) is usually progressive and causes an increase in cardiac workload, left ventricular hypertrophy and heart failure. Symptoms can include palpitations, fatigue, shortness of breath and chest pain on exertion. Mortality rates are high in symptomatic patients.
# Current treatments
Conventional treatment for a significantly diseased aortic valve is surgical replacement with an artificial (biological or mechanical) prosthesis. Transcatheter aortic valve implantation may also be considered. Bioprosthetic valves do not perform as well as native valves and have limited durability, which may be an issue for younger patients. Lifelong anticoagulation is needed in patients with mechanical valves, which increases the risk of haemorrhagic complications and is not optimal in women wishing to become pregnant. In some patients with aortic regurgitation, the aortic valve may be repaired with patches as an alternative to replacement.
Aortic valve reconstruction with bovine pericardium may be considered in patients who cannot or who refuse to take anticoagulation, patients with an aorta too narrow for a standard prosthetic valve and young patients who wish to avoid long-term anticoagulation.
# The procedure
With the patient under general anaesthesia, the heart is accessed by a sternotomy and cardiopulmonary bypass is established. The heart is stopped with cardioplegic arrest, the aorta is opened and the valve is inspected. The diseased valve cusps are carefully removed and the intercommissural distances are measured. Commercially available bovine pericardium is trimmed to the desired size using a template, and sutured to the annulus to replace the removed cusp(s). The aorta is closed, normal circulation is restored and the chest is closed. The function of the valve is assessed intraoperatively by transoesophageal echocardiography.
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{'Recommendations': 'Current evidence on the safety and efficacy of aortic valve reconstruction with processed bovine pericardium is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should address patient selection and report long-term outcomes, particularly the durability of the valve.', 'The condition, current treatments and procedure': '# The condition\n\nAortic valve disease (stenosis or regurgitation) is usually progressive and causes an increase in cardiac workload, left ventricular hypertrophy and heart failure. Symptoms can include palpitations, fatigue, shortness of breath and chest pain on exertion. Mortality rates are high in symptomatic patients.\n\n# Current treatments\n\nConventional treatment for a significantly diseased aortic valve is surgical replacement with an artificial (biological or mechanical) prosthesis. Transcatheter aortic valve implantation may also be considered. Bioprosthetic valves do not perform as well as native valves and have limited durability, which may be an issue for younger patients. Lifelong anticoagulation is needed in patients with mechanical valves, which increases the risk of haemorrhagic complications and is not optimal in women wishing to become pregnant. In some patients with aortic regurgitation, the aortic valve may be repaired with patches as an alternative to replacement.\n\nAortic valve reconstruction with bovine pericardium may be considered in patients who cannot or who refuse to take anticoagulation, patients with an aorta too narrow for a standard prosthetic valve and young patients who wish to avoid long-term anticoagulation.\n\n# The procedure\n\nWith the patient under general anaesthesia, the heart is accessed by a sternotomy and cardiopulmonary bypass is established. The heart is stopped with cardioplegic arrest, the aorta is opened and the valve is inspected. The diseased valve cusps are carefully removed and the intercommissural distances are measured. Commercially available bovine pericardium is trimmed to the desired size using a template, and sutured to the annulus to replace the removed cusp(s). The aorta is closed, normal circulation is restored and the chest is closed. The function of the valve is assessed intraoperatively by transoesophageal echocardiography.'}
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https://www.nice.org.uk/guidance/ipg604
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Evidence-based recommendations on aortic valve reconstruction with processed bovine pericardium. This involves replacing a damaged aortic valve with a new valve made from chemically treated cow pericardium.
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7bc77bc8e98f71277328c374c96892e2a7fd8646
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nice
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Raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women
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Raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women
Evidence-based recommendations on raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
# Guidance
This guidance relates only to treatments for the primary prevention of fragility fractures in postmenopausal women who have osteoporosis. Osteoporosis is defined by a T-score of −2.5 standard deviations (SD) or below on dual-energy X-ray absorptiometry (DXA) scanning. However, the diagnosis may be assumed in women aged 75 years or older if the responsible clinician considers a DXA scan to be clinically inappropriate or unfeasible.
This guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered.
This guidance does not cover the following:
The treatment of women who have sustained a clinically apparent osteoporotic fragility fracture (for recommendations for the treatment of women with a prior osteoporotic fragility fracture, see the accompanying NICE technology appraisal, 'Raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women').
The use of raloxifene for the primary prevention of osteoporotic fragility fractures in women with normal bone mineral density (BMD) or osteopenia (that is, women with a T-score between −1 and −2.5 SD below peak BMD).
The use of this drug for the primary prevention of osteoporotic fragility fractures in women who are on long-term systemic corticosteroid treatment.
This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
The recommendation for strontium ranelate has been withdrawn because strontium ranelate is no longer marketed in the UK.
Raloxifene is not recommended as a treatment option for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.
This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
For the purposes of this guidance, intolerance of alendronate or risedronate is defined as persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment, and that occurs even though the instructions for administration have been followed correctly.
For the purposes of this guidance, primary prevention refers to opportunistic identification, during visits to a healthcare professional for any reason, of postmenopausal women who are at risk of osteoporotic fragility fractures and who could benefit from drug treatment. It does not imply a dedicated screening programme.
Women who are currently receiving treatment, but for whom treatment would not have been recommended according to sections 1.1 to 1.4, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
T-score relates to the measurement of bone mineral density (BMD) using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) from peak BMD.# Clinical need and practice
Osteoporosis is a progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
Bone formation exceeds bone resorption in youth, but by the third decade of life there is a gradual loss of bone mass. Osteoporosis is therefore usually an age-related disease. It can affect both sexes, but women are at greater risk because the decrease in oestrogen production after the menopause accelerates bone loss to a variable degree.
The World Health Organization (WHO) has established diagnostic criteria for osteoporosis based on the measurement of BMD, expressed as the T-score, which is the number of SD below the mean BMD of young adults at their peak bone mass:
normal BMD: T-score of −1 SD or above
-steopenia: T-score of between −1 and −2.5 SD
-steoporosis: T-score of −2.5 SD or below
established (severe) osteoporosis: T-score of −2.5 SD or below with one or more associated fractures.
T-score measurements vary depending on the site and method of investigation. Measurement of BMD using central (hip and/or spine) DXA scanning can estimate fracture risk.
It is estimated that more than 2 million women have osteoporosis (that is, have a T-score of −2.5 SD or below) in England and Wales. Osteoporosis is most common in older white women. After the menopause, the prevalence of osteoporosis increases markedly with age, from approximately 2% at 50 years rising to more than 25% at 80 years.
Fragility fracture is the clinically apparent and relevant outcome in osteoporosis (referred to as 'osteoporotic fragility fracture' in the following text). It is often referred to as a low-trauma fracture; that is, a fracture sustained as the result of a force equivalent to the force of a fall from a height equal to, or less than, that of an ordinary chair. In the absence of fracture, osteoporosis is asymptomatic and often remains undiagnosed. Osteoporotic fragility fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain and reduced quality of life.
In women aged over 50 years, the lifetime risk of a vertebral fracture is estimated to be one in three, and that of hip fracture one in five. Postmenopausal women with an initial fracture are at substantially greater risk of subsequent fractures. For instance, a woman with a vertebral fracture has an increased relative risk (RR) of 4.4 for a further vertebral fracture, 2.3 for a hip fracture, and 1.4 for a wrist fracture.
It is estimated that annually there are 180,000 osteoporosis-related symptomatic fractures in England and Wales. Of these, 70,000 are hip fractures, 25,000 are clinical vertebral fractures, and 41,000 are wrist fractures.
After a hip fracture, a high proportion of women are permanently unable to walk independently or to perform other activities of daily living and, consequently, many are unable to live independently. Hip fractures are also associated with increased mortality; estimates of the relative mortality risk vary from 2 to greater than 10 in the 12 months following hip fracture. However, it is unclear to what extent this can be attributed to fracture alone as opposed to pre-existing comorbidity.
Vertebral fractures can be associated with curvature of the spine and loss of height and can result in pain, breathing difficulties, gastrointestinal problems and difficulties in performing activities of daily living. It is thought that the majority of vertebral fractures (50–70%) do not come to clinical attention. Vertebral fractures are also associated with increased mortality; UK-specific data indicate a 4.4-fold increase in mortality related to vertebral fracture. However, as with hip fractures, it is unclear to what extent this may be due to comorbidities.
In addition to increasing age and low BMD, other clinical factors have been associated with increased fracture risk. Some of these clinical risk factors are at least partly independent of BMD, and include parental history of hip fracture, alcohol intake of 4 or more units per day, prior fracture, long-term systemic use of corticosteroids (the latter two of which are not covered in this guidance), and rheumatoid arthritis.
Factors that are known to be indicators of low BMD include low body mass index (BMI) (defined as less than 22 kg/m2), and medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause.# The technologies
# Bisphosphonates: alendronate, etidronate and risedronate
The bisphosphonates alendronate, etidronate and risedronate are inhibitors of bone resorption and increase BMD by altering osteoclast activation and function.
Alendronate is an oral bisphosphonate that has a UK marketing authorisation as a once-weekly preparation (70 mg) for the treatment of postmenopausal osteoporosis. It also has a marketing authorisation at a daily dose of 10 mg for the treatment of osteoporosis in postmenopausal women to prevent fractures. Non-proprietary alendronate (Teva UK) costs £4.12 for four 70 mg tablets and £8.30 for twenty-eight 10 mg tablets (excluding VAT; NHS Drug Tariff, 24 February 2008). At these prices the drug costs for 1 year are £53.56 for once-weekly (70 mg) tablets and £108.20 for daily (10 mg) tablets. Proprietary alendronate (Fosamax; Merck Sharp & Dohme) is priced at £22.80 for four 70 mg tablets and £23.12 for twenty-eight 10 mg tablets (excluding VAT; 'British national formulary' edition 54). At these prices, the drug costs for 1 year are £296.40 for once-weekly (70 mg) tablets and £301.39 for daily (10 mg) tablets. Costs may vary in different settings because of negotiated procurement discounts.
Etidronate (Didronel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation for the treatment of osteoporosis. The drug is administered in 90-day cycles, with each cycle consisting of etidronate (400 mg/day) for 14 days followed by calcium carbonate (1.25 g/day) for the remaining 76 days. The price per 90-day pack is £21.12 (excluding VAT; BNF 54), which equates to a yearly cost of £85.65. Costs may vary in different settings because of negotiated procurement discounts.
Risedronate (Actonel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation at a dosage of 5 mg/day or 35 mg/week for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures, and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Prices are £19.10 for twenty-eight 5 mg tablets and £20.30 for four 35 mg tablets (excluding VAT; BNF 54), which equates to yearly costs of £248.98 for the daily treatment or £264.63 for the once-weekly treatment. Costs may vary in different settings because of negotiated procurement discounts.
Gastrointestinal side effects are common with oral bisphosphonates. In people with oesophageal abnormalities and other factors that delay oesophageal transit or emptying, risedronate should be used cautiously and alendronate is contraindicated. For full details of side effects and contraindications, see the summaries of product characteristics.
Bisphosphonates have relatively complex instructions for administration. Alendronate and risedronate must be taken with 200 ml and 120 ml of water, respectively. Before and immediately after administration patients should not eat or drink, and must remain upright for stipulated time periods. Etidronate should be taken with water at the midpoint of a 4-hour fast (that is, 2 hours after and 2 hours before food, vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium).
# Selective oestrogen receptor modulator: raloxifene
Selective oestrogen receptor modulators (SERMs) are drugs with selective activity in various organ systems, acting as weak oestrogen-receptor agonists in some systems and as oestrogen antagonists in others. The aim of treatment with SERMs is to maximise the beneficial effects of oestrogen on bone and to minimise the adverse effects on the breast and endometrium.
Raloxifene (Evista; Eli Lilly) has marketing authorisation for the treatment of osteoporosis in postmenopausal women. The recommended dosage is 60 mg/day. The prices of 28- and 84-tablet packs are £17.06 and £59.59, respectively (excluding VAT; BNF 54), which equate to yearly costs of £222.39 and £258.93, respectively. Costs may vary in different settings because of negotiated procurement discounts.
Raloxifene is contraindicated in people with a history of venous thromboembolism (VTE), hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding or endometrial cancer. Raloxifene should not be co-administered with systemic oestrogens, and in patients with breast cancer it should not be used for osteoporosis treatment or prevention until treatment of the breast cancer, including adjuvant treatment, has been completed. Raloxifene is associated with an increased risk of venous thromboembolic events, particularly during the first 4 months of treatment, which is similar to the reported risk associated with hormone replacement therapy. For full details of side effects and contraindications, see the summary of product characteristics.
# Strontium ranelate
Strontium ranelate (Protelos; Servier Laboratories) is a divalent strontium salt of ranelic acid (strontium is an element with properties similar to calcium). It is thought to have a dual effect on bone metabolism, increasing bone formation and decreasing bone resorption. It has a UK marketing authorisation for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. The recommended dose is one 2 g sachet taken daily as a suspension in water. The price of a 28-sachet pack is £25.60 (excluding VAT; BNF 54), which equates to a yearly cost of £333.71. Costs may vary in different settings because of negotiated procurement discounts.
The absorption of strontium ranelate is reduced by food, milk and products derived from milk. It should therefore be administered between meals, ideally at bedtime and preferably at least 2 hours after eating.
The summary of product characteristics states that strontium ranelate is not recommended in patients with severe renal impairment and that it should be used with caution in patients at increased risk of VTE. Treatment with strontium ranelate should be discontinued during treatment with oral tetracycline or quinolone antibiotics. For full details of side effects, drug interactions and contraindications, see the summary of product characteristics.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
## Efficacy
The Assessment Group for this appraisal (School of Health and Related Research, University of Sheffield ) reviewed data from published randomised controlled trials (RCTs) in postmenopausal women in which fracture or health-related quality of life was an endpoint and where one of the five drugs of interest was compared with a relevant comparator, such as no treatment, placebo or one of the other included interventions. The majority of studies used placebo or no treatment as a control. Most studies ensured that women in all trial arms had normal calcium levels (that is, normal serum concentrations) or adequate supplementation, and some studies used additional dietary supplementation with vitamin D.
For this appraisal, reductions in RR associated with treatment were pooled regardless of the baseline BMD and fracture status of the participants in the studies. It was also assumed that these reductions in RR remained constant at all ages, although little evidence was available for the effectiveness of the drugs in women aged 80 years or older.
For vertebral fractures, some studies used clinical (that is, symptomatic) fractures as their endpoint whereas others used fractures that were identified radiographically. Vertebral fractures identified radiographically, which are termed 'radiographic fractures' or 'morphometric fractures', include both symptomatic and asymptomatic fractures. There are different definitions of a vertebral radiographic fracture, but those definitions that require a 20% reduction in vertebral height are generally recognised as producing more reliable results than those that require a 15% reduction.
For non-vertebral fracture types, individual data on hip, leg, pelvis, wrist, hand, foot, rib and humerus fractures were sometimes provided, whereas some studies only presented data for all non-vertebral fractures grouped together.
Sixteen RCTs of alendronate in postmenopausal women were included in the assessment report: two studies in women with low or normal BMD; one in women with osteopenia; eight in women with osteopenia or osteoporosis; four in women with osteoporosis; and one in women with established osteoporosis. Overall, 15 studies compared alendronate with placebo or with no treatment. All the studies were conducted in women who had adequate levels of calcium, from either dietary intake or calcium supplementation.
Two studies, one comparing alendronate with oestrogen alone or with oestrogen and alendronate combined, and the other comparing alendronate with teriparatide (which has a marketing authorisation only for secondary and not primary prevention), found no statistically significant differences between the groups in numbers of clinically apparent fractures of any type in women with osteoporosis. However, back pain was reported less frequently by women in the teriparatide group compared with women in the alendronate group (6% versus 19%, p = 0.012).
In addition to the 16 RCTs, a 2-year study demonstrated the equivalence of weekly and daily doses of alendronate, in terms of clinical fracture incidence and gastrointestinal adverse events. However, this study was not included in the analysis because it did not include the specified comparators.
The meta-analysis for alendronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.56 (95% confidence interval 0.46 to 0.68, four RCTs, n = 7039), an RR of hip fracture of 0.62 (95% CI 0.40 to 0.98, three RCTs, n = 7455), an RR of wrist fracture of 0.67 (95% CI 0.34 to 1.31, four RCTs, n = 7931) and an RR for other non-vertebral fractures of 0.81 (95% CI 0.68 to 0.97, six RCTs, n = 9973).
A post-hoc analysis of data from the largest study on alendronate, the 'Fracture intervention trial' (FIT) RCT (non-vertebral fracture population), suggested that alendronate may be less effective at reducing fractures in women with T-scores above (that is, better than) −2.5 SD than in women with osteoporosis. These results were not statistically significant.
Gastrointestinal adverse events, including nausea, dyspepsia, mild oesophagitis/gastritis and abdominal pain, were reported in at least one third of the participants in studies of alendronate. However, only one study found the increased frequency of these symptoms to be statistically significant relative to placebo. This is consistent with post-marketing studies that indicate that approximately one third of alendronate users experience gastrointestinal adverse events. To avoid oesophagitis, the summary of product characteristics now recommends that alendronate should be taken on rising for the day, with a full glass of water. It is possible that these instructions were not followed in all of the studies, particularly the earlier ones.
Prescription-event monitoring studies in patients for whom alendronate was prescribed (n = 11,916) by GPs in England demonstrated a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 32.2 per 1000 patient-months in the first month of treatment to 10.9 per 1000 patient-months in months 2 to 6. Because these studies lacked a comparator, it is not possible to assess the extent to which these rates of upper gastrointestinal events may be above baseline levels in those not taking bisphosphonates.
One study reported health-related quality of life outcomes. At 12 months there were statistically significant improvements in the alendronate group compared with the control group in scores for pain, social isolation, energy level and physical ability.
Twelve RCTs of etidronate in postmenopausal women were reviewed: three studies in women with low-to-normal BMD; two in women with osteopenia or osteoporosis; one in women with osteoporosis; one in women with osteoporosis or established osteoporosis; and five in women with established osteoporosis. Four studies included active comparators, and eight compared etidronate with placebo or with no treatment (although in six of these, study participants in all arms received calcium, either alone or with vitamin D). Some studies did not use the exact treatment regimen that currently has a UK marketing authorisation (that is, 90-day cycles of etidronate 400 mg/day for 14 days, followed by calcium carbonate 1.25 g/day for the remaining 76 days). None of the studies reported health-related quality of life outcomes.
The meta-analysis of RCTs for etidronate relative to placebo carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.40 (95% CI 0.20 to 0.83, three RCTs, n = 341), an RR of hip fracture of 0.50 (95% CI 0.05 to 5.34, two RCTs, n = 180), and an RR for other non-vertebral fractures of 1.04 (95% CI 0.64 to 1.69; four RCTs, n = 410). There were no data for wrist fracture.
An observational study in a general practice setting in the UK reported on fracture rates in people with a diagnosis of osteoporosis who were receiving etidronate compared with those who were not taking a bisphosphonate. People taking etidronate had an RR of non-vertebral fracture of 0.80 (95% CI 0.70 to 0.92). The RR of hip fracture was 0.66 (95% CI 0.51 to 0.85) and that of wrist fracture was 0.81 (95% CI 0.58 to 1.14).
Higher rates of gastrointestinal adverse effects were found in the etidronate groups of four RCTs, although the differences were not always statistically significant. However, non-RCT evidence and testimonies from clinical specialists and patient experts suggested that etidronate may be associated with fewer gastrointestinal adverse effects than other bisphosphonates.
The systematic review carried out by ScHARR in 2006 identified a cohort study conducted in the UK that indicated that etidronate may be associated with a much lower rate of upper gastrointestinal adverse effects than alendronate or risedronate.
Seven RCTs of risedronate in postmenopausal women were reviewed: one study in women with normal BMD; one in women with osteopenia; one in women with osteopenia or osteoporosis; one in women with osteoporosis or specific risk factors for hip fracture, such as a recent fall; and three in women with established osteoporosis. All compared risedronate with placebo (although, with the exception of those in the normal BMD study, all women also received calcium) and none reported on health-related quality of life outcomes.
The meta-analysis for risedronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.61 (95% CI 0.50 to 0.75, three RCTs, n = 2301), an RR of hip fracture of 0.74 (95% CI 0.59 to 0.93, three RCTs, n = 11,770), an RR of wrist fracture of 0.68 (95% CI 0.43 to 1.08, two RCTs, n = 2439) and an RR for other non-vertebral fractures of 0.76 (95% CI 0.64 to 0.91, five RCTs, n = 12,399).
In all of the studies, rates of gastrointestinal adverse events were similar in the risedronate and placebo groups.
Prescription-event monitoring studies in patients for whom risedronate was prescribed (n = 13,643) by GPs in England suggested a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 26.9 per 1000 patient-months in the first month of treatment to 8.1 per 1000 patient-months in months 2 to 6.
A meta-analysis of pooled data from the alendronate and risedronate studies, carried out by ScHARR in 2006, resulted in an RR of vertebral fracture of 0.58 (95% CI 0.51 to 0.67, seven RCTs, n = 9340), an RR of hip fracture of 0.71 (95% CI 0.58 to 0.87, six RCTs, n = 19,233), an RR of wrist fracture of 0.69 (95% CI 0.45 to 1.05, six RCTs, n = 1037) and an RR for other non-vertebral fractures of 0.78 (95% CI 0.69 to 0.88, 11 RCTs, n = 22,372).
Three RCTs of raloxifene in postmenopausal women were identified, but only two were included in the Assessment Group's meta-analysis: the largest study (the 'Multiple outcomes of raloxifene evaluation' study) was carried out in women with osteoporosis, of whom 37% had a vertebral fracture at entry, and a smaller study was conducted in women with established osteoporosis. Both compared raloxifene with placebo (in both studies, women in both arms received calcium and vitamin D). Both studies examined raloxifene at dosages of 60 mg/day (the dosage specified in the UK marketing authorisation for the treatment of postmenopausal osteoporosis) and 120 mg/day. Neither reported on health-related quality of life outcomes. The mean age of women in the studies was 67–68 years. The MORE study was extended further to assess fracture, breast cancer, and cardiovascular and uterine safety outcomes. A third study examined the additive effect of raloxifene compared with placebo in women with a femoral neck T-score of −2 SD or below, with or without prior fracture, who were also receiving fluoride, calcium and vitamin D. Because of the use of fluoride as a co-intervention, these results were not included in the Assessment Group's meta-analysis.
The meta-analysis for raloxifene relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.65 (95% CI 0.53 to 0.79, one RCT, n = 4551), an RR of hip fracture of 1.13 (95% CI 0.66 to 1.96, two RCTs, n = 6971), an RR of wrist fracture of 0.89 (95% CI 0.68 to 1.15, one RCT, n = 6828), and an RR for other non-vertebral fractures of 0.92 (95% CI 0.79 to 1.07, one RCT, n = 6828).
The most serious adverse effect associated with raloxifene was the approximately three-fold increased risk of VTE. Statistically significantly higher incidences of hot flushes, arthralgia, dizziness, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes were also found with raloxifene compared with placebo. The impact of raloxifene on cardiovascular disease is unclear, but there is evidence that it lowers serum concentrations of fibrinogen as well as both total and low-density lipoprotein (LDL) cholesterol levels (that is, serum concentrations) without increasing high-density lipoprotein (HDL) cholesterol.
The MORE study shows that raloxifene protects against breast cancer, with the RR at 4 years for all types of breast cancer reported as 0.38 (95% CI 0.24 to 0.58), and that for invasive breast cancer as 0.28 (95% CI 0.17 to 0.46).
Three RCTs of strontium ranelate in postmenopausal women were identified: one study in women with osteoporosis and two in women with osteoporosis or established osteoporosis. All three studies compared strontium ranelate with placebo, and provided calcium and vitamin D supplementation to ensure an adequate intake.
The Assessment Group reported the results of a published meta-analysis that gave an RR for vertebral fracture of 0.60 (95% CI 0.53 to 0.69, two RCTs, n = 6551) and an RR for all non-vertebral fractures (including wrist fracture) of 0.84 (95% CI 0.73 to 0.97, two RCTs, n = 6551). Efficacy in reducing the rate of hip fracture was established in one study; the RR for hip fracture in the whole study population was 0.85 (95% CI 0.61 to 1.19, one RCT, n = 4932). A post-hoc subgroup analysis in women aged 74 or older with a T-score of −2.4 SD resulted in an RR for hip fracture of 0.64 (95% CI 0.412 to 0.997, one RCT, n = 1977).
In general, strontium ranelate was not associated with an increased risk of adverse effects and for the most part adverse effects were mild and transient; nausea, diarrhoea and creatine kinase elevations were the most commonly reported. A serious adverse event associated with strontium ranelate treatment was an increased incidence (RR = 1.42) of VTE and pulmonary embolism. This finding has been investigated further with the extension of ongoing studies and by post-marketing surveillance.
One study published results on health-related quality of life outcomes. It reported that strontium ranelate had quality of life benefits compared with placebo, as assessed by the QUALIOST osteoporosis-specific questionnaire and by the general health perception score of the short form (SF)-36 general scale.
## Persistence and compliance
Data from 14 RCTs indicated that between 81% and 100% of patients persisted with bisphosphonates in the first year of treatment, with lower rates of persistence of between 51% and 89% in the third year of treatment (eight RCTs).
A prescription-event monitoring study of patients for whom alendronate was prescribed (n = 11,916) by GPs in England indicated that 24% discontinued treatment within 1 year. In a similar study of patients for whom risedronate was prescribed (n = 11,742) in primary care in England, 30% appeared to have discontinued treatment within 6 months. In another 12 studies reviewed, persistence at 1 year ranged from 16% to 90%.
Paid claims data from the USA suggested that only 18% of women starting raloxifene treatment continued to take their medication uninterrupted, and an investigation of a pharmacy prescription database indicated that only 44% were continuing treatment at the end of year 2.
Compliance data were reported for two RCTs of strontium ranelate and were similar in the strontium ranelate and placebo arms (ranging from 83% to 93%) at up to 3 years.
## Acid-suppressive medication and fracture risk
Two cohort and two case–control studies reported on a potential relationship between acid-suppressive medication (proton pump inhibitors or histamine H2 receptor antagonists) and fracture risk. One of the case–control studies, which used the UK General Practice Research Database (GPRD), found that 1 year or more of acid-suppressive medication was associated with an increase in fracture risk. The other case–control study reported a reduction of fracture risk associated with use of histamine H2 receptor antagonists, and that use of other acid-suppressive medication might increase fracture risk. Both studies, however, were unable to demonstrate convincingly that fracture risk was independent of underlying disease that might determine differences in fracture risk.
A prospective cohort study excluded women taking medication for fracture prevention and reported an increase in non-vertebral fracture in those taking acid-suppressive medication compared with those who were not. Findings appeared similar for users of proton pump inhibitors or histamine H2 receptor antagonists, but differences in fracture risk were not statistically significant for those using proton pump inhibitors compared with those not using acid-suppressive medication. One large retrospective cohort study using the UK GPRD compared women taking acid-suppressive medication plus bisphosphonates with those taking bisphosphonates alone. This GPRD study reported an increase in fracture risk for some fracture sites with concomitant use of acid-suppressive medication and bisphosphonates, but a reduction in risk for other fracture sites. The information on patients included in this GPRD study was incomplete and details of adjustments for confounders were not reported. The two cohort studies were not fully published, and their analysis may have been prone to confounding.
## Additional submission from the manufacturer of strontium ranelate
Following the Court of Appeal Order of April 2010, NICE requested an additional submission from the manufacturer of strontium ranelate (Servier), setting out their views on the most appropriate estimate of strontium ranelate's efficacy in reducing the rate of hip fracture.
Servier explained that the pivotal phase III RCT (Treatment of Peripheral Osteoporosis Study ) was started before the increased regulatory emphasis on the prevention of hip fracture as a key measure of efficacy of treatments for osteoporosis (because of the significant morbidity associated with hip fracture). TROPOS had not been designed or powered to demonstrate the effect of strontium ranelate treatment on rates of hip fracture. In support of its application for regulatory approval of strontium ranelate, Servier was therefore asked by the European Medicines Agency (EMA) to investigate the efficacy of strontium ranelate in reducing the rate of hip fracture in a post-hoc subgroup analysis of TROPOS participants who met the definition of established osteoporosis (that is, a BMD T-score of −2.5 or below and one or more associated fractures). Instead of the requested subgroup, Servier provided the EMA with data for a different subgroup of trial participants whom they identified as being at high risk for hip fracture. This subgroup comprised women aged 74 or older who had a femoral T-score of −2.4 or below. This subgroup represented 42% of TROPOS participants and had an RR of hip fracture of 0.64 (95% CI 0.412 to 0.997).
Servier described the method used to identify this high-risk subgroup. The placebo arms of two RCTs (TROPOS and another trial designed to assess the efficacy of strontium ranelate in reducing vertebral fractures, Spinal Osteoporosis Therapeutic Intervention ) were pooled and the influence on fracture rates of three of the main risk factors for fragility fracture – age, BMD and prior fracture – was explored. Servier found that, in the pooled placebo arms of these two RCTs, prior fracture had no effect on the rate of hip fracture, so this factor was not considered further. To select an age group in which the risk of hip fracture was elevated, Servier investigated various possible age cut-offs, and identified the age at which the difference in the rate of hip fracture between women older and younger than the cut-off was greatest. This process led to the selection of an age cut-off of 74 years. Servier stated that this cut-off was consistent with epidemiological data, in particular a study by Donaldson et al. (1990), which Servier interpreted as showing a rising rate of hip fracture among women in the general population above the age of 74. The selected BMD cut-off was closely aligned to the WHO definition of osteoporosis (a T-score of −2.5 SD or below; see section 2.3). Servier emphasised that, having identified factors related to a high risk of hip fracture by screening the pooled data from the placebo arms of two RCTs, a single post-hoc analysis of the effect of strontium ranelate in this subgroup had been performed, without the need for multiple exploratory analyses of fracture risk reduction adopting different criteria for the subgroup selection.
After Servier had submitted data on efficacy in its chosen subgroup to the EMA, the EMA requested further analyses to confirm the effect of strontium ranelate on the rate of hip fracture. Servier provided additional evidence, including data from longer follow-up periods and analyses of trial participants with demonstrated compliance to treatment. Servier indicated that this additional evidence supported the view that an RR of 0.64 is a valid estimate of the efficacy of strontium ranelate in reducing the rate of hip fracture.
In their additional submission to NICE following the Court of Appeal Order in April 2010, Servier also suggested a hypothesis for a possible increased effect of strontium ranelate in older women: most osteoporosis drugs work by reducing the loss of existing bone, but strontium ranelate also stimulates the creation of new bone. Because the creation of new bone is increasingly impaired as women age, Servier stated that it is possible that strontium ranelate is able to provide additional benefit to older women.
Servier argued that the RR of 0.64 derived from the post-hoc analysis of the high-risk subgroup should be used in cost-effectiveness analyses to quantify the effect of strontium ranelate in reducing the rate of hip fracture because, in its view, it represents a more robust estimate of efficacy than the RR for the whole trial population. Servier stated that, unlike the analysis of the whole trial population, the subgroup analysis was suitably powered to demonstrate the effect of strontium ranelate in reducing the rate of hip fracture. Because of this, in Servier's opinion, the estimate was statistically robust.
Servier's view was that the estimate derived from the high-risk subgroup could be assumed to apply to all women taking strontium ranelate, but it acknowledged issues surrounding extrapolation from the high-risk subgroup to a broader population. Servier therefore indicated that it might also be concluded that the RR of 0.64 could only be applied to a population corresponding to the high-risk subgroup.
## Review of Servier's additional submission by the Decision Support Unit
The DSU was commissioned to review Servier's additional submission, and to comment on the scientific validity of the post-hoc subgroup analysis provided by Servier. The DSU advised that any set of data will show some variation in response to treatment across different subgroups simply by chance. The DSU explained that, because of this, the correct statistical procedure for establishing a subgroup of trial participants with a significantly different response to treatment is via a test for interaction (that is, a formal test, using regression methods, of the hypothesis that the effect is different in one group of participants from that observed in the rest of the trial population). The DSU noted that no such test had been reported by Servier.
The DSU stated that the method used by Servier to identify the high-risk subgroup (see section 4.1.39) was logically likely to yield an unduly large relative effect, and the DSU stated that this would lead to a biased estimate of RR. This was because the method used to identify the age cut-off to define the subgroup was 'data-dependent' – that is, most of the data that were used to define the subgroup (the rate of hip fracture in the placebo arm of TROPOS) were also used to estimate the efficacy of strontium ranelate in the selected subgroup. In this way, the rate of hip fracture in the placebo group was certain to be high, relative to other potential age cut-offs, with no guarantee that this was also the case in the strontium ranelate group. Therefore, the DSU stated that the estimate of RR derived from the subgroup was likely to be artificially inflated.
The DSU also noted that, whilst Servier indicated that there were epidemiological data to support the chosen age cut-off (see section 4.1.39), the study by Donaldson et al. (1990) suggested that the rate of hip fracture rises to a notable level after 75 years of age, not 74.
The DSU advised that Servier's argument of enhanced statistical power in the subgroup analysis was incorrect. The DSU explained that, in an analysis of RR, statistical power is dependent on the number of events (in this case, hip fractures) and that choosing a smaller group of participants will tend to reduce, rather than increase, power unless the RR is markedly greater in that subgroup. Because of this, the DSU disagreed with Servier's claim that the subgroup analysis was 'fully powered'.
The DSU was asked to comment on the most appropriate approach, from a statistical viewpoint, to the use of data from the whole trial population of TROPOS and the high-risk subgroup, in determining the relative efficacy of strontium ranelate. The DSU responded that, if the relative effect were to be applied to women in the general population, an intention-to-treat analysis of all randomised trial participants would yield the most appropriate estimate of efficacy. The DSU also commented that, if more than one trial is available, a pooled analysis of RRs from the intention-to-treat data of all relevant trials would be preferable. A meta-analysis of the data from SOTI and TROPOS would have provided the most appropriate overall measure of efficacy.
The DSU also advised that even as an estimate of efficacy in the high-risk subgroup, the RR of 0.64 was likely to be too extreme because of the likelihood of selection bias arising from the way in which the subgroup had been identified (see section 4.1.45). The DSU also emphasised that, to estimate the cost effectiveness of strontium ranelate in a particular subgroup, it would not be sufficient simply to adopt an RR of hip fracture from that group. It would also be important to populate the rest of the economic decision model with evidence specific to the subgroup in question.
NICE invited Servier to respond to the DSU's report. Servier provided a document reiterating its previous views that the subgroup analysis performed to evaluate the efficacy of strontium ranelate in reducing the rate of hip fracture was based on sound scientific principles and valid statistical methods. Servier did not respond to other specific issues raised in the DSU report.
# Cost effectiveness
## Manufacturers' models
For proprietary alendronate, compared with no treatment, the manufacturer's model provided an incremental cost-effectiveness ratio (ICER) of £8622 per quality-adjusted life year (QALY) gained for 70-year-old women with a T-score below −2.5 SD. The manufacturer's results were more favourable than the results of Assessment Group's 2003 model. This could be because the manufacturer's model was not adjusted for baseline fracture prevalence, or because it used different utilities for vertebral fractures, different efficacy data, different risk groups and a longer time horizon.
For etidronate, compared with no treatment, the manufacturer's model provided an ICER of £18,634 per QALY gained for 70-year-old women with a T-score below −2.5 SD. The manufacturer's model included morphometric vertebral fractures and corticosteroid use as risk factors for further fractures. It is unclear whether the manufacturer's ICER was for women with or without a prior osteoporotic fragility fracture.
For risedronate, compared with no treatment, the manufacturer provided data from two models. The ICER derived from the manufacturer's own model was £577 per QALY gained for women aged 74 years. In the second model provided by the manufacturer, which was commissioned from an external body, the ICER was more than £35,000 per QALY gained for all women without a prior osteoporotic fragility fracture and with a T-score of −2.5 SD. However, for women at slightly higher risk of fracture and aged 70 years or older, the corresponding ICER was £13,500 per QALY gained or less. The ICER calculated using the manufacturer's own model was difficult to verify from the information given. The ICERs generated by the second model were more consistent with the figures provided by the Assessment Group's 2003 model, although they did differ somewhat. This may be because of different cost and RR inputs.
For raloxifene, compared with no treatment, the manufacturer provided data for different age groups and different risk levels. All of the analyses included the breast cancer benefits. It was not clear how the different risk levels were defined. The ICERs ranged from £12,000 to £22,000 per QALY gained, and were more favourable than the Assessment Group's 2003 analysis, even when the Assessment Group included the breast cancer benefits. In the Assessment Group's 2003 model, the RR for the breast cancer effect was higher (0.38) than the RR for invasive breast cancer used in the manufacturer's model (0.28), and the breast cancer risk was adjusted for the association between low BMD and decreased risk of breast cancer. Additionally, the manufacturer's model was not adjusted for baseline fracture prevalence, and included different utilities for vertebral fractures, different efficacy data, different risk groups, and a longer time horizon than the Assessment Group's model.
For strontium ranelate, compared with no treatment, the manufacturer provided a model developed by an external organisation. The ICER was £45,028 per QALY gained for 65-year-old women with a T-score of −2.5 SD and £26,686 per QALY gained for 80-year-old women with a T-score of −2.5 SD. The manufacturer's results were more favourable than the Assessment Group's 2005 results because different modelling assumptions were used. For example, fewer health-state transition possibilities were incorporated. Compared with the Assessment Group's model, the manufacturer's model used more favourable efficacy data for hip fracture from the post-hoc 'high-risk' subgroup of women (see sections 4.1.28 and 4.1.38 to 4.1.43), and slightly more favourable efficacy data for wrist and proximal humerus fracture. Higher hip-fracture costs were used in the manufacturer's model.
## The Assessment Group's model
The Assessment Group provided a cost–utility model with two components (described in detail in the 2005 Strontium Ranelate Assessment Report). As a first step, the model calculated absolute fracture risk from the epidemiological literature on a number of independent clinical risk factors. These data were prepared under the auspices of the WHO and were provided for this appraisal under an academic-in-confidence agreement. As a second step, the model applied RR reductions for fracture taken from the meta-analysis described in section 4.1.22. A single estimate of efficacy was used for alendronate and risedronate based on pooled data for these two drugs. Following advice from the original Osteoporosis Guideline Development Group, it was assumed that RRs remained constant across all ages, T-scores and fracture status. The most recent analyses carried out by ScHARR were based on the price of non-proprietary alendronate in February 2008 (£53.56 per year for once-weekly 70 mg tablets; £108.20 per year for daily 10 mg tablets).
All osteoporotic fragility fractures in women aged 50 years or older were included in the modelling. The RR for hip fracture was assumed to apply also to pelvis and other femoral fractures. The RR for non-vertebral fracture was assumed to apply also to proximal humerus, rib, sternum, scapula, tibia, fibula and wrist fractures. Where confidence intervals for RRs spanned unity, it was assumed that there was no effect of treatment, except in the case of strontium ranelate. In this case, an RR of 0.85 for hip fracture was used to acknowledge the effect reported in the high-risk subgroup of the study. The model used UK-specific epidemiological data on femoral neck BMD.
The model assumed an initial utility in the year of fracture and a higher utility in subsequent years. The time horizon for predicting morbidity was 10 years, consisting of 5 years of treatment with sustained efficacy plus 5 years of linear decline to no effect. However, treatment-related decreases in mortality rate extended beyond the 10-year time horizon. For this, the life expectancy for a woman at the threshold T-score for osteoporosis was calculated from standard life tables, and any increase in mortality rate due to fracture would continue until death or an age of 110 years. In the base case, vertebral-fracture utility was assumed to be lower than hip-fracture utility, and a sensitivity analysis was carried out in which the utility for vertebral fracture was assumed to be the same as that for hip fracture. The percentage of women assumed to move from community living to a nursing home following a hip fracture increased with increasing age. An age-dependent gradient of hip-fracture risk was used, and an association between vertebral or proximal humerus fracture and increased mortality in women with osteoporosis was included. No follow-up BMD scans were included in the model; this reflects current clinical practice in the UK.
The model included an assumption about the costs and disutility associated with treatment-related side effects for all drugs, based on the findings of prescription-event monitoring studies in patients treated with alendronate. For the base case, the model assumed 50% persistence with treatment. In addition to the base case, the Assessment Group undertook a number of sensitivity analyses using alternative assumptions, including: persistence with treatment (25% or 75% at 5 years); reduction in the efficacy of the drugs at reducing the risk of fracture associated with risk factors other than age, prior fracture and low BMD to 0% or 50% (with a consequent upward adjustment of the RR for the risk factors of age, prior fracture and low BMD); disutility of vertebral fracture; updated fracture costs; and the disutility and costs of treatment-related side effects. It was assumed that women who experience bisphosphonate-related side effects had 91% of the utility of women who do not have such side effects. In the base case analysis for all of the drugs under consideration this was applied to 2.35% of women in the first treatment month and 0.35% of women thereafter and, in sensitivity analyses for bisphosphonates, to 24% of women in the first treatment month and 3.5% of women thereafter. In the case of strontium ranelate, the effect on VTE was not included in the model. Discount rates of 6% per year for costs and 1.5% per year for health benefits were applied, in accordance with NICE methods relevant to this appraisal.
For raloxifene, 4-year follow-up data from the MORE study were used, and it was assumed that women with low BMD have a lower breast cancer risk than women with normal BMD. The cost effectiveness was modelled excluding the breast cancer benefit, the risk of VTE and the effect on cardiovascular events.
The independent clinical risk factors for fracture used in the model were based on the data prepared under the auspices of the WHO (see section 4.2.6) and included BMI, prior fracture, previous or current use of corticosteroids, parental history of fracture, current smoking, alcohol intake of more than 2 units per day, and rheumatoid arthritis. The study provided prevalence data for the different risk factors, and risk ratios for hip fracture and osteoporotic fracture for each risk factor, including T-score and age. Using these risk ratios, absolute risk of fracture was calculated.
The estimates of cost effectiveness were generated for different levels of absolute risk derived from a large number of combinations of T-score (in bands 0.5 SD wide), age and number of independent clinical risk factors for fracture. For practical reasons relating to the number of potential combinations, single-point RRs of fracture, calculated from the log-normal efficacy distributions, were used in the model. Results were presented for population groups categorised according to age, T-score and number of independent clinical risk factors.
As women without fracture do not usually present to clinicians, the Assessment Group also estimated the impact that the costs of identifying women at risk would have on the cost effectiveness of the drugs. This required both a calculation of the ICER for treatment, and a calculation of the distribution of risk assessment cost over the population who would benefit from treatment. A net-benefit approach was used to do this. The net-benefit approach is analogous to the more traditional cost per QALY gained approach, but also requires a value of willingness to pay (WTP) for an additional QALY gained. For the calculation of the net benefit of an intervention, the WTP is first multiplied by the incremental QALY gained associated with the intervention, then the incremental cost associated with the intervention is subtracted. For this appraisal, the total net benefit for each age group and DXA scanning approach was calculated by subtracting the cost of DXA scanning from the net benefit of treating all women who can be treated cost effectively.
A stepped net-benefit approach was used to estimate, in reverse order, the cost effectiveness of risk assessment, DXA scanning and treatment of women without a prior fracture. A WTP value of £20,000 per QALY gained was applied in the modelling.
Step 1. ICERs for treatment versus no treatment were calculated for each intervention for various combinations of age, T-score and number of independent clinical risk factors for fracture (see section 4.2.11). The net benefit of treatment per woman was calculated using the following formula: Net benefit = (£20,000 × incremental QALYs gained) – incremental costs. For women for whom the ICER for treatment was more than £20,000 per QALY gained, the net benefit was set to zero.
Step 2. The net benefit per woman was multiplied by the number of women in the population estimated to fall within each combination of age, T-score and number of independent clinical risk factors for fracture (based on the data used to develop the algorithm prepared for the WHO). The net benefits for each group were then added together to give a total net benefit of treatment for women with no, one, two or three independent clinical risk factors within each age group.
Step 3. The cost of DXA scanning all of the women in each age/independent clinical risk factor group was subtracted from the net benefit of treatment for that group (calculated as described in step 2). This provides the net benefit of treatment and DXA scanning for the group, assuming that the number of independent clinical risk factors is known. A positive net benefit indicates that DXA scanning of women in that age/independent clinical risk factor group and treating those groups of women in whom the ICER for treatment is £20,000 per QALY gained or less provides an ICER for the entire strategy of less than £20,000 per QALY gained.
Step 4. When the resulting values of net benefit of treatment and scanning were negative they were set to zero. For each age group, the total net benefit of scanning and treatment was calculated by adding together the net benefits for each age/independent clinical risk factor group. The cost of opportunistic assessment for all women in this age group was then subtracted to give the net benefit of risk assessment, scanning and treatment. A positive net benefit indicates an ICER of less than £20,000 per QALY gained for risk assessment, DXA scanning and treating women (at a specific T-score related to the ICER for treatment only) of that particular group. Cost per QALY gained data were presented for each strategy.
First, the Assessment Group calculated ICERs (cost per QALY gained for alendronate compared with no treatment) without identification costs for all combinations of age, T-score and number of independent clinical risk factors for fracture. The cost per QALY gained, compared with no treatment, became more favourable with increasing age and number of independent clinical risk factors, and decreasing T-score (that is, with increasing annual absolute risk of fracture).
Then, the Assessment Group presented the results of the economic analyses in the form of identification and treatment strategies (based on age, T-score and number of independent clinical risk factors for fracture) that resulted in an ICER of £20,000 or less (cost per QALY gained compared with no treatment). The analyses shown below included the following assumptions: persistence at 5 years set to 50%; the efficacy of bisphosphonates on fracture risks associated with factors other than age, BMD and prior fracture status set to 50% of that observed for the total population in the trials (with a consequent upward adjustment of the RR associated with age, BMD and prior fracture); costs set to health resource group values including home-help costs; utility multiplier associated with vertebral fracture set to 0.792 in the first year of fracture and 0.909 in subsequent years (as for hip fracture); costs of bisphosphonate-related gastrointestinal symptoms incurred over 5 years; utility multiplier associated with bisphosphonate-related gastrointestinal symptoms set to 0.91 (included utility losses for non-compliant patients); and alendronate at a cost of £53.56 or £108.20 per year.
For alendronate priced at £53.56 per year (once-weekly treatment), and when assuming that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:
A strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 65 years resulted in an ICER of more than £20,000 per QALY gained.
A strategy of risk assessment, DXA scanning and treatment with alendronate in women who are confirmed to have osteoporosis (that is, a T-score of −2.5 SD or below) resulted in an ICER of less than £20,000 per QALY gained for all women aged 70 years or older, and for women aged 65–69 years who have an independent clinical risk factor for fracture.
In a sensitivity analysis for alendronate priced at £53.56 per year (with other assumptions as in sections 4.2.16 and 4.2.17), acid-suppressive medication was assumed to affect fracture risk. The data inputs for this were taken from one GPRD study (see section 4.1.35) and represent the midpoint values pooled for patients using acid-suppressive medication. This sensitivity analysis produced the following results:
A strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 70 years resulted in an ICER of more than £20,000 per QALY gained.
A strategy of risk assessment, DXA scanning and treatment with alendronate in women who are confirmed to have osteoporosis (that is, a T-score of −2.5 SD or below) resulted in an ICER of less than £20,000 per QALY gained for all women aged 70 years or older. The ICER for treatment with alendronate (but excluding identification costs) for a woman aged 70–74 years with a T-score of −2.5 SD (using the assumptions described in sections 4.2.16 and 4.2.17) was £5496 per QALY gained without acid-suppressive medication and £13,236 per QALY gained with acid-suppressive medication. If this woman has an independent clinical risk factor for fracture, the ICERs would be £1567 per QALY gained without and £7727 per QALY gained with acid-suppressive medication.
For alendronate priced at £108.20 per year (daily treatment), and when assuming that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:
A strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 70 years resulted in an ICER of more than £20,000 per QALY gained.
A strategy of risk assessment, DXA scanning and treatment with alendronate in women who are confirmed to have osteoporosis (that is, a T-score of −2.5 SD or below) resulted in an ICER of less than £20,000 per QALY gained for all women aged 75 years or older and for women aged 70–74 years who have an independent clinical risk factor for fracture. For women aged 70–74 years but with no independent clinical risk factor, the T-score needs to be −3 SD or below to give an ICER of less than £20,000 per QALY gained.
Risedronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per year for alendronate); that is, these three drugs have a higher acquisition cost than alendronate, but are not more efficacious. Analyses were conducted as for alendronate (see section 4.2.16). For risedronate, base-case assumptions for bisphosphonate-related side effects were modelled; that is 2.35% of women in the first treatment month and 0.35% thereafter experienced side effects (see section 4.2.9). In addition a sensitivity analysis was performed, using the assumption that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects. For raloxifene and strontium ranelate, base-case assumptions for side effects were used. In previous economic modelling and before the most recent price reduction for non-proprietary alendronate, etidronate's cost effectiveness was comparable to that of non-proprietary alendronate, but the calculations were based on a weaker clinical evidence base than for alendronate. Therefore the modelling for etidronate was not updated after the most recent price reduction for alendronate.
For risedronate, raloxifene and strontium ranelate, additional analyses were conducted to explore identification and treatment strategies that could be cost effective for these interventions when compared with no intervention. All results showed less favourable cost effectiveness than non-proprietary alendronate. For example, for women aged 65–69 years with an independent clinical risk factor for fracture, the ICERs (without considering costs related to risk assessment and DXA scanning) for risedronate and strontium ranelate (each compared with no treatment) were more than £45,000 and £90,000 per QALY gained, respectively. For these women, treatment with weekly non-proprietary alendronate, including risk assessment and DXA scanning costs, resulted in an ICER of less than £20,000 per QALY gained.
Further analyses were carried out assuming second-line use; that is, costs for risk assessment or DXA scanning were excluded because BMD was assumed to be known from the first-line management.
In the economic modelling carried out for this appraisal in 2006, lower ages and higher T-scores resulted in ICERs of less than £20,000 per QALY gained for etidronate compared with risedronate; that is, etidronate was more cost effective than risedronate. Because of the concerns expressed about the weaker clinical evidence base for etidronate, the modelling for this bisphosphonate was not updated.
For risedronate in second-line use, when assuming that 2.35% of women in the first treatment month and 0.35% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:
Treatment with risedronate in women younger than 65 years resulted in an ICER of more than £20,000 per QALY gained.
Treatment with risedronate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £20,000 per QALY gained. Including women aged 65–69 years with no independent clinical risk factors for fracture increased the ICER to more than £20,000 per QALY gained.
T-scores (SD) at (or below) which risedronate in second-line use resulted in an ICER of less than £20,000 per QALY gained
Age (years)
Number of independent clinical risk factors for fracture (section 1.5)
– a
-r older
−2.0b
a ICER more than £20,000 per QALY gained.
b Women with osteopenia are not included in the guidance (see sections 1 and 4.3.6).
For raloxifene, the model produced the following results.
Treatment with raloxifene in women of any age resulted in an ICER of more than £20,000 per QALY gained.
For strontium ranelate, the model produced the following results.
Treatment with strontium ranelate in women younger than 65 years resulted in an ICER of more than £20,000 per QALY gained.
Treatment with strontium ranelate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £20,000 per QALY gained. Including women aged 65–69 years with no independent clinical risk factors for fracture increased the ICER to more than £20,000 per QALY gained.
T-scores (SD) at (or below) which strontium ranelate in second-line use resulted in an ICER of less than £20,000 per QALY gained
Age (years)
Number of independent clinical risk factors for fracture (section 1.5)
– a
-r older
a ICER more than £20,000 per QALY gained
If it was assumed that acid-suppressive medication affects fracture risk, the ICER for treatment with risedronate (compared with no treatment, but excluding identification costs) for a woman aged 75 years with a T-score of −3 SD increased from £16,374 to £23,351 per QALY gained (using base-case assumptions about side effects). The corresponding ICER for strontium ranelate was £37,880 per QALY gained compared with no treatment (using base-case assumptions about side effects). For a woman aged 75 years with a T-score of −3.5 SD and one independent clinical risk factor for fracture, the ICER for risedronate increased from £5116 to £10,505 per QALY gained when acid-suppressive medication was assumed to affect fracture risk (using base-case assumptions about side effects). The corresponding ICER for strontium ranelate was £20,935 per QALY gained compared with no treatment (using base-case assumptions about side effects).
## Consultee comments on the Assessment Group's economic model
Following the outcome of the judicial review and the court ruling of March 2009, NICE was able to offer the Assessment Group's executable economic model for consultation. Consultees and commentators who requested the model and returned the necessary confidentiality undertakings received a CD-ROM containing the executable version of the economic model, a document with instructions for running the model and a pro-forma for commenting on the model. Comments on the Assessment Group's model were received from Servier Laboratories (the manufacturer of strontium ranelate), the Bone Research Society (BRS), the National Osteoporosis Society (NOS) and the Society for Endocrinology. Comments received from each of these consultees are summarised in the sections below.
These four consultees expressed the view that the documentation provided with the Assessment Group's model was insufficient, that the model supplied to them was incomplete and that some inputs could not be altered. They also stated that the application of the fracture risk algorithm developed under the auspices of the WHO could not be assessed. They felt that the model could not be validated and that its validity had not been demonstrated in documents made available during development of the guidance.
Servier commented that the fracture risks entered in the Assessment Group's model differed from estimates that Servier calculated using the FRAX fracture risk calculation tool (see section 4.3.47 for further information about the FRAX tool). Servier commented that mortality risk associated with clinical risk factors had been omitted from the model. In Servier's opinion, these differences called into question whether the WHO fracture risk algorithm had been applied correctly in the Assessment Group's model.
Other comments questioned the use of a fixed value for BMI in the model. Consultees commented that no clear explanation was provided of the rationale for the choice of BMI value, that a range of BMI values should have been used, and that the use of a fixed BMI value resulted in underestimation of the cost effectiveness of treatment for some women at risk of fracture.
Servier commented on the selection and weighting of the independent clinical risk factors for fracture used in the Assessment Group's model. Servier, BRS and NOS suggested that the risk associated with alcohol intake was incorrect in the model and that this would have adversely affected estimation of the cost effectiveness of treatment for women at risk of fracture. They suggested that a threshold alcohol intake of 3 or more units per day, as used in the FRAX fracture risk calculation tool, should have been applied. They also stated that the Assessment Group's model and the guidance were inconsistent with each other, and that these differences resulted in the risk of fracture being underestimated in the model. Servier also noted that the Assessment Group's model gave an equal weighting to each of the independent clinical risk factors for fracture. Servier suggested that this was a less precise approach than that used in the FRAX tool, which used different weightings (some higher and some lower than those in the Assessment Group's model) for each fracture risk for specific risk factors. Servier stated that the FRAX tool assesses fracture risk and cost effectiveness more accurately and 'deals more fairly' with variation between women at risk of fracture. Servier also noted that one of the risk multipliers for fracture risk included in the Assessment Group's model was not consistent with that given in the assessment report.
Servier and NOS noted that the Assessment Group's model had a time horizon limited to 10 years and criticised how mortality beyond 10 years had been taken into account in the economic evaluation. Servier expressed the view that, as a consequence of this, the model was inaccurate and underestimated the cost effectiveness of treatment for women at risk of fracture. Servier also identified two values ('wristbonusat2.5' and 'phbonusat2.5', related to QALY calculations) that were included in the model, but not described in assessment reports.
Servier commented that using the same disutility for side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates.
BRS and NOS thought that the proportion of women with low BMD in England and Wales was substantially underestimated in the Assessment Group's model. These consultees were also concerned that although both smoking and previous or current glucocorticoid (corticosteroid) use had been included as additional independent clinical risk factors for fracture in the Assessment Group's model, they were not defined as risk factors in the recommendations (see section 1.5). In addition, both consultees thought that interactions between several clinical risk factors were not incorporated in the model, thereby reducing the cost effectiveness of treatment for women at risk of fracture, especially younger women.
All four consultees commented on elements of the Assessment Group's economic evaluation that had been considered and agreed by the Appraisal Committee before it directed the Assessment Group to develop the economic model using specific assumptions. These Committee-directed assumptions included the compliance rate, costs associated with fracture, utility values used for vertebral fracture, and the strategy for identifying women at high risk. Servier also commented on the discount rates used in the model.
Servier reported that it had prepared a 'comparative' model which was run using assumptions similar to those in the Assessment Group's model. This model was referred to in a report to support the mathematical foundation of revised analyses discussed as part of Servier's comments on the Assessment Group's model. This report was made available to the Appraisal Committee to inform its consideration of comments by Servier on the DSU report (see below and section 4.3).
## Decision Support Unit (DSU) report on consultee comments on the Assessment Group's economic model
The DSU was commissioned to review the comments from consultees on the Assessment Group's executable economic model and report to the Appraisal Committee. The DSU considered issues that were relevant to the economic model. Key issues were grouped under the common themes of model transparency and ability to assess its validity, methodology (approach) and model inputs.
The DSU assessed comments on the transparency and validity of the Assessment Group's model. With regard to the consultees' observation that some model inputs were fixed and that in their view the model provided for consultation was incomplete and not fully executable, the DSU confirmed that certain inputs were intentionally fixed and the ability to alter these inputs was not a feature of the model or necessary for some parameters with minimal uncertainty that are commonly fixed in other economic models. In response to comments on the consultees' inability to assess the application of the WHO algorithm, the DSU explained that the WHO algorithm itself was not embedded within the model. The DSU confirmed that absolute fracture risks were correctly calculated using the WHO algorithm before being entered into the model. The DSU noted that documentation had been provided to consultees in the form of publicly available reports and peer-reviewed manuscripts produced by the Assessment Group, and that instructions on the operation of the Assessment Group's model were also offered to consultees and commentators.
With regard to comments on the modelling approach adopted in the Assessment Group's model, the DSU responded by confirming that alcohol consumption of more than 2 units per day was included in the model, and that the coefficients used in the model were consistent with the WHO algorithm (as supplied to the Assessment Group at the time the model was developed). The DSU also explored how the model considered corticosteroid-related fracture risk, and confirmed that corticosteroid use was included in the model and that the coefficient used for this risk factor was consistent with that calculated using the WHO algorithm. The DSU noted that the fracture risk of women using corticosteroids would have contributed to the overall fracture risk of the whole modelled population and thereby reduced the ICER associated with the treatment of all women at risk of fracture.
The DSU confirmed that each clinical risk factor for fracture was given equal weighting in the model. In response to consultee comments expressing the view that this was a less precise approach than that used in the FRAX tool, the DSU noted two points. Firstly, no individual risk calculation tool was publicly available when the model was developed. Secondly, the DSU referred to the 2005 Strontium Ranelate Assessment Report, which compared suggested treatment thresholds (combinations of age, T-score and number of independent clinical risk factors for fracture) from the Assessment Group's model with treatment thresholds indicated by absolute fracture risk. The DSU suggested that the use of absolute fracture risk alone did not accurately predict cost effectiveness, and therefore would not provide a robust basis for the Committee's decision-making.
Consultee comments on the modelling approach also addressed the time horizon and population data used and the grouping of age in 5-year bands. The DSU confirmed that the consequences of fracture were considered beyond 10 years, and provided further explanation of the modelling approach. The DSU additionally undertook exploratory analyses of the impact of mortality after the 10-year time horizon and of incorporating mortality associated with vertebral fracture and proximal humerus fracture. They reported that the change in the results produced by the model was minimal when mortality risk beyond 10 years was doubled. The DSU also confirmed that UK epidemiological data from a study by Holt et al. were used in the Assessment Group's model, and undertook an exploratory analysis around the assumptions of the distribution of T-scores used in the model. For some age bands modelled, the T‑scores did not follow a statistically normal distribution, but the DSU noted that the assumption of a normal distribution made it more likely that treatments for women at risk of fracture would be judged to be cost effective. The DSU considered a comment on the calculation of cost-effectiveness estimates averaged for the 5-year age bands implemented in the model. It disagreed with the alternative suggested by the consultee and noted that the Committee had considered and agreed that initial identification by age band was a workable strategy for selecting women at risk of fracture in clinical practice. It also noted that alternative strategies (which did not use age bands) may in fact be more resource-consuming and less likely to be judged as cost effective.
The DSU reviewed consultee comments on inputs used in the Assessment Group's model. It confirmed that the WHO algorithm (as supplied) had been correctly implemented in the model to produce estimates of fracture risk for each T-score band. The DSU suggested that the differences in the estimates of fracture risk obtained using the FRAX fracture risk calculation tool and the Assessment Group's model did not necessarily suggest that the WHO algorithm had been incorrectly applied (see section 4.3.47), and that these differences could occur for a number of reasons. For example, the use of a midpoint age to represent an age band of 5 years could lead to differences in estimates of fracture risk. The DSU confirmed that no increase in mortality associated with clinical risk factors was used in the model. The DSU suggested that inclusion of such mortality effects would be likely to increase the ICERs for women with those clinical risk factors. The DSU explained that this is because fewer QALY benefits would accrue in the model for women who die of causes related to risk factors. In response to a further comment from Servier, the DSU agreed that, for women without clinical risk factors, the inclusion of these mortality effects in the model may have the opposite effect (that is, a decrease in ICERs). Therefore the overall effect of including the increased mortality associated with clinical risk factors would be small.
The DSU also confirmed that a fixed value for BMI of 26 kg/m2 was used in the Assessment Group's model. This was the mean BMI in the UK epidemiological dataset from the Holt study used in the model. In an exploratory analysis using the WHO algorithm, the DSU showed that using a BMI of 26 kg/m2 resulted in higher estimated fracture risk than a BMI of 20 or 32 kg/m2 when BMD is known, and this was confirmed by the estimates supplied by one consultee. The DSU suggested that the BMI value used in the model may favour treatment of women at risk of fracture compared with alternative BMI values. The DSU also pointed out that BMI is a weak predictor of fracture when BMD is known (as specified in the identification strategy in the guidance).
The DSU investigated the risk multipliers used for fracture risk in the Assessment Group's model and the consultee comment that interactions between clinical risk factors had been omitted. It confirmed that the risk multipliers used for fracture risk had been correctly calculated from the WHO algorithm and that all interactions between risk factors had been included. The DSU also noted that the inconsistency between one of the risk multipliers for fracture risk included in the Assessment Group's model compared with the assessment report was the result of a typographical error. Accordingly there was no impact on the results of the model.
The DSU did not respond in detail to comments on assumptions in the model that had already been documented and agreed by the Appraisal Committee and which were available to consultees and commentators earlier in the development of the appraisal guidance. The DSU did, however, list these issues in its report and cited where they had been considered by the Committee or had been available for comment during development of the guidance. Features of the economic evaluation previously discussed and agreed by the Committee included the following (the sections of this document where these points are covered are given in parentheses):
discount rates used in model (4.2.9)
treatment compliance (4.2.9)
costs associated with fracture (4.2.16)
strategy for identifying women at high risk of fracture (4.2.16)
utility values used for vertebral fracture (4.2.16 and 4.3.12)
equal disutility for the side effects of strontium ranelate and bisphosphonates (4.2.9)
sensitivity analyses on disutility (4.3.14).
The DSU concluded that, in its view, adequate documentation on the Assessment Group's model had been provided for consultees. It highlighted that the WHO algorithm used to generate estimates of fracture risk was not integrated within the Assessment Group's model; rather, the fracture risks derived from the algorithm were entered into the model. Comparisons with fracture risks derived using the FRAX fracture risk calculation tool were made by several consultees on the basis that the WHO algorithm supplied to the Assessment Group and the FRAX tool are assumed to be identical. The DSU could not verify these analyses without access to the FRAX algorithm. The DSU agreed that some parameters in the Assessment Group's model were fixed. These included those with minimal uncertainty, as well as those that are commonly fixed in other economic models. Sensitivity analyses conducted by the DSU suggested that none of the consultees' suggestions relating to the modelling approach would lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The DSU concluded that, in its view, no issues raised by consultees would either affect the validity of the Assessment Group's model or raise significant doubts about the appropriateness of using the model to inform the deliberations of the Committee.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alendronate, etidronate, risedronate, raloxifene and strontium ranelate, having considered evidence on the nature of osteoporosis and the value placed on the benefits of these drugs by women with the condition, those who represent them, and clinical specialists. It also considered the consultation comments received in response to the previous appraisal consultation documents, the extra analysis undertaken by ScHARR in November 2006 and February 2008, and comments received from consultees and commentators after an appeal against an earlier final appraisal determination was upheld in December 2007. Following the outcome of a judicial review and court ruling in March 2009, the Committee considered the comments received from consultees after release of the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report. It also took into account the effective use of NHS resources. The Committee was aware of a previous decision of the National Screening Committee not to recommend screening to prevent osteoporotic fracture because of concerns about the accuracy of BMD assessment for the prediction of fracture and because there was no trial evidence indicating that such screening would reduce the incidence of fractures.
The Committee considered the clinical effectiveness data for the bisphosphonates (alendronate, etidronate and risedronate), strontium ranelate and raloxifene. It noted that all these drugs have proven efficacy in reducing the incidence of vertebral fragility fractures in women with osteoporosis, but that there were differences between the drugs in the degree of certainty that treatment results in a reduction in hip fracture (considered a crucial goal in osteoporosis management). In the case of alendronate and risedronate, the Committee accepted that there was sufficiently robust evidence to suggest a reduction in hip-fracture risk. The Committee noted that the available RCTs for etidronate were of insufficient size to show statistically significant reductions in hip-fracture risk, but that observational data lent support to a reduction in hip-fracture risk.
The Committee noted that strontium ranelate was effective in preventing vertebral and non-vertebral fractures, and the drug resulted in a non-significant 15% reduction in hip-fracture risk. The Committee was also aware of the result of a post-hoc subgroup analysis showing a statistically significant reduction in the incidence of hip fractures in women aged 74 or older who had a T-score of −2.4 SD or below.
The Committee noted that the evidence for raloxifene showed an effect on risk of vertebral fractures, but did not show an effect on risk of hip fractures. In addition, there was evidence for a beneficial side effect of raloxifene on the incidence of breast cancer.
The Committee did not consider it appropriate to make recommendations for the treatment of women on long-term corticosteroid treatment because this patient group is at greatly increased risk of fracture and therefore requires special consideration. The Committee was aware that for women without prior fracture but on corticosteroid treatment, the fracture risk is as high as, or even higher than, the fracture risk for women with a prior fracture. The Committee therefore felt that it would be disadvantageous for this group to be included in the current guidance.
Recommendations for the treatment of women with osteopenia (T-score of between –1 and –2.5 SD below peak BMD) were not made, for two reasons. Firstly, it was agreed after the scope was issued in 2002 that the outcome in this appraisal should be 'the prevention of osteoporotic fractures' and this has been understood by the Committee to be a fragility fracture experienced by women with osteoporosis, not osteopenia. Secondly, not all of the drugs under appraisal have a UK marketing authorisation for treatment of women with osteopenia.
## Cost-effectiveness modelling
Because women who have not had a fracture would not normally present to clinicians, the Committee considered it necessary to consider the costs involved in the assessment of fracture risk and of DXA scanning in its appraisal of the drugs for the primary prevention of osteoporotic fragility fractures.
The Committee acknowledged the efforts of the Assessment Group to build on the model used previously, particularly in using epidemiological data and a fracture risk algorithm developed under the auspices of the WHO to calculate transition probabilities and to model the identification approaches. The Committee noted that fracture risk is clearly related to age, low BMD and prior fracture. The Committee accepted that most of the independent clinical risk factors for fracture listed in section 4.2.11 are likely to be associated with an increased fracture risk. The Committee was not persuaded that 'current smoking' is a statistically significant risk factor in women, but noted that alcohol consumption of 4 or more units per day is a statistically significant risk factor. However, even for the statistically significant risk factors, the Committee was concerned that there was not sufficient evidence for a proven treatment effect on fracture risk related to risk factors other than low BMD, age and prior fracture.
With these caveats in mind, the Committee concluded that the Assessment Group's model was a useful basis for exploring the estimates of cost effectiveness; the model used data for a wide age range (age 50–75 years and older) and all osteoporotic fracture sites. Although the Assessment Group's model considered a shorter time period (10 years for predicting morbidity, see section 4.2.8) than the manufacturers' models, the Committee thought that this was appropriate considering the age groups involved and the uncertainties around health effects over a longer period.
The Committee discussed the assumptions underpinning the economic modelling undertaken by the Assessment Group. It noted that the most recent modelling explored some of the uncertainties identified by the Committee surrounding the results of the previous modelling; these related to the costs and disutility associated with treatment-related side effects and to non-compliance or non-persistence with treatment in a proportion of patients. The Committee also noted the effect of the recent price reductions for non-proprietary alendronate (70 mg weekly and 10 mg daily doses) on the cost effectiveness of the drug.
The Committee considered the base-case assumptions and those used in additional analyses. The Committee noted that the costs associated with fractures used in the base-case analysis were those used in the original assessment report developed in 2003 and considered that these were likely to be outdated. The Committee agreed that costs based on health resource groups, including home-help costs, were likely to provide the most accurate reflection of the cost of fractures to the NHS and personal social services, and it decided to incorporate these costs into the base-case analysis.
The Committee considered the utility multiplier used in the base-case analysis for the first year after a vertebral fracture and noted that it was based on a hospitalised patient group and not on a typical group of patients with vertebral fractures. Consequently it was considerably lower than the utility value modelled for a hip fracture. Although the Committee acknowledged that vertebral fracture can lead to greatly reduced quality of life, it considered that its true value would not greatly outweigh the utility decrement associated with a hip fracture. Therefore, the Committee considered it reasonable to assume that the disutility in the first year after a vertebral fracture was equivalent to the disutility in the first year after a hip fracture and decided to include this assumption in the base-case analysis.
The Committee was not persuaded that the drugs under consideration had been unequivocally shown to reduce fracture risk that was attributable to risk factors not mediated through low BMD and age. The Committee concluded that the uncertainty surrounding the efficacy of the drugs on risk factors not mediated through low BMD and age should be factored into its decision-making by using an analysis that assumed 50% efficacy of the drugs on fractures associated with risk factors other than age and low BMD. Although the Committee recognised that 50% was necessarily an arbitrary figure, the use of either 0% or 100% was considered both extreme and less plausible. In the analysis accepted by the Committee, the assumption of 50% efficacy of the drugs on fracture risk associated with other risk factors was adjusted by using a correspondingly greater efficacy of the drugs on fractures associated with the key independent clinical risk factors (age, BMD and prior fracture).
The Committee considered the assumptions used in the modelling for the side effects of bisphosphonates, in which women who experience bisphosphonate-related side effects had 91% of the utility of women who did not have such side effects. In the base case, this was applied to 2.35% of patients in the first treatment month and 0.35% of patients thereafter. Taking into account the persistence data (sections 4.1.31 and 4.1.32) and the comments received from consultees and commentators that about 25–30% of women experience gastrointestinal side effects when first taking a bisphosphonate, the Committee agreed that it was important to consider the results of a sensitivity analysis assuming that 24% of women were experiencing bisphosphonate-related side effects in the first treatment month and 3.5% of women thereafter.
The Committee acknowledged that the modelling of the identification strategies made assumptions necessary about the value of a QALY gained that could be considered an acceptable use of NHS resources. The Committee acknowledged this to be £20,000, as modelled, because there were no additional factors, as referred to in the 'Guide to the methods of technology appraisal' (see www.nice.org.uk), that could be considered to increase this value in this situation: that is, in primary prevention where an asymptomatic group of adult patients with a high number needed to treat to avoid a fracture is under consideration.
The Committee discussed a number of concerns surrounding other issues that were not represented in the model but which may have had an impact on the cost-effectiveness estimates. These included: possible long-term adverse effects of bisphosphonates on the formation of new bone; the probability that more GP time would be involved in identifying women with risk factors associated with osteoporosis; the likelihood that DXA scanning outside a clinical trial environment would not be as effective as in the clinical trials; and the possibility that the proportion of women who experience side effects may exceed the model's base-case assumptions. Finally, the Committee noted that current discount rates used by the Treasury, the Department of Health and NICE result in a cost-effectiveness calculation less favourable to the drugs than the discount rates used in the analysis considered by the Committee. Although a quantitative analysis of the uncertainties surrounding all these issues was not available, the Committee agreed that, for first-line treatment with a bisphosphonate, these uncertainties could be collectively approximated through the sensitivity analysis for side effects (see section 4.3.14). The Committee was persuaded, however, that the results of the sensitivity analysis need only apply to first-line treatment with a bisphosphonate, because many of the factors that led to the adoption of the sensitivity analysis did not apply for second-line treatment.
## Alendronate
The Committee considered the results of the economic model following the price reduction for non-proprietary alendronate, the newly included assumptions and the sensitivity analyses (see sections 4.3.8 to 4.3.14). The Committee agreed that, when considering the use of alendronate as a first-line treatment, the sensitivity analysis that captured the uncertainties in the economic model (see section 4.3.14) was the most appropriate. This led the Committee to conclude that alendronate (based on the price of £53.56 per year for once-weekly treatment) would be an appropriate use of NHS resources for the treatment of postmenopausal women who are confirmed to have osteoporosis (that is, a T-score of −2.5 SD or below) who are aged 65 years or older and who have at least one independent clinical risk factor for fracture. The Committee also concluded that, in addition, women aged 70 years and older could be considered for DXA scanning if there was an indication that they might have low BMD, and treated with alendronate if osteoporosis was confirmed. The Committee's reason for restricting DXA scanning for women aged 70 years or older (who visit their GP for any reason) to those with indicators of low BMD was to avoid unnecessarily scanning many women who are well and asymptomatic and who are relatively unlikely to have a low BMD. The Committee was advised by the clinical specialists from the original Guideline Development Group for the NICE clinical guideline on osteoporosis that, in women aged 75 years or older with two or more clinical risk factors, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible. This is because a very high proportion of these women would be likely to have a T-score of −2.5 SD or below.
Having reviewed the evidence on independent clinical risk factors for fracture and the views of the clinical specialists, the Committee agreed that the appropriate independent clinical risk factors for fracture are: parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee also concluded that there are indicators of low BMD, and these are low BMI (defined as less than 22 kg/m2) and medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause. The Committee acknowledged that rheumatoid arthritis is a condition that indicates low BMD, but was also proven to be an independent clinical risk factor for fracture. The Committee noted that prior fracture and long-term systemic corticosteroid use are also relevant clinical risk factors; women with prior fracture or who are on long-term systemic corticosteroid treatment will be considered in NICE technology appraisal guidance on the secondary prevention of osteoporosis.
The Committee noted that the prices of the different brands of alendronate vary greatly and concluded that alendronate should be prescribed on the basis of the lowest acquisition cost available.
The Committee considered postmenopausal women below the age of 65 years for whom opportunistic identification was not normally cost effective. The Committee recognised that a small number of postmenopausal women below the age of 65 years who present to healthcare practitioners with conditions that are indicators of low BMD are at high risk of osteoporotic fracture and would not need opportunistic identification. Therefore the Committee concluded that women under 65 years of age with rheumatoid arthritis, ankylosing spondylitis, Crohn's disease or any condition that has resulted in prolonged immobility, provided that they also have an independent clinical risk factor for fracture, should be considered for DXA scanning, and treated with alendronate if osteoporosis is confirmed.
## Considerations for the other drugs under appraisal
The Committee noted that risedronate, etidronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per year for alendronate); that is, these drugs have a higher acquisition cost than alendronate, but are not more efficacious. The Committee was also aware that, for women for whom weekly non-proprietary alendronate could be recommended based on cost effectiveness, the ICERs for risedronate and strontium ranelate were very high, even without inclusion of identification costs (see examples in section 4.2.21).
The Committee considered an approach where the higher costs of risedronate and strontium ranelate were incorporated into the analysis by combining costs based on the estimated use of alendronate, risedronate and strontium ranelate. However, the overall cost effectiveness of such a combined approach for fracture prevention would be less favourable than that of alendronate. As a consequence, some women who would be eligible for treatment with alendronate as recommended in section 1.1 would not be offered treatment using such a combined approach. For this reason, the Committee did not consider the combined approach to be appropriate.
The Committee considered treatment options available for a woman who is intolerant to alendronate or unable to comply with instructions for administration despite reasonable measures to support continuation of alendronate treatment. The Committee noted that all other treatment options have higher acquisition costs and/or different effectiveness profiles, which would reduce the cost effectiveness of preventive treatment if these drugs were used. The Committee observed that the identification costs associated with finding women who could be cost-effectively treated with one of the other drugs would be negligible, because they would have already undergone an assessment and had a DXA scan in order to be assessed for first-line treatment with alendronate. Therefore, it agreed that the recommendations for this situation should be based on the modelling that excluded identification costs. The Committee also agreed that, when considering second-line or subsequent treatment, the base-case assumptions for side effects could be applied; that is, a 0.91 utility multiplier should be applied to 2.35% of patients in the first treatment month and 0.35% of patients thereafter.
The Committee considered women who cannot take alendronate because of a contraindication or a disability that prevents them from complying with the instructions for administration. Because such a contraindication or disability would be known before the risk assessment, this would comprise a first-line treatment situation, where identification costs are included. Alternative drugs become cost effective at a higher age and lower BMD in a first-line treatment situation, compared with a second-line treatment situation where identification costs are not included. However, such an approach was considered inappropriate by the Committee because it would unfairly disadvantage women who cannot take alendronate because of a contraindication or a disability. Therefore the Committee concluded that women who cannot take alendronate for these reasons should have access to alternative drugs in the same way as women who cannot tolerate alendronate (that is second-line treatment, where the analysis excluded identification and assessment costs).
The Committee concluded that risedronate could be recommended for women who are unable to comply with the special instructions for the administration of alendronate, or have a contraindication to or are intolerant of alendronate, and who have a combination of T-score, age and number of independent clinical risk factors for fracture where treatment with risedronate resulted in an ICER of less than £20,000 per QALY gained without the consideration of identification costs, as outlined in sections 4.2.23–24. The Committee agreed that in women aged 75 years or older, where the T-score needed to make treatment cost-effective was −2.5 SD or below, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible (see section 4.3.17).
The Committee considered the cost effectiveness of etidronate, and noted that in previous modelling etidronate had a better cost-effectiveness profile than risedronate; since then there has been no change in the evidence base that would affect the relative position of these two drugs. In view of its concerns surrounding the clinical evidence base for etidronate, and taking into account the views of clinical specialists and consultees, the Committee decided that etidronate should not be recommended in preference to risedronate. However, the Committee agreed that guidance on the use of etidronate should be included in the recommendations, and concluded that etidronate can be recommended as an alternative treatment option for women who cannot take alendronate, as outlined for risedronate in section 4.3.25. In deciding between risedronate and etidronate, clinicians and patients need to balance the overall effectiveness profile of the drugs against their tolerability and adverse effects in individual patients.
Following the Court of Appeal Order of April 2010, the Committee considered the clinical and cost effectiveness of strontium ranelate, focusing on the most appropriate estimate for the efficacy in reducing the rate of hip fracture. The Committee considered the additional submission from Servier (see sections 4.1.37 to 4.1.43), a report by the DSU (see sections 4.1.44 to 4.1.49) reviewing this new submission and Servier's response to the DSU report (see section 4.1.50). At its meeting on 20 October 2010, the Committee heard from representatives of Servier and a representative of the DSU.
The Committee first considered whether it was plausible that strontium ranelate has a greater or lesser relative benefit in any subgroup of the population for which it has a marketing authorisation (that is, whether a different RR for hip fracture could be assumed to apply to some women). The Committee was aware of the advice received from the original Osteoporosis Guideline Development Group that drugs for osteoporosis have constant RR reductions irrespective of age, BMD and prior fracture status (see section 4.2.6).
The Committee noted the DSU's advice that the correct statistical procedure for investigating if a subgroup of trial participants has a significantly different response to treatment is a test for interaction (see section 4.1.44). No test for interaction had been undertaken for the high-risk subgroup from TROPOS. The Committee also noted that it had not received evidence of a differential benefit, supported by a test for interaction, in any subgroup of any trial of osteoporosis drugs.
The Committee noted Servier's view that an age cut-off of 74 years was justified by the epidemiological findings of Donaldson et al. (see section 4.1.39). It understood from the DSU that this paper suggests that the rate of hip fracture rises to a notable level after 75 years of age (see section 4.1.46). The Committee also noted that Donaldson et al. state that the absolute risk of hip fracture increases 'steadily' with age: although women are at greater risk of hip fracture as they grow older, there is no particular age at which the risk jumps from low to high. The Committee therefore concluded that Donaldson et al.'s study did not provide support for the use of a specific age cut-off of 74 years.
The Committee recognised the hypothesis advanced by Servier that there may be biological grounds for assuming an additional effect for strontium ranelate in older women (see section 4.1.41). However, it considered that it should be possible to demonstrate any such effect by statistical and biochemical tests, and it heard from Servier's representatives that no such evidence had been collected. The Committee concluded that a hypothesis alone, without supporting evidence, was insufficient to demonstrate a differential benefit for strontium ranelate in older women.
For these reasons, the Committee concluded that it could not justify discounting previous advice that drugs for osteoporosis are assumed to have the same relative effect regardless of age, BMD and prior fracture status. Therefore, it agreed that it was most appropriate for the cost-effectiveness model to rely on a single RR to quantify the effect of strontium ranelate in preventing hip fractures in all postmenopausal women with osteoporosis. As a result, the Committee did not concur with the view that it might choose to provide a specific recommendation only for women corresponding to the high-risk subgroup analysed by Servier, based on an assumption of differential effectiveness of strontium ranelate in those women.
The Committee then considered the value that represents the most appropriate estimate of effect (RR) for strontium ranelate in preventing hip fractures. It discussed Servier's view that the best estimate of effect for the whole population would be that observed in the high-risk subgroup – an RR of 0.64 (see section 4.1.42). The Committee emphasised that, in order to adopt this figure for the whole population, it would first need to be confident that it was a robust estimate of treatment effect. It discussed the process by which the high-risk subgroup had been selected by Servier. It noted that the pooled data from the placebo arms of TROPOS and SOTI had been screened to establish a subgroup at increased risk of hip fracture (see section 4.1.39). The Committee agreed with the DSU's advice that the method used to identify the age cut-off for the subgroup was 'data-dependent' and, therefore, the RR for strontium ranelate derived from this approach was likely to be inflated (see section 4.1.45).
The Committee also discussed whether it would be appropriate to use an RR derived from a subgroup of trial participants to quantify the effect of a drug in the whole population for which it has a marketing authorisation. It considered Servier's assertion that, in contrast to the whole trial population, the high-risk subgroup of TROPOS provided a statistically robust demonstration of the effect of strontium ranelate in preventing hip fractures (see section 4.1.42). It acknowledged that TROPOS did not include enough participants to demonstrate a statistically significant benefit for strontium ranelate in preventing hip fractures and that, because of this, it would be appropriate to consider using an estimate of effect that was more precise (that is, subject to less statistical uncertainty) than that derived from the whole trial population. The Committee accepted the DSU's advice that the precision of an RR is primarily influenced by the absolute number of observed events (in this case the absolute number of fractures), which would be greatest in the whole trial population. Additionally, it noted that the size of the groups – and, therefore, the rate of events – is important, so that, in theory, it is possible that an estimate of effect from a subgroup may be more statistically precise than the estimate from the whole trial population from which the subgroup is derived. However, in the case of TROPOS, the estimates from the subgroup and the whole trial population had 95% confidence intervals of very similar width. Therefore, the Committee did not accept that the RR in the subgroup was more precise than the RR in the whole trial population. As a result, the Committee concluded that there was no reason to assume that the subgroup analysis was any more statistically robust than the analysis of the whole trial population. The Committee also noted that it is incorrect to infer that one estimate is more accurate than another just because it achieved conventional standards of statistical significance whereas the other did not.
Taking all this into account, the Committee decided that it would not be appropriate to adopt an RR of 0.64 in assessing the cost effectiveness of strontium ranelate, because the method for the subgroup selection was likely to favour strontium ranelate, and because the RR derived in this way was no more precise that the RR from the overall population.
The Committee further noted that when values derived from subgroups have been considered in NICE technology appraisals, the evidence has been used to inform specific recommendations applying only to groups of people with the same characteristics as those in the trial subgroup. The Committee reiterated its conclusion that it had not received unambiguous evidence of differential benefit from strontium ranelate in any particular group (see sections 4.3.27 to 4.3.32). The Committee was aware that, in order to make recommendations for cost-effective treatment to prevent fractures in postmenopausal women with osteoporosis, it was necessary to consider separate populations defined by age, T-score and independent clinical risk factors. However, these populations are defined because the absolute likelihood of fracture increases in the presence of these risk factors and not because of variations in the relative benefit of treatment.
The Committee next considered the possibility of adopting an RR of 1.00 to quantify the effect of strontium ranelate in reducing hip fractures. It noted that the 95% confidence interval around the RR from the whole TROPOS population spanned unity (the upper limit was greater than 1). This means that, at the 95% confidence level, the observed results could from a statistical point of view be interpreted as being consistent with strontium ranelate having no effect. The Committee noted that, when the other drugs within this appraisal had been associated with RRs with 95% confidence intervals spanning 1, the model had assumed no effect (RR = 1.00). Therefore, it might be considered consistent to apply the same logic to the estimation of the effectiveness of strontium ranelate. However, the Committee heard the DSU's advice that it is important to base cost-effectiveness analysis on the most plausible estimate for each parameter, with associated uncertainty explored in sensitivity analysis. The Committee also agreed with the DSU's view that the available evidence suggests that strontium ranelate is effective in reducing the risk of hip fracture. For these reasons, the Committee concluded that it would be inappropriate to assume that strontium ranelate has no effect on the incidence of hip fractures, and rejected the use of an RR of 1.00 in the model.
Finally, the Committee discussed using an effect estimate of 0.85 – the RR of hip fracture observed in the whole TROPOS population. It noted the DSU's advice that, in the absence of a robust demonstration of differential benefit in one or more subgroup of a trial, it is most appropriate to rely on an intention-to-treat analysis of the whole trial population (see section 4.1.48). Having concluded that it had not seen evidence of a differential benefit for a specific subgroup in TROPOS, and having rejected the use of the alternative values 0.64 and 1.00 for the whole population, the Committee concluded it had no reason to depart from this principle. It therefore concluded that an RR of 0.85 represented the most appropriate estimate of effect for strontium ranelate in preventing hip fractures in postmenopausal women with osteoporosis. As a result, the Committee agreed that the Assessment Group had been correct to use an RR of 0.85 in its cost-effectiveness calculations to reflect the effect of strontium ranelate in reducing the rate of hip fractures (see section 4.2.7).
The Committee concluded that strontium ranelate can be recommended for women who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate, and who have a combination of T-score, age and number of independent clinical risk factors for fracture where treatment with strontium ranelate resulted in an ICER less than £20,000 per QALY gained without the consideration of identification costs, as outlined in section 4.2.26.
The Committee agreed a definition of alendronate, risedronate or etidronate intolerance as: persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment with alendronate or risedronate and that occurs even though the instructions for administration have been followed correctly.
The Committee discussed the reported benefits of raloxifene on breast cancer risk, and heard from the clinical specialists that the possibility of preventing vertebral fractures and breast cancer simultaneously could be attractive, particularly to younger postmenopausal women. The Committee also heard from the specialists that evidence on the effect of raloxifene in reducing cardiovascular risk is not considered to be robust and that there is some concern over the increased risk of VTE (see section 4.1.25).
The Committee noted that a higher proportion of the overall benefit associated with raloxifene was attributable to its effect on the prevention of breast cancer than to its effect on the prevention of osteoporotic fragility fractures. The Committee agreed that, in principle, the side effects of using a drug should be considered; however, there were a number of reasons why the Committee considered that the breast cancer benefit should not be the sole factor in deciding whether raloxifene is a cost-effective option for treatment for the primary prevention of osteoporotic fragility fractures, as follows:
From the evidence presented, raloxifene was not as effective as the bisphosphonates for treating osteoporosis.
Full assessment of raloxifene's effect on the prevention of breast cancer and its cost effectiveness in this indication would require consideration of how it compares with other drugs that could be used for breast cancer prevention.
The Committee noted that treatment with raloxifene did not result in an ICER of less than £20,000 per QALY gained in any age group, even when identification costs were excluded from the modelling. Therefore, the Committee did not consider raloxifene to be a cost-effective use of NHS resources for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
## Women who cannot take alendronate
The Committee carefully considered the position of women who cannot take alendronate because of a condition which either makes alendronate contraindicated or which prevents individuals from complying with the instructions for administration for alendronate. In doing so the Committee noted that at least some women in this patient group were likely to be 'disabled' as defined by the Disability Discrimination Act 1995. The Committee was aware of its duties under that Act to avoid unlawful discrimination, to have due regard to the need to promote equality of opportunity for disabled people, and the need to take steps to take account of disabled people's disabilities, as well as its broader legal duties to ensure that its guidance is fair and reasonable.
The Committee noted that the drugs other than alendronate are cost effective only for patients at higher risk of fracture than the risk levels at which alendronate is cost effective. If these other drugs are recommended for use by patients who cannot take alendronate only when those patients meet the criteria at which these alternative drugs become cost effective, these patients will not receive preventative treatment unless they are at higher risk of fracture than the risk levels at which alendronate is recommended. The Committee therefore considered whether, for women who cannot receive alendronate, the other drugs should be recommended at the same risk levels as alendronate (that is using the criteria established as being cost effective for alendronate) in order to provide access to preventative treatment for all patients with the same level of risk. The Committee reviewed the ICERs for risedronate and strontium ranelate within the criteria established to be cost effective for alendronate. The Committee noted that the prices for risedronate and strontium ranelate are approximately five to six times higher than the price for non-proprietary weekly alendronate, and that the ICERs for these drugs compared with no treatment were very high. For example, the ICER for strontium ranelate for women aged 65–69 years with an independent clinical risk factor for fracture was approximately £90,000 per QALY gained (see section 4.2.21). The Committee noted that strontium ranelate would be the most likely choice to be considered for women who are unable to comply with the instructions for administration of alendronate, because the instructions for administration of alendronate and risedronate are similar. The Committee took the view that recommending drugs other than alendronate using the same criteria as alendronate for women who cannot take alendronate would not be justified in this case because of the very high ICERs for the alternative drugs. In reaching this decision the Committee had regard to the fact that the impact of refusing the more favourable recommendation is that there is no generally recommended preventative treatment for a particular group of patients who are at the lower end of fracture risk for which treatment was considered, but that the alternative drugs are recommended when these patients are at higher risk of fracture.
The Committee considered that it is important to maximise the number of patients who are able to take alendronate. Some women will be unable to take alendronate in any circumstances because of contraindication, intolerance or inability to comply with the instructions for administration. However, some women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate would be able to receive the drug if they received assistance in taking it. The Committee concluded that all reasonable steps should be taken to provide women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate, with such practical support and assistance with administration (for example through district nurse visits or other home support services), as will enable them to take the drug.
## FRAX fracture risk calculation tool
The Committee was aware of the availability of the FRAX internet-based tool, which can be used to calculate a 10-year absolute risk of fracture, developed under the auspices of the WHO. This assessment tool was based on the same epidemiological data that were used in the Assessment Group's model. However, the Committee was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX. Firstly, the Committee did not agree that all clinical risk factors included in the WHO algorithm were appropriate (see sections 4.2.11 and 4.3.8). Secondly, the Committee was aware that absolute fracture risk is not directly related to cost effectiveness, as outlined in the 2005 Strontium Ranelate Assessment Report. This is because absolute fracture risk is the total for all fracture sites, but different fracture sites have different impacts on quality of life, costs and mortality. Therefore cost effectiveness is dependent on the contribution from each fracture site to the total fracture risk. Thirdly, the Committee had agreed that treatment benefit had not been proven for fracture risk associated with all independent clinical risk factors (section 4.3.8). Therefore, the Committee concluded that using a combination of T-score, age and number of independent clinical risk factors for fracture is more appropriate for defining treatment recommendations in this appraisal.
## Evidence on use of acid suppressive medication and fracture risk
The Committee was made aware of data indicating that acid-suppressive medication leads to a small increase in fracture risk and that co-administration of acid-suppressive medication and bisphosphonates may lead to an increased fracture risk compared with bisphosphonate administration alone. The Committee was not persuaded by this evidence; it noted that the data are observational and have not been reported in full, and are different for different fracture sites and for different acid suppressors. Furthermore, the Committee was informed, during consultation, of analyses showing that acid-suppressive medication given in addition to risedronate did not increase fracture risk. The Committee concluded that caution should be exercised when considering the evidence about co-prescription of acid-suppressive medication and bisphosphonates.
The Committee noted sensitivity analyses that included the assumption of an increase in fracture risk for women for whom acid-suppressive medications are co-prescribed (see section 4.2.18). The analysis for treatment strategies did not decrease the T-scores at which the ICERs for alendronate fell below £20,000 to the T-scores established for strategies including strontium ranelate. The Committee also noted that the ICERs for treatment compared with no treatment for an individual woman with a relevant combination of age and T-score were not more favourable for strontium ranelate than for risedronate even if an effect of acid-suppressive medication was assumed. The Committee considered that the evidence for this effect was not sufficiently robust. However, it concluded that the relative positions of alendronate, risedronate and strontium ranelate would remain unchanged even if an effect of acid-suppressive medication was assumed. The Committee therefore concluded that it was not necessary to change its recommendations (section 1) to take account of acid-suppressive medication.
## Calcium and vitamin D prerequisites for treatment
The Committee discussed the effect of calcium and vitamin D on the clinical effectiveness of the drugs considered. In the studies that formed the basis of this guidance, all participants were said to have adequate calcium and vitamin D levels. The Committee appreciated that the general population, particularly the elderly population, cannot be assumed to have an adequate dietary intake of calcium and vitamin D. It was also considered important to note that adequate levels (normal serum concentrations) of calcium and vitamin D are needed to ensure optimum effects of the treatments for osteoporosis. The Committee concluded that calcium and/or vitamin D supplementation should be provided unless clinicians are confident that women who receive treatment for osteoporosis have an adequate calcium intake and are vitamin D replete.
## Consultation on the Assessment Group's economic model
Following the outcome of the judicial review and the court ruling of March 2009, the Appraisal Committee considered the comments received from consultees on the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report.
The Committee considered the comments from consultees that the Assessment Group's model was not sufficiently transparent, lacked adequate documentation and could not be validated. It noted the number of consultations that took place during the appraisal guidance development, that the consultation documents had included descriptions of the model, and that assumptions and parameter values used had also been provided to consultees. The Committee was aware that instructions on how to run the model were released with the model and that consultees were able to run the model with changed input parameters. The Committee was satisfied with the exploration by the DSU of the functionality and validity of the model. The Committee noted that Servier stated that it had constructed its own economic model in order to validate the Assessment Group's model and to demonstrate the mathematical rationale to support its comments. The Committee noted that the results from Servier's model were very similar to those from the Assessment Group's model when similar assumptions and parameter inputs were used. The Committee was not persuaded by the consultees' doubt about the validity of the model, particularly since differences between the results obtained using Servier's model and the Assessment Group's model were largely because of differences in the assumptions used.
The Committee considered the comments from consultees that some inputs in the Assessment Group's model could not be changed and that it was unclear how fracture risk was calculated. The Committee noted that some of the fixed input parameters were inputs that do not need changing (such as the discount rate and standard mortality rates). Other fixed input values, such as the BMI and issues around the time horizon, were discussed separately (see sections 4.3.56 and 4.3.59 respectively). The Committee concluded that it was reasonable for some inputs in the model to be fixed. The Committee noted that fracture risks were calculated by the Assessment Group using the WHO algorithm in a separate spreadsheet and then entered into the model. It understood that the WHO algorithm itself was provided to the Assessment Group in 2005 as academic in confidence and that at that time NICE did not have permission from the owner of the algorithm to release it to consultees. The Committee understood that although the WHO fracture risk algorithm itself was not embedded in the economic model, the model could not be released because the algorithm could have been back-calculated from the fracture risks entered in the model and because the numbers of women with risk factors from the algorithm were included in the model.
The Committee considered the comments from consultees that the fracture risks entered into the model, calculated using the WHO algorithm, were different from fracture risks estimated using the FRAX tool. The Committee was aware that some differences could be because of the Assessment Group's use of midpoint ages in each 5-year age grouping. It also heard that the Assessment Group had verified the application of the WHO algorithm as provided in 2005, including all interactions between clinical risk factors, and was satisfied that the DSU had adequately assessed its application as being correct in the model. Because neither the DSU nor NICE has access to the algorithm used for the construction of the FRAX tool, the Committee was not in a position to comment further on differences between the two ways of estimating fracture risk. It concluded that differences between fracture risk estimates produced using the FRAX tool and those used in the Assessment Group's model were not in themselves a reason to doubt the correct use of the WHO algorithm within the Assessment Group's model.
The Committee considered the comments from consultees that mortality associated with clinical risk factors had been omitted from the Assessment Group's model, and noted the confirmation from the DSU that this was the case. It was persuaded that the inclusion of such additional mortality effects would increase the complexity of the model, and may increase the ICERs for the treatment of women with such clinical risk factors but decrease the ICERs for the treatment of women without such risk factors. The Committee agreed that the overall effect of including mortality associated with clinical risk factors in the model was unlikely to lead to a marked change in the overall results.
The Committee reviewed the consultee comments relating to the fixed BMI value of 26 kg/m2 used in the Assessment Group's model. It noted the rationale for selecting this value (see section 4.2.44). It also noted that in the DSU's exploratory analysis using the WHO algorithm, no increase in fracture risk was identified for women with a higher or lower BMI when BMD was known. The Committee was aware of its recommendation to assess BMD in all women under the age of 75 years for whom treatment is being considered, and noted that BMI is a weak predictor of fracture when BMD is known. Therefore the Committee concluded that the use of a fixed BMI value of 26 kg/m2 did not lead to an unfavourable assessment of the cost effectiveness of the interventions.
The Committee considered comments from consultees that the fracture risk associated with alcohol consumption used in the model was incorrect. It noted that the DSU had determined that the WHO algorithm had been correctly implemented, and understood that alcohol consumption of more than 2 units per day was included as a risk factor in the model. The Committee also noted that in its recommendations it had chosen to use a higher level of alcohol consumption in the risk identification strategy, because only alcohol consumption of 4 or more units per day was identified as a statistically significant risk factor for fracture for women – the population considered in the guidance. The Committee also considered a consultee comment that stated that it was unclear whether smoking and corticosteroid use had been included in the model as risk factors. It noted that the DSU had determined that the WHO algorithm had been correctly implemented with regard to both smoking and corticosteroid use in the model. The Committee noted that the effect of smoking in women was not statistically significant when assessing risk of osteoporotic fractures taken as a whole. The Committee was therefore satisfied that risks associated with corticosteroids, smoking and alcohol consumption had been faithfully applied in the Assessment Group's model, and agreed that the levels of alcohol consumption and smoking that should be used in the risk identification strategy were a matter for the Committee to consider and determine. The Committee took the view that it is not appropriate to identify women at high risk of fracture on the basis of risks that were not statistically significant (such as smoking and consumption of fewer than 4 units of alcohol per day) and that, in addition, the impact of these risk factors could arguably be approached by a strategy of smoking cessation and reducing alcohol consumption. The Committee noted comments from the consultees that the Assessment Group's model should have been amended to reflect the Committee's agreed inclusion of risk factors. However, the Committee took the pragmatic view that such amendments would have added unnecessarily to the mathematical complexity of an already complex clinical situation. It noted that women who had taken corticosteroids were included in the model and therefore contributed to the underlying fracture risk, with the effect of reducing the ICERs for the treatment of the population of women considered in the recommendations.
The Committee considered consultee comments that giving equal weighting to different clinical risk factors for fracture in the Assessment Group's model was inaccurate. The Committee considered the complex results presented originally in the 2005 Strontium Ranelate Assessment Report related to the inclusion of different risk factors and combinations of risk factors. The Committee noted that it had previously agreed that a clinically workable risk identification and treatment strategy should include the grouping of risk factors as the only practical way forward. At the time of the model's development, no individual risk calculation tool was available. Even if such a tool had been used in the development of the guidance, the prediction of cost effectiveness from overall absolute fracture risk alone, as suggested by consultees, would not be appropriate, for two reasons. Firstly, risk factors have different effects on different fracture types, and the cost effectiveness of treatment depends on the relative contributions of each risk factor to fracture risk. Secondly, the effectiveness of the drugs in reducing fracture risk was limited to only some of the clinical risk factors (age, T-score of −2.5 SD or below and prior fracture). The Committee heard from the DSU that there was considerable uncertainty about the cost effectiveness of treating women based on absolute risk alone (see section 4.3.47). Therefore, the Committee concluded that, when developing the guidance, simplification of the model was justified to in order to produce workable recommendations.
The Committee reviewed a comment from a consultee that the methods used to model effects beyond 10 years were not adequately described. It noted that the DSU confirmed that consequences beyond 10 years were considered in the Assessment Group's model, and an expanded description of the methods used was provided in an annex to the DSU report. The Committee also noted that the DSU carried out a sensitivity analysis in order to establish the impact of any possible underestimation of the mortality risk after the 10-year time horizon. It noted that doubling of the mortality risk led to only very small changes in the results. The Committee therefore concluded that mortality effects beyond the 10-year time horizon had been reasonably accounted for in the model and that sufficient description of these methods had been made available to consultees.
The Committee considered comments from consultees that the population data on the distribution of BMD (T-score) were not appropriate. It noted the DSU response confirming that the UK epidemiological dataset from the Holt study had been correctly implemented in the Assessment Group's model, and that the assumptions about the normality of the distributions used were likely to favour treatment for women at risk of fracture. The Committee also noted that the particular UK epidemiological dataset used in the model had been originally suggested by consultees for this appraisal. The Committee concluded that the population data had been used appropriately in the model.
The Committee considered a comment from a consultee that using a single estimate of cost effectiveness for 5-year age groupings of women at risk of fracture could exclude women from being offered treatment. It noted that this identification method was a Committee decision, and that identification strategies based on other factors could make treatments less cost effective.
The Committee reviewed comments from a consultee that the application of the same disutility for the side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates. The Committee was aware that the side effects observed for strontium ranelate in the clinical trials did not include gastrointestinal effects, but did include an increased risk of VTE. Because the increased risk of VTE was not included in the Assessment Group's model, the Committee had agreed that it was appropriate to include a disutility equivalent to the bisphosphonate base-case side-effect disutility to take account of this adverse effect.
The Committee reviewed comments from consultees about model assumptions or inputs that the Committee had directed the Assessment Group to use. It noted that issues such as treatment compliance, discount rates, costs of fracture, utility values for vertebral fracture and side-effect profiles used in the model had been considered and agreed by the Committee and reported in the guidance. The Committee also agreed that it had considered identification strategies for women at risk of fracture and, noting the advice of clinical specialists, it had recommended that women should have their BMD assessed by DXA scanning, except in certain circumstances as defined in the guidance. The Committee concluded that views expressed by consultees on the choice of modelling assumptions, input parameters and risk identification strategy were not about the operation of the Assessment Group's model, but were about Committee decisions that had already been discussed during development of the guidance.
The Committee also considered the consultees' view that the FRAX tool provides a 'mechanism to compute cost-effectiveness' according to clinical risk factors and that each of the current recommendations covers a wide range of absolute risk values, depending on the individual risk factors involved. The Committee understood that the FRAX tool is not an economic model, but a tool to estimate fracture risk. The Committee acknowledged that the current set of recommendations involved necessary simplifications from the more complex algorithm used to develop the Assessment Group's model. It was also aware that a direct prediction of cost effectiveness from absolute fracture risk alone would be inappropriate (see section 4.3.47).
The Committee concluded that the Assessment Group had provided an executable economic model and had implemented the WHO algorithm (as supplied) correctly. The Committee agreed with the DSU's comments that alterations to the modelling approach, as suggested by consultees, would not lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The Committee confirmed that the model provided a suitable framework to allow it to make recommendations on the cost-effective use of treatment for women at risk of fracture. The Committee noted that assumptions used in the Assessment Group's model had been considered and agreed by the Committee in developing the guidance. It agreed that it would not be useful to request further analysis from the Assessment Group at this stage. The Committee further agreed that any exploration of how absolute fracture risk could be used in making treatment decisions would require a new assessment and appraisal. Therefore the Committee concluded that the recommendations based on the Assessment Group's model were appropriate, and that the recommendations should remain unchanged.
The Committee noted the comments from some consultees that the guidance should be reviewed soon because the price of some of the appraised drugs had changed. The Committee noted that any possible price reductions could be offset by the use of the currently applicable discount rate, and that any review should also take into consideration how NICE might assess diagnostic tools such as absolute fracture risk prediction tools.
T-scores were calculated according to trial-specific normative data, using a threshold of −3.0 or below, which is equivalent to a T-score of −2.4 or below when measured according to the standards subsequently adopted by the WHO. The latter classification is used throughout this guidance document.
The remit of the original osteoporosis guideline has since been amended; see Osteoporosis and Osteoporosis fragility fracture risk.# Recommendations for further research
Given the evidence that the benefits of one of the bisphosphonates (alendronate) may continue for several years after the end of treatment, the Committee recommends that research should be carried out to define the optimal duration of treatment with individual bisphosphonates.
The Committee recommends research into the long-term effects of bisphosphonates on bone quality, given the inhibitory effects on bone resorption of these drugs.# Review of guidance
The guidance on these technologies will be considered for review by the Guidance Executive as soon as the short clinical guideline on risk assessment has been published. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJanuary 2011
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{'Guidance': "This guidance relates only to treatments for the primary prevention of fragility fractures in postmenopausal women who have osteoporosis. Osteoporosis is defined by a T-score of −2.5\xa0standard deviations (SD) or below on dual-energy X-ray absorptiometry (DXA) scanning. However, the diagnosis may be assumed in women aged 75\xa0years or older if the responsible clinician considers a DXA scan to be clinically inappropriate or unfeasible.\n\nThis guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered.\n\nThis guidance does not cover the following:\n\nThe treatment of women who have sustained a clinically apparent osteoporotic fragility fracture (for recommendations for the treatment of women with a prior osteoporotic fragility fracture, see the accompanying NICE technology appraisal, 'Raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women').\n\nThe use of raloxifene for the primary prevention of osteoporotic fragility fractures in women with normal bone mineral density (BMD) or osteopenia (that is, women with a T-score between −1\xa0and −2.5\xa0SD below peak BMD).\n\nThe use of this drug for the primary prevention of osteoporotic fragility fractures in women who are on long-term systemic corticosteroid treatment.\n\nThis recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.\n\nThis recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.\n\nThe recommendation for strontium ranelate has been withdrawn because strontium ranelate is no longer marketed in the UK.\n\nRaloxifene is not recommended as a treatment option for the primary prevention of osteoporotic fragility fractures in postmenopausal women.\n\nFor the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.\n\nThis recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.\n\nFor the purposes of this guidance, intolerance of alendronate or risedronate is defined as persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment, and that occurs even though the instructions for administration have been followed correctly.\n\nFor the purposes of this guidance, primary prevention refers to opportunistic identification, during visits to a healthcare professional for any reason, of postmenopausal women who are at risk of osteoporotic fragility fractures and who could benefit from drug treatment. It does not imply a dedicated screening programme.\n\nWomen who are currently receiving treatment, but for whom treatment would not have been recommended according to sections\xa01.1 to 1.4, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.\n\n T-score relates to the measurement of bone mineral density (BMD) using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) from peak BMD.", 'Clinical need and practice': "Osteoporosis is a progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.\n\nBone formation exceeds bone resorption in youth, but by the third decade of life there is a gradual loss of bone mass. Osteoporosis is therefore usually an age-related disease. It can affect both sexes, but women are at greater risk because the decrease in oestrogen production after the menopause accelerates bone loss to a variable degree.\n\nThe World Health Organization (WHO) has established diagnostic criteria for osteoporosis based on the measurement of BMD, expressed as the T-score, which is the number of SD below the mean BMD of young adults at their peak bone mass:\n\nnormal BMD: T-score of −1\xa0SD or above\n\nosteopenia: T-score of between −1 and −2.5\xa0SD\n\nosteoporosis: T-score of −2.5\xa0SD or below\n\nestablished (severe) osteoporosis: T-score of −2.5\xa0SD or below with one or more associated fractures.\n\nT-score measurements vary depending on the site and method of investigation. Measurement of BMD using central (hip and/or spine) DXA scanning can estimate fracture risk.\n\nIt is estimated that more than 2\xa0million women have osteoporosis (that is, have a T-score of −2.5\xa0SD or below) in England and Wales. Osteoporosis is most common in older white women. After the menopause, the prevalence of osteoporosis increases markedly with age, from approximately 2% at 50\xa0years rising to more than 25% at 80\xa0years.\n\nFragility fracture is the clinically apparent and relevant outcome in osteoporosis (referred to as 'osteoporotic fragility fracture' in the following text). It is often referred to as a low-trauma fracture; that is, a fracture sustained as the result of a force equivalent to the force of a fall from a height equal to, or less than, that of an ordinary chair. In the absence of fracture, osteoporosis is asymptomatic and often remains undiagnosed. Osteoporotic fragility fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain and reduced quality of life.\n\nIn women aged over 50\xa0years, the lifetime risk of a vertebral fracture is estimated to be one in three, and that of hip fracture one in five. Postmenopausal women with an initial fracture are at substantially greater risk of subsequent fractures. For instance, a woman with a vertebral fracture has an increased relative risk (RR) of 4.4 for a further vertebral fracture, 2.3 for a hip fracture, and 1.4 for a wrist fracture.\n\nIt is estimated that annually there are 180,000 osteoporosis-related symptomatic fractures in England and Wales. Of these, 70,000 are hip fractures, 25,000 are clinical vertebral fractures, and 41,000 are wrist fractures.\n\nAfter a hip fracture, a high proportion of women are permanently unable to walk independently or to perform other activities of daily living and, consequently, many are unable to live independently. Hip fractures are also associated with increased mortality; estimates of the relative mortality risk vary from 2 to greater than 10 in the 12\xa0months following hip fracture. However, it is unclear to what extent this can be attributed to fracture alone as opposed to pre-existing comorbidity.\n\nVertebral fractures can be associated with curvature of the spine and loss of height and can result in pain, breathing difficulties, gastrointestinal problems and difficulties in performing activities of daily living. It is thought that the majority of vertebral fractures (50–70%) do not come to clinical attention. Vertebral fractures are also associated with increased mortality; UK-specific data indicate a 4.4-fold increase in mortality related to vertebral fracture. However, as with hip fractures, it is unclear to what extent this may be due to comorbidities.\n\nIn addition to increasing age and low BMD, other clinical factors have been associated with increased fracture risk. Some of these clinical risk factors are at least partly independent of BMD, and include parental history of hip fracture, alcohol intake of 4 or more units per\xa0day, prior fracture, long-term systemic use of corticosteroids (the latter two of which are not covered in this guidance), and rheumatoid arthritis.\n\nFactors that are known to be indicators of low BMD include low body mass index (BMI) (defined as less than 22\xa0kg/m2), and medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause.", 'The technologies': "# Bisphosphonates: alendronate, etidronate and risedronate\n\nThe bisphosphonates alendronate, etidronate and risedronate are inhibitors of bone resorption and increase BMD by altering osteoclast activation and function.\n\nAlendronate is an oral bisphosphonate that has a UK marketing authorisation as a once-weekly preparation (70\xa0mg) for the treatment of postmenopausal osteoporosis. It also has a marketing authorisation at a daily dose of 10\xa0mg for the treatment of osteoporosis in postmenopausal women to prevent fractures. Non-proprietary alendronate (Teva UK) costs £4.12 for four 70\xa0mg tablets and £8.30 for twenty-eight 10\xa0mg tablets (excluding VAT; NHS Drug Tariff, 24 February 2008). At these prices the drug costs for 1\xa0year are £53.56 for once-weekly (70\xa0mg) tablets and £108.20 for daily (10\xa0mg) tablets. Proprietary alendronate (Fosamax; Merck Sharp & Dohme) is priced at £22.80 for four 70\xa0mg tablets and £23.12 for twenty-eight 10\xa0mg tablets (excluding VAT; 'British national formulary' [BNF] edition 54). At these prices, the drug costs for 1\xa0year are £296.40 for once-weekly (70\xa0mg) tablets and £301.39 for daily (10\xa0mg) tablets. Costs may vary in different settings because of negotiated procurement discounts.\n\nEtidronate (Didronel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation for the treatment of osteoporosis. The drug is administered in 90-day cycles, with each cycle consisting of etidronate (400\xa0mg/day) for 14\xa0days followed by calcium carbonate (1.25\xa0g/day) for the remaining 76\xa0days. The price per 90-day pack is £21.12 (excluding VAT; BNF 54), which equates to a yearly cost of £85.65. Costs may vary in different settings because of negotiated procurement discounts.\n\nRisedronate (Actonel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation at a dosage of 5\xa0mg/day or 35\xa0mg/week for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures, and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Prices are £19.10 for twenty-eight 5\xa0mg tablets and £20.30 for four 35\xa0mg tablets (excluding VAT; BNF 54), which equates to yearly costs of £248.98 for the daily treatment or £264.63 for the once-weekly treatment. Costs may vary in different settings because of negotiated procurement discounts.\n\nGastrointestinal side effects are common with oral bisphosphonates. In people with oesophageal abnormalities and other factors that delay oesophageal transit or emptying, risedronate should be used cautiously and alendronate is contraindicated. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nBisphosphonates have relatively complex instructions for administration. Alendronate and risedronate must be taken with 200\xa0ml and 120\xa0ml of water, respectively. Before and immediately after administration patients should not eat or drink, and must remain upright for stipulated time periods. Etidronate should be taken with water at the midpoint of a 4-hour fast (that is, 2\xa0hours after and 2\xa0hours before food, vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium).\n\n# Selective oestrogen receptor modulator: raloxifene\n\nSelective oestrogen receptor modulators (SERMs) are drugs with selective activity in various organ systems, acting as weak oestrogen-receptor agonists in some systems and as oestrogen antagonists in others. The aim of treatment with SERMs is to maximise the beneficial effects of oestrogen on bone and to minimise the adverse effects on the breast and endometrium.\n\nRaloxifene (Evista; Eli Lilly) has marketing authorisation for the treatment of osteoporosis in postmenopausal women. The recommended dosage is 60\xa0mg/day. The prices of 28- and 84-tablet packs are £17.06 and £59.59, respectively (excluding VAT; BNF 54), which equate to yearly costs of £222.39 and £258.93, respectively. Costs may vary in different settings because of negotiated procurement discounts.\n\nRaloxifene is contraindicated in people with a history of venous thromboembolism (VTE), hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding or endometrial cancer. Raloxifene should not be co-administered with systemic oestrogens, and in patients with breast cancer it should not be used for osteoporosis treatment or prevention until treatment of the breast cancer, including adjuvant treatment, has been completed. Raloxifene is associated with an increased risk of venous thromboembolic events, particularly during the first 4\xa0months of treatment, which is similar to the reported risk associated with hormone replacement therapy. For full details of side effects and contraindications, see the summary of product characteristics.\n\n# Strontium ranelate\n\nStrontium ranelate (Protelos; Servier Laboratories) is a divalent strontium salt of ranelic acid (strontium is an element with properties similar to calcium). It is thought to have a dual effect on bone metabolism, increasing bone formation and decreasing bone resorption. It has a UK marketing authorisation for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. The recommended dose is one 2\xa0g sachet taken daily as a suspension in water. The price of a 28-sachet pack is £25.60 (excluding VAT; BNF 54), which equates to a yearly cost of £333.71. Costs may vary in different settings because of negotiated procurement discounts.\n\nThe absorption of strontium ranelate is reduced by food, milk and products derived from milk. It should therefore be administered between meals, ideally at bedtime and preferably at least 2\xa0hours after eating.\n\nThe summary of product characteristics states that strontium ranelate is not recommended in patients with severe renal impairment and that it should be used with caution in patients at increased risk of VTE. Treatment with strontium ranelate should be discontinued during treatment with oral tetracycline or quinolone antibiotics. For full details of side effects, drug interactions and contraindications, see the summary of product characteristics.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\n## Efficacy\n\nThe Assessment Group for this appraisal (School of Health and Related Research, University of Sheffield [ScHARR]) reviewed data from published randomised controlled trials (RCTs) in postmenopausal women in which fracture or health-related quality of life was an endpoint and where one of the five drugs of interest was compared with a relevant comparator, such as no treatment, placebo or one of the other included interventions. The majority of studies used placebo or no treatment as a control. Most studies ensured that women in all trial arms had normal calcium levels (that is, normal serum concentrations) or adequate supplementation, and some studies used additional dietary supplementation with vitamin D.\n\nFor this appraisal, reductions in RR associated with treatment were pooled regardless of the baseline BMD and fracture status of the participants in the studies. It was also assumed that these reductions in RR remained constant at all ages, although little evidence was available for the effectiveness of the drugs in women aged 80\xa0years or older.\n\nFor vertebral fractures, some studies used clinical (that is, symptomatic) fractures as their endpoint whereas others used fractures that were identified radiographically. Vertebral fractures identified radiographically, which are termed 'radiographic fractures' or 'morphometric fractures', include both symptomatic and asymptomatic fractures. There are different definitions of a vertebral radiographic fracture, but those definitions that require a 20% reduction in vertebral height are generally recognised as producing more reliable results than those that require a 15% reduction.\n\nFor non-vertebral fracture types, individual data on hip, leg, pelvis, wrist, hand, foot, rib and humerus fractures were sometimes provided, whereas some studies only presented data for all non-vertebral fractures grouped together.\n\nSixteen RCTs of alendronate in postmenopausal women were included in the assessment report: two studies in women with low or normal BMD; one in women with osteopenia; eight in women with osteopenia or osteoporosis; four in women with osteoporosis; and one in women with established osteoporosis. Overall, 15 studies compared alendronate with placebo or with no treatment. All the studies were conducted in women who had adequate levels of calcium, from either dietary intake or calcium supplementation.\n\nTwo studies, one comparing alendronate with oestrogen alone or with oestrogen and alendronate combined, and the other comparing alendronate with teriparatide (which has a marketing authorisation only for secondary and not primary prevention), found no statistically significant differences between the groups in numbers of clinically apparent fractures of any type in women with osteoporosis. However, back pain was reported less frequently by women in the teriparatide group compared with women in the alendronate group (6% versus 19%, p\xa0=\xa00.012).\n\nIn addition to the 16 RCTs, a 2-year study demonstrated the equivalence of weekly and daily doses of alendronate, in terms of clinical fracture incidence and gastrointestinal adverse events. However, this study was not included in the analysis because it did not include the specified comparators.\n\nThe meta-analysis for alendronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.56 (95%\xa0confidence interval [CI] 0.46 to 0.68, four RCTs, n\xa0=\xa07039), an RR of hip fracture of 0.62 (95%\xa0CI 0.40 to 0.98, three RCTs, n\xa0=\xa07455), an RR of wrist fracture of 0.67 (95%\xa0CI 0.34 to 1.31, four RCTs, n\xa0=\xa07931) and an RR for other non-vertebral fractures of 0.81 (95%\xa0CI 0.68 to 0.97, six RCTs, n\xa0=\xa09973).\n\nA post-hoc analysis of data from the largest study on alendronate, the 'Fracture intervention trial' (FIT) RCT (non-vertebral fracture population), suggested that alendronate may be less effective at reducing fractures in women with T-scores above (that is, better than) −2.5\xa0SD than in women with osteoporosis. These results were not statistically significant.\n\nGastrointestinal adverse events, including nausea, dyspepsia, mild oesophagitis/gastritis and abdominal pain, were reported in at least one third of the participants in studies of alendronate. However, only one study found the increased frequency of these symptoms to be statistically significant relative to placebo. This is consistent with post-marketing studies that indicate that approximately one third of alendronate users experience gastrointestinal adverse events. To avoid oesophagitis, the summary of product characteristics now recommends that alendronate should be taken on rising for the day, with a full glass of water. It is possible that these instructions were not followed in all of the studies, particularly the earlier ones.\n\nPrescription-event monitoring studies in patients for whom alendronate was prescribed (n\xa0=\xa011,916) by GPs in England demonstrated a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 32.2 per 1000 patient-months in the first month of treatment to 10.9 per 1000 patient-months in months 2 to 6. Because these studies lacked a comparator, it is not possible to assess the extent to which these rates of upper gastrointestinal events may be above baseline levels in those not taking bisphosphonates.\n\nOne study reported health-related quality of life outcomes. At 12\xa0months there were statistically significant improvements in the alendronate group compared with the control group in scores for pain, social isolation, energy level and physical ability.\n\nTwelve RCTs of etidronate in postmenopausal women were reviewed: three studies in women with low-to-normal BMD; two in women with osteopenia or osteoporosis; one in women with osteoporosis; one in women with osteoporosis or established osteoporosis; and five in women with established osteoporosis. Four studies included active comparators, and eight compared etidronate with placebo or with no treatment (although in six of these, study participants in all arms received calcium, either alone or with vitamin D). Some studies did not use the exact treatment regimen that currently has a UK marketing authorisation (that is, 90-day cycles of etidronate 400\xa0mg/day for 14\xa0days, followed by calcium carbonate 1.25\xa0g/day for the remaining 76\xa0days). None of the studies reported health-related quality of life outcomes.\n\nThe meta-analysis of RCTs for etidronate relative to placebo carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.40 (95%\xa0CI 0.20 to 0.83, three RCTs, n\xa0=\xa0341), an RR of hip fracture of 0.50 (95%\xa0CI 0.05 to 5.34, two RCTs, n\xa0=\xa0180), and an RR for other non-vertebral fractures of 1.04 (95%\xa0CI 0.64 to 1.69; four RCTs, n\xa0=\xa0410). There were no data for wrist fracture.\n\nAn observational study in a general practice setting in the UK reported on fracture rates in people with a diagnosis of osteoporosis who were receiving etidronate compared with those who were not taking a bisphosphonate. People taking etidronate had an RR of non-vertebral fracture of 0.80 (95%\xa0CI 0.70 to 0.92). The RR of hip fracture was 0.66 (95%\xa0CI 0.51 to 0.85) and that of wrist fracture was 0.81 (95%\xa0CI 0.58 to 1.14).\n\nHigher rates of gastrointestinal adverse effects were found in the etidronate groups of four RCTs, although the differences were not always statistically significant. However, non-RCT evidence and testimonies from clinical specialists and patient experts suggested that etidronate may be associated with fewer gastrointestinal adverse effects than other bisphosphonates.\n\nThe systematic review carried out by ScHARR in 2006 identified a cohort study conducted in the UK that indicated that etidronate may be associated with a much lower rate of upper gastrointestinal adverse effects than alendronate or risedronate.\n\nSeven RCTs of risedronate in postmenopausal women were reviewed: one study in women with normal BMD; one in women with osteopenia; one in women with osteopenia or osteoporosis; one in women with osteoporosis or specific risk factors for hip fracture, such as a recent fall; and three in women with established osteoporosis. All compared risedronate with placebo (although, with the exception of those in the normal BMD study, all women also received calcium) and none reported on health-related quality of life outcomes.\n\nThe meta-analysis for risedronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.61 (95%\xa0CI 0.50 to 0.75, three RCTs, n\xa0=\xa02301), an RR of hip fracture of 0.74 (95%\xa0CI 0.59 to 0.93, three RCTs, n\xa0=\xa011,770), an RR of wrist fracture of 0.68 (95%\xa0CI 0.43 to 1.08, two RCTs, n\xa0=\xa02439) and an RR for other non-vertebral fractures of 0.76 (95%\xa0CI 0.64 to 0.91, five RCTs, n\xa0=\xa012,399).\n\nIn all of the studies, rates of gastrointestinal adverse events were similar in the risedronate and placebo groups.\n\nPrescription-event monitoring studies in patients for whom risedronate was prescribed (n\xa0=\xa013,643) by GPs in England suggested a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 26.9 per 1000 patient-months in the first month of treatment to 8.1 per 1000 patient-months in months 2 to 6.\n\nA meta-analysis of pooled data from the alendronate and risedronate studies, carried out by ScHARR in 2006, resulted in an RR of vertebral fracture of 0.58 (95%\xa0CI 0.51 to 0.67, seven RCTs, n\xa0=\xa09340), an RR of hip fracture of 0.71 (95%\xa0CI 0.58 to 0.87, six RCTs, n\xa0=\xa019,233), an RR of wrist fracture of 0.69 (95%\xa0CI 0.45 to 1.05, six RCTs, n\xa0=\xa01037) and an RR for other non-vertebral fractures of 0.78 (95%\xa0CI 0.69 to 0.88, 11 RCTs, n\xa0=\xa022,372).\n\nThree RCTs of raloxifene in postmenopausal women were identified, but only two were included in the Assessment Group's meta-analysis: the largest study (the 'Multiple outcomes of raloxifene evaluation' [MORE] study) was carried out in women with osteoporosis, of whom 37% had a vertebral fracture at entry, and a smaller study was conducted in women with established osteoporosis. Both compared raloxifene with placebo (in both studies, women in both arms received calcium and vitamin D). Both studies examined raloxifene at dosages of 60\xa0mg/day (the dosage specified in the UK marketing authorisation for the treatment of postmenopausal osteoporosis) and 120\xa0mg/day. Neither reported on health-related quality of life outcomes. The mean age of women in the studies was 67–68\xa0years. The MORE study was extended further to assess fracture, breast cancer, and cardiovascular and uterine safety outcomes. A third study examined the additive effect of raloxifene compared with placebo in women with a femoral neck T-score of −2\xa0SD or below, with or without prior fracture, who were also receiving fluoride, calcium and vitamin D. Because of the use of fluoride as a co-intervention, these results were not included in the Assessment Group's meta-analysis.\n\nThe meta-analysis for raloxifene relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.65 (95%\xa0CI 0.53 to 0.79, one RCT, n\xa0=\xa04551), an RR of hip fracture of 1.13 (95%\xa0CI 0.66 to 1.96, two RCTs, n\xa0=\xa06971), an RR of wrist fracture of 0.89 (95%\xa0CI 0.68 to 1.15, one RCT, n\xa0=\xa06828), and an RR for other non-vertebral fractures of 0.92 (95%\xa0CI 0.79 to 1.07, one RCT, n\xa0=\xa06828).\n\nThe most serious adverse effect associated with raloxifene was the approximately three-fold increased risk of VTE. Statistically significantly higher incidences of hot flushes, arthralgia, dizziness, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes were also found with raloxifene compared with placebo. The impact of raloxifene on cardiovascular disease is unclear, but there is evidence that it lowers serum concentrations of fibrinogen as well as both total and low-density lipoprotein (LDL) cholesterol levels (that is, serum concentrations) without increasing high-density lipoprotein (HDL) cholesterol.\n\nThe MORE study shows that raloxifene protects against breast cancer, with the RR at 4\xa0years for all types of breast cancer reported as 0.38 (95%\xa0CI 0.24 to 0.58), and that for invasive breast cancer as 0.28 (95%\xa0CI 0.17 to 0.46).\n\nThree RCTs of strontium ranelate in postmenopausal women were identified: one study in women with osteoporosis and two in women with osteoporosis or established osteoporosis. All three studies compared strontium ranelate with placebo, and provided calcium and vitamin D supplementation to ensure an adequate intake.\n\nThe Assessment Group reported the results of a published meta-analysis that gave an RR for vertebral fracture of 0.60 (95%\xa0CI 0.53 to 0.69, two RCTs, n\xa0=\xa06551) and an RR for all non-vertebral fractures (including wrist fracture) of 0.84 (95%\xa0CI 0.73 to 0.97, two RCTs, n\xa0=\xa06551). Efficacy in reducing the rate of hip fracture was established in one study; the RR for hip fracture in the whole study population was 0.85 (95%\xa0CI 0.61 to 1.19, one RCT, n\xa0=\xa04932). A post-hoc subgroup analysis in women aged 74\xa0or older with a T-score of −2.4\xa0SD resulted in an RR for hip fracture of 0.64 (95%\xa0CI 0.412 to 0.997, one RCT, n\xa0=\xa01977).\n\nIn general, strontium ranelate was not associated with an increased risk of adverse effects and for the most part adverse effects were mild and transient; nausea, diarrhoea and creatine kinase elevations were the most commonly reported. A serious adverse event associated with strontium ranelate treatment was an increased incidence (RR\xa0=\xa01.42) of VTE and pulmonary embolism. This finding has been investigated further with the extension of ongoing studies and by post-marketing surveillance.\n\nOne study published results on health-related quality of life outcomes. It reported that strontium ranelate had quality of life benefits compared with placebo, as assessed by the QUALIOST osteoporosis-specific questionnaire and by the general health perception score of the short form (SF)-36 general scale.\n\n## Persistence and compliance\n\nData from 14 RCTs indicated that between 81% and 100% of patients persisted with bisphosphonates in the first year of treatment, with lower rates of persistence of between 51% and 89% in the third year of treatment (eight RCTs).\n\nA prescription-event monitoring study of patients for whom alendronate was prescribed (n\xa0=\xa011,916) by GPs in England indicated that 24% discontinued treatment within 1\xa0year. In a similar study of patients for whom risedronate was prescribed (n\xa0=\xa011,742) in primary care in England, 30% appeared to have discontinued treatment within 6\xa0months. In another 12 studies reviewed, persistence at 1\xa0year ranged from 16% to 90%.\n\nPaid claims data from the USA suggested that only 18% of women starting raloxifene treatment continued to take their medication uninterrupted, and an investigation of a pharmacy prescription database indicated that only 44% were continuing treatment at the end of year\xa02.\n\nCompliance data were reported for two RCTs of strontium ranelate and were similar in the strontium ranelate and placebo arms (ranging from 83% to 93%) at up to 3\xa0years.\n\n## Acid-suppressive medication and fracture risk\n\nTwo cohort and two case–control studies reported on a potential relationship between acid-suppressive medication (proton pump inhibitors or histamine H2 receptor antagonists) and fracture risk. One of the case–control studies, which used the UK General Practice Research Database (GPRD), found that 1\xa0year or more of acid-suppressive medication was associated with an increase in fracture risk. The other case–control study reported a reduction of fracture risk associated with use of histamine H2 receptor antagonists, and that use of other acid-suppressive medication might increase fracture risk. Both studies, however, were unable to demonstrate convincingly that fracture risk was independent of underlying disease that might determine differences in fracture risk.\n\nA prospective cohort study excluded women taking medication for fracture prevention and reported an increase in non-vertebral fracture in those taking acid-suppressive medication compared with those who were not. Findings appeared similar for users of proton pump inhibitors or histamine H2 receptor antagonists, but differences in fracture risk were not statistically significant for those using proton pump inhibitors compared with those not using acid-suppressive medication. One large retrospective cohort study using the UK GPRD compared women taking acid-suppressive medication plus bisphosphonates with those taking bisphosphonates alone. This GPRD study reported an increase in fracture risk for some fracture sites with concomitant use of acid-suppressive medication and bisphosphonates, but a reduction in risk for other fracture sites. The information on patients included in this GPRD study was incomplete and details of adjustments for confounders were not reported. The two cohort studies were not fully published, and their analysis may have been prone to confounding.\n\n## Additional submission from the manufacturer of strontium ranelate\n\nFollowing the Court of Appeal Order of April 2010, NICE requested an additional submission from the manufacturer of strontium ranelate (Servier), setting out their views on the most appropriate estimate of strontium ranelate's efficacy in reducing the rate of hip fracture.\n\nServier explained that the pivotal phase III RCT (Treatment of Peripheral Osteoporosis Study [TROPOS]) was started before the increased regulatory emphasis on the prevention of hip fracture as a key measure of efficacy of treatments for osteoporosis (because of the significant morbidity associated with hip fracture). TROPOS had not been designed or powered to demonstrate the effect of strontium ranelate treatment on rates of hip fracture. In support of its application for regulatory approval of strontium ranelate, Servier was therefore asked by the European Medicines Agency (EMA) to investigate the efficacy of strontium ranelate in reducing the rate of hip fracture in a post-hoc subgroup analysis of TROPOS participants who met the definition of established osteoporosis (that is, a BMD T-score of −2.5 or below and one or more associated fractures). Instead of the requested subgroup, Servier provided the EMA with data for a different subgroup of trial participants whom they identified as being at high risk for hip fracture. This subgroup comprised women aged 74 or older who had a femoral T-score of −2.4 or below. This subgroup represented 42% of TROPOS participants and had an RR of hip fracture of 0.64 (95% CI 0.412 to 0.997).\n\nServier described the method used to identify this high-risk subgroup. The placebo arms of two RCTs (TROPOS and another trial designed to assess the efficacy of strontium ranelate in reducing vertebral fractures, Spinal Osteoporosis Therapeutic Intervention [SOTI]) were pooled and the influence on fracture rates of three of the main risk factors for fragility fracture – age, BMD and prior fracture – was explored. Servier found that, in the pooled placebo arms of these two RCTs, prior fracture had no effect on the rate of hip fracture, so this factor was not considered further. To select an age group in which the risk of hip fracture was elevated, Servier investigated various possible age cut-offs, and identified the age at which the difference in the rate of hip fracture between women older and younger than the cut-off was greatest. This process led to the selection of an age cut-off of 74\xa0years. Servier stated that this cut-off was consistent with epidemiological data, in particular a study by Donaldson et al. (1990), which Servier interpreted as showing a rising rate of hip fracture among women in the general population above the age of 74. The selected BMD cut-off was closely aligned to the WHO definition of osteoporosis (a T-score of −2.5 SD or below; see section 2.3). Servier emphasised that, having identified factors related to a high risk of hip fracture by screening the pooled data from the placebo arms of two RCTs, a single post-hoc analysis of the effect of strontium ranelate in this subgroup had been performed, without the need for multiple exploratory analyses of fracture risk reduction adopting different criteria for the subgroup selection.\n\nAfter Servier had submitted data on efficacy in its chosen subgroup to the EMA, the EMA requested further analyses to confirm the effect of strontium ranelate on the rate of hip fracture. Servier provided additional evidence, including data from longer follow-up periods and analyses of trial participants with demonstrated compliance to treatment. Servier indicated that this additional evidence supported the view that an RR of 0.64 is a valid estimate of the efficacy of strontium ranelate in reducing the rate of hip fracture.\n\nIn their additional submission to NICE following the Court of Appeal Order in April 2010, Servier also suggested a hypothesis for a possible increased effect of strontium ranelate in older women: most osteoporosis drugs work by reducing the loss of existing bone, but strontium ranelate also stimulates the creation of new bone. Because the creation of new bone is increasingly impaired as women age, Servier stated that it is possible that strontium ranelate is able to provide additional benefit to older women.\n\nServier argued that the RR of 0.64 derived from the post-hoc analysis of the high-risk subgroup should be used in cost-effectiveness analyses to quantify the effect of strontium ranelate in reducing the rate of hip fracture because, in its view, it represents a more robust estimate of efficacy than the RR for the whole trial population. Servier stated that, unlike the analysis of the whole trial population, the subgroup analysis was suitably powered to demonstrate the effect of strontium ranelate in reducing the rate of hip fracture. Because of this, in Servier's opinion, the estimate was statistically robust.\n\nServier's view was that the estimate derived from the high-risk subgroup could be assumed to apply to all women taking strontium ranelate, but it acknowledged issues surrounding extrapolation from the high-risk subgroup to a broader population. Servier therefore indicated that it might also be concluded that the RR of 0.64 could only be applied to a population corresponding to the high-risk subgroup.\n\n## Review of Servier's additional submission by the Decision Support Unit\n\nThe DSU was commissioned to review Servier's additional submission, and to comment on the scientific validity of the post-hoc subgroup analysis provided by Servier. The DSU advised that any set of data will show some variation in response to treatment across different subgroups simply by chance. The DSU explained that, because of this, the correct statistical procedure for establishing a subgroup of trial participants with a significantly different response to treatment is via a test for interaction (that is, a formal test, using regression methods, of the hypothesis that the effect is different in one group of participants from that observed in the rest of the trial population). The DSU noted that no such test had been reported by Servier.\n\nThe DSU stated that the method used by Servier to identify the high-risk subgroup (see section 4.1.39) was logically likely to yield an unduly large relative effect, and the DSU stated that this would lead to a biased estimate of RR. This was because the method used to identify the age cut-off to define the subgroup was 'data-dependent' – that is, most of the data that were used to define the subgroup (the rate of hip fracture in the placebo arm of TROPOS) were also used to estimate the efficacy of strontium ranelate in the selected subgroup. In this way, the rate of hip fracture in the placebo group was certain to be high, relative to other potential age cut-offs, with no guarantee that this was also the case in the strontium ranelate group. Therefore, the DSU stated that the estimate of RR derived from the subgroup was likely to be artificially inflated.\n\nThe DSU also noted that, whilst Servier indicated that there were epidemiological data to support the chosen age cut-off (see section 4.1.39), the study by Donaldson et al. (1990) suggested that the rate of hip fracture rises to a notable level after 75\xa0years of age, not 74.\n\nThe DSU advised that Servier's argument of enhanced statistical power in the subgroup analysis was incorrect. The DSU explained that, in an analysis of RR, statistical power is dependent on the number of events (in this case, hip fractures) and that choosing a smaller group of participants will tend to reduce, rather than increase, power unless the RR is markedly greater in that subgroup. Because of this, the DSU disagreed with Servier's claim that the subgroup analysis was 'fully powered'.\n\nThe DSU was asked to comment on the most appropriate approach, from a statistical viewpoint, to the use of data from the whole trial population of TROPOS and the high-risk subgroup, in determining the relative efficacy of strontium ranelate. The DSU responded that, if the relative effect were to be applied to women in the general population, an intention-to-treat analysis of all randomised trial participants would yield the most appropriate estimate of efficacy. The DSU also commented that, if more than one trial is available, a pooled analysis of RRs from the intention-to-treat data of all relevant trials would be preferable. A meta-analysis of the data from SOTI and TROPOS would have provided the most appropriate overall measure of efficacy.\n\nThe DSU also advised that even as an estimate of efficacy in the high-risk subgroup, the RR of 0.64 was likely to be too extreme because of the likelihood of selection bias arising from the way in which the subgroup had been identified (see section 4.1.45). The DSU also emphasised that, to estimate the cost effectiveness of strontium ranelate in a particular subgroup, it would not be sufficient simply to adopt an RR of hip fracture from that group. It would also be important to populate the rest of the economic decision model with evidence specific to the subgroup in question.\n\nNICE invited Servier to respond to the DSU's report. Servier provided a document reiterating its previous views that the subgroup analysis performed to evaluate the efficacy of strontium ranelate in reducing the rate of hip fracture was based on sound scientific principles and valid statistical methods. Servier did not respond to other specific issues raised in the DSU report.\n\n# Cost effectiveness\n\n## Manufacturers' models\n\nFor proprietary alendronate, compared with no treatment, the manufacturer's model provided an incremental cost-effectiveness ratio (ICER) of £8622 per quality-adjusted life year (QALY) gained for 70-year-old women with a T-score below −2.5\xa0SD. The manufacturer's results were more favourable than the results of Assessment Group's 2003 model. This could be because the manufacturer's model was not adjusted for baseline fracture prevalence, or because it used different utilities for vertebral fractures, different efficacy data, different risk groups and a longer time horizon.\n\nFor etidronate, compared with no treatment, the manufacturer's model provided an ICER of £18,634 per QALY gained for 70-year-old women with a T-score below −2.5\xa0SD. The manufacturer's model included morphometric vertebral fractures and corticosteroid use as risk factors for further fractures. It is unclear whether the manufacturer's ICER was for women with or without a prior osteoporotic fragility fracture.\n\nFor risedronate, compared with no treatment, the manufacturer provided data from two models. The ICER derived from the manufacturer's own model was £577 per QALY gained for women aged 74\xa0years. In the second model provided by the manufacturer, which was commissioned from an external body, the ICER was more than £35,000 per QALY gained for all women without a prior osteoporotic fragility fracture and with a T-score of −2.5\xa0SD. However, for women at slightly higher risk of fracture and aged 70\xa0years or older, the corresponding ICER was £13,500 per QALY gained or less. The ICER calculated using the manufacturer's own model was difficult to verify from the information given. The ICERs generated by the second model were more consistent with the figures provided by the Assessment Group's 2003 model, although they did differ somewhat. This may be because of different cost and RR inputs.\n\nFor raloxifene, compared with no treatment, the manufacturer provided data for different age groups and different risk levels. All of the analyses included the breast cancer benefits. It was not clear how the different risk levels were defined. The ICERs ranged from £12,000 to £22,000 per QALY gained, and were more favourable than the Assessment Group's 2003 analysis, even when the Assessment Group included the breast cancer benefits. In the Assessment Group's 2003 model, the RR for the breast cancer effect was higher (0.38) than the RR for invasive breast cancer used in the manufacturer's model (0.28), and the breast cancer risk was adjusted for the association between low BMD and decreased risk of breast cancer. Additionally, the manufacturer's model was not adjusted for baseline fracture prevalence, and included different utilities for vertebral fractures, different efficacy data, different risk groups, and a longer time horizon than the Assessment Group's model.\n\nFor strontium ranelate, compared with no treatment, the manufacturer provided a model developed by an external organisation. The ICER was £45,028 per QALY gained for 65-year-old women with a T-score of −2.5\xa0SD and £26,686 per QALY gained for 80-year-old women with a T-score of −2.5\xa0SD. The manufacturer's results were more favourable than the Assessment Group's 2005 results because different modelling assumptions were used. For example, fewer health-state transition possibilities were incorporated. Compared with the Assessment Group's model, the manufacturer's model used more favourable efficacy data for hip fracture from the post-hoc 'high-risk' subgroup of women (see sections 4.1.28 and 4.1.38 to 4.1.43), and slightly more favourable efficacy data for wrist and proximal humerus fracture. Higher hip-fracture costs were used in the manufacturer's model.\n\n## The Assessment Group's model\n\nThe Assessment Group provided a cost–utility model with two components (described in detail in the 2005 Strontium Ranelate Assessment Report). As a first step, the model calculated absolute fracture risk from the epidemiological literature on a number of independent clinical risk factors. These data were prepared under the auspices of the WHO and were provided for this appraisal under an academic-in-confidence agreement. As a second step, the model applied RR reductions for fracture taken from the meta-analysis described in section\xa04.1.22. A single estimate of efficacy was used for alendronate and risedronate based on pooled data for these two drugs. Following advice from the original Osteoporosis Guideline Development Group, it was assumed that RRs remained constant across all ages, T-scores and fracture status. The most recent analyses carried out by ScHARR were based on the price of non-proprietary alendronate in February 2008 (£53.56 per year for once-weekly 70\xa0mg tablets; £108.20 per year for daily 10\xa0mg tablets).\n\nAll osteoporotic fragility fractures in women aged 50\xa0years or older were included in the modelling. The RR for hip fracture was assumed to apply also to pelvis and other femoral fractures. The RR for non-vertebral fracture was assumed to apply also to proximal humerus, rib, sternum, scapula, tibia, fibula and wrist fractures. Where confidence intervals for RRs spanned unity, it was assumed that there was no effect of treatment, except in the case of strontium ranelate. In this case, an RR of 0.85 for hip fracture was used to acknowledge the effect reported in the high-risk subgroup of the study. The model used UK-specific epidemiological data on femoral neck BMD.\n\nThe model assumed an initial utility in the year of fracture and a higher utility in subsequent years. The time horizon for predicting morbidity was 10\xa0years, consisting of 5\xa0years of treatment with sustained efficacy plus 5\xa0years of linear decline to no effect. However, treatment-related decreases in mortality rate extended beyond the 10-year time horizon. For this, the life expectancy for a woman at the threshold T-score for osteoporosis was calculated from standard life tables, and any increase in mortality rate due to fracture would continue until death or an age of 110\xa0years. In the base case, vertebral-fracture utility was assumed to be lower than hip-fracture utility, and a sensitivity analysis was carried out in which the utility for vertebral fracture was assumed to be the same as that for hip fracture. The percentage of women assumed to move from community living to a nursing home following a hip fracture increased with increasing age. An age-dependent gradient of hip-fracture risk was used, and an association between vertebral or proximal humerus fracture and increased mortality in women with osteoporosis was included. No follow-up BMD scans were included in the model; this reflects current clinical practice in the UK.\n\nThe model included an assumption about the costs and disutility associated with treatment-related side effects for all drugs, based on the findings of prescription-event monitoring studies in patients treated with alendronate. For the base case, the model assumed 50% persistence with treatment. In addition to the base case, the Assessment Group undertook a number of sensitivity analyses using alternative assumptions, including: persistence with treatment (25% or 75% at 5\xa0years); reduction in the efficacy of the drugs at reducing the risk of fracture associated with risk factors other than age, prior fracture and low BMD to 0% or 50% (with a consequent upward adjustment of the RR for the risk factors of age, prior fracture and low BMD); disutility of vertebral fracture; updated fracture costs; and the disutility and costs of treatment-related side effects. It was assumed that women who experience bisphosphonate-related side effects had 91% of the utility of women who do not have such side effects. In the base case analysis for all of the drugs under consideration this was applied to 2.35% of women in the first treatment month and 0.35% of women thereafter and, in sensitivity analyses for bisphosphonates, to 24% of women in the first treatment month and 3.5% of women thereafter. In the case of strontium ranelate, the effect on VTE was not included in the model. Discount rates of 6% per year for costs and 1.5% per year for health benefits were applied, in accordance with NICE methods relevant to this appraisal.\n\nFor raloxifene, 4-year follow-up data from the MORE study were used, and it was assumed that women with low BMD have a lower breast cancer risk than women with normal BMD. The cost effectiveness was modelled excluding the breast cancer benefit, the risk of VTE and the effect on cardiovascular events.\n\nThe independent clinical risk factors for fracture used in the model were based on the data prepared under the auspices of the WHO (see section\xa04.2.6) and included BMI, prior fracture, previous or current use of corticosteroids, parental history of fracture, current smoking, alcohol intake of more than 2\xa0units per day, and rheumatoid arthritis. The study provided prevalence data for the different risk factors, and risk ratios for hip fracture and osteoporotic fracture for each risk factor, including T-score and age. Using these risk ratios, absolute risk of fracture was calculated.\n\nThe estimates of cost effectiveness were generated for different levels of absolute risk derived from a large number of combinations of T-score (in bands 0.5\xa0SD wide), age and number of independent clinical risk factors for fracture. For practical reasons relating to the number of potential combinations, single-point RRs of fracture, calculated from the log-normal efficacy distributions, were used in the model. Results were presented for population groups categorised according to age, T-score and number of independent clinical risk factors.\n\nAs women without fracture do not usually present to clinicians, the Assessment Group also estimated the impact that the costs of identifying women at risk would have on the cost effectiveness of the drugs. This required both a calculation of the ICER for treatment, and a calculation of the distribution of risk assessment cost over the population who would benefit from treatment. A net-benefit approach was used to do this. The net-benefit approach is analogous to the more traditional cost per QALY gained approach, but also requires a value of willingness to pay (WTP) for an additional QALY gained. For the calculation of the net benefit of an intervention, the WTP is first multiplied by the incremental QALY gained associated with the intervention, then the incremental cost associated with the intervention is subtracted. For this appraisal, the total net benefit for each age group and DXA scanning approach was calculated by subtracting the cost of DXA scanning from the net benefit of treating all women who can be treated cost effectively.\n\nA stepped net-benefit approach was used to estimate, in reverse order, the cost effectiveness of risk assessment, DXA scanning and treatment of women without a prior fracture. A WTP value of £20,000 per QALY gained was applied in the modelling.\n\nStep 1. ICERs for treatment versus no treatment were calculated for each intervention for various combinations of age, T-score and number of independent clinical risk factors for fracture (see section\xa04.2.11). The net benefit of treatment per woman was calculated using the following formula: Net benefit\xa0=\xa0(£20,000 × incremental QALYs gained) – incremental costs. For women for whom the ICER for treatment was more than £20,000 per QALY gained, the net benefit was set to zero.\n\nStep 2. The net benefit per woman was multiplied by the number of women in the population estimated to fall within each combination of age, T-score and number of independent clinical risk factors for fracture (based on the data used to develop the algorithm prepared for the WHO). The net benefits for each group were then added together to give a total net benefit of treatment for women with no, one, two or three independent clinical risk factors within each age group.\n\nStep 3. The cost of DXA scanning all of the women in each age/independent clinical risk factor group was subtracted from the net benefit of treatment for that group (calculated as described in step 2). This provides the net benefit of treatment and DXA scanning for the group, assuming that the number of independent clinical risk factors is known. A positive net benefit indicates that DXA scanning of women in that age/independent clinical risk factor group and treating those groups of women in whom the ICER for treatment is £20,000 per QALY gained or less provides an ICER for the entire strategy of less than £20,000 per QALY gained.\n\nStep 4. When the resulting values of net benefit of treatment and scanning were negative they were set to zero. For each age group, the total net benefit of scanning and treatment was calculated by adding together the net benefits for each age/independent clinical risk factor group. The cost of opportunistic assessment for all women in this age group was then subtracted to give the net benefit of risk assessment, scanning and treatment. A positive net benefit indicates an ICER of less than £20,000 per QALY gained for risk assessment, DXA scanning and treating women (at a specific T-score related to the ICER for treatment only) of that particular group. Cost per QALY gained data were presented for each strategy.\n\nFirst, the Assessment Group calculated ICERs (cost per QALY gained for alendronate compared with no treatment) without identification costs for all combinations of age, T-score and number of independent clinical risk factors for fracture. The cost per QALY gained, compared with no treatment, became more favourable with increasing age and number of independent clinical risk factors, and decreasing T-score (that is, with increasing annual absolute risk of fracture).\n\nThen, the Assessment Group presented the results of the economic analyses in the form of identification and treatment strategies (based on age, T-score and number of independent clinical risk factors for fracture) that resulted in an ICER of £20,000 or less (cost per QALY gained compared with no treatment). The analyses shown below included the following assumptions: persistence at 5\xa0years set to 50%; the efficacy of bisphosphonates on fracture risks associated with factors other than age, BMD and prior fracture status set to 50% of that observed for the total population in the trials (with a consequent upward adjustment of the RR associated with age, BMD and prior fracture); costs set to health resource group values including home-help costs; utility multiplier associated with vertebral fracture set to 0.792 in the first year of fracture and 0.909 in subsequent years (as for hip fracture); costs of bisphosphonate-related gastrointestinal symptoms incurred over 5\xa0years; utility multiplier associated with bisphosphonate-related gastrointestinal symptoms set to 0.91 (included utility losses for non-compliant patients); and alendronate at a cost of £53.56 or £108.20 per year.\n\nFor alendronate priced at £53.56 per year (once-weekly treatment), and when assuming that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 65\xa0years resulted in an ICER of more than £20,000 per QALY gained.\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women who are confirmed to have osteoporosis (that is, a T-score of −2.5\xa0SD or below) resulted in an ICER of less than £20,000 per QALY gained for all women aged 70\xa0years or older, and for women aged 65–69\xa0years who have an independent clinical risk factor for fracture.\n\nIn a sensitivity analysis for alendronate priced at £53.56 per year (with other assumptions as in sections 4.2.16 and 4.2.17), acid-suppressive medication was assumed to affect fracture risk. The data inputs for this were taken from one GPRD study (see section\xa04.1.35) and represent the midpoint values pooled for patients using acid-suppressive medication. This sensitivity analysis produced the following results:\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 70\xa0years resulted in an ICER of more than £20,000 per QALY gained.\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women who are confirmed to have osteoporosis (that is, a T-score of −2.5\xa0SD or below) resulted in an ICER of less than £20,000 per QALY gained for all women aged 70\xa0years or older. The ICER for treatment with alendronate (but excluding identification costs) for a woman aged 70–74\xa0years with a T-score of −2.5 SD (using the assumptions described in sections 4.2.16 and 4.2.17) was £5496 per QALY gained without acid-suppressive medication and £13,236 per QALY gained with acid-suppressive medication. If this woman has an independent clinical risk factor for fracture, the ICERs would be £1567 per QALY gained without and £7727 per QALY gained with acid-suppressive medication.\n\nFor alendronate priced at £108.20 per year (daily treatment), and when assuming that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 70\xa0years resulted in an ICER of more than £20,000 per QALY gained.\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women who are confirmed to have osteoporosis (that is, a T-score of −2.5\xa0SD or below) resulted in an ICER of less than £20,000 per QALY gained for all women aged 75\xa0years or older and for women aged 70–74\xa0years who have an independent clinical risk factor for fracture. For women aged 70–74\xa0years but with no independent clinical risk factor, the T-score needs to be −3\xa0SD or below to give an ICER of less than £20,000 per QALY gained.\n\nRisedronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per year for alendronate); that is, these three drugs have a higher acquisition cost than alendronate, but are not more efficacious. Analyses were conducted as for alendronate (see section 4.2.16). For risedronate, base-case assumptions for bisphosphonate-related side effects were modelled; that is 2.35% of women in the first treatment month and 0.35% thereafter experienced side effects (see section 4.2.9). In addition a sensitivity analysis was performed, using the assumption that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects. For raloxifene and strontium ranelate, base-case assumptions for side effects were used. In previous economic modelling and before the most recent price reduction for non-proprietary alendronate, etidronate's cost effectiveness was comparable to that of non-proprietary alendronate, but the calculations were based on a weaker clinical evidence base than for alendronate. Therefore the modelling for etidronate was not updated after the most recent price reduction for alendronate.\n\nFor risedronate, raloxifene and strontium ranelate, additional analyses were conducted to explore identification and treatment strategies that could be cost effective for these interventions when compared with no intervention. All results showed less favourable cost effectiveness than non-proprietary alendronate. For example, for women aged 65–69\xa0years with an independent clinical risk factor for fracture, the ICERs (without considering costs related to risk assessment and DXA scanning) for risedronate and strontium ranelate (each compared with no treatment) were more than £45,000 and £90,000 per QALY gained, respectively. For these women, treatment with weekly non-proprietary alendronate, including risk assessment and DXA scanning costs, resulted in an ICER of less than £20,000 per QALY gained.\n\nFurther analyses were carried out assuming second-line use; that is, costs for risk assessment or DXA scanning were excluded because BMD was assumed to be known from the first-line management.\n\nIn the economic modelling carried out for this appraisal in 2006, lower ages and higher T-scores resulted in ICERs of less than £20,000 per QALY gained for etidronate compared with risedronate; that is, etidronate was more cost effective than risedronate. Because of the concerns expressed about the weaker clinical evidence base for etidronate, the modelling for this bisphosphonate was not updated.\n\nFor risedronate in second-line use, when assuming that 2.35% of women in the first treatment month and 0.35% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:\n\nTreatment with risedronate in women younger than 65\xa0years resulted in an ICER of more than £20,000 per QALY gained.\n\nTreatment with risedronate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £20,000 per QALY gained. Including women aged 65–69\xa0years with no independent clinical risk factors for fracture increased the ICER to more than £20,000 per QALY gained.\n\nT-scores (SD) at (or below) which risedronate in second-line use resulted in an ICER of less than £20,000 per QALY gained\n\nAge (years)\n\nNumber of independent clinical risk factors for fracture (section\xa01.5)\n\n\n\n\n\n\n\n–69\n\n– a\n\n−3.5\n\n−3.0\n\n–74\n\n−3.5\n\n−3.0\n\n−2.5\n\nor older\n\n−3.0\n\n−3.0\n\n−2.0b\n\na ICER more than £20,000 per QALY gained.\n\nb Women with osteopenia are not included in the guidance (see sections 1 and 4.3.6).\n\nFor raloxifene, the model produced the following results.\n\nTreatment with raloxifene in women of any age resulted in an ICER of more than £20,000 per QALY gained.\n\nFor strontium ranelate, the model produced the following results.\n\nTreatment with strontium ranelate in women younger than 65\xa0years resulted in an ICER of more than £20,000 per QALY gained.\n\nTreatment with strontium ranelate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £20,000 per QALY gained. Including women aged 65–69\xa0years with no independent clinical risk factors for fracture increased the ICER to more than £20,000 per QALY gained.\n\nT-scores (SD) at (or below) which strontium ranelate in second-line use resulted in an ICER of less than £20,000 per QALY gained\n\nAge (years)\n\nNumber of independent clinical risk factors for fracture (section\xa01.5)\n\n\n\n\n\n\n\n–69\n\n– a\n\n−4.5\n\n−4.0\n\n–74\n\n−4.5\n\n−4.0\n\n−3.5\n\nor older\n\n−4.0\n\n−4.0\n\n−3.0\n\na ICER more than £20,000 per QALY gained\n\nIf it was assumed that acid-suppressive medication affects fracture risk, the ICER for treatment with risedronate (compared with no treatment, but excluding identification costs) for a woman aged 75\xa0years with a T-score of −3 SD increased from £16,374 to £23,351 per QALY gained (using base-case assumptions about side effects). The corresponding ICER for strontium ranelate was £37,880 per QALY gained compared with no treatment (using base-case assumptions about side effects). For a woman aged 75\xa0years with a T-score of −3.5 SD and one independent clinical risk factor for fracture, the ICER for risedronate increased from £5116 to £10,505 per QALY gained when acid-suppressive medication was assumed to affect fracture risk (using base-case assumptions about side effects). The corresponding ICER for strontium ranelate was £20,935 per QALY gained compared with no treatment (using base-case assumptions about side effects).\n\n## Consultee comments on the Assessment Group's economic model\n\nFollowing the outcome of the judicial review and the court ruling of March 2009, NICE was able to offer the Assessment Group's executable economic model for consultation. Consultees and commentators who requested the model and returned the necessary confidentiality undertakings received a CD-ROM containing the executable version of the economic model, a document with instructions for running the model and a pro-forma for commenting on the model. Comments on the Assessment Group's model were received from Servier Laboratories (the manufacturer of strontium ranelate), the Bone Research Society (BRS), the National Osteoporosis Society (NOS) and the Society for Endocrinology. Comments received from each of these consultees are summarised in the sections below.\n\nThese four consultees expressed the view that the documentation provided with the Assessment Group's model was insufficient, that the model supplied to them was incomplete and that some inputs could not be altered. They also stated that the application of the fracture risk algorithm developed under the auspices of the WHO could not be assessed. They felt that the model could not be validated and that its validity had not been demonstrated in documents made available during development of the guidance.\n\nServier commented that the fracture risks entered in the Assessment Group's model differed from estimates that Servier calculated using the FRAX fracture risk calculation tool (see section 4.3.47 for further information about the FRAX tool). Servier commented that mortality risk associated with clinical risk factors had been omitted from the model. In Servier's opinion, these differences called into question whether the WHO fracture risk algorithm had been applied correctly in the Assessment Group's model.\n\nOther comments questioned the use of a fixed value for BMI in the model. Consultees commented that no clear explanation was provided of the rationale for the choice of BMI value, that a range of BMI values should have been used, and that the use of a fixed BMI value resulted in underestimation of the cost effectiveness of treatment for some women at risk of fracture.\n\nServier commented on the selection and weighting of the independent clinical risk factors for fracture used in the Assessment Group's model. Servier, BRS and NOS suggested that the risk associated with alcohol intake was incorrect in the model and that this would have adversely affected estimation of the cost\xa0effectiveness of treatment for women at risk of fracture. They suggested that a threshold alcohol intake of 3\xa0or\xa0more units per day, as used in the FRAX fracture risk calculation tool, should have been applied. They also stated that the Assessment Group's model and the guidance were inconsistent with each other, and that these differences resulted in the risk of fracture being underestimated in the model. Servier also noted that the Assessment Group's model gave an equal weighting to each of the independent clinical risk factors for fracture. Servier suggested that this was a less precise approach than that used in the FRAX tool, which used different weightings (some higher and some lower than those in the Assessment Group's model) for each fracture risk for specific risk factors. Servier stated that the FRAX tool assesses fracture risk and cost effectiveness more accurately and 'deals more fairly' with variation between women at risk of fracture. Servier also noted that one of the risk multipliers for fracture risk included in the Assessment Group's model was not consistent with that given in the assessment report.\n\nServier and NOS noted that the Assessment Group's model had a time horizon limited to 10\xa0years and criticised how mortality beyond 10\xa0years had been taken into account in the economic evaluation. Servier expressed the view that, as a consequence of this, the model was inaccurate and underestimated the cost effectiveness of treatment for women at risk of fracture. Servier also identified two values ('wristbonusat2.5' and 'phbonusat2.5', related to QALY calculations) that were included in the model, but not described in assessment reports.\n\nServier commented that using the same disutility for side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates.\n\nBRS and NOS thought that the proportion of women with low BMD in England and Wales was substantially underestimated in the Assessment Group's model. These consultees were also concerned that although both smoking and previous or current glucocorticoid (corticosteroid) use had been included as additional independent clinical risk factors for fracture in the Assessment Group's model, they were not defined as risk factors in the recommendations (see section 1.5). In addition, both consultees thought that interactions between several clinical risk factors were not incorporated in the model, thereby reducing the cost effectiveness of treatment for women at risk of fracture, especially younger women.\n\nAll four consultees commented on elements of the Assessment Group's economic evaluation that had been considered and agreed by the Appraisal Committee before it directed the Assessment Group to develop the economic model using specific assumptions. These Committee-directed assumptions included the compliance rate, costs associated with fracture, utility values used for vertebral fracture, and the strategy for identifying women at high risk. Servier also commented on the discount rates used in the model.\n\nServier reported that it had prepared a 'comparative' model which was run using assumptions similar to those in the Assessment Group's model. This model was referred to in a report to support the mathematical foundation of revised analyses discussed as part of Servier's comments on the Assessment Group's model. This report was made available to the Appraisal Committee to inform its consideration of comments by Servier on the DSU report (see below and section 4.3).\n\n## Decision Support Unit (DSU) report on consultee comments on the Assessment Group's economic model\n\nThe DSU was commissioned to review the comments from consultees on the Assessment Group's executable economic model and report to the Appraisal Committee. The DSU considered issues that were relevant to the economic model. Key issues were grouped under the common themes of model transparency and ability to assess its validity, methodology (approach) and model inputs.\n\nThe DSU assessed comments on the transparency and validity of the Assessment Group's model. With regard to the consultees' observation that some model inputs were fixed and that in their view the model provided for consultation was incomplete and not fully executable, the DSU confirmed that certain inputs were intentionally fixed and the ability to alter these inputs was not a feature of the model or necessary for some parameters with minimal uncertainty that are commonly fixed in other economic models. In response to comments on the consultees' inability to assess the application of the WHO algorithm, the DSU explained that the WHO algorithm itself was not embedded within the model. The DSU confirmed that absolute fracture risks were correctly calculated using the WHO algorithm before being entered into the model. The DSU noted that documentation had been provided to consultees in the form of publicly available reports and peer-reviewed manuscripts produced by the Assessment Group, and that instructions on the operation of the Assessment Group's model were also offered to consultees and commentators.\n\nWith regard to comments on the modelling approach adopted in the Assessment Group's model, the DSU responded by confirming that alcohol consumption of more than 2\xa0units per day was included in the model, and that the coefficients used in the model were consistent with the WHO algorithm (as supplied to the Assessment Group at the time the model was developed). The DSU also explored how the model considered corticosteroid-related fracture risk, and confirmed that corticosteroid use was included in the model and that the coefficient used for this risk factor was consistent with that calculated using the WHO algorithm. The DSU noted that the fracture risk of women using corticosteroids would have contributed to the overall fracture risk of the whole modelled population and thereby reduced the ICER associated with the treatment of all women at risk of fracture.\n\nThe DSU confirmed that each clinical risk factor for fracture was given equal weighting in the model. In response to consultee comments expressing the view that this was a less precise approach than that used in the FRAX tool, the DSU noted two points. Firstly, no individual risk calculation tool was publicly available when the model was developed. Secondly, the DSU referred to the 2005 Strontium Ranelate Assessment Report, which compared suggested treatment thresholds (combinations of age, T-score and number of independent clinical risk factors for fracture) from the Assessment Group's model with treatment thresholds indicated by absolute fracture risk. The DSU suggested that the use of absolute fracture risk alone did not accurately predict cost effectiveness, and therefore would not provide a robust basis for the Committee's decision-making.\n\nConsultee comments on the modelling approach also addressed the time horizon and population data used and the grouping of age in 5-year bands. The DSU confirmed that the consequences of fracture were considered beyond 10\xa0years, and provided further explanation of the modelling approach. The DSU additionally undertook exploratory analyses of the impact of mortality after the 10-year time horizon and of incorporating mortality associated with vertebral fracture and proximal humerus fracture. They reported that the change in the results produced by the model was minimal when mortality risk beyond 10\xa0years was doubled. The DSU also confirmed that UK epidemiological data from a study by Holt et al. were used in the Assessment Group's model, and undertook an exploratory analysis around the assumptions of the distribution of T-scores used in the model. For some age bands modelled, the T‑scores did not follow a statistically normal distribution, but the DSU noted that the assumption of a normal distribution made it more likely that treatments for women at risk of fracture would be judged to be cost effective. The DSU considered a comment on the calculation of cost-effectiveness estimates averaged for the 5-year age bands implemented in the model. It disagreed with the alternative suggested by the consultee and noted that the Committee had considered and agreed that initial identification by age band was a workable strategy for selecting women at risk of fracture in clinical practice. It also noted that alternative strategies (which did not use age bands) may in fact be more resource-consuming and less likely to be judged as cost effective.\n\nThe DSU reviewed consultee comments on inputs used in the Assessment Group's model. It confirmed that the WHO algorithm (as supplied) had been correctly implemented in the model to produce estimates of fracture risk for each T-score band. The DSU suggested that the differences in the estimates of fracture risk obtained using the FRAX fracture risk calculation tool and the Assessment Group's model did not necessarily suggest that the WHO algorithm had been incorrectly applied (see section 4.3.47), and that these differences could occur for a number of reasons. For example, the use of a midpoint age to represent an age band of 5\xa0years could lead to differences in estimates of fracture risk. The DSU confirmed that no increase in mortality associated with clinical risk factors was used in the model. The DSU suggested that inclusion of such mortality effects would be likely to increase the ICERs for women with those clinical risk factors. The DSU explained that this is because fewer QALY benefits would accrue in the model for women who die of causes related to risk factors. In response to a further comment from Servier, the DSU agreed that, for women without clinical risk factors, the inclusion of these mortality effects in the model may have the opposite effect (that is, a decrease in ICERs). Therefore the overall effect of including the increased mortality associated with clinical risk factors would be small.\n\nThe DSU also confirmed that a fixed value for BMI of 26\xa0kg/m2 was used in the Assessment Group's model. This was the mean BMI in the UK epidemiological dataset from the Holt study used in the model. In an exploratory analysis using the WHO algorithm, the DSU showed that using a BMI of 26\xa0kg/m2 resulted in higher estimated fracture risk than a BMI of 20 or 32\xa0kg/m2 when BMD is known, and this was confirmed by the estimates supplied by one consultee. The DSU suggested that the BMI value used in the model may favour treatment of women at risk of fracture compared with alternative BMI values. The DSU also pointed out that BMI is a weak predictor of fracture when BMD is known (as specified in the identification strategy in the guidance).\n\nThe DSU investigated the risk multipliers used for fracture risk in the Assessment Group's model and the consultee comment that interactions between clinical risk factors had been omitted. It confirmed that the risk multipliers used for fracture risk had been correctly calculated from the WHO algorithm and that all interactions between risk factors had been included. The DSU also noted that the inconsistency between one of the risk multipliers for fracture risk included in the Assessment Group's model compared with the assessment report was the result of a typographical error. Accordingly there was no impact on the results of the model.\n\nThe DSU did not respond in detail to comments on assumptions in the model that had already been documented and agreed by the Appraisal Committee and which were available to consultees and commentators earlier in the development of the appraisal guidance. The DSU did, however, list these issues in its report and cited where they had been considered by the Committee or had been available for comment during development of the guidance. Features of the economic evaluation previously discussed and agreed by the Committee included the following (the sections of this document where these points are covered are given in parentheses):\n\ndiscount rates used in model (4.2.9)\n\ntreatment compliance (4.2.9)\n\ncosts associated with fracture (4.2.16)\n\nstrategy for identifying women at high risk of fracture (4.2.16)\n\nutility values used for vertebral fracture (4.2.16 and 4.3.12)\n\nequal disutility for the side effects of strontium ranelate and bisphosphonates (4.2.9)\n\nsensitivity analyses on disutility (4.3.14).\n\nThe DSU concluded that, in its view, adequate documentation on the Assessment Group's model had been provided for consultees. It highlighted that the WHO algorithm used to generate estimates of fracture risk was not integrated within the Assessment Group's model; rather, the fracture risks derived from the algorithm were entered into the model. Comparisons with fracture risks derived using the FRAX fracture risk calculation tool were made by several consultees on the basis that the WHO algorithm supplied to the Assessment Group and the FRAX tool are assumed to be identical. The DSU could not verify these analyses without access to the FRAX algorithm. The DSU agreed that some parameters in the Assessment Group's model were fixed. These included those with minimal uncertainty, as well as those that are commonly fixed in other economic models. Sensitivity analyses conducted by the DSU suggested that none of the consultees' suggestions relating to the modelling approach would lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The DSU concluded that, in its view, no issues raised by consultees would either affect the validity of the Assessment Group's model or raise significant doubts about the appropriateness of using the model to inform the deliberations of the Committee.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alendronate, etidronate, risedronate, raloxifene and strontium ranelate, having considered evidence on the nature of osteoporosis and the value placed on the benefits of these drugs by women with the condition, those who represent them, and clinical specialists. It also considered the consultation comments received in response to the previous appraisal consultation documents, the extra analysis undertaken by ScHARR in November 2006 and February 2008, and comments received from consultees and commentators after an appeal against an earlier final appraisal determination was upheld in December 2007. Following the outcome of a judicial review and court ruling in March 2009, the Committee considered the comments received from consultees after release of the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report. It also took into account the effective use of NHS resources. The Committee was aware of a previous decision of the National Screening Committee not to recommend screening to prevent osteoporotic fracture because of concerns about the accuracy of BMD assessment for the prediction of fracture and because there was no trial evidence indicating that such screening would reduce the incidence of fractures.\n\nThe Committee considered the clinical effectiveness data for the bisphosphonates (alendronate, etidronate and risedronate), strontium ranelate and raloxifene. It noted that all these drugs have proven efficacy in reducing the incidence of vertebral fragility fractures in women with osteoporosis, but that there were differences between the drugs in the degree of certainty that treatment results in a reduction in hip fracture (considered a crucial goal in osteoporosis management). In the case of alendronate and risedronate, the Committee accepted that there was sufficiently robust evidence to suggest a reduction in hip-fracture risk. The Committee noted that the available RCTs for etidronate were of insufficient size to show statistically significant reductions in hip-fracture risk, but that observational data lent support to a reduction in hip-fracture risk.\n\nThe Committee noted that strontium ranelate was effective in preventing vertebral and non-vertebral fractures, and the drug resulted in a non-significant 15% reduction in hip-fracture risk. The Committee was also aware of the result of a post-hoc subgroup analysis showing a statistically significant reduction in the incidence of hip fractures in women aged 74\xa0or older who had a T-score of −2.4\xa0SD or below.\n\nThe Committee noted that the evidence for raloxifene showed an effect on risk of vertebral fractures, but did not show an effect on risk of hip fractures. In addition, there was evidence for a beneficial side effect of raloxifene on the incidence of breast cancer.\n\nThe Committee did not consider it appropriate to make recommendations for the treatment of women on long-term corticosteroid treatment because this patient group is at greatly increased risk of fracture and therefore requires special consideration. The Committee was aware that for women without prior fracture but on corticosteroid treatment, the fracture risk is as high as, or even higher than, the fracture risk for women with a prior fracture. The Committee therefore felt that it would be disadvantageous for this group to be included in the current guidance.\n\nRecommendations for the treatment of women with osteopenia (T-score of between –1 and –2.5\xa0SD below peak BMD) were not made, for two reasons. Firstly, it was agreed after the scope was issued in 2002 that the outcome in this appraisal should be 'the prevention of osteoporotic fractures' and this has been understood by the Committee to be a fragility fracture experienced by women with osteoporosis, not osteopenia. Secondly, not all of the drugs under appraisal have a UK marketing authorisation for treatment of women with osteopenia.\n\n## Cost-effectiveness modelling\n\nBecause women who have not had a fracture would not normally present to clinicians, the Committee considered it necessary to consider the costs involved in the assessment of fracture risk and of DXA scanning in its appraisal of the drugs for the primary prevention of osteoporotic fragility fractures.\n\nThe Committee acknowledged the efforts of the Assessment Group to build on the model used previously, particularly in using epidemiological data and a fracture risk algorithm developed under the auspices of the WHO to calculate transition probabilities and to model the identification approaches. The Committee noted that fracture risk is clearly related to age, low BMD and prior fracture. The Committee accepted that most of the independent clinical risk factors for fracture listed in section\xa04.2.11 are likely to be associated with an increased fracture risk. The Committee was not persuaded that 'current smoking' is a statistically significant risk factor in women, but noted that alcohol consumption of 4 or more units per day is a statistically significant risk factor. However, even for the statistically significant risk factors, the Committee was concerned that there was not sufficient evidence for a proven treatment effect on fracture risk related to risk factors other than low BMD, age and prior fracture.\n\nWith these caveats in mind, the Committee concluded that the Assessment Group's model was a useful basis for exploring the estimates of cost effectiveness; the model used data for a wide age range (age 50–75\xa0years and older) and all osteoporotic fracture sites. Although the Assessment Group's model considered a shorter time period (10\xa0years for predicting morbidity, see section 4.2.8) than the manufacturers' models, the Committee thought that this was appropriate considering the age groups involved and the uncertainties around health effects over a longer period.\n\nThe Committee discussed the assumptions underpinning the economic modelling undertaken by the Assessment Group. It noted that the most recent modelling explored some of the uncertainties identified by the Committee surrounding the results of the previous modelling; these related to the costs and disutility associated with treatment-related side effects and to non-compliance or non-persistence with treatment in a proportion of patients. The Committee also noted the effect of the recent price reductions for non-proprietary alendronate (70\xa0mg\xa0weekly and 10\xa0mg daily doses) on the cost effectiveness of the drug.\n\nThe Committee considered the base-case assumptions and those used in additional analyses. The Committee noted that the costs associated with fractures used in the base-case analysis were those used in the original assessment report developed in 2003 and considered that these were likely to be outdated. The Committee agreed that costs based on health resource groups, including home-help costs, were likely to provide the most accurate reflection of the cost of fractures to the NHS and personal social services, and it decided to incorporate these costs into the base-case analysis.\n\nThe Committee considered the utility multiplier used in the base-case analysis for the first year after a vertebral fracture and noted that it was based on a hospitalised patient group and not on a typical group of patients with vertebral fractures. Consequently it was considerably lower than the utility value modelled for a hip fracture. Although the Committee acknowledged that vertebral fracture can lead to greatly reduced quality of life, it considered that its true value would not greatly outweigh the utility decrement associated with a hip fracture. Therefore, the Committee considered it reasonable to assume that the disutility in the first year after a vertebral fracture was equivalent to the disutility in the first year after a hip fracture and decided to include this assumption in the base-case analysis.\n\nThe Committee was not persuaded that the drugs under consideration had been unequivocally shown to reduce fracture risk that was attributable to risk factors not mediated through low BMD and age. The Committee concluded that the uncertainty surrounding the efficacy of the drugs on risk factors not mediated through low BMD and age should be factored into its decision-making by using an analysis that assumed 50% efficacy of the drugs on fractures associated with risk factors other than age and low BMD. Although the Committee recognised that 50% was necessarily an arbitrary figure, the use of either 0% or 100% was considered both extreme and less plausible. In the analysis accepted by the Committee, the assumption of 50% efficacy of the drugs on fracture risk associated with other risk factors was adjusted by using a correspondingly greater efficacy of the drugs on fractures associated with the key independent clinical risk factors (age, BMD and prior fracture).\n\nThe Committee considered the assumptions used in the modelling for the side effects of bisphosphonates, in which women who experience bisphosphonate-related side effects had 91% of the utility of women who did not have such side effects. In the base case, this was applied to 2.35% of patients in the first treatment month and 0.35% of patients thereafter. Taking into account the persistence data (sections\xa04.1.31 and 4.1.32) and the comments received from consultees and commentators that about 25–30% of women experience gastrointestinal side effects when first taking a bisphosphonate, the Committee agreed that it was important to consider the results of a sensitivity analysis assuming that 24% of women were experiencing bisphosphonate-related side effects in the first treatment month and 3.5% of women thereafter.\n\nThe Committee acknowledged that the modelling of the identification strategies made assumptions necessary about the value of a QALY gained that could be considered an acceptable use of NHS resources. The Committee acknowledged this to be £20,000, as modelled, because there were no additional factors, as referred to in the 'Guide to the methods of technology appraisal' (see www.nice.org.uk), that could be considered to increase this value in this situation: that is, in primary prevention where an asymptomatic group of adult patients with a high number needed to treat to avoid a fracture is under consideration.\n\nThe Committee discussed a number of concerns surrounding other issues that were not represented in the model but which may have had an impact on the cost-effectiveness estimates. These included: possible long-term adverse effects of bisphosphonates on the formation of new bone; the probability that more GP time would be involved in identifying women with risk factors associated with osteoporosis; the likelihood that DXA scanning outside a clinical trial environment would not be as effective as in the clinical trials; and the possibility that the proportion of women who experience side effects may exceed the model's base-case assumptions. Finally, the Committee noted that current discount rates used by the Treasury, the Department of Health and NICE result in a cost-effectiveness calculation less favourable to the drugs than the discount rates used in the analysis considered by the Committee. Although a quantitative analysis of the uncertainties surrounding all these issues was not available, the Committee agreed that, for first-line treatment with a bisphosphonate, these uncertainties could be collectively approximated through the sensitivity analysis for side effects (see section\xa04.3.14). The Committee was persuaded, however, that the results of the sensitivity analysis need only apply to first-line treatment with a bisphosphonate, because many of the factors that led to the adoption of the sensitivity analysis did not apply for second-line treatment.\n\n## Alendronate\n\nThe Committee considered the results of the economic model following the price reduction for non-proprietary alendronate, the newly included assumptions and the sensitivity analyses (see sections\xa04.3.8 to 4.3.14). The Committee agreed that, when considering the use of alendronate as a first-line treatment, the sensitivity analysis that captured the uncertainties in the economic model (see section\xa04.3.14) was the most appropriate. This led the Committee to conclude that alendronate (based on the price of £53.56 per year for once-weekly treatment) would be an appropriate use of NHS resources for the treatment of postmenopausal women who are confirmed to have osteoporosis (that is, a T-score of −2.5\xa0SD or below) who are aged 65\xa0years or older and who have at least one independent clinical risk factor for fracture. The Committee also concluded that, in addition, women aged 70\xa0years and older could be considered for DXA scanning if there was an indication that they might have low BMD, and treated with alendronate if osteoporosis was confirmed. The Committee's reason for restricting DXA scanning for women aged 70\xa0years or older (who visit their GP for any reason) to those with indicators of low BMD was to avoid unnecessarily scanning many women who are well and asymptomatic and who are relatively unlikely to have a low BMD. The Committee was advised by the clinical specialists from the original Guideline Development Group for the NICE clinical guideline on osteoporosis that, in women aged 75\xa0years or older with two or more clinical risk factors, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible. This is because a very high proportion of these women would be likely to have a T-score of −2.5 SD or below.\n\nHaving reviewed the evidence on independent clinical risk factors for fracture and the views of the clinical specialists, the Committee agreed that the appropriate independent clinical risk factors for fracture are: parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee also concluded that there are indicators of low BMD, and these are low BMI (defined as less than 22\xa0kg/m2) and medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause. The Committee acknowledged that rheumatoid arthritis is a condition that indicates low BMD, but was also proven to be an independent clinical risk factor for fracture. The Committee noted that prior fracture and long-term systemic corticosteroid use are also relevant clinical risk factors; women with prior fracture or who are on long-term systemic corticosteroid treatment will be considered in NICE technology appraisal guidance on the secondary prevention of osteoporosis.\n\nThe Committee noted that the prices of the different brands of alendronate vary greatly and concluded that alendronate should be prescribed on the basis of the lowest acquisition cost available.\n\nThe Committee considered postmenopausal women below the age of 65\xa0years for whom opportunistic identification was not normally cost effective. The Committee recognised that a small number of postmenopausal women below the age of 65\xa0years who present to healthcare practitioners with conditions that are indicators of low BMD are at high risk of osteoporotic fracture and would not need opportunistic identification. Therefore the Committee concluded that women under 65\xa0years of age with rheumatoid arthritis, ankylosing spondylitis, Crohn's disease or any condition that has resulted in prolonged immobility, provided that they also have an independent clinical risk factor for fracture, should be considered for DXA scanning, and treated with alendronate if osteoporosis is confirmed.\n\n## Considerations for the other drugs under appraisal\n\nThe Committee noted that risedronate, etidronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per year for alendronate); that is, these drugs have a higher acquisition cost than alendronate, but are not more efficacious. The Committee was also aware that, for women for whom weekly non-proprietary alendronate could be recommended based on cost effectiveness, the ICERs for risedronate and strontium ranelate were very high, even without inclusion of identification costs (see examples in section 4.2.21).\n\nThe Committee considered an approach where the higher costs of risedronate and strontium ranelate were incorporated into the analysis by combining costs based on the estimated use of alendronate, risedronate and strontium ranelate. However, the overall cost effectiveness of such a combined approach for fracture prevention would be less favourable than that of alendronate. As a consequence, some women who would be eligible for treatment with alendronate as recommended in section 1.1 would not be offered treatment using such a combined approach. For this reason, the Committee did not consider the combined approach to be appropriate.\n\nThe Committee considered treatment options available for a woman who is intolerant to alendronate or unable to comply with instructions for administration despite reasonable measures to support continuation of alendronate treatment. The Committee noted that all other treatment options have higher acquisition costs and/or different effectiveness profiles, which would reduce the cost effectiveness of preventive treatment if these drugs were used. The Committee observed that the identification costs associated with finding women who could be cost-effectively treated with one of the other drugs would be negligible, because they would have already undergone an assessment and had a DXA scan in order to be assessed for first-line treatment with alendronate. Therefore, it agreed that the recommendations for this situation should be based on the modelling that excluded identification costs. The Committee also agreed that, when considering second-line or subsequent treatment, the base-case assumptions for side effects could be applied; that is, a 0.91 utility multiplier should be applied to 2.35% of patients in the first treatment month and 0.35% of patients thereafter.\n\nThe Committee considered women who cannot take alendronate because of a contraindication or a disability that prevents them from complying with the instructions for administration. Because such a contraindication or disability would be known before the risk assessment, this would comprise a first-line treatment situation, where identification costs are included. Alternative drugs become cost effective at a higher age and lower BMD in a first-line treatment situation, compared with a second-line treatment situation where identification costs are not included. However, such an approach was considered inappropriate by the Committee because it would unfairly disadvantage women who cannot take alendronate because of a contraindication or a disability. Therefore the Committee concluded that women who cannot take alendronate for these reasons should have access to alternative drugs in the same way as women who cannot tolerate alendronate (that is second-line treatment, where the analysis excluded identification and assessment costs).\n\nThe Committee concluded that risedronate could be recommended for women who are unable to comply with the special instructions for the administration of alendronate, or have a contraindication to or are intolerant of alendronate, and who have a combination of T-score, age and number of independent clinical risk factors for fracture where treatment with risedronate resulted in an ICER of less than £20,000 per QALY gained without the consideration of identification costs, as outlined in sections\xa04.2.23–24. The Committee agreed that in women aged 75\xa0years or older, where the T-score needed to make treatment cost-effective was −2.5 SD or below, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible (see section 4.3.17).\n\nThe Committee considered the cost effectiveness of etidronate, and noted that in previous modelling etidronate had a better cost-effectiveness profile than risedronate; since then there has been no change in the evidence base that would affect the relative position of these two drugs. In view of its concerns surrounding the clinical evidence base for etidronate, and taking into account the views of clinical specialists and consultees, the Committee decided that etidronate should not be recommended in preference to risedronate. However, the Committee agreed that guidance on the use of etidronate should be included in the recommendations, and concluded that etidronate can be recommended as an alternative treatment option for women who cannot take alendronate, as outlined for risedronate in section\xa04.3.25. In deciding between risedronate and etidronate, clinicians and patients need to balance the overall effectiveness profile of the drugs against their tolerability and adverse effects in individual patients.\n\nFollowing the Court of Appeal Order of April 2010, the Committee considered the clinical and cost effectiveness of strontium ranelate, focusing on the most appropriate estimate for the efficacy in reducing the rate of hip fracture. The Committee considered the additional submission from Servier (see sections 4.1.37 to 4.1.43), a report by the DSU (see sections 4.1.44 to 4.1.49) reviewing this new submission and Servier's response to the DSU report (see section 4.1.50). At its meeting on 20 October 2010, the Committee heard from representatives of Servier and a representative of the DSU.\n\nThe Committee first considered whether it was plausible that strontium ranelate has a greater or lesser relative benefit in any subgroup of the population for which it has a marketing authorisation (that is, whether a different RR for hip fracture could be assumed to apply to some women). The Committee was aware of the advice received from the original Osteoporosis Guideline Development Group that drugs for osteoporosis have constant RR reductions irrespective of age, BMD and prior fracture status (see section 4.2.6).\n\nThe Committee noted the DSU's advice that the correct statistical procedure for investigating if a subgroup of trial participants has a significantly different response to treatment is a test for interaction (see section 4.1.44). No test for interaction had been undertaken for the high-risk subgroup from TROPOS. The Committee also noted that it had not received evidence of a differential benefit, supported by a test for interaction, in any subgroup of any trial of osteoporosis drugs.\n\nThe Committee noted Servier's view that an age cut-off of 74\xa0years was justified by the epidemiological findings of Donaldson et al. (see section 4.1.39). It understood from the DSU that this paper suggests that the rate of hip fracture rises to a notable level after 75\xa0years of age (see section 4.1.46). The Committee also noted that Donaldson et al. state that the absolute risk of hip fracture increases 'steadily' with age: although women are at greater risk of hip fracture as they grow older, there is no particular age at which the risk jumps from low to high. The Committee therefore concluded that Donaldson et al.'s study did not provide support for the use of a specific age cut-off of 74\xa0years.\n\nThe Committee recognised the hypothesis advanced by Servier that there may be biological grounds for assuming an additional effect for strontium ranelate in older women (see section 4.1.41). However, it considered that it should be possible to demonstrate any such effect by statistical and biochemical tests, and it heard from Servier's representatives that no such evidence had been collected. The Committee concluded that a hypothesis alone, without supporting evidence, was insufficient to demonstrate a differential benefit for strontium ranelate in older women.\n\nFor these reasons, the Committee concluded that it could not justify discounting previous advice that drugs for osteoporosis are assumed to have the same relative effect regardless of age, BMD and prior fracture status. Therefore, it agreed that it was most appropriate for the cost-effectiveness model to rely on a single RR to quantify the effect of strontium ranelate in preventing hip fractures in all postmenopausal women with osteoporosis. As a result, the Committee did not concur with the view that it might choose to provide a specific recommendation only for women corresponding to the high-risk subgroup analysed by Servier, based on an assumption of differential effectiveness of strontium ranelate in those women.\n\nThe Committee then considered the value that represents the most appropriate estimate of effect (RR) for strontium ranelate in preventing hip fractures. It discussed Servier's view that the best estimate of effect for the whole population would be that observed in the high-risk subgroup – an RR of 0.64 (see section 4.1.42). The Committee emphasised that, in order to adopt this figure for the whole population, it would first need to be confident that it was a robust estimate of treatment effect. It discussed the process by which the high-risk subgroup had been selected by Servier. It noted that the pooled data from the placebo arms of TROPOS and SOTI had been screened to establish a subgroup at increased risk of hip fracture (see section 4.1.39). The Committee agreed with the DSU's advice that the method used to identify the age cut-off for the subgroup was 'data-dependent' and, therefore, the RR for strontium ranelate derived from this approach was likely to be inflated (see section 4.1.45).\n\nThe Committee also discussed whether it would be appropriate to use an RR derived from a subgroup of trial participants to quantify the effect of a drug in the whole population for which it has a marketing authorisation. It considered Servier's assertion that, in contrast to the whole trial population, the high-risk subgroup of TROPOS provided a statistically robust demonstration of the effect of strontium ranelate in preventing hip fractures (see section 4.1.42). It acknowledged that TROPOS did not include enough participants to demonstrate a statistically significant benefit for strontium ranelate in preventing hip fractures and that, because of this, it would be appropriate to consider using an estimate of effect that was more precise (that is, subject to less statistical uncertainty) than that derived from the whole trial population. The Committee accepted the DSU's advice that the precision of an RR is primarily influenced by the absolute number of observed events (in this case the absolute number of fractures), which would be greatest in the whole trial population. Additionally, it noted that the size of the groups – and, therefore, the rate of events – is important, so that, in theory, it is possible that an estimate of effect from a subgroup may be more statistically precise than the estimate from the whole trial population from which the subgroup is derived. However, in the case of TROPOS, the estimates from the subgroup and the whole trial population had 95% confidence intervals of very similar width. Therefore, the Committee did not accept that the RR in the subgroup was more precise than the RR in the whole trial population. As a result, the Committee concluded that there was no reason to assume that the subgroup analysis was any more statistically robust than the analysis of the whole trial population. The Committee also noted that it is incorrect to infer that one estimate is more accurate than another just because it achieved conventional standards of statistical significance whereas the other did not.\n\nTaking all this into account, the Committee decided that it would not be appropriate to adopt an RR of 0.64 in assessing the cost effectiveness of strontium ranelate, because the method for the subgroup selection was likely to favour strontium ranelate, and because the RR derived in this way was no more precise that the RR from the overall population.\n\nThe Committee further noted that when values derived from subgroups have been considered in NICE technology appraisals, the evidence has been used to inform specific recommendations applying only to groups of people with the same characteristics as those in the trial subgroup. The Committee reiterated its conclusion that it had not received unambiguous evidence of differential benefit from strontium ranelate in any particular group (see sections 4.3.27 to 4.3.32). The Committee was aware that, in order to make recommendations for cost-effective treatment to prevent fractures in postmenopausal women with osteoporosis, it was necessary to consider separate populations defined by age, T-score and independent clinical risk factors. However, these populations are defined because the absolute likelihood of fracture increases in the presence of these risk factors and not because of variations in the relative benefit of treatment.\n\nThe Committee next considered the possibility of adopting an RR of 1.00 to quantify the effect of strontium ranelate in reducing hip fractures. It noted that the 95% confidence interval around the RR from the whole TROPOS population spanned unity (the upper limit was greater than 1). This means that, at the 95% confidence level, the observed results could from a statistical point of view be interpreted as being consistent with strontium ranelate having no effect. The Committee noted that, when the other drugs within this appraisal had been associated with RRs with 95% confidence intervals spanning 1, the model had assumed no effect (RR\xa0=\xa01.00). Therefore, it might be considered consistent to apply the same logic to the estimation of the effectiveness of strontium ranelate. However, the Committee heard the DSU's advice that it is important to base cost-effectiveness analysis on the most plausible estimate for each parameter, with associated uncertainty explored in sensitivity analysis. The Committee also agreed with the DSU's view that the available evidence suggests that strontium ranelate is effective in reducing the risk of hip fracture. For these reasons, the Committee concluded that it would be inappropriate to assume that strontium ranelate has no effect on the incidence of hip fractures, and rejected the use of an RR of 1.00 in the model.\n\nFinally, the Committee discussed using an effect estimate of 0.85 – the RR of hip fracture observed in the whole TROPOS population. It noted the DSU's advice that, in the absence of a robust demonstration of differential benefit in one or more subgroup of a trial, it is most appropriate to rely on an intention-to-treat analysis of the whole trial population (see section 4.1.48). Having concluded that it had not seen evidence of a differential benefit for a specific subgroup in TROPOS, and having rejected the use of the alternative values 0.64 and 1.00 for the whole population, the Committee concluded it had no reason to depart from this principle. It therefore concluded that an RR of 0.85 represented the most appropriate estimate of effect for strontium ranelate in preventing hip fractures in postmenopausal women with osteoporosis. As a result, the Committee agreed that the Assessment Group had been correct to use an RR of 0.85 in its cost-effectiveness calculations to reflect the effect of strontium ranelate in reducing the rate of hip fractures (see section 4.2.7).\n\nThe Committee concluded that strontium ranelate can be recommended for women who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate, and who have a combination of T-score, age and number of independent clinical risk factors for fracture where treatment with strontium ranelate resulted in an ICER less than £20,000 per QALY gained without the consideration of identification costs, as outlined in section\xa04.2.26.\n\nThe Committee agreed a definition of alendronate, risedronate or etidronate intolerance as: persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment with alendronate or risedronate and that occurs even though the instructions for administration have been followed correctly.\n\nThe Committee discussed the reported benefits of raloxifene on breast cancer risk, and heard from the clinical specialists that the possibility of preventing vertebral fractures and breast cancer simultaneously could be attractive, particularly to younger postmenopausal women. The Committee also heard from the specialists that evidence on the effect of raloxifene in reducing cardiovascular risk is not considered to be robust and that there is some concern over the increased risk of VTE (see section\xa04.1.25).\n\nThe Committee noted that a higher proportion of the overall benefit associated with raloxifene was attributable to its effect on the prevention of breast cancer than to its effect on the prevention of osteoporotic fragility fractures. The Committee agreed that, in principle, the side effects of using a drug should be considered; however, there were a number of reasons why the Committee considered that the breast cancer benefit should not be the sole factor in deciding whether raloxifene is a cost-effective option for treatment for the primary prevention of osteoporotic fragility fractures, as follows:\n\nFrom the evidence presented, raloxifene was not as effective as the bisphosphonates for treating osteoporosis.\n\nFull assessment of raloxifene's effect on the prevention of breast cancer and its cost effectiveness in this indication would require consideration of how it compares with other drugs that could be used for breast cancer prevention.\n\nThe Committee noted that treatment with raloxifene did not result in an ICER of less than £20,000 per QALY gained in any age group, even when identification costs were excluded from the modelling. Therefore, the Committee did not consider raloxifene to be a cost-effective use of NHS resources for the primary prevention of osteoporotic fragility fractures in postmenopausal women.\n\n## Women who cannot take alendronate\n\nThe Committee carefully considered the position of women who cannot take alendronate because of a condition which either makes alendronate contraindicated or which prevents individuals from complying with the instructions for administration for alendronate. In doing so the Committee noted that at least some women in this patient group were likely to be 'disabled' as defined by the Disability Discrimination Act 1995. The Committee was aware of its duties under that Act to avoid unlawful discrimination, to have due regard to the need to promote equality of opportunity for disabled people, and the need to take steps to take account of disabled people's disabilities, as well as its broader legal duties to ensure that its guidance is fair and reasonable.\n\nThe Committee noted that the drugs other than alendronate are cost effective only for patients at higher risk of fracture than the risk levels at which alendronate is cost effective. If these other drugs are recommended for use by patients who cannot take alendronate only when those patients meet the criteria at which these alternative drugs become cost effective, these patients will not receive preventative treatment unless they are at higher risk of fracture than the risk levels at which alendronate is recommended. The Committee therefore considered whether, for women who cannot receive alendronate, the other drugs should be recommended at the same risk levels as alendronate (that is using the criteria established as being cost effective for alendronate) in order to provide access to preventative treatment for all patients with the same level of risk. The Committee reviewed the ICERs for risedronate and strontium ranelate within the criteria established to be cost effective for alendronate. The Committee noted that the prices for risedronate and strontium ranelate are approximately five to six times higher than the price for non-proprietary weekly alendronate, and that the ICERs for these drugs compared with no treatment were very high. For example, the ICER for strontium ranelate for women aged 65–69\xa0years with an independent clinical risk factor for fracture was approximately £90,000 per QALY gained (see section 4.2.21). The Committee noted that strontium ranelate would be the most likely choice to be considered for women who are unable to comply with the instructions for administration of alendronate, because the instructions for administration of alendronate and risedronate are similar. The Committee took the view that recommending drugs other than alendronate using the same criteria as alendronate for women who cannot take alendronate would not be justified in this case because of the very high ICERs for the alternative drugs. In reaching this decision the Committee had regard to the fact that the impact of refusing the more favourable recommendation is that there is no generally recommended preventative treatment for a particular group of patients who are at the lower end of fracture risk for which treatment was considered, but that the alternative drugs are recommended when these patients are at higher risk of fracture.\n\nThe Committee considered that it is important to maximise the number of patients who are able to take alendronate. Some women will be unable to take alendronate in any circumstances because of contraindication, intolerance or inability to comply with the instructions for administration. However, some women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate would be able to receive the drug if they received assistance in taking it. The Committee concluded that all reasonable steps should be taken to provide women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate, with such practical support and assistance with administration (for example through district nurse visits or other home support services), as will enable them to take the drug.\n\n## FRAX fracture risk calculation tool\n\nThe Committee was aware of the availability of the FRAX internet-based tool, which can be used to calculate a 10-year absolute risk of fracture, developed under the auspices of the WHO. This assessment tool was based on the same epidemiological data that were used in the Assessment Group's model. However, the Committee was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX. Firstly, the Committee did not agree that all clinical risk factors included in the WHO algorithm were appropriate (see sections 4.2.11 and 4.3.8). Secondly, the Committee was aware that absolute fracture risk is not directly related to cost effectiveness, as outlined in the 2005 Strontium Ranelate Assessment Report. This is because absolute fracture risk is the total for all fracture sites, but different fracture sites have different impacts on quality of life, costs and mortality. Therefore cost effectiveness is dependent on the contribution from each fracture site to the total fracture risk. Thirdly, the Committee had agreed that treatment benefit had not been proven for fracture risk associated with all independent clinical risk factors (section\xa04.3.8). Therefore, the Committee concluded that using a combination of T-score, age and number of independent clinical risk factors for fracture is more appropriate for defining treatment recommendations in this appraisal.\n\n## Evidence on use of acid suppressive medication and fracture risk\n\nThe Committee was made aware of data indicating that acid-suppressive medication leads to a small increase in fracture risk and that co-administration of acid-suppressive medication and bisphosphonates may lead to an increased fracture risk compared with bisphosphonate administration alone. The Committee was not persuaded by this evidence; it noted that the data are observational and have not been reported in full, and are different for different fracture sites and for different acid suppressors. Furthermore, the Committee was informed, during consultation, of analyses showing that acid-suppressive medication given in addition to risedronate did not increase fracture risk. The Committee concluded that caution should be exercised when considering the evidence about co-prescription of acid-suppressive medication and bisphosphonates.\n\nThe Committee noted sensitivity analyses that included the assumption of an increase in fracture risk for women for whom acid-suppressive medications are co-prescribed (see section 4.2.18). The analysis for treatment strategies did not decrease the T-scores at which the ICERs for alendronate fell below £20,000 to the T-scores established for strategies including strontium ranelate. The Committee also noted that the ICERs for treatment compared with no treatment for an individual woman with a relevant combination of age and T-score were not more favourable for strontium ranelate than for risedronate even if an effect of acid-suppressive medication was assumed. The Committee considered that the evidence for this effect was not sufficiently robust. However, it concluded that the relative positions of alendronate, risedronate and strontium ranelate would remain unchanged even if an effect of acid-suppressive medication was assumed. The Committee therefore concluded that it was not necessary to change its recommendations (section 1) to take account of acid-suppressive medication.\n\n## Calcium and vitamin D prerequisites for treatment\n\nThe Committee discussed the effect of calcium and vitamin D on the clinical effectiveness of the drugs considered. In the studies that formed the basis of this guidance, all participants were said to have adequate calcium and vitamin D levels. The Committee appreciated that the general population, particularly the elderly population, cannot be assumed to have an adequate dietary intake of calcium and vitamin D. It was also considered important to note that adequate levels (normal serum concentrations) of calcium and vitamin D are needed to ensure optimum effects of the treatments for osteoporosis. The Committee concluded that calcium and/or vitamin D supplementation should be provided unless clinicians are confident that women who receive treatment for osteoporosis have an adequate calcium intake and are vitamin D replete.\n\n## Consultation on the Assessment Group's economic model\n\nFollowing the outcome of the judicial review and the court ruling of March 2009, the Appraisal Committee considered the comments received from consultees on the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report.\n\nThe Committee considered the comments from consultees that the Assessment Group's model was not sufficiently transparent, lacked adequate documentation and could not be validated. It noted the number of consultations that took place during the appraisal guidance development, that the consultation documents had included descriptions of the model, and that assumptions and parameter values used had also been provided to consultees. The Committee was aware that instructions on how to run the model were released with the model and that consultees were able to run the model with changed input parameters. The Committee was satisfied with the exploration by the DSU of the functionality and validity of the model. The Committee noted that Servier stated that it had constructed its own economic model in order to validate the Assessment Group's model and to demonstrate the mathematical rationale to support its comments. The Committee noted that the results from Servier's model were very similar to those from the Assessment Group's model when similar assumptions and parameter inputs were used. The Committee was not persuaded by the consultees' doubt about the validity of the model, particularly since differences between the results obtained using Servier's model and the Assessment Group's model were largely because of differences in the assumptions used.\n\nThe Committee considered the comments from consultees that some inputs in the Assessment Group's model could not be changed and that it was unclear how fracture risk was calculated. The Committee noted that some of the fixed input parameters were inputs that do not need changing (such as the discount rate and standard mortality rates). Other fixed input values, such as the BMI and issues around the time horizon, were discussed separately (see sections 4.3.56 and 4.3.59 respectively). The Committee concluded that it was reasonable for some inputs in the model to be fixed. The Committee noted that fracture risks were calculated by the Assessment Group using the WHO algorithm in a separate spreadsheet and then entered into the model. It understood that the WHO algorithm itself was provided to the Assessment Group in 2005 as academic in confidence and that at that time NICE did not have permission from the owner of the algorithm to release it to consultees. The Committee understood that although the WHO fracture risk algorithm itself was not embedded in the economic model, the model could not be released because the algorithm could have been back-calculated from the fracture risks entered in the model and because the numbers of women with risk factors from the algorithm were included in the model.\n\nThe Committee considered the comments from consultees that the fracture risks entered into the model, calculated using the WHO algorithm, were different from fracture risks estimated using the FRAX tool. The Committee was aware that some differences could be because of the Assessment Group's use of midpoint ages in each 5-year age grouping. It also heard that the Assessment Group had verified the application of the WHO algorithm as provided in 2005, including all interactions between clinical risk factors, and was satisfied that the DSU had adequately assessed its application as being correct in the model. Because neither the DSU nor NICE has access to the algorithm used for the construction of the FRAX tool, the Committee was not in a position to comment further on differences between the two ways of estimating fracture risk. It concluded that differences between fracture risk estimates produced using the FRAX tool and those used in the Assessment Group's model were not in themselves a reason to doubt the correct use of the WHO algorithm within the Assessment Group's model.\n\nThe Committee considered the comments from consultees that mortality associated with clinical risk factors had been omitted from the Assessment Group's model, and noted the confirmation from the DSU that this was the case. It was persuaded that the inclusion of such additional mortality effects would increase the complexity of the model, and may increase the ICERs for the treatment of women with such clinical risk factors but decrease the ICERs for the treatment of women without such risk factors. The Committee agreed that the overall effect of including mortality associated with clinical risk factors in the model was unlikely to lead to a marked change in the overall results.\n\nThe Committee reviewed the consultee comments relating to the fixed BMI value of 26\xa0kg/m2 used in the Assessment Group's model. It noted the rationale for selecting this value (see section 4.2.44). It also noted that in the DSU's exploratory analysis using the WHO algorithm, no increase in fracture risk was identified for women with a higher or lower BMI when BMD was known. The Committee was aware of its recommendation to assess BMD in all women under the age of 75\xa0years for whom treatment is being considered, and noted that BMI is a weak predictor of fracture when BMD is known. Therefore the Committee concluded that the use of a fixed BMI value of 26\xa0kg/m2 did not lead to an unfavourable assessment of the cost effectiveness of the interventions.\n\nThe Committee considered comments from consultees that the fracture risk associated with alcohol consumption used in the model was incorrect. It noted that the DSU had determined that the WHO algorithm had been correctly implemented, and understood that alcohol consumption of more than 2\xa0units per day was included as a risk factor in the model. The Committee also noted that in its recommendations it had chosen to use a higher level of alcohol consumption in the risk identification strategy, because only alcohol consumption of 4\xa0or more units per day was identified as a statistically significant risk factor for fracture for women – the population considered in the guidance. The Committee also considered a consultee comment that stated that it was unclear whether smoking and corticosteroid use had been included in the model as risk factors. It noted that the DSU had determined that the WHO algorithm had been correctly implemented with regard to both smoking and corticosteroid use in the model. The Committee noted that the effect of smoking in women was not statistically significant when assessing risk of osteoporotic fractures taken as a whole. The Committee was therefore satisfied that risks associated with corticosteroids, smoking and alcohol consumption had been faithfully applied in the Assessment Group's model, and agreed that the levels of alcohol consumption and smoking that should be used in the risk identification strategy were a matter for the Committee to consider and determine. The Committee took the view that it is not appropriate to identify women at high risk of fracture on the basis of risks that were not statistically significant (such as smoking and consumption of fewer than 4\xa0units of alcohol per day) and that, in addition, the impact of these risk factors could arguably be approached by a strategy of smoking cessation and reducing alcohol consumption. The Committee noted comments from the consultees that the Assessment Group's model should have been amended to reflect the Committee's agreed inclusion of risk factors. However, the Committee took the pragmatic view that such amendments would have added unnecessarily to the mathematical complexity of an already complex clinical situation. It noted that women who had taken corticosteroids were included in the model and therefore contributed to the underlying fracture risk, with the effect of reducing the ICERs for the treatment of the population of women considered in the recommendations.\n\nThe Committee considered consultee comments that giving equal weighting to different clinical risk factors for fracture in the Assessment Group's model was inaccurate. The Committee considered the complex results presented originally in the 2005 Strontium Ranelate Assessment Report related to the inclusion of different risk factors and combinations of risk factors. The Committee noted that it had previously agreed that a clinically workable risk identification and treatment strategy should include the grouping of risk factors as the only practical way forward. At the time of the model's development, no individual risk calculation tool was available. Even if such a tool had been used in the development of the guidance, the prediction of cost effectiveness from overall absolute fracture risk alone, as suggested by consultees, would not be appropriate, for two reasons. Firstly, risk factors have different effects on different fracture types, and the cost effectiveness of treatment depends on the relative contributions of each risk factor to fracture risk. Secondly, the effectiveness of the drugs in reducing fracture risk was limited to only some of the clinical risk factors (age, T-score of −2.5\xa0SD or below and prior fracture). The Committee heard from the DSU that there was considerable uncertainty about the cost effectiveness of treating women based on absolute risk alone (see section 4.3.47). Therefore, the Committee concluded that, when developing the guidance, simplification of the model was justified to in order to produce workable recommendations.\n\nThe Committee reviewed a comment from a consultee that the methods used to model effects beyond 10\xa0years were not adequately described. It noted that the DSU confirmed that consequences beyond 10\xa0years were considered in the Assessment Group's model, and an expanded description of the methods used was provided in an annex to the DSU report. The Committee also noted that the DSU carried out a sensitivity analysis in order to establish the impact of any possible underestimation of the mortality risk after the 10-year time horizon. It noted that doubling of the mortality risk led to only very small changes in the results. The Committee therefore concluded that mortality effects beyond the 10-year time horizon had been reasonably accounted for in the model and that sufficient description of these methods had been made available to consultees.\n\nThe Committee considered comments from consultees that the population data on the distribution of BMD (T-score) were not appropriate. It noted the DSU response confirming that the UK epidemiological dataset from the Holt study had been correctly implemented in the Assessment Group's model, and that the assumptions about the normality of the distributions used were likely to favour treatment for women at risk of fracture. The Committee also noted that the particular UK epidemiological dataset used in the model had been originally suggested by consultees for this appraisal. The Committee concluded that the population data had been used appropriately in the model.\n\nThe Committee considered a comment from a consultee that using a single estimate of cost effectiveness for 5-year age groupings of women at risk of fracture could exclude women from being offered treatment. It noted that this identification method was a Committee decision, and that identification strategies based on other factors could make treatments less cost effective.\n\nThe Committee reviewed comments from a consultee that the application of the same disutility for the side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates. The Committee was aware that the side effects observed for strontium ranelate in the clinical trials did not include gastrointestinal effects, but did include an increased risk of VTE. Because the increased risk of VTE was not included in the Assessment Group's model, the Committee had agreed that it was appropriate to include a disutility equivalent to the bisphosphonate base-case side-effect disutility to take account of this adverse effect.\n\nThe Committee reviewed comments from consultees about model assumptions or inputs that the Committee had directed the Assessment Group to use. It noted that issues such as treatment compliance, discount rates, costs of fracture, utility values for vertebral fracture and side-effect profiles used in the model had been considered and agreed by the Committee and reported in the guidance. The Committee also agreed that it had considered identification strategies for women at risk of fracture and, noting the advice of clinical specialists, it had recommended that women should have their BMD assessed by DXA scanning, except in certain circumstances as defined in the guidance. The Committee concluded that views expressed by consultees on the choice of modelling assumptions, input parameters and risk identification strategy were not about the operation of the Assessment Group's model, but were about Committee decisions that had already been discussed during development of the guidance.\n\nThe Committee also considered the consultees' view that the FRAX tool provides a 'mechanism to compute cost-effectiveness' according to clinical risk factors and that each of the current recommendations covers a wide range of absolute risk values, depending on the individual risk factors involved. The Committee understood that the FRAX tool is not an economic model, but a tool to estimate fracture risk. The Committee acknowledged that the current set of recommendations involved necessary simplifications from the more complex algorithm used to develop the Assessment Group's model. It was also aware that a direct prediction of cost effectiveness from absolute fracture risk alone would be inappropriate (see section 4.3.47).\n\nThe Committee concluded that the Assessment Group had provided an executable economic model and had implemented the WHO algorithm (as supplied) correctly. The Committee agreed with the DSU's comments that alterations to the modelling approach, as suggested by consultees, would not lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The Committee confirmed that the model provided a suitable framework to allow it to make recommendations on the cost-effective use of treatment for women at risk of fracture. The Committee noted that assumptions used in the Assessment Group's model had been considered and agreed by the Committee in developing the guidance. It agreed that it would not be useful to request further analysis from the Assessment Group at this stage. The Committee further agreed that any exploration of how absolute fracture risk could be used in making treatment decisions would require a new assessment and appraisal. Therefore the Committee concluded that the recommendations based on the Assessment Group's model were appropriate, and that the recommendations should remain unchanged.\n\nThe Committee noted the comments from some consultees that the guidance should be reviewed soon because the price of some of the appraised drugs had changed. The Committee noted that any possible price reductions could be offset by the use of the currently applicable discount rate, and that any review should also take into consideration how NICE might assess diagnostic tools such as absolute fracture risk prediction tools.\n\n T-scores were calculated according to trial-specific normative data, using a threshold of −3.0 or below, which is equivalent to a T-score of −2.4 or below when measured according to the standards subsequently adopted by the WHO. The latter classification is used throughout this guidance document.\n\n The remit of the original osteoporosis guideline has since been amended; see Osteoporosis and Osteoporosis fragility fracture risk.", 'Recommendations for further research': 'Given the evidence that the benefits of one of the bisphosphonates (alendronate) may continue for several years after the end of treatment, the Committee recommends that research should be carried out to define the optimal duration of treatment with individual bisphosphonates.\n\nThe Committee recommends research into the long-term effects of bisphosphonates on bone quality, given the inhibitory effects on bone resorption of these drugs.', 'Review of guidance': 'The guidance on these technologies will be considered for review by the Guidance Executive as soon as the short clinical guideline on risk assessment has been published. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJanuary 2011'}
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https://www.nice.org.uk/guidance/ta160
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Evidence-based recommendations on raloxifene for the primary prevention of osteoporotic fragility fractures in postmenopausal women.
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995bf4f44636d2bc603d6ed05aa4fdd162247c0e
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Raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
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Raloxifene and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
Evidence-based recommendations on raloxifene and teriparatide for preventing osteoporotic fragility fractures in postmenopausal women who have osteoporosis.
# Guidance
This guidance relates only to treatments for the secondary prevention of fragility fractures in postmenopausal women who have osteoporosis and have sustained a clinically apparent osteoporotic fragility fracture. Osteoporosis is defined by a T-score of −2.5 standard deviations (SD) or below on dual-energy X-ray absorptiometry (DXA) scanning. However, the diagnosis may be assumed in women aged 75 years or older if the responsible clinician considers a DXA scan to be clinically inappropriate or unfeasible.
This guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered.
This guidance does not cover the following:
The use of raloxifene or teriparatide for the secondary prevention of osteoporotic fragility fractures in women with normal bone mineral density (BMD) or osteopenia (that is, women with a T-score between −1 and −2.5 SD below peak BMD).
The use of these drugs for the secondary prevention of osteoporotic fragility fractures in women who are on long-term systemic corticosteroid treatment.
This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
This recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.
The recommendation for strontium ranelate has been withdrawn because strontium ranelate is no longer marketed in the UK. Raloxifene is recommended as an alternative treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women:
who are unable to comply with the special instructions for the administration of alendronate and risedronate, or have a contraindication to or are intolerant of alendronate and risedronate (as defined in section 1.6) and
who also have a combination of T-score, age and number of independent clinical risk factors for fracture (see section 1.5) as indicated in the following table.
T-scores (SD) at (or below) which raloxifene is recommended when alendronate and risedronate cannot be taken
Number
of
independent
clinical
risk
factors
for
fracture
(section
Age
(years)
– a
-r older
a Treatment with raloxifene is not recommended.
If a woman aged 75 years or older who has one or more independent clinical risk factors for fracture or indicators of low BMD has not previously had her BMD measured, a DXA scan may not be required if the responsible clinician considers it to be clinically inappropriate or unfeasible.
For the purposes of this guidance, indicators of low BMD are low body mass index (defined as less than 22 kg/m2), medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause.
Teriparatide is recommended as an alternative treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women:
who are unable to take alendronate and risedronate, or have a contraindication to or are intolerant of alendronate and risedronate (as defined in section 1.6), or who have had an unsatisfactory response (as defined in section 1.8) to treatment with alendronate or risedronate and
who are 65 years or older and have a T-score of –4.0 SD or below, or a T-score of –3.5 SD or below plus more than two fractures, or who are aged 55–64 years and have a T-score of –4 SD or below plus more than two fractures.
For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.
For the purposes of this guidance, intolerance of alendronate or risedronate is defined as persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment, and that occurs even though the instructions for administration have been followed correctly.
The recommendation for strontium ranelate has been withdrawn because strontium ranelate is no longer marketed in the UK.
For the purposes of this guidance, an unsatisfactory response is defined as occurring when a woman has another fragility fracture despite adhering fully to treatment for 1 year and there is evidence of a decline in BMD below her pre-treatment baseline.
Women who are currently receiving treatment with one of the drugs covered by this guidance, but for whom treatment would not have been recommended according to sections 1.1 to 1.4, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
T-score relates to the measurement of bone mineral density (BMD) using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) from peak BMD.
Rheumatoid arthritis is also a medical condition indicative of low BMD.# Clinical need and practice
Osteoporosis is a progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
Bone formation exceeds bone resorption in youth, but by the third decade of life there is a gradual loss of bone mass. Osteoporosis is therefore usually an age-related disease. It can affect both sexes, but women are at greater risk because the decrease in oestrogen production after the menopause accelerates bone loss to a variable degree.
The World Health Organization (WHO) has established diagnostic criteria for osteoporosis based on the measurement of BMD, expressed as the T-score, which is the number of SD below the mean BMD of young adults at their peak bone mass:
normal BMD: T-score of −1 SD or above
-steopenia: T-score of between −1 and −2.5 SD
-steoporosis: T-score of −2.5 SD or below
established (severe) osteoporosis: T-score of −2.5 SD or below with one or more associated fractures.
T-score measurements vary depending on the site and method of investigation. Measurement of BMD using central (hip and/or spine) DXA scanning can estimate fracture risk.
It is estimated that more than 2 million women have osteoporosis (that is, have a T-score of −2.5 SD or below) in England and Wales. Osteoporosis is most common in older white women. After the menopause, the prevalence of osteoporosis increases markedly with age, from approximately 2% at 50 years rising to more than 25% at 80 years.
Fragility fracture is the clinically apparent and relevant outcome in osteoporosis (referred to as 'osteoporotic fragility fracture' in the following text). It is often referred to as a low-trauma fracture; that is, a fracture sustained as the result of a force equivalent to the force of a fall from a height equal to, or less than, that of an ordinary chair. In the absence of fracture, osteoporosis is asymptomatic and often remains undiagnosed. Osteoporotic fragility fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain and reduced quality of life.
In women aged over 50 years, the lifetime risk of a vertebral fracture is estimated to be one in three, and that of hip fracture one in five. Postmenopausal women with an initial fracture are at substantially greater risk of subsequent fractures. For instance, a woman with a vertebral fracture has an increased relative risk (RR) of 4.4 for a further vertebral fracture, 2.3 for a hip fracture, and 1.4 for a wrist fracture.
It is estimated that annually there are 180,000 osteoporosis-related symptomatic fractures in England and Wales. Of these, 70,000 are hip fractures, 25,000 are clinical vertebral fractures, and 41,000 are wrist fractures.
After a hip fracture, a high proportion of women are permanently unable to walk independently or to perform other activities of daily living and, consequently, many are unable to live independently. Hip fractures are also associated with increased mortality; estimates of the relative mortality risk vary from 2 to greater than 10 in the 12 months following hip fracture. However, it is unclear to what extent this can be attributed to fracture alone as opposed to pre-existing comorbidity.
Vertebral fractures can be associated with curvature of the spine and loss of height and can result in pain, breathing difficulties, gastrointestinal problems and difficulties in performing activities of daily living. It is thought that the majority of vertebral fractures (50–70%) do not come to clinical attention. Vertebral fractures are also associated with increased mortality; UK-specific data indicate a 4.4-fold increase in mortality related to vertebral fracture. However, as with hip fractures, it is unclear to what extent this may be due to comorbidities.
In addition to increasing age and low BMD, other clinical factors have been associated with increased fracture risk. Some of these clinical risk factors are at least partly independent of BMD, and include parental history of hip fracture, alcohol intake of 4 or more units per day, long-term systemic use of corticosteroids (which is not covered in this guidance), and rheumatoid arthritis.
Factors that are known to be indicators of low BMD include low body mass index (BMI) (defined as less than 22 kg/m2), and medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause.# The technologies
# Bisphosphonates: alendronate, etidronate and risedronate
The bisphosphonates alendronate, etidronate and risedronate are inhibitors of bone resorption and increase BMD by altering osteoclast activation and function.
Alendronate is an oral bisphosphonate that has a UK marketing authorisation as a once-weekly preparation (70 mg) for the treatment of postmenopausal osteoporosis. It also has a marketing authorisation at a daily dose of 10 mg for the treatment of osteoporosis in postmenopausal women to prevent fractures. Non-proprietary alendronate (Teva UK) costs £4.12 for four 70 mg tablets and £8.30 for twenty-eight 10 mg tablets (excluding VAT; NHS Drug Tariff, 24 February 2008). At these prices the drug costs for 1 year are £53.56 for once-weekly (70 mg) tablets and £108.20 for daily (10 mg) tablets. Proprietary alendronate (Fosamax; Merck Sharp & Dohme) is priced at £22.80 for four 70 mg tablets and £23.12 for twenty-eight 10 mg tablets (excluding VAT; 'British national formulary' edition 54). At these prices, the drug costs for 1 year are £296.40 for once-weekly (70 mg) tablets and £301.39 for daily (10 mg) tablets. Costs may vary in different settings because of negotiated procurement discounts.
Etidronate (Didronel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation for the treatment of osteoporosis. The drug is administered in 90-day cycles, with each cycle consisting of etidronate (400 mg/day) for 14 days followed by calcium carbonate (1.25 g/day) for the remaining 76 days. The price per 90-day pack is £21.12 (excluding VAT; BNF 54), which equates to a yearly cost of £85.65. Costs may vary in different settings because of negotiated procurement discounts.
Risedronate (Actonel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation at a dosage of 5 mg/day or 35 mg/week for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures, and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Prices are £19.10 for twenty-eight 5 mg tablets and £20.30 for four 35 mg tablets (excluding VAT; BNF 54), which equates to yearly costs of £248.98 for the daily treatment or £264.63 for the once-weekly treatment. Costs may vary in different settings because of negotiated procurement discounts.
Gastrointestinal side effects are common with oral bisphosphonates. In people with oesophageal abnormalities and other factors that delay oesophageal transit or emptying, risedronate should be used cautiously and alendronate is contraindicated. For full details of side effects and contraindications, see the summaries of product characteristics.
Bisphosphonates have relatively complex instructions for administration. Alendronate and risedronate must be taken with 200 ml and 120 ml of water, respectively. Before and immediately after administration patients should not eat or drink, and must remain upright for stipulated time periods. Etidronate should be taken with water at the midpoint of a 4-hour fast (that is, 2 hours after and 2 hours before food, vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium).
# Selective oestrogen receptor modulator: raloxifene
Selective oestrogen receptor modulators (SERMs) are drugs with selective activity in various organ systems, acting as weak oestrogen-receptor agonists in some systems and as oestrogen antagonists in others. The aim of treatment with SERMs is to maximise the beneficial effects of oestrogen on bone and to minimise the adverse effects on the breast and endometrium.
Raloxifene (Evista; Eli Lilly) has marketing authorisation for the treatment of osteoporosis in postmenopausal women. The recommended dosage is 60 mg/day. The prices of 28- and 84-tablet packs are £17.06 and £59.59, respectively (excluding VAT; BNF 54), which equate to yearly costs of £222.39 and £258.93, respectively. Costs may vary in different settings because of negotiated procurement discounts.
Raloxifene is contraindicated in people with a history of venous thromboembolism (VTE), hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding or endometrial cancer. Raloxifene should not be co-administered with systemic oestrogens, and in patients with breast cancer it should not be used for osteoporosis treatment or prevention until treatment of the breast cancer, including adjuvant treatment, has been completed. Raloxifene is associated with an increased risk of venous thromboembolic events, particularly during the first 4 months of treatment, which is similar to the reported risk associated with hormone replacement therapy. For full details of side effects and contraindications, see the summary of product characteristics.
# Strontium ranelate
Strontium ranelate (Protelos; Servier Laboratories) is a divalent strontium salt of ranelic acid (strontium is an element with properties similar to calcium). It is thought to have a dual effect on bone metabolism, increasing bone formation and decreasing bone resorption. It has a UK marketing authorisation for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. The recommended dose is one 2 g sachet taken daily as a suspension in water. The price of a 28-sachet pack is £25.60 (excluding VAT; BNF 54), which equates to a yearly cost of £333.71. Costs may vary in different settings because of negotiated procurement discounts.
The absorption of strontium ranelate is reduced by food, milk and products derived from milk. It should therefore be administered between meals, ideally at bedtime and preferably at least 2 hours after eating.
The summary of product characteristics states that strontium ranelate is not recommended in patients with severe renal impairment and that it should be used with caution in patients at increased risk of VTE. Treatment with strontium ranelate should be discontinued during treatment with oral tetracycline or quinolone antibiotics. For full details of side effects, drug interactions and contraindications, see the summary of product characteristics.
# Parathyroid hormone: teriparatide
Teriparatide (Forsteo; Eli Lilly & Company) is a recombinant fragment of human parathyroid hormone and, as an anabolic agent, it stimulates new formation of bone and increases resistance to fracture.
Teriparatide has a marketing authorisation in the UK for the treatment of established osteoporosis in postmenopausal women. The recommended dose is 20 micrograms administered once daily by subcutaneous injection in the thigh or abdomen. Patients taking teriparatide must receive training in the injection technique. At the time of appraisal, the maximum total duration of treatment was restricted, by the marketing authorisation, to 18 months (see the summary of product characteristics for current information). The price of a 28-day pre-filled pen is £271.88 (excluding VAT; BNF 54), which equates to a yearly cost of £3544.15.
Particular contraindications include pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease of bone), unexplained elevations of alkaline phosphatase, and previous radiation treatment to the skeleton. For full details of side effects and contraindications, see the summary of product characteristics.# Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
# Clinical effectiveness
## Efficacy
The Assessment Group for this appraisal (School of Health and Related Research, University of Sheffield ) reviewed data from published randomised controlled trials (RCTs) in postmenopausal women in which fracture or health-related quality of life was an endpoint and where one of the six drugs of interest was compared with a relevant comparator, such as no treatment, placebo or one of the other included interventions. The majority of studies used placebo or no treatment as a control. Most studies ensured that women in all trial arms had normal calcium levels (that is, normal serum concentrations) or adequate supplementation, and some studies used additional dietary supplementation with vitamin D.
For this appraisal, reductions in RR associated with treatment were pooled regardless of the baseline BMD and fracture status of the participants in the studies. It was also assumed that these reductions in RR remained constant at all ages, although little evidence was available for the effectiveness of the drugs in women aged 80 years or older.
For vertebral fractures, some studies used clinical (that is, symptomatic) fractures as their endpoint whereas others used fractures that were identified radiographically. Vertebral fractures identified radiographically, which are termed 'radiographic fractures' or 'morphometric fractures', include both symptomatic and asymptomatic fractures. There are different definitions of a vertebral radiographic fracture, but those definitions that require a 20% reduction in vertebral height are generally recognised as producing more reliable results than those that require a 15% reduction.
For non-vertebral fracture types, individual data on hip, leg, pelvis, wrist, hand, foot, rib and humerus fractures were sometimes provided, whereas some studies only presented data for all non-vertebral fractures grouped together.
Sixteen RCTs of alendronate in postmenopausal women were included in the assessment report: two studies in women with low or normal BMD; one in women with osteopenia; eight in women with osteopenia or osteoporosis; four in women with osteoporosis; and one in women with established osteoporosis. Overall, 15 studies compared alendronate with placebo or with no treatment. All the studies were conducted in women who had adequate levels of calcium, from either dietary intake or calcium supplementation.
Two studies, one comparing alendronate with oestrogen alone or with oestrogen and alendronate combined, and the other comparing alendronate with teriparatide, found no statistically significant differences between the groups in numbers of clinically apparent fractures of any type in women with osteoporosis. However, back pain was reported less frequently by women in the teriparatide group compared with women in the alendronate group (6% versus 19%, p = 0.012).
In addition to the 16 RCTs, a 2-year study demonstrated the equivalence of weekly and daily doses of alendronate, in terms of clinical fracture incidence and gastrointestinal adverse events. However, this study was not included in the analysis because it did not include the specified comparators.
The meta-analysis for alendronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.56 (95% confidence interval 0.46 to 0.68, four RCTs, n = 7039), an RR of hip fracture of 0.62 (95% CI 0.40 to 0.98, three RCTs, n = 7455), an RR of wrist fracture of 0.67 (95% CI 0.34 to 1.31, four RCTs, n = 7931) and an RR for other non-vertebral fractures of 0.81 (95% CI 0.68 to 0.97, six RCTs, n = 9973).
A post-hoc analysis of data from the largest study on alendronate, the 'Fracture intervention trial' (FIT) RCT (non-vertebral fracture population), suggested that alendronate may be less effective at reducing fractures in women with T-scores above (that is, better than) −2.5 SD than in women with osteoporosis. These results were not statistically significant.
Gastrointestinal adverse events, including nausea, dyspepsia, mild oesophagitis/gastritis and abdominal pain, were reported in at least one third of the participants in studies of alendronate. However, only one study found the increased frequency of these symptoms to be statistically significant relative to placebo. This is consistent with post-marketing studies that indicate that approximately one third of alendronate users experience gastrointestinal adverse events. To avoid oesophagitis, the summary of product characteristics now recommends that alendronate should be taken on rising for the day, with a full glass of water. It is possible that these instructions were not followed in all of the studies, particularly the earlier ones.
Prescription-event monitoring studies in patients for whom alendronate was prescribed (n = 11,916) by GPs in England demonstrated a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 32.2 per 1000 patient-months in the first month of treatment to 10.9 per 1000 patient-months in months 2 to 6. Because these studies lacked a comparator, it is not possible to assess the extent to which these rates of upper gastrointestinal events may be above baseline levels in those not taking bisphosphonates.
One study reported health-related quality of life outcomes. At 12 months there were statistically significant improvements in the alendronate group compared with the control group in scores for pain, social isolation, energy level and physical ability.
Twelve RCTs of etidronate in postmenopausal women were reviewed: three studies in women with low-to-normal BMD; two in women with osteopenia or osteoporosis; one in women with osteoporosis; one in women with osteoporosis or established osteoporosis; and five in women with established osteoporosis. Four studies included active comparators, and eight compared etidronate with placebo or with no treatment (although in six of these, study participants in all arms received calcium, either alone or with vitamin D). Some studies did not use the exact treatment regimen that currently has a UK marketing authorisation (that is, 90-day cycles of etidronate 400 mg/day for 14 days, followed by calcium carbonate 1.25 g/day for the remaining 76 days). None of the studies reported health-related quality of life outcomes.
The meta-analysis of RCTs for etidronate relative to placebo carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.40 (95% CI 0.20 to 0.83, three RCTs, n = 341), an RR of hip fracture of 0.50 (95% CI 0.05 to 5.34, two RCTs, n = 180), and an RR for other non-vertebral fractures of 1.04 (95% CI 0.64 to 1.69; four RCTs, n = 410). There were no data for wrist fracture.
An observational study in a general practice setting in the UK reported on fracture rates in people with a diagnosis of osteoporosis who were receiving etidronate compared with those who were not taking a bisphosphonate. People taking etidronate had an RR of non-vertebral fracture of 0.80 (95% CI 0.70 to 0.92). The RR of hip fracture was 0.66 (95% CI 0.51 to 0.85) and that of wrist fracture was 0.81 (95% CI 0.58 to 1.14).
Higher rates of gastrointestinal adverse effects were found in the etidronate groups of four RCTs, although the differences were not always statistically significant. However, non-RCT evidence and testimonies from clinical specialists and patient experts suggested that etidronate may be associated with fewer gastrointestinal adverse effects than other bisphosphonates.
The systematic review carried out by ScHARR in 2006 identified a cohort study conducted in the UK that indicated that etidronate may be associated with a much lower rate of upper gastrointestinal adverse effects than alendronate or risedronate.
Seven RCTs of risedronate in postmenopausal women were reviewed: one study in women with normal BMD; one in women with osteopenia; one in women with osteopenia or osteoporosis; one in women with osteoporosis or specific risk factors for hip fracture, such as a recent fall; and three in women with established osteoporosis. All compared risedronate with placebo (although, with the exception of those in the normal BMD study, all women also received calcium) and none reported on health-related quality of life outcomes.
The meta-analysis for risedronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.61 (95% CI 0.50 to 0.75, three RCTs, n = 2301), an RR of hip fracture of 0.74 (95% CI 0.59 to 0.93, three RCTs, n = 11,770), an RR of wrist fracture of 0.68 (95% CI 0.43 to 1.08, two RCTs, n = 2439) and an RR for other non-vertebral fractures of 0.76 (95% CI 0.64 to 0.91, five RCTs, n = 12,399).
In all of the studies, rates of gastrointestinal adverse events were similar in the risedronate and placebo groups.
Prescription-event monitoring studies in patients for whom risedronate was prescribed (n = 13,643) by GPs in England suggested a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia ranged from 26.9 per 1000 patient-months in the first month of treatment to 8.1 per 1000 patient-months in months 2 to 6.
A meta-analysis of pooled data from the alendronate and risedronate studies, carried out by ScHARR in 2006, resulted in an RR of vertebral fracture of 0.58 (95% CI 0.51 to 0.67, seven RCTs, n = 9340), an RR of hip fracture of 0.71 (95% CI 0.58 to 0.87, six RCTs, n = 19,233), an RR of wrist fracture of 0.69 (95% CI 0.45 to 1.05, six RCTs, n = 1037) and an RR for other non-vertebral fractures of 0.78 (95% CI 0.69 to 0.88, 11 RCTs, n = 22,372).
Three RCTs of raloxifene in postmenopausal women were identified, but only two were included in the Assessment Group's meta-analysis: the largest study (the 'Multiple outcomes of raloxifene evaluation' study) was carried out in women with osteoporosis, of whom 37% had a vertebral fracture at entry, and a smaller study was conducted in women with established osteoporosis. Both compared raloxifene with placebo (in both studies, women in both arms received calcium and vitamin D). Both studies examined raloxifene at dosages of 60 mg/day (the dosage specified in the UK marketing authorisation for the treatment of postmenopausal osteoporosis) and 120 mg/day. Neither reported on health-related quality of life outcomes. The mean age of women in the studies was 67–68 years. The MORE study was extended further to assess fracture, breast cancer, and cardiovascular and uterine safety outcomes. A third study examined the additive effect of raloxifene compared with placebo in women with a femoral neck T-score of −2 SD or below, with or without prior fracture, who were also receiving fluoride, calcium and vitamin D. Because of the use of fluoride as a co-intervention, these results were not included in the Assessment Group's meta-analysis.
The meta-analysis for raloxifene relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.65 (95% CI 0.53 to 0.79, one RCT, n = 4551), an RR of hip fracture of 1.13 (95% CI 0.66 to 1.96, two RCTs, n = 6971), an RR of wrist fracture of 0.89 (95% CI 0.68 to 1.15, one RCT, n = 6828), and an RR for other non-vertebral fractures of 0.92 (95% CI 0.79 to 1.07, one RCT, n = 6828).
The most serious adverse effect associated with raloxifene was the approximately three-fold increased risk of VTE. Statistically significantly higher incidences of hot flushes, arthralgia, dizziness, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes were also found with raloxifene compared with placebo. The impact of raloxifene on cardiovascular disease is unclear, but there is evidence that it lowers serum concentrations of fibrinogen as well as both total and low-density lipoprotein (LDL) cholesterol levels (that is, serum concentrations) without increasing high-density lipoprotein (HDL) cholesterol.
The MORE study shows that raloxifene protects against breast cancer, with the RR at 4 years for all types of breast cancer reported as 0.38 (95% CI 0.24 to 0.58), and that for invasive breast cancer as 0.28 (95% CI 0.17 to 0.46).
Three RCTs of strontium ranelate in postmenopausal women were identified: one study in women with osteoporosis and two in women with osteoporosis or established osteoporosis. All three studies compared strontium ranelate with placebo, and provided calcium and vitamin D supplementation to ensure an adequate intake.
The Assessment Group reported the results of a published meta-analysis that gave an RR for vertebral fracture of 0.60 (95% CI 0.53 to 0.69, two RCTs, n = 6551) and an RR for all non-vertebral fractures (including wrist fracture) of 0.84 (95% CI 0.73 to 0.97, two RCTs, n = 6551). Efficacy in reducing the rate of hip fracture was established in one study; the RR for hip fracture in the whole study population was 0.85 (95% CI 0.61 to 1.19, one RCT, n = 4932). A post-hoc subgroup analysis in women aged 74 or older with a T-score of −2.4 SD resulted in an RR for hip fracture of 0.64 (95% CI 0.412 to 0.997, one RCT, n = 1977).
In general, strontium ranelate was not associated with an increased risk of adverse effects and for the most part adverse effects were mild and transient; nausea, diarrhoea and creatine kinase elevations were the most commonly reported. A serious adverse event associated with strontium ranelate treatment was an increased incidence (RR = 1.42) of VTE and pulmonary embolism. This finding has been investigated further with the extension of ongoing studies and by post-marketing surveillance.
One study published results on health-related quality of life outcomes. It reported that strontium ranelate had quality of life benefits compared with placebo, as assessed by the QUALIOST osteoporosis-specific questionnaire and by the general health perception score of the short form (SF)-36 general scale.
Three RCTs of teriparatide in postmenopausal women were considered: one small study compared teriparatide with alendronate in women with osteoporosis (but was not targeted at women with fractures), and two were placebo-controlled (although study participants also received vitamin D either with calcium or with nutritional advice to ensure adequate calcium intake). The largest trial was conducted in women with established osteoporosis, and the other in women who either had established osteoporosis or had osteoporosis and had been receiving hormone replacement therapy for at least 2 years.
For vertebral fractures (using a 20% reduction in vertebral height as the fracture definition) and grouped non-vertebral fractures in women with established osteoporosis, the largest placebo-controlled RCT found RRs of 0.35 (95% CI 0.22 to 0.55) and 0.65 (95% CI 0.43 to 0.98), respectively, in favour of teriparatide. When considered separately, the study did not demonstrate that teriparatide prevents hip and wrist fractures in women with established osteoporosis (RR for hip fractures 0.5; 95% CI 0.09 to 2.73; RR for wrist fractures 0.54; 95% CI 0.22 to 1.35). In this placebo-controlled trial, teriparatide reduced the incidence of new or worsened back pain reported as an adverse event.
Data from a follow-up observational study cited in the manufacturer's submission (published in abstract form or available as an unpublished manuscript only) suggest that 18 months after the end of treatment with teriparatide there was a 41% reduction in vertebral fracture risk compared with placebo (p = 0.004). Further data from the same study 31 months after the end of treatment with teriparatide suggest that proportionally fewer women who had received teriparatide reported non-vertebral fractures compared with those who had received placebo (13.3% in the placebo group; 8.5% in the 20 micrograms/day teriparatide group; 7.3% in the 40 micrograms/day teriparatide group; p = 0.03 for both treatment groups versus placebo). No information was given on vertebral fractures for the 31-month follow-up.
The study comparing 40 micrograms/day teriparatide (twice the dose specified in the marketing authorisation) with 10 mg/day alendronate found an RR of non-vertebral fracture in women with osteoporosis of 0.30 (95% CI 0.09 to 1.05). The study did not provide data on vertebral fractures. Back pain was reported less frequently in the teriparatide group (6% versus 19%, p = 0.012).
Nausea and headaches occurred more frequently with 40 micrograms/day teriparatide in the main placebo-controlled trial. In the smaller placebo-controlled trial, a proportion of women taking teriparatide were reported to suffer mild discomfort at the injection site. A systematic review of parathyroid hormone reported that treatment in a small proportion of women was associated with hypercalcaemia.
## Persistence and compliance
Data from 14 RCTs indicated that between 81% and 100% of patients persisted with bisphosphonates in the first year of treatment, with lower rates of persistence of between 51% and 89% in the third year of treatment (eight RCTs).
A prescription-event monitoring study of patients for whom alendronate was prescribed (n = 11,916) by GPs in England indicated that 24% discontinued treatment within 1 year. In a similar study of patients for whom risedronate was prescribed (n = 11,742) in primary care in England, 30% appeared to have discontinued treatment within 6 months. In another 12 studies reviewed, persistence at 1 year ranged from 16% to 90%.
Paid claims data from the USA suggested that only 18% of women starting raloxifene treatment continued to take their medication uninterrupted, and an investigation of a pharmacy prescription database indicated that only 44% were continuing treatment at the end of year 2.
Compliance data were reported for two RCTs of strontium ranelate and were similar in the strontium ranelate and placebo arms (ranging from 83% to 93%) at up to 3 years.
The main placebo-controlled RCT reported that adherence with injections varied from 79% to 83% and that there were no statistically significant differences between the teriparatide and placebo groups. The smaller placebo-controlled trial found that, after 3 years, 78% of women receiving teriparatide completed treatment, compared with 100% on placebo.
## Acid-suppressive medication and fracture risk
Two cohort and two case–control studies reported on a potential relationship between acid-suppressive medication (proton pump inhibitors or histamine H2 receptor antagonists) and fracture risk. One of the case–control studies, which used the UK General Practice Research Database (GPRD), found that 1 year or more of acid-suppressive medication was associated with an increase in fracture risk. The other case–control study reported a reduction of fracture risk associated with use of histamine H2 receptor antagonists, and that use of other acid-suppressive medication might increase fracture risk. Both studies, however, were unable to demonstrate convincingly that fracture risk was independent of underlying disease that might determine differences in fracture risk.
A prospective cohort study excluded women taking medication for fracture prevention and reported an increase in non-vertebral fracture in those taking acid-suppressive medication compared with those who were not. Findings appeared similar for users of proton pump inhibitors or histamine H2 receptor antagonists, but differences in fracture risk were not statistically significant for those using proton pump inhibitors compared with those not using acid-suppressive medication. One large retrospective cohort study using the UK GPRD compared women taking acid-suppressive medication plus bisphosphonates with those taking bisphosphonates alone. This GPRD study reported an increase in fracture risk for some fracture sites with concomitant use of acid-suppressive medication and bisphosphonates, but a reduction in risk for other fracture sites. The information on patients included in this GPRD study was incomplete and details of adjustments for confounders were not reported. The two cohort studies were not fully published, and their analysis may have been prone to confounding.
## Additional submission from the manufacturer of strontium ranelate
Following the Court of Appeal Order of April 2010, NICE requested an additional submission from the manufacturer of strontium ranelate (Servier), setting out their views on the most appropriate estimate of strontium ranelate's efficacy in reducing the rate of hip fracture.
Servier explained that the pivotal phase III RCT (Treatment of Peripheral Osteoporosis Study ) was started before the increased regulatory emphasis on the prevention of hip fracture as a key measure of efficacy of treatments for osteoporosis (because of the significant morbidity associated with hip fracture). TROPOS had not been designed or powered to demonstrate the effect of strontium ranelate treatment on rates of hip fracture. In support of its application for regulatory approval of strontium ranelate, Servier was therefore asked by the European Medicines Agency (EMA) to investigate the efficacy of strontium ranelate in reducing the rate of hip fracture in a post-hoc subgroup analysis of TROPOS participants who met the definition of established osteoporosis (that is, a BMD T-score of −2.5 or below and one or more associated fractures). Instead of the requested subgroup, Servier provided the EMA with data for a different subgroup of trial participants whom they identified as being at high risk for hip fracture. This subgroup comprised women aged 74 or older who had a femoral T-score of −2.4 or below. This subgroup represented 42% of TROPOS participants and had an RR of hip fracture of 0.64 (95% CI 0.412 to 0.997).
Servier described the method used to identify this high-risk subgroup. The placebo arms of two RCTs (TROPOS and another trial designed to assess the efficacy of strontium ranelate in reducing vertebral fractures, Spinal Osteoporosis Therapeutic Intervention ) were pooled and the influence on fracture rates of three of the main risk factors for fragility fracture – age, BMD and prior fracture – was explored. Servier found that, in the pooled placebo arms of these two RCTs, prior fracture had no effect on the rate of hip fracture, so this factor was not considered further. To select an age group in which the risk of hip fracture was elevated, Servier investigated various possible age cut-offs, and identified the age at which the difference in the rate of hip fracture between women older and younger than the cut-off was greatest. This process led to the selection of an age cut-off of 74 years. Servier stated that this cut-off was consistent with epidemiological data, in particular a study by Donaldson et al. (1990), which Servier interpreted as showing a rising rate of hip fracture among women in the general population above the age of 74. The selected BMD cut-off was closely aligned to the WHO definition of osteoporosis (a T-score of −2.5 SD or below; see section 2.3). Servier emphasised that, having identified factors related to a high risk of hip fracture by screening the pooled data from the placebo arms of two RCTs, a single post-hoc analysis of the effect of strontium ranelate in this subgroup had been performed, without the need for multiple exploratory analyses of fracture risk reduction adopting different criteria for the subgroup selection.
After Servier had submitted data on efficacy in its chosen subgroup to the EMA, the EMA requested further analyses to confirm the effect of strontium ranelate on the rate of hip fracture. Servier provided additional evidence, including data from longer follow-up periods and analyses of trial participants with demonstrated compliance to treatment. Servier indicated that this additional evidence supported the view that an RR of 0.64 is a valid estimate of the efficacy of strontium ranelate in reducing the rate of hip fracture.
In their additional submission to NICE following the Court of Appeal Order in April 2010, Servier also suggested a hypothesis for a possible increased effect of strontium ranelate in older women: most osteoporosis drugs work by reducing the loss of existing bone, but strontium ranelate also stimulates the creation of new bone. Because the creation of new bone is increasingly impaired as women age, Servier stated that it is possible that strontium ranelate is able to provide additional benefit to older women.
Servier argued that the RR of 0.64 derived from the post-hoc analysis of the high-risk subgroup should be used in cost-effectiveness analyses to quantify the effect of strontium ranelate in reducing the rate of hip fracture because, in its view, it represents a more robust estimate of efficacy than the RR for the whole trial population. Servier stated that, unlike the analysis of the whole trial population, the subgroup analysis was suitably powered to demonstrate the effect of strontium ranelate in reducing the rate of hip fracture. Because of this, in Servier's opinion, the estimate was statistically robust.
Servier's view was that the estimate derived from the high-risk subgroup could be assumed to apply to all women taking strontium ranelate, but it acknowledged issues surrounding extrapolation from the high-risk subgroup to a broader population. Servier therefore indicated that it might also be concluded that the RR of 0.64 could only be applied to a population corresponding to the high-risk subgroup.
## Review of Servier's additional submission by the Decision Support Unit
The DSU was commissioned to review Servier's additional submission, and to comment on the scientific validity of the post-hoc subgroup analysis provided by Servier. The DSU advised that any set of data will show some variation in response to treatment across different subgroups simply by chance. The DSU explained that, because of this, the correct statistical procedure for establishing a subgroup of trial participants with a significantly different response to treatment is via a test for interaction (that is, a formal test, using regression methods, of the hypothesis that the effect is different in one group of participants from that observed in the rest of the trial population). The DSU noted that no such test had been reported by Servier.
The DSU stated that the method used by Servier to identify the high-risk subgroup (see section 4.1.45) was logically likely to yield an unduly large relative effect, and the DSU stated that this would lead to a biased estimate of RR. This was because the method used to identify the age cut-off to define the subgroup was 'data-dependent' – that is, most of the data that were used to define the subgroup (the rate of hip fracture in the placebo arm of TROPOS) were also used to estimate the efficacy of strontium ranelate in the selected subgroup. In this way, the rate of hip fracture in the placebo group was certain to be high, relative to other potential age cut-offs, with no guarantee that this was also the case in the strontium ranelate group. Therefore, the DSU stated that the estimate of RR derived from the subgroup was likely to be artificially inflated.
The DSU also noted that, whilst Servier indicated that there were epidemiological data to support the chosen age cut-off (see section 4.1.45), the study by Donaldson et al. (1990) suggested that the rate of hip fracture rises to a notable level after 75 years of age, not 74.
The DSU advised that Servier's argument of enhanced statistical power in the subgroup analysis was incorrect. The DSU explained that, in an analysis of RR, statistical power is dependent on the number of events (in this case, hip fractures) and that choosing a smaller group of participants will tend to reduce, rather than increase, power unless the RR is markedly greater in that subgroup. Because of this, the DSU disagreed with Servier's claim that the subgroup analysis was 'fully powered'.
The DSU was asked to comment on the most appropriate approach, from a statistical viewpoint, to the use of data from the whole trial population of TROPOS and the high-risk subgroup, in determining the relative efficacy of strontium ranelate. The DSU responded that, if the relative effect were to be applied to women in the general population, an intention-to-treat analysis of all randomised trial participants would yield the most appropriate estimate of efficacy. The DSU also commented that, if more than one trial is available, a pooled analysis of RRs from the intention-to-treat data of all relevant trials would be preferable. A meta-analysis of the data from SOTI and TROPOS would have provided the most appropriate overall measure of efficacy.
The DSU also advised that even as an estimate of efficacy in the high-risk subgroup, the RR of 0.64 was likely to be too extreme because of the likelihood of selection bias arising from the way in which the subgroup had been identified (see section 4.1.51). The DSU also emphasised that, to estimate the cost effectiveness of strontium ranelate in a particular subgroup, it would not be sufficient simply to adopt an RR of hip fracture from that group. It would also be important to populate the rest of the economic decision model with evidence specific to the subgroup in question.
NICE invited Servier to respond to the DSU's report. Servier provided a document reiterating its previous views that the subgroup analysis performed to evaluate the efficacy of strontium ranelate in reducing the rate of hip fracture was based on sound scientific principles and valid statistical methods. Servier did not respond to other specific issues raised in the DSU report.
# Cost effectiveness
## Manufacturers' models
For proprietary alendronate, compared with no treatment, the manufacturer's model provided an incremental cost-effectiveness ratio (ICER) of £3135 per quality-adjusted life year (QALY) gained for 70-year-old women with a T-score below −1.6 SD. The manufacturer's results were more favourable than the results of Assessment Group's 2003 model. This could be because the manufacturer's model was not adjusted for baseline fracture prevalence, or because it used different utilities for vertebral fractures, different efficacy data, different risk groups and a longer time horizon.
For etidronate, compared with no treatment, the manufacturer's model provided an ICER of £18,634 per QALY gained for 70-year-old women with a T-score below −2.5 SD. The manufacturer's model included morphometric vertebral fractures and corticosteroid use as risk factors for further fractures. It is unclear whether the manufacturer's ICER was for women with or without a prior osteoporotic fragility fracture.
For risedronate, compared with no treatment, the manufacturer provided data from two models. The ICER derived from the manufacturer's own model was £577 per QALY gained for women aged 74 years. In the second model provided by the manufacturer, which was commissioned from an external body, the ICER was higher, varying from £35,800 per QALY gained in women aged 60 years to £4800 per QALY gained in women aged 80 years, for women with a prior vertebral osteoporotic fragility fracture and a T-score of −2.5 SD. For women at slightly higher risk of fracture, the ICERs were £18,600 per QALY gained or less for all age groups. The ICER calculated using the manufacturer's own model was difficult to verify from the information given. The ICERs generated by the second model were more consistent with the figures provided by the Assessment Group's 2003 model, although they did differ somewhat. This may be because of different cost and RR inputs.
For raloxifene, compared with no treatment, the manufacturer provided data for different age groups and different risk levels. All of the analyses included the breast cancer benefits. It was not clear how the different risk levels were defined. The ICERs ranged from £12,000 to £22,000 per QALY gained, and were slightly more favourable than the Assessment Group's 2003 analysis, even when the Assessment Group included the breast cancer benefits. In the Assessment Group's 2003 model, the RR for the breast cancer effect was higher (0.38) than the RR for invasive breast cancer used in the manufacturer's model (0.28), and the breast cancer risk was adjusted for the association between low BMD and decreased risk of breast cancer. Additionally, the manufacturer's model was not adjusted for baseline fracture prevalence, and included different utilities for vertebral fractures, different efficacy data, different risk groups, and a longer time horizon than the Assessment Group's model.
For strontium ranelate, compared with no treatment, the manufacturer provided two models: one developed in-house and the other commissioned from an external body. The first model showed that, for women aged over 75 years with previous fractures and a T-score of −2.5 SD, strontium ranelate was cost-effective at a maximum acceptable incremental cost-effectiveness ratio of £30,000 per QALY gained. The results of this model were comparable with those generated by the Assessment Group's 2005 model. The second model resulted in an ICER of £6341 per QALY gained for 70-year-old women with a previous vertebral fracture and a T-score of −2.5 SD, decreasing to £5002 per QALY gained in women aged 80 years. The manufacturer's results were more favourable than the Assessment Group's 2005 results because different modelling assumptions were used. For example, fewer health-state transition possibilities were incorporated. Compared with the Assessment Group's model, the manufacturer's model used more favourable efficacy data for hip fracture from the post-hoc 'high-risk' subgroup of women (see sections 4.1.28 and 4.1.44 to 4.1.49), and slightly more favourable efficacy data for wrist and proximal humerus fracture. Higher hip-fracture costs were used in the manufacturer's model.
For teriparatide, compared with no treatment, the manufacturer provided ICERs for women aged 69 years. For women with fractures that had occurred more than 6 months previously (historical fracture), the ICER was £35,400 per QALY gained and for women with a more recent fracture the ICER was £28,863 per QALY gained. The manufacturer supplied additional economic analyses with ICERs of £18,845 and £12,106 per QALY gained for historical and recent fracture, respectively, based on changes to the assumptions of sustained efficacy for non-vertebral fractures and of the RR for specific risk groups. The manufacturer's model and the Assessment Group's 2003 model differed in a number of assumptions. The manufacturer's model was not adjusted for baseline fracture prevalence and used different utilities. The Assessment Group's 2003 model used more favourable assumptions on the duration of sustained efficacy after the end of treatment.
## The Assessment Group's model
The Assessment Group provided a cost–utility model with two components (described in detail in the 2005 Strontium Ranelate Assessment Report). As a first step, the model calculated absolute fracture risk from the epidemiological literature on a number of independent clinical risk factors. These data were prepared under the auspices of the WHO and were provided for this appraisal under an academic-in-confidence agreement. As a second step, the model applied RR reductions for fracture taken from the meta-analysis described in section 4.1.22. A single estimate of efficacy was used for alendronate and risedronate based on pooled data for these two drugs. Following advice from the original Osteoporosis Guideline Development Group, it was assumed that RRs remained constant across all ages, T-scores and fracture status. The most recent analyses carried out by ScHARR were based on the price of non-proprietary alendronate in February 2008 (£53.56 per year for once-weekly 70 mg tablets; £108.20 per year for daily 10 mg tablets).
All osteoporotic fragility fractures in women aged 50 years or older were included in the modelling. The RR for hip fracture was assumed to apply also to pelvis and other femoral fractures. The RR for non-vertebral fracture was assumed to apply also to proximal humerus, rib, sternum, scapula, tibia, fibula and wrist fractures. Where confidence intervals for RRs spanned unity, it was assumed that there was no effect of treatment, except in the case of strontium ranelate. In this case, an RR of 0.85 for hip fracture was used to acknowledge the effect reported in the high-risk subgroup of the study. The model used UK-specific epidemiological data on femoral neck BMD.
The model assumed an initial utility in the year of fracture and a higher utility in subsequent years. The time horizon for predicting morbidity was 10 years, consisting of 5 years of treatment with sustained efficacy plus 5 years of linear decline to no effect. However, treatment-related decreases in mortality rate extended beyond the 10-year time horizon. For this, the life expectancy for a woman at the threshold T-score for osteoporosis was calculated from standard life tables, and any increase in mortality rate due to fracture would continue until death or an age of 110 years. In the base case, vertebral-fracture utility was assumed to be lower than hip-fracture utility, and a sensitivity analysis was carried out in which the utility for vertebral fracture was assumed to be the same as that for hip fracture. The percentage of women assumed to move from community living to a nursing home following a hip fracture increased with increasing age. An age-dependent gradient of hip-fracture risk was used, and an association between vertebral or proximal humerus fracture and increased mortality in women with osteoporosis was included. No follow-up BMD scans were included in the model; this reflects current clinical practice in the UK.
The model included an assumption about the costs and disutility associated with treatment-related side effects for all drugs, based on the findings of prescription-event monitoring studies in patients treated with alendronate. For the base case, the model assumed 50% persistence with treatment. In addition to the base case, the Assessment Group undertook a number of sensitivity analyses using alternative assumptions, including: persistence with treatment (25% or 75% at 5 years); reduction in the efficacy of the drugs at reducing the risk of fracture associated with risk factors other than age, prior fracture and low BMD to 0% or 50% (with a consequent upward adjustment of the RR for the risk factors of age, prior fracture and low BMD); disutility of vertebral fracture; updated fracture costs; and the disutility and costs of treatment-related side effects. It was assumed that women who experience bisphosphonate-related side effects had 91% of the utility of women who do not have such side effects. In the base case analysis for all of the drugs under consideration this was applied to 2.35% of women in the first treatment month and 0.35% of women thereafter and, in sensitivity analyses for bisphosphonates, to 24% of women in the first treatment month and 3.5% of women thereafter. In the case of strontium ranelate, the effect on VTE was not included in the model. Discount rates of 6% per year for costs and 1.5% per year for health benefits were applied, in accordance with NICE methods relevant to this appraisal.
For raloxifene, 4-year follow-up data from the MORE study were used, and it was assumed that women with low BMD have a lower breast cancer risk than women with normal BMD. The cost effectiveness was modelled excluding the breast cancer benefit, the risk of VTE and the effect on cardiovascular events.
The independent clinical risk factors for fracture used in the model were based on the data prepared under the auspices of the WHO (see section 4.2.7) and included BMI, prior fracture, previous or current use of corticosteroids, parental history of fracture, current smoking, alcohol intake of more than 2 units per day, and rheumatoid arthritis. The study provided prevalence data for the different risk factors, and risk ratios for hip fracture and osteoporotic fracture for each risk factor, including T-score and age. Using these risk ratios, absolute risk of fracture was calculated.
The estimates of cost effectiveness were generated for different levels of absolute risk derived from a large number of combinations of T-score (in bands 0.5 SD wide), age and number of independent clinical risk factors for fracture. For practical reasons relating to the number of potential combinations, single-point RRs of fracture, calculated from the log-normal efficacy distributions, were used in the model. Results were presented for population groups categorised according to age, T-score and number of independent clinical risk factors.
Women with a fracture who present to clinicians require a DXA scan for osteoporosis to be established. Therefore, the Assessment Group also estimated the impact of DXA scanning on the cost effectiveness of the drugs. This required both a calculation of the ICER for treatment, and a calculation of the distribution of risk assessment cost over the population who would benefit from treatment. A net-benefit approach was used to do this. The net-benefit approach is analogous to the more traditional cost per QALY gained approach, but also requires a value of willingness to pay (WTP) for an additional QALY gained. For the calculation of the net benefit of an intervention, the WTP is first multiplied by the incremental QALY gained associated with the intervention, then the incremental cost associated with the intervention is subtracted. For this appraisal, the total net benefit for each age group and DXA scanning approach was calculated by subtracting the cost of DXA scanning from the net benefit of treating all women who can be treated cost effectively.
A stepped net-benefit approach was used to estimate, in reverse order, the cost effectiveness of risk assessment, DXA scanning and treatment of women with a prior fracture. Two WTP values, £20,000 or £30,000 per QALY gained, were applied in the modelling.
Step 1. ICERs for treatment versus no treatment were calculated for each intervention for various combinations of age, T-score and number of independent clinical risk factors for fracture (see section 4.2.12). The net benefit of treatment per woman was calculated using the following formula: Net benefit = £30,000 (or £20,000) × incremental QALYs – incremental costs.For women for whom the ICER for treatment was more than £30,000 (or £20,000) per QALY gained, the net benefit was set to zero.
Step 2. The net benefit per woman was multiplied by the number of women in the population estimated to fall within each combination of age, T-score and number of independent clinical risk factors for fracture (based on the data used to develop the algorithm prepared for the WHO). The net benefits for each group were then added together to give a total net benefit of treatment for women with no, one, two or three independent clinical risk factors within each age group.
Step 3. The cost of DXA scanning all of the women in each age/independent clinical risk factor group was subtracted from the net benefit of treatment for that group (calculated as described in step 2). This provides the net benefit of treatment and DXA scanning for the group, assuming that the number of independent clinical risk factors is known. A positive net benefit indicates that DXA scanning of women in that age/independent clinical risk factor group and treating those groups of women in whom the ICER for treatment is £30,000 (or £20,000) or less provides an ICER for the entire strategy of less than £30,000 (or £20,000) per QALY gained.
Step 4. When the resulting values of net benefit of treatment and scanning were negative they were set to zero. For each age group, the total net benefit of scanning and treatment was calculated by adding together the net benefits for each age/independent clinical risk factor group. The cost of opportunistic assessment for all women in this age group was then subtracted to give the net benefit of risk assessment, scanning and treatment. A positive net benefit indicates an ICER of less than £30,000 (or £20,000) per QALY gained for risk assessment, DXA scanning and treating women (at a specific T-score related to the ICER for treatment only) of that particular group. Cost per QALY gained data were presented for each strategy.
First, the Assessment Group calculated ICERs (cost per QALY gained for alendronate compared with no treatment) without identification costs for all combinations of age, T-score and number of independent clinical risk factors for fracture. The cost per QALY gained, compared with no treatment, became more favourable with increasing age and number of independent clinical risk factors, and decreasing T-score (that is, with increasing annual absolute risk of fracture).
Then, the Assessment Group presented the results of the economic analyses in the form of identification and treatment strategies (based on age, T-score and number of independent clinical risk factors for fracture) that resulted in an ICER of £30,000 or less (cost per QALY gained compared with no treatment). The analyses shown below included the following assumptions: persistence at 5 years set to 50%; the efficacy of bisphosphonates on fracture risks associated with factors other than age, BMD and prior fracture status set to 50% of that observed for the total population in the trials (with a consequent upward adjustment of the RR associated with age, BMD and prior fracture); costs set to health resource group values including home-help costs; utility multiplier associated with vertebral fracture set to 0.792 in the first year of fracture and 0.909 in subsequent years (as for hip fracture); costs of bisphosphonate-related gastrointestinal symptoms incurred over 5 years; utility multiplier associated with bisphosphonate-related gastrointestinal symptoms set to 0.91 (included utility losses for non-compliant patients); and alendronate at a cost of £53.56 or £108.20 per year.
For alendronate priced at £53.56 per year (once-weekly treatment), and when assuming that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:
A strategy of risk assessment, DXA scanning and treatment with alendronate resulted in an ICER of less than £30,000 per QALY gained for all women aged 55 years or older with confirmed osteoporosis (that is, a T-score of –2.5 SD), and for postmenopausal women aged 50–54 years with confirmed osteoporosis and two independent clinical risk factors for fracture.
In a sensitivity analysis for alendronate priced at £53.56 per year (with other assumptions as in section 4.2.17 and 4.2.18), acid-suppressive medication was assumed to affect fracture risk. The data inputs for this were taken from one GPRD study (see section 4.1.41) and represent the midpoint values pooled for patients using acid-suppressive medication. This sensitivity analysis produced the following results:
A strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 55 years resulted in an ICER of more than £30,000 per QALY gained.
A strategy of risk assessment, DXA scanning and treatment with alendronate resulted in an ICER of less than £30,000 per QALY gained for all women aged 65 years or older with confirmed osteoporosis (that is, a T-score of –2.5 SD or below), for postmenopausal women aged 60–64 years with confirmed osteoporosis and one independent clinical risk factor for fracture, and postmenopausal women aged 55–59 years with confirmed osteoporosis and two independent clinical risk factors for fracture.The ICER for treatment with alendronate (but excluding identification costs) for a woman aged 60–64 years with a T-score of −2.5 SD (using the assumptions described in sections 4.2.17 and 4.2.18) was £9005 per QALY gained without acid-suppressive medication and £21,656 per QALY gained with acid-suppressive medication. If this woman had an independent clinical risk factor for fracture, the ICERs would be £3969 per QALY gained without and £12,250 per QALY gained with acid-suppressive medication.
For alendronate priced at £108.20 per year (daily treatment), and when assuming that 24% of women were experiencing bisphosphonate-related side effects in the first treatment month and 3.5% of women thereafter, the model produced the following results:
A strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 55 years resulted in an ICER of more than £30,000 per QALY gained.
A strategy of risk assessment, DXA scanning and treatment with alendronate resulted in an ICER of less than £30,000 per QALY gained for women aged 65 years or older with confirmed osteoporosis (that is a T-score of –2.5 SD or below), for postmenopausal women aged 60–64 years with confirmed osteoporosis and one independent clinical risk factor for fracture, and for postmenopausal women aged 55–59 years with confirmed osteoporosis and two independent clinical risk factors.
Risedronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per year for alendronate); that is, these three drugs have a higher acquisition cost than alendronate, but are not more efficacious. Analyses were conducted as for alendronate (see section 4.2.17). For risedronate, base-case assumptions for bisphosphonate-related side effects were modelled; that is 2.35% of women in the first treatment month and 0.35% thereafter experienced side effects (see section 4.2.10). In addition a sensitivity analysis was performed, using the assumption that 24% of women in the first treatment month and 3.5% of women thereafter experienced bisphosphonate-related side effects. For raloxifene and strontium ranelate, base-case assumptions for side effects were used. In previous economic modelling and before the most recent price reduction for non-proprietary alendronate, etidronate's cost effectiveness was comparable to that of non-proprietary alendronate, but the calculations were based on a weaker clinical evidence base than for alendronate. Therefore the modelling for etidronate was not updated after the most recent price reduction for alendronate.
For risedronate, raloxifene, strontium ranelate and teriparatide, additional analyses were conducted to explore identification and treatment strategies that could be cost effective for these interventions when compared with no intervention. All results showed less favourable cost effectiveness than non-proprietary alendronate. For example, for women aged 55–59 years with an independent clinical risk factor for fracture, the ICERs (without considering costs related to risk assessment and DXA scanning) for risedronate and strontium ranelate (each compared with no treatment) were more than £40,000 and £55,000 per QALY gained, respectively. For these two groups of women, treatment with weekly non-proprietary alendronate, including risk assessment and DXA scanning costs, resulted in an ICER of less than £30,000 per QALY gained.
Further analyses were carried out assuming second-line use; that is, costs for risk assessment or DXA scanning were excluded because BMD was assumed to be known from the first-line management.
In the economic modelling carried out for this appraisal in 2006, lower ages and higher T-scores resulted in ICERs of less than £30,000 per QALY gained for etidronate compared with risedronate; that is, etidronate was more cost effective than risedronate. Because of the concerns expressed about the weaker clinical evidence base for etidronate, the modelling for this bisphosphonate was not updated.
For risedronate in second-line use, when assuming that 2.35% of women in the first treatment month and 0.35% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:
Treatment with risedronate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained. Including women aged 50–54 years with no independent clinical risk factors for fracture increased the ICER to more than £30,000 per QALY gained.
Age
(years)
Number
of
independent
clinical
risk
factors
for
fracture
(section
– a
-r older
−2.0b
a ICER more than £20,000 per QALY gained.
b Women with osteopenia are not included in the guidance (see sections 1 and 4.3.6).
For strontium ranelate in second-line use, the model produced the following results:
Treatment with strontium ranelate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained. Including women aged 50–54 years with no independent clinical risk factors for fracture increased the ICER to more than £30,000 per QALY gained.
Age
(years)
Number
of
independent
clinical
risk
factors
for
fracture
(section
– a
-r older
a ICER more than £20,000 per QALY gained
For raloxifene in second-line use, using base-case assumptions on side effects, the model produced the following results:
Treatment with raloxifene in women younger than 70 years resulted in an ICER of more than £30,000 per QALY gained.
Treatment with raloxifene in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained.
Number
of
independent
clinical
risk
factors
for
fracture
(section
Age
(years)
-r older
For teriparatide, the model produced the following results.
Treatment with teriparatide in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained. Including women aged 50–54 years with no independent clinical risk factors for fracture would increase the ICER to more than £30,000 per QALY gained.
Number
of
independent
clinical
risk
factors
for
fracture
(section
Age
(years)
– a
-r older
a ICER more than £30,000 per QALY gained
If it was assumed that acid-suppressive medication affects fracture risk, the ICER for treatment with risedronate (compared with no treatment, but excluding identification costs) for a woman aged 70 years with a T-score of −3 SD increased from £12,273 to £17,848 per QALY gained (using base-case assumptions about side effects). The corresponding ICER for strontium ranelate was £28,026 per QALY gained compared with no treatment (using base-case assumptions about side effects). For a woman aged 70 years with a T-score of −3.5 SD and one independent clinical risk factor for fracture, the ICER for risedronate increased from £3028 to £7688 per QALY gained when acid-suppressive medication was assumed to affect fracture risk (using base-case assumptions about side effects).The corresponding ICER for strontium ranelate was £14,986 per QALY gained compared with no treatment (using base-case assumptions about side effects).
## Consultee comments on the Assessment Group's economic model
Following the outcome of the judicial review and the court ruling of March 2009, NICE was able to offer the Assessment Group's executable economic model for consultation. Consultees and commentators who requested the model and returned the necessary confidentiality undertakings received a CD-ROM containing the executable version of the economic model, a document with instructions for running the model and a pro-forma for commenting on the model. Comments on the Assessment Group's model were received from Servier Laboratories (the manufacturer of strontium ranelate), the Bone Research Society (BRS), the National Osteoporosis Society (NOS) and the Society for Endocrinology. Comments received from each of these consultees are summarised in the sections below.
These four consultees expressed the view that the documentation provided with the Assessment Group's model was insufficient, that the model supplied to them was incomplete and that some inputs could not be altered. They also stated that the application of the fracture risk algorithm developed under the auspices of the WHO could not be assessed. They felt that the model could not be validated and that its validity had not been demonstrated in documents made available during development of the guidance.
Servier commented that the fracture risks entered in the Assessment Group's model differed from estimates that Servier calculated using the FRAX fracture risk calculation tool (see section 4.3.48 for further information about the FRAX tool). Servier commented that mortality risk associated with clinical risk factors had been omitted from the model. In Servier's opinion, these differences called into question whether the WHO fracture risk algorithm had been applied correctly in the Assessment Group's model.
Other comments questioned the use of a fixed value for BMI in the model. Consultees commented that no clear explanation was provided of the rationale for the choice of BMI value, that a range of BMI values should have been used, and that the use of a fixed BMI value resulted in underestimation of the cost effectiveness of treatment for some women at risk of fracture.
Servier commented on the selection and weighting of the independent clinical risk factors for fracture used in the Assessment Group's model. Servier, BRS and NOS suggested that the risk associated with alcohol intake was incorrect in the model and that this would have adversely affected estimation of the cost effectiveness of treatment for women at risk of fracture. They suggested that a threshold alcohol intake of 3 or more units per day, as used in the FRAX fracture risk calculation tool, should have been applied. They also stated that the Assessment Group's model and the guidance were inconsistent with each other, and that these differences resulted in the risk of fracture being underestimated in the model. Servier also noted that the Assessment Group's model gave an equal weighting to each of the independent clinical risk factors for fracture. Servier suggested that this was a less precise approach than that used in the FRAX tool, which used different weightings (some higher and some lower than those in the Assessment Group's model) for each fracture risk for specific risk factors. Servier stated that the FRAX tool assesses fracture risk and cost effectiveness more accurately and 'deals more fairly' with variation between women at risk of fracture. Servier also noted that one of the risk multipliers for fracture risk included in the Assessment Group's model was not consistent with that given in the assessment report.
Servier and NOS noted that the Assessment Group's model had a time horizon limited to 10 years and criticised how mortality beyond 10 years had been taken into account in the economic evaluation. Servier expressed the view that, as a consequence of this, the model was inaccurate and underestimated the cost effectiveness of treatment for women at risk of fracture. Servier also identified two values ('wristbonusat2.5' and 'phbonusat2.5', related to QALY calculations) that were included in the model, but not described in assessment reports.
Servier commented that using the same disutility for side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates.
BRS and NOS thought that the proportion of women with low BMD in England and Wales was substantially underestimated in the Assessment Group's model. These consultees were also concerned that although both smoking and previous or current glucocorticoid (corticosteroid) use had been included as additional independent clinical risk factors for fracture in the Assessment Group's model, they were not defined as risk factors in the recommendations (see section 1.5). In addition, both consultees thought that interactions between several clinical risk factors were not incorporated in the model, thereby reducing the cost effectiveness of treatment for women at risk of fracture, especially younger women.
All four consultees commented on elements of the Assessment Group's economic evaluation that had been considered and agreed by the Appraisal Committee before it directed the Assessment Group to develop the economic model using specific assumptions. These Committee-directed assumptions included the compliance rate, costs associated with fracture, utility values used for vertebral fracture, and the strategy for identifying women at high risk. Servier also commented on the discount rates used in the model.
Servier reported that it had prepared a 'comparative' model which was run using assumptions similar to those in the Assessment Group's model. This model was referred to in a report to support the mathematical foundation of revised analyses discussed as part of Servier's comments on the Assessment Group's model. This report was made available to the Appraisal Committee to inform its consideration of comments by Servier on the DSU report (see below and section 4.3).
## Decision Support Unit (DSU) report on consultee comments on the Assessment Group's economic model
The DSU was commissioned to review the comments from consultees on the Assessment Group's executable economic model and report to the Appraisal Committee. The DSU considered issues that were relevant to the economic model. Key issues were grouped under the common themes of model transparency and ability to assess its validity, methodology (approach) and model inputs.
The DSU assessed comments on the transparency and validity of the Assessment Group's model. With regard to the consultees' observation that some model inputs were fixed and that in their view the model provided for consultation was incomplete and not fully executable, the DSU confirmed that certain inputs were intentionally fixed and the ability to alter these inputs was not a feature of the model or necessary for some parameters with minimal uncertainty that are commonly fixed in other economic models. In response to comments on the consultees' inability to assess the application of the WHO algorithm, the DSU explained that the WHO algorithm itself was not embedded within the model. The DSU confirmed that absolute fracture risks were correctly calculated using the WHO algorithm before being entered into the model. The DSU noted that documentation had been provided to consultees in the form of publicly available reports and peer-reviewed manuscripts produced by the Assessment Group, and that instructions on the operation of the Assessment Group's model were also offered to consultees and commentators.
With regard to comments on the modelling approach adopted in the Assessment Group's model, the DSU responded by confirming that alcohol consumption of more than 2 units per day was included in the model, and that the coefficients used in the model were consistent with the WHO algorithm (as supplied to the Assessment Group at the time the model was developed). The DSU also explored how the model considered corticosteroid-related fracture risk, and confirmed that corticosteroid use was included in the model and that the coefficient used for this risk factor was consistent with that calculated using the WHO algorithm. The DSU noted that the fracture risk of women using corticosteroids would have contributed to the overall fracture risk of the whole modelled population and thereby reduced the ICER associated with the treatment of all women at risk of fracture.
The DSU confirmed that each clinical risk factor for fracture was given equal weighting in the model. In response to consultee comments expressing the view that this was a less precise approach than that used in the FRAX tool, the DSU noted two points. Firstly, no individual risk calculation tool was publicly available when the model was developed. secondly, the DSU referred to the 2005 Strontium Ranelate Assessment Report, which compared suggested treatment thresholds (combinations of age, T-score and number of independent clinical risk factors for fracture) from the Assessment Group's model with treatment thresholds indicated by absolute fracture risk. The DSU suggested that the use of absolute fracture risk alone did not accurately predict cost effectiveness, and therefore would not provide a robust basis for the Committee's decision-making.
Consultee comments on the modelling approach also addressed the time horizon and population data used and the grouping of age in 5-year bands. The DSU confirmed that the consequences of fracture were considered beyond 10 years, and provided further explanation of the modelling approach. The DSU additionally undertook exploratory analyses of the impact of mortality after the 10-year time horizon and of incorporating mortality associated with vertebral fracture and proximal humerus fracture. They reported that the change in the results produced by the model was minimal when mortality risk beyond 10 years was doubled. The DSU also confirmed that UK epidemiological data from a study by Holt et al. were used in the Assessment Group's model, and undertook an exploratory analysis around the assumptions of the distribution of T-scores used in the model. For some age bands modelled, the T-scores did not follow a statistically normal distribution, but the DSU noted that the assumption of a normal distribution made it more likely that treatments for women at risk of fracture would be judged to be cost effective. The DSU considered a comment on the calculation of cost-effectiveness estimates averaged for the 5-year age bands implemented in the model. It disagreed with the alternative suggested by the consultee and noted that the Committee had considered and agreed that initial identification by age band was a workable strategy for selecting women at risk of fracture in clinical practice. It also noted that alternative strategies (which did not use age bands) may in fact be more resource-consuming and less likely to be judged as cost effective.
The DSU reviewed consultee comments on inputs used in the Assessment Group's model. It confirmed that the WHO algorithm (as supplied) had been correctly implemented in the model to produce estimates of fracture risk for each T-score band. The DSU suggested that the differences in the estimates of fracture risk obtained using the FRAX fracture risk calculation tool and the Assessment Group's model did not necessarily suggest that the WHO algorithm had been incorrectly applied (see section 4.3.48), and that these differences could occur for a number of reasons. For example, the use of a midpoint age to represent an age band of 5 years could lead to differences in estimates of fracture risk. The DSU confirmed that no increase in mortality associated with clinical risk factors was used in the model. The DSU suggested that inclusion of such mortality effects would be likely to increase the ICERs for women with those clinical risk factors. The DSU explained that this is because fewer QALY benefits would accrue in the model for women who die of causes related to risk factors. In response to a further comment from Servier, the DSU agreed that, for women without clinical risk factors, the inclusion of these mortality effects in the model may have the opposite effect (that is, a decrease in ICERs). Therefore the overall effect of including the increased mortality associated with clinical risk factors would be small.
The DSU also confirmed that a fixed value for BMI of 26 kg/m2 was used in the Assessment Group's model. This was the mean BMI in the UK epidemiological dataset from the Holt study used in the model. In an exploratory analysis using the WHO algorithm, the DSU showed that using a BMI of 26 kg/m2 resulted in higher estimated fracture risk than a BMI of 20 or 32 kg/m2 when BMD is known, and this was confirmed by the estimates supplied by one consultee. The DSU suggested that the BMI value used in the model may favour treatment of women at risk of fracture compared with alternative BMI values. The DSU also pointed out that BMI is a weak predictor of fracture when BMD is known (as specified in the identification strategy in the guidance).
The DSU investigated the risk multipliers used for fracture risk in the Assessment Group's model and the consultee comment that interactions between clinical risk factors had been omitted. It confirmed that the risk multipliers used for fracture risk had been correctly calculated from the WHO algorithm and that all interactions between risk factors had been included. The DSU also noted that the inconsistency between one of the risk multipliers for fracture risk included in the Assessment Group's model compared with the assessment report was the result of a typographical error. Accordingly there was no impact on the results of the model.
The DSU did not respond in detail to comments on assumptions in the model that had already been documented and agreed by the Appraisal Committee and which were available to consultees and commentators earlier in the development of the appraisal guidance. The DSU did, however, list these issues in its report and cited where they had been considered by the Committee or had been available for comment during development of the guidance. Features of the economic evaluation previously discussed and agreed by the Committee included the following (the sections of this document where these points are covered are given in parentheses):
discount rates used in model (4.2.10)
treatment compliance (4.2.10)
costs associated with fracture (4.2.17)
strategy for identifying women at high risk of fracture (4.2.17)
utility values used for vertebral fracture (4.2.17 and 4.3.13)
equal disutility for the side effects of strontium ranelate and bisphosphonates (4.2.10)
sensitivity analyses on disutility (4.3.15).
The DSU concluded that, in its view, adequate documentation on the Assessment Group's model had been provided for consultees. It highlighted that the WHO algorithm used to generate estimates of fracture risk was not integrated within the Assessment Group's model; rather, the fracture risks derived from the algorithm were entered into the model. Comparisons with fracture risks derived using the FRAX fracture risk calculation tool were made by several consultees on the basis that the WHO algorithm supplied to the Assessment Group and the FRAX tool are assumed to be identical. The DSU could not verify these analyses without access to the FRAX algorithm. The DSU agreed that some parameters in the Assessment Group's model were fixed. These included those with minimal uncertainty, as well as those that are commonly fixed in other economic models. Sensitivity analyses conducted by the DSU suggested that none of the consultees' suggestions relating to the modelling approach would lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The DSU concluded that, in its view, no issues raised by consultees would either affect the validity of the Assessment Group's model or raise significant doubts about the appropriateness of using the model to inform the deliberations of the Committee.
# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alendronate, etidronate, risedronate, strontium ranelate, raloxifene and teriparatide, having considered evidence on the nature of osteoporosis and the value placed on the benefits of these drugs by women with the condition, those who represent them, and clinical specialists. It also considered the consultation comments received in response to the previous appraisal consultation documents, the extra analysis undertaken by ScHARR in November 2006 and February 2008, and comments received from consultees and commentators after an appeal against an earlier final appraisal determination was upheld in December 2007. Following the outcome of a judicial review and court ruling in March 2009, the Committee considered the comments received from consultees after release of the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report. It also took into account the effective use of NHS resources.
The Committee considered the extent to which NICE technology appraisal 87 should be updated in the light of the introduction of a new drug (strontium ranelate), new pricing for alendronate and etidronate, and new cost-effectiveness modelling developed as part of the technology appraisal on primary prevention.
The Committee considered the clinical effectiveness data for the bisphosphonates (alendronate, etidronate and risedronate), strontium ranelate, raloxifene and teriparatide. It noted that all these drugs have proven efficacy in reducing the incidence of vertebral fragility fractures in women with osteoporosis, but that there were differences between the drugs in the degree of certainty that treatment results in a reduction in hip fracture (considered a crucial goal in osteoporosis management). In the case of alendronate and risedronate, the Committee accepted that there was sufficiently robust evidence to suggest a reduction in hip-fracture risk. The Committee noted that the available RCTs for etidronate were of insufficient size to show statistically significant reductions in hip-fracture risk, but that observational data lent support to a reduction in hip-fracture risk.
The Committee noted that strontium ranelate was effective in preventing vertebral and non-vertebral fractures, and the drug resulted in a non-significant 15% reduction in hip-fracture risk. The Committee was also aware of the result of a post-hoc subgroup analysis showing a statistically significant reduction in the incidence of hip fractures in women aged 74 or older who had a T-score of −2.4 SD or below.
The Committee noted that the evidence for raloxifene showed an effect on risk of vertebral fractures, but did not show an effect on risk of hip fractures. In addition, there was evidence for a beneficial side effect of raloxifene on the incidence of breast cancer.
The Committee noted that teriparatide was effective in preventing vertebral and grouped non-vertebral fractures in women with osteoporosis who have had a fracture, compared with placebo. The Committee also considered the favourable findings for teriparatide from one head-to-head RCT of teriparatide and alendronate, and that it conferred relatively favourable back-pain relief. However, the Committee was concerned about the small size of the head-to-head study, the fact that the study was not targeted at women with fractures, and the high dose of teriparatide used. Therefore it considered that the evaluation of the overall advantages of teriparatide over bisphosphonates requires more research to establish relative clinical effectiveness.
The Committee did not consider it appropriate to make recommendations for the treatment of women on long-term corticosteroid treatment because this patient group is at greatly increased risk of fracture and therefore requires special consideration, particularly if they have had a prior fracture. The Appraisal Committee therefore felt that it would be disadvantageous for this group to be included in the current guidance.
Recommendations for the treatment of women with osteopenia (T-score of between –1 and –2.5 SD below peak BMD) were not made, for two reasons. Firstly, it was agreed after the scope was issued in 2002 that the outcome in this appraisal should be 'the prevention of osteoporotic fractures' and this has been understood by the Committee to be a fragility fracture experienced by women with osteoporosis, not osteopenia. Secondly, not all of the drugs under appraisal have a UK marketing authorisation for treatment of women with osteopenia.
The Committee noted that fracture risk is clearly related to age, low BMD and previous fracture. The Committee accepted that most other risk factors (see sections 2.11 and 2.12) were likely to be associated with an increased fracture risk. The Committee was concerned that there was not sufficient evidence for a proven treatment effect on fracture risk related to risk factors other than low BMD, age and prior fracture. The Committee therefore concluded that preventative drug treatment should be targeted at women whose absolute risk of fracture is driven by low BMD and age, and that the recommendations should be made on the basis of age and BMD in the form of T-scores below which treatment is recommended.
## Cost-effectiveness modelling
The Committee acknowledged the efforts of the Assessment Group to build on the model used previously, particularly in using epidemiological data and a fracture risk algorithm developed under the auspices of the WHO to calculate transition probabilities and to model the identification approaches. The Committee concluded that the Assessment Group's model was likely to give the best estimates of cost effectiveness because it used data from a wide age range (age 50–75 years or older), and was updated to use all osteoporotic fracture sites, more recent utility values, prevalence and risk-factor data, and an adjusted prevalence of fractures in the average population. Although the Assessment Group's model considered a shorter time period (10 years for predicting morbidity, see section 4.2.9) than the manufacturers' models, the Committee thought that this was appropriate considering the age groups involved and the uncertainties around health effects over a longer period.
The Committee discussed the assumptions underpinning the economic modelling undertaken by the Assessment Group. It noted that the most recent modelling explored some of the uncertainties identified by the Committee surrounding the results of the previous modelling; these related to the costs and disutility associated with treatment-related side effects and to non-compliance or non-persistence with treatment in a proportion of patients. The Committee also noted the effect of the recent price reductions for non-proprietary alendronate (70 mg weekly and 10 mg daily doses) on the cost effectiveness of the drug.
The Committee considered the base-case assumptions and those used in additional analyses. The Committee noted that the costs associated with fractures used in the base-case analysis were those used in the original assessment report developed in 2003 and considered that these were likely to be outdated. The Committee agreed that costs based on health resource groups, including home-help costs, were likely to provide the most accurate reflection of the cost of fractures to the NHS and personal social services, and it decided to incorporate these costs into the base-case analysis.
The Committee considered the utility multiplier used in the base-case analysis for the first year after a vertebral fracture and noted that it was based on a hospitalised patient group and not on a typical group of patients with vertebral fractures. Consequently it was considerably lower than the utility value modelled for a hip fracture. Although the Committee acknowledged that vertebral fracture can lead to greatly reduced quality of life, it considered that its true value would not greatly outweigh the utility decrement associated with a hip fracture. Therefore, the Committee considered it reasonable to assume that the disutility in the first year after a vertebral fracture was equivalent to the disutility in the first year after a hip fracture and decided to include this assumption in the base-case analysis.
The Committee was not persuaded that the drugs under consideration had been unequivocally shown to reduce fracture risk that was attributable to risk factors not mediated through low BMD and age. The Committee concluded that the uncertainty surrounding the efficacy of the drugs on risk factors not mediated through low BMD and age should be factored into its decision-making by using an analysis that assumed 50% efficacy of the drugs on fractures associated with risk factors other than age and low BMD. Although the Committee recognised that 50% was necessarily an arbitrary figure, the use of either 0% or 100% was considered both extreme and less plausible. In the analysis accepted by the Committee, the assumption of 50% efficacy of the drugs on fracture risk associated with other risk factors was adjusted by using a correspondingly greater efficacy of the drugs on fractures associated with the key independent clinical risk factors (age, BMD and prior fracture).
The Committee considered the assumptions used in the modelling for the side effects of bisphosphonates, in which women who experience bisphosphonate-related side effects had 91% of the utility of women who did not have such side effects. In the base case, this was applied to 2.35% of patients in the first treatment month and 0.35% of patients thereafter. Taking into account the persistence data (sections 4.1.36 and 4.1.37) and the comments received from consultees and commentators that about 25–30% of women experience gastrointestinal side effects when first taking a bisphosphonate, the Committee agreed that it was important to consider the results of a sensitivity analysis assuming that 24% of women were experiencing bisphosphonate-related side effects in the first treatment month and 3.5% of women thereafter.
The Committee acknowledged that the modelling made assumptions necessary about the value of a QALY gained that could be considered an acceptable use of NHS resources. The Committee considered that women who have already sustained an osteoporotic fracture live with the pain and distress caused by the fracture. The Committee considered that women with an osteoporotic fracture constitute a different population from the primary prevention population and that there were some factors that justified considering a higher ICER range in line with the 'Guide to the methods of technology appraisal'.
The Committee discussed a number of concerns surrounding other issues that were not represented in the model but which may have had an impact on the cost-effectiveness estimates. These included: possible long-term adverse effects of bisphosphonates on the formation of new bone; the likelihood that DXA scanning outside a clinical trial environment would not be as effective as in the clinical trials; and the possibility that the proportion of women who experience side effects may exceed the model's base-case assumptions. Finally, the Committee noted that current discount rates used by the Treasury, the Department of Health and NICE result in a cost-effectiveness calculation less favourable to the drugs than the discount rates used in the analysis considered by the Committee. Although a quantitative analysis of the uncertainties surrounding all these issues was not available, the Committee agreed that, for first-line treatment with a bisphosphonate, these uncertainties could be collectively approximated through the sensitivity analysis for side effects (see section 4.3.15). The Committee was persuaded, however, that the results of the sensitivity analysis need only apply to first-line treatment with a bisphosphonate, because many of the factors that led to the adoption of the sensitivity analysis did not apply for second-line treatment.
## Alendronate
The Committee considered the results of the economic model following the price reduction for non-proprietary alendronate, the newly included assumptions and the sensitivity analyses (see sections 4.3.9 to 4.3.15). The Committee agreed that, when considering the use of alendronate as a first-line treatment, the sensitivity analysis that captured the uncertainties in the economic model (see section 4.3.14) was the most appropriate. This led the Committee to conclude that alendronate (based on the price of £53.56 per year for once-weekly treatment) would be an appropriate use of NHS resources for secondary preventative treatment in postmenopausal women with fragility fractures and confirmed osteoporosis (that is, a T-score of –2.5 SD or below). The Committee was advised by the clinical specialists from the original Guideline Development Group for the NICE clinical guideline on osteoporosis that, in women aged 75 years or older with a prior fracture, a DXA scan may not be required if the responsible clinician considers it to be clinically inappropriate or unfeasible. This is because a very high proportion of these women would be likely to have a T-score of −2.5 SD or below.
The Committee noted that the prices of the different brands of alendronate vary greatly and concluded that alendronate should be prescribed on the basis of the lowest acquisition cost available.
## Considerations for the other drugs under appraisal
The Committee noted that risedronate, etidronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per year for alendronate); that is, these drugs have a higher acquisition cost than alendronate, but are not more efficacious. The Committee was also aware that, for women for whom weekly non-proprietary alendronate could be recommended based on cost effectiveness, the ICERs for risedronate and strontium ranelate were very high, even without inclusion of identification costs (see examples in section 4.2.22).
The Committee considered an approach where the higher costs of risedronate, strontium ranelate and teriparatide were incorporated into the analysis by combining costs based on the estimated use of alendronate, risedronate and strontium ranelate and teriparatide. However, the overall cost effectiveness of such a combined approach for fracture prevention would be less favourable than that of alendronate. As a consequence, some women who would be eligible for treatment with alendronate as recommended in section 1.1 would not be offered treatment using such a combined approach. For this reason, the Committee did not consider the combined approach to be appropriate.
The Committee considered treatment options available for a woman who is intolerant to alendronate or unable to comply with instructions for administration despite reasonable measures to support continuation of alendronate treatment. The Committee noted that all other treatment options have higher acquisition costs and/or different effectiveness profiles, which would reduce the cost effectiveness of preventive treatment if these drugs were used. The Committee observed that the identification costs associated with finding women who could be cost-effectively treated with one of the other drugs would be negligible, because they would have already undergone an assessment and had a DXA scan in order to be assessed for first-line treatment with alendronate. Therefore, it agreed that the recommendations for this situation should be based on the modelling that excluded identification costs. The Committee also agreed that, when considering second-line or subsequent treatment, the base-case assumptions for side effects could be applied; that is, a 0.91 utility multiplier should be applied to 2.35% of patients in the first treatment month and 0.35% of patients thereafter.
The Committee considered women who cannot take alendronate because of a contraindication or a disability that prevents them from complying with the instructions for administration. Because such a contraindication or disability would be known before the risk assessment, this would comprise a first-line treatment situation, where identification costs are included. Alternative drugs become cost effective at a higher age and lower BMD in a first-line treatment situation, compared with a second-line treatment situation where identification costs are not included. However, such an approach was considered inappropriate by the Committee because it would unfairly disadvantage women who cannot take alendronate because of a contraindication or a disability. Therefore the Committee concluded that women who cannot take alendronate for these reasons should have access to alternative drugs in the same way as women who cannot tolerate alendronate (that is second-line treatment, where the analysis excluded identification and assessment costs).
The Committee concluded that risedronate could be recommended for women who are unable to comply with the special instructions for the administration of alendronate, or have a contraindication to or are intolerant of alendronate, and who have a T-score of –2.5 SD or below plus a combination of age and number of independent clinical risk factors for fracture where treatment with risedronate resulted in an ICER of less than £30,000 per QALY gained without the consideration of identification costs, as outlined in section 4.2.25. The Committee agreed that in women aged 75 years or older, where the T-score needed to make treatment cost-effective was −2.5 SD or below, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible (see section 4.3.18).
Having reviewed the evidence on independent clinical risk factors for fractures and the views of the clinical specialists, the Committee agreed that the appropriate independent clinical risk factors indicating an increased risk of fracture were: parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee noted that long-term systemic corticosteroid use is also a relevant clinical risk factor.
The Committee considered the cost effectiveness of etidronate, and noted that in previous modelling etidronate had a better cost-effectiveness profile than risedronate; since then there has been no change in the evidence base that would affect the relative position of these two drugs. In view of its concerns surrounding the clinical evidence base for etidronate, and taking into account the views of clinical specialists and consultees, the Committee decided that etidronate should not be recommended in preference to risedronate. However, the Committee agreed that guidance on the use of etidronate should be included in the recommendations, and concluded that etidronate can be recommended as an alternative treatment option for women who cannot take alendronate, as outlined for risedronate in section 4.3.24. In deciding between risedronate and etidronate, clinicians and patients need to balance the overall effectiveness profile of the drugs against their tolerability and adverse effects in individual patients.
Following the Court of Appeal Order of April 2010, the Committee considered the clinical and cost effectiveness of strontium ranelate, focusing on the most appropriate estimate for the efficacy in reducing the rate of hip fracture. The Committee considered the additional submission from Servier (see sections 4.1.43 to 4.1.49), a report by the DSU (see sections 4.1.50 to 4.1.55) reviewing this new submission and Servier's response to the DSU report (see section 4.1.56). At its meeting on 20 October 2010, the Committee heard from representatives of Servier and a representative of the DSU.
The Committee first considered whether it was plausible that strontium ranelate has a greater or lesser relative benefit in any subgroup of the population for which it has a marketing authorisation (that is, whether a different RR for hip fracture could be assumed to apply to some women). The Committee was aware of the advice received from the original Osteoporosis Guideline Development Group that drugs for osteoporosis have constant RR reductions irrespective of age, BMD and prior fracture status (see section 4.2.7).
The Committee noted the DSU's advice that the correct statistical procedure for investigating if a subgroup of trial participants has a significantly different response to treatment is a test for interaction (see section 4.1.50). No test for interaction had been undertaken for the high-risk subgroup from TROPOS. The Committee also noted that it had not received evidence of a differential benefit, supported by a test for interaction, in any subgroup of any trial of osteoporosis drugs.
The Committee noted Servier's view that an age cut-off of 74 years was justified by the epidemiological findings of Donaldson et al. (see section 4.1.45). It understood from the DSU that this paper suggests that the rate of hip fracture rises to a notable level after 75 years of age (see section 4.1.52). The Committee also noted that Donaldson et al. state that the absolute risk of hip fracture increases 'steadily' with age: although women are at greater risk of hip fracture as they grow older, there is no particular age at which the risk jumps from low to high. The Committee therefore concluded that Donaldson et al.'s study did not provide support for the use of a specific age cut-off of 74 years.
The Committee recognised the hypothesis advanced by Servier that there may be biological grounds for assuming an additional effect for strontium ranelate in older women (see section 4.1.47). However, it considered that it should be possible to demonstrate any such effect by statistical and biochemical tests, and it heard from Servier's representatives that no such evidence had been collected. The Committee concluded that a hypothesis alone, without supporting evidence, was insufficient to demonstrate a differential benefit for strontium ranelate in older women.
For these reasons, the Committee concluded that it could not justify discounting previous advice that drugs for osteoporosis are assumed to have the same relative effect regardless of age, BMD and prior fracture status. Therefore, it agreed that it was most appropriate for the cost-effectiveness model to rely on a single RR to quantify the effect of strontium ranelate in preventing hip fractures in all postmenopausal women with osteoporosis. As a result, the Committee did not concur with the view that it might choose to provide a specific recommendation only for women corresponding to the high-risk subgroup analysed by Servier, based on an assumption of differential effectiveness of strontium ranelate in those women.
The Committee then considered the value that represents the most appropriate estimate of effect (RR) for strontium ranelate in preventing hip fractures. It discussed Servier's view that the best estimate of effect for the whole population would be that observed in the high-risk subgroup – an RR of 0.64 (see section 4.1.48). The Committee emphasised that, in order to adopt this figure for the whole population, it would first need to be confident that it was a robust estimate of treatment effect. It discussed the process by which the high-risk subgroup had been selected by Servier. It noted that the pooled data from the placebo arms of TROPOS and SOTI had been screened to establish a subgroup at increased risk of hip fracture (see section 4.1.45). The Committee agreed with the DSU's advice that the method used to identify the age cut-off for the subgroup was 'data-dependent' and, therefore, the RR for strontium ranelate derived from this approach was likely to be inflated (see section 4.1.51).
The Committee also discussed whether it would be appropriate to use an RR derived from a subgroup of trial participants to quantify the effect of a drug in the whole population for which it has a marketing authorisation. It considered Servier's assertion that, in contrast to the whole trial population, the high-risk subgroup of TROPOS provided a statistically robust demonstration of the effect of strontium ranelate in preventing hip fractures (see section 4.1.48). It acknowledged that TROPOS did not include enough participants to demonstrate a statistically significant benefit for strontium ranelate in preventing hip fractures and that, because of this, it would be appropriate to consider using an estimate of effect that was more precise (that is, subject to less statistical uncertainty) than that derived from the whole trial population. The Committee accepted the DSU's advice that the precision of an RR is primarily influenced by the absolute number of observed events (in this case the absolute number of fractures), which would be greatest in the whole trial population. Additionally, it noted that the size of the groups – and, therefore, the rate of events – is important, so that, in theory, it is possible that an estimate of effect from a subgroup may be more statistically precise than the estimate from the whole trial population from which the subgroup is derived. However, in the case of TROPOS, the estimates from the subgroup and the whole trial population had 95% confidence intervals of very similar width. Therefore, the Committee did not accept that the RR in the subgroup was more precise than the RR in the whole trial population. As a result, the Committee concluded that there was no reason to assume that the subgroup analysis was any more statistically robust than the analysis of the whole trial population. The Committee also noted that it is incorrect to infer that one estimate is more accurate than another just because it achieved conventional standards of statistical significance whereas the other did not.
Taking all this into account, the Committee decided that it would not be appropriate to adopt an RR of 0.64 in assessing the cost effectiveness of strontium ranelate, because the method for the subgroup selection was likely to favour strontium ranelate, and because the RR derived in this way was no more precise that the RR from the overall population.
The Committee further noted that when values derived from subgroups have been considered in NICE technology appraisals, the evidence has been used to inform specific recommendations applying only to groups of people with the same characteristics as those in the trial subgroup. The Committee reiterated its conclusion that it had not received unambiguous evidence of differential benefit from strontium ranelate in any particular group (see sections 4.3.27 to 4.3.32). The Committee was aware that, in order to make recommendations for cost-effective treatment to prevent fractures in postmenopausal women with osteoporosis, it was necessary to consider separate populations defined by age, T-score and independent clinical risk factors. However, these populations are defined because the absolute likelihood of fracture increases in the presence of these risk factors and not because of variations in the relative benefit of treatment.
The Committee next considered the possibility of adopting an RR of 1.00 to quantify the effect of strontium ranelate in reducing hip fractures. It noted that the 95% confidence interval around the RR from the whole TROPOS population spanned unity (the upper limit was greater than 1). This means that, at the 95% confidence level, the observed results could from a statistical point of view be interpreted as being consistent with strontium ranelate having no effect. The Committee noted that, when the other drugs within this appraisal had been associated with RRs with 95% confidence intervals spanning 1, the model had assumed no effect (RR = 1.00). Therefore, it might be considered consistent to apply the same logic to the estimation of the effectiveness of strontium ranelate. However, the Committee heard the DSU's advice that it is important to base cost-effectiveness analysis on the most plausible estimate for each parameter, with associated uncertainty explored in sensitivity analysis. The Committee also agreed with the DSU's view that the available evidence suggests that strontium ranelate is effective in reducing the risk of hip fracture. For these reasons, the Committee concluded that it would be inappropriate to assume that strontium ranelate has no effect on the incidence of hip fractures, and rejected the use of an RR of 1.00 in the model.
Finally, the Committee discussed using an effect estimate of 0.85 – the RR of hip fracture observed in the whole TROPOS population. It noted the DSU's advice that, in the absence of a robust demonstration of differential benefit in one or more subgroup of a trial, it is most appropriate to rely on an intention-to-treat analysis of the whole trial population (see section 4.1.54). Having concluded that it had not seen evidence of a differential benefit for a specific subgroup in TROPOS, and having rejected the use of the alternative values 0.64 and 1.00 for the whole population, the Committee concluded it had no reason to depart from this principle. It therefore concluded that an RR of 0.85 represented the most appropriate estimate of effect for strontium ranelate in preventing hip fractures in postmenopausal women with osteoporosis. As a result, the Committee agreed that the Assessment Group had been correct to use an RR of 0.85 in its cost-effectiveness calculations to reflect the effect of strontium ranelate in reducing the rate of hip fractures (see section 4.2.8).
The Committee concluded that strontium ranelate can be recommended for women who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate, and who have a T-score of −2.5 SD or below plus a combination of age and number of independent clinical risk factors for fracture where treatment with strontium ranelate resulted in an ICER of less than £30,000 per QALY gained, without the consideration of identification costs, as outlined in section 4.2.26. The Committee agreed that in women aged 75 years or older, where the T-score needed to make treatment cost-effective was −2.5 SD or below, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible (see 4.3.18).
The Committee agreed a definition of alendronate, risedronate or etidronate intolerance as: persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment and that occurs even though the instructions for administration have been followed correctly.
The Committee discussed the reported benefits of raloxifene on breast cancer risk, and heard from the clinical specialists that the possibility of preventing vertebral fractures and breast cancer simultaneously could be attractive, particularly to younger postmenopausal women. The Committee also heard from the specialists that evidence on the effect of raloxifene in reducing cardiovascular risk is not considered to be robust and that there is some concern over the increased risk of VTE (see section 4.1.25).
The Committee noted that a higher proportion of the overall benefit associated with raloxifene was attributable to its effect on the prevention of breast cancer than to its effect on the prevention of osteoporotic fragility fractures. The Committee agreed that, in principle, the side effects of using a drug should be considered; however, there were a number of reasons why the Committee considered that the breast cancer benefit should not be the sole factor in deciding whether raloxifene is a cost-effective option for treatment for the secondary prevention of osteoporotic fragility fractures, as follows:
From the evidence presented, raloxifene was not as effective as the bisphosphonates for treating osteoporosis.
Full assessment of raloxifene's effect on the prevention of breast cancer and its cost effectiveness in this indication would require consideration of how it compares with other drugs that could be used for breast cancer prevention.
The Committee noted that second-line treatment with raloxifene did not result in ICERs lower than £30,000 per QALY gained for women younger than 70 years, and for older women the T-scores at which ICERs were lower than £30,000 per QALY gained were very low. However, the Committee concluded that, the possible benefits in addition to fracture prevention meant that, in cases where women are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have contraindications to or are intolerant of alendronate and either risedronate or etidronate, raloxifene could be recommended for the same groups of women for whom treatment with strontium ranelate resulted in an ICER of less than £30,000 per QALY gained without the consideration of identification costs, as outlined in section 4.3.27. The Committee considered that in the younger women in these groups, raloxifene was a plausible choice. When deciding between strontium ranelate and raloxifene, clinicians and patients need to balance the overall proven effectiveness profile of these two drugs against their tolerability and other effects in individual patients.
The Committee noted the very high ICER for teriparatide when compared with pooled results for alendronate and risedronate in an analysis carried out by ScHARR before the latest price reduction for alendronate, and that there has been no change in the cost effectiveness evidence for teriparatide since. Noting the most recent modelling results for teriparatide, the Committee concluded that a change from the recommendations for teriparatide in NICE technology appraisal 87 for women aged 65 years and older is not warranted. Furthermore, the Committee considered that the updated modelling indicated that women aged 55–64 years who have a T score of –4 SD or below and more than two fractures could be cost-effectively treated with teriparatide.
## Women who cannot take alendronate
The Committee carefully considered the position of women who cannot take alendronate because of a condition which either makes alendronate contraindicated or which prevents individuals from complying with the instructions for administration for alendronate. In doing so the Committee noted that at least some women in this patient group were likely to be 'disabled' as defined by the Disability Discrimination Act 1995. The Committee was aware of its duties under that Act to avoid unlawful discrimination, to have due regard to the need to promote equality of opportunity for disabled people, and the need to take steps to take account of disabled people's disabilities, as well as its broader legal duties to ensure that its guidance is fair and reasonable.
The Committee noted that the drugs other than alendronate are cost effective only for patients at higher risk of fracture than the risk levels at which alendronate is cost effective. If these other drugs are recommended for use by patients who cannot take alendronate only when those patients meet the criteria at which these alternative drugs become cost effective, these patients will not receive preventative treatment unless they are at higher risk of fracture than the risk levels at which alendronate is recommended. The Committee therefore considered whether, for women who cannot receive alendronate, the other drugs should be recommended at the same risk levels as alendronate (that is using the criteria established as being cost effective for alendronate) in order to provide access to preventative treatment for all patients with the same level of risk. The Committee reviewed the ICERs for risedronate and strontium ranelate within the criteria established to be cost effective for alendronate. The Committee noted that the prices for risedronate and strontium ranelate are approximately five to six times higher than the price for non-proprietary weekly alendronate, and that the ICERs for these drugs compared with no treatment were very high. For example, the ICER for strontium ranelate for women aged 55–59 years with an independent clinical risk factor for fracture was approximately £55,000 per QALY gained (see section 4.2.22). The Committee noted that strontium ranelate would be the most likely choice to be considered for women who are unable to comply with the instructions for administration of alendronate, because the instructions for administration of alendronate and risedronate are similar. The Committee took the view that recommending drugs other than alendronate using the same criteria as alendronate for women who cannot take alendronate would not be justified in this case because of the very high ICERs for the alternative drugs. In reaching this decision the Committee had regard to the fact that the impact of refusing the more favourable recommendation is that there is no generally recommended preventative treatment for a particular group of patients who are at the lower end of fracture risk for which treatment was considered, but that the alternative drugs are recommended when these patients are at higher risk of fracture.
The Committee considered that it is important to maximise the number of patients who are able to take alendronate. Some women will be unable to take alendronate in any circumstances because of contraindication, intolerance or inability to comply with the instructions for administration. However, some women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate would be able to receive the drug if they received assistance in taking it. The Committee concluded that all reasonable steps should be taken to provide women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate, with such practical support and assistance with administration (for example through district nurse visits or other home support services), as will enable them to take the drug.
## FRAX fracture risk calculation tool
The Committee was aware of the availability of the FRAX internet-based tool, which can be used to calculate a 10-year absolute risk of fracture, developed under the auspices of the WHO. This assessment tool was based on the same epidemiological data that were used in the Assessment Group's model. However, the Committee was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX. Firstly, the Committee did not agree that all clinical risk factors included in the WHO algorithm were appropriate (see sections 4.2.12 and 4.3.9). Secondly, the Committee was aware that absolute fracture risk is not directly related to cost effectiveness, as outlined in the strontium ranelate assessment report issued in 2005. This is because absolute fracture risk is the total for all fracture sites, but different fracture sites have different impacts on quality of life, costs and mortality. Therefore, cost effectiveness is dependent on the contribution from each fracture site to the total fracture risk. Thirdly, the Committee had agreed that treatment benefit had not been proven for fracture risk associated with all independent clinical risk factors (section 4.3.9). Therefore, the Committee concluded that using a combination of T-score, age and number of independent clinical risk factors for fracture is more appropriate for defining treatment recommendations in this appraisal.
## Evidence on use of acid suppressive medication and fracture risk
The Committee was made aware of data indicating that acid-suppressive medication leads to a small increase in fracture risk and that co-administration of acid-suppressive medication and bisphosphonates may lead to an increased fracture risk compared with bisphosphonate administration alone. The Committee was not persuaded by this evidence; it noted that the data are observational and have not been reported in full, and are different for different fracture sites and for different acid suppressors. Furthermore, the Committee was informed, during consultation, of analyses showing that acid-suppressive medication given in addition to risedronate did not increase fracture risk. The Committee concluded that caution should be exercised when considering the evidence about co-prescription of acid-suppressive medication and bisphosphonates.
The Committee noted sensitivity analyses that included the assumption of an increase in fracture risk for women for whom acid-suppressive medications are co-prescribed (see section 4.2.19). The analysis for treatment strategies did not decrease the T-scores at which the ICERs for alendronate fell below £30,000 to the T-scores established for strategies including strontium ranelate or raloxifene. The Committee also noted that the ICERs for treatment compared with no treatment for an individual woman with a relevant combination of age and T-score were not more favourable for strontium ranelate than for risedronate even if an effect of acid-suppressive medication was assumed. The Committee considered that the evidence for this effect was not sufficiently robust. However, it concluded that the relative positions of alendronate, risedronate and strontium ranelate would remain unchanged even if an effect of acid-suppressive medication was assumed. The Committee therefore concluded that it was not necessary to change its recommendations (section 1) to take account of acid-suppressive medication.
## Calcium and vitamin D prerequisites for treatment
The Committee discussed the effect of calcium and vitamin D on the clinical effectiveness of the drugs considered. In the studies that formed the basis of this guidance, all participants were said to have adequate calcium and vitamin D levels. The Committee appreciated that the general population, particularly the elderly population, cannot be assumed to have an adequate dietary intake of calcium and vitamin D. It was also considered important to note that adequate levels (normal serum concentrations) of calcium and vitamin D are needed to ensure optimum effects of the treatments for osteoporosis. The Committee concluded that calcium and/or vitamin D supplementation should be provided unless clinicians are confident that women who receive treatment for osteoporosis have an adequate calcium intake and are vitamin D replete.
## Consultation on the Assessment Group's economic model
Following the outcome of the judicial review and the court ruling of March 2009, the Appraisal Committee considered the comments received from consultees on the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report.
The Committee considered the comments from consultees that the Assessment Group's model was not sufficiently transparent, lacked adequate documentation and could not be validated. It noted the number of consultations that took place during the appraisal guidance development, that the consultation documents had included descriptions of the model, and that assumptions and parameter values used had also been provided to consultees. The Committee was aware that instructions on how to run the model were released with the model and that consultees were able to run the model with changed input parameters. The Committee was satisfied with the exploration by the DSU of the functionality and validity of the model. The Committee noted that Servier stated that it had constructed its own economic model in order to validate the Assessment Group's model and to demonstrate the mathematical rationale to support its comments. The Committee noted that the results from Servier's model were very similar to those from the Assessment Group's model when similar assumptions and parameter inputs were used. The Committee was not persuaded by the consultees' doubt about the validity of the model, particularly since differences between the results obtained using Servier's model and the Assessment Group's model were largely because of differences in the assumptions used.
The Committee considered the comments from consultees that some inputs in the Assessment Group's model could not be changed and that it was unclear how fracture risk was calculated. The Committee noted that some of the fixed input parameters were inputs that do not need changing (such as the discount rate and standard mortality rates). Other fixed input values, such as the BMI and issues around the time horizon, were discussed separately (see sections 4.3.57 and 4.3.51 respectively). The Committee concluded that it was reasonable for some inputs in the model to be fixed. The Committee noted that fracture risks were calculated by the Assessment Group using the WHO algorithm in a separate spreadsheet and then entered into the model. It understood that the WHO algorithm itself was provided to the Assessment Group in 2005 as academic in confidence and that at that time NICE did not have permission from the owner of the algorithm to release it to consultees. The Committee understood that although the WHO fracture risk algorithm itself was not embedded in the economic model, the model could not be released because the algorithm could have been back-calculated from the fracture risks entered in the model and because the numbers of women with risk factors from the algorithm were included in the model.
The Committee considered the comments from consultees that the fracture risks entered into the model, calculated using the WHO algorithm, were different from fracture risks estimated using the FRAX tool. The Committee was aware that some differences could be because of the Assessment Group's use of midpoint ages in each 5-year age grouping. It also heard that the Assessment Group had verified the application of the WHO algorithm as provided in 2005, including all interactions between clinical risk factors, and was satisfied that the DSU had adequately assessed its application as being correct in the model. Because neither the DSU nor NICE has access to the algorithm used for the construction of the FRAX tool, the Committee was not in a position to comment further on differences between the two ways of estimating fracture risk. It concluded that differences between fracture risk estimates produced using the FRAX tool and those used in the Assessment Group's model were not in themselves a reason to doubt the correct use of the WHO algorithm within the Assessment Group's model.
The Committee considered the comments from consultees that mortality associated with clinical risk factors had been omitted from the Assessment Group's model, and noted the confirmation from the DSU that this was the case. It was persuaded that the inclusion of such additional mortality effects would increase the complexity of the model, and may increase the ICERs for the treatment of women with such clinical risk factors but decrease the ICERs for the treatment of women without such risk factors. The Committee agreed that the overall effect of including mortality associated with clinical risk factors in the model was unlikely to lead to a marked change in the overall results.
The Committee reviewed the consultee comments relating to the fixed BMI value of 26 kg/m2 used in the Assessment Group's model. It noted the rationale for selecting this value (see section 4.2.46). It also noted that in the DSU's exploratory analysis using the WHO algorithm, no increase in fracture risk was identified for women with a higher or lower BMI when BMD was known. The Committee was aware of its recommendation to assess BMD in all women under the age of 75 years for whom treatment is being considered, and noted that BMI is a weak predictor of fracture when BMD is known. Therefore the Committee concluded that the use of a fixed BMI value of 26 kg/m2 did not lead to an unfavourable assessment of the cost effectiveness of the interventions.
The Committee considered comments from consultees that the fracture risk associated with alcohol consumption used in the model was incorrect. It noted that the DSU had determined that the WHO algorithm had been correctly implemented, and understood that alcohol consumption of more than 2 units per day was included as a risk factor in the model. The Committee also noted that in its recommendations it had chosen to use a higher level of alcohol consumption in the risk identification strategy, because only alcohol consumption of 4 or more units per day was identified as a statistically significant risk factor for fracture for women – the population considered in the guidance. The Committee also considered a consultee comment that stated that it was unclear whether smoking and corticosteroid use had been included in the model as risk factors. It noted that the DSU had determined that the WHO algorithm had been correctly implemented with regard to both smoking and corticosteroid use in the model. The Committee noted that the effect of smoking in women was not statistically significant when assessing risk of osteoporotic fractures taken as a whole. The Committee was therefore satisfied that risks associated with corticosteroids, smoking and alcohol consumption had been faithfully applied in the Assessment Group's model, and agreed that the levels of alcohol consumption and smoking that should be used in the risk identification strategy were a matter for the Committee to consider and determine. The Committee took the view that it is not appropriate to identify women at high risk of fracture on the basis of risks that were not statistically significant (such as smoking and consumption of fewer than 4 units of alcohol per day) and that, in addition, the impact of these risk factors could arguably be approached by a strategy of smoking cessation and reducing alcohol consumption. The Committee noted comments from the consultees that the Assessment Group's model should have been amended to reflect the Committee's agreed inclusion of risk factors. However, the Committee took the pragmatic view that such amendments would have added unnecessarily to the mathematical complexity of an already complex clinical situation. It noted that women who had taken corticosteroids were included in the model and therefore contributed to the underlying fracture risk, with the effect of reducing the ICERs for the treatment of the population of women considered in the recommendations.
The Committee considered consultee comments that giving equal weighting to different clinical risk factors for fracture in the Assessment Group's model was inaccurate. The Committee considered the complex results presented originally in the 2005 Strontium Ranelate Assessment Report related to the inclusion of different risk factors and combinations of risk factors. The Committee noted that it had previously agreed that a clinically workable risk identification and treatment strategy should include the grouping of risk factors as the only practical way forward. At the time of the model's development, no individual risk calculation tool was available. Even if such a tool had been used in the development of the guidance, the prediction of cost effectiveness from overall absolute fracture risk alone, as suggested by consultees, would not be appropriate, for two reasons. Firstly, risk factors have different effects on different fracture types, and the cost effectiveness of treatment depends on the relative contributions of each risk factor to fracture risk. Secondly, the effectiveness of the drugs in reducing fracture risk was limited to only some of the clinical risk factors (age, T-score of −2.5 SD or below and prior fracture). The Committee heard from the DSU that there was considerable uncertainty about the cost effectiveness of treating women based on absolute risk alone (see section 4.3.48). Therefore, the Committee concluded that, when developing the guidance, simplification of the model was justified to in order to produce workable recommendations.
The Committee reviewed a comment from a consultee that the methods used to model effects beyond 10 years were not adequately described. It noted that the DSU confirmed that consequences beyond 10 years were considered in the Assessment Group's model, and an expanded description of the methods used was provided in an annex to the DSU report. The Committee also noted that the DSU carried out a sensitivity analysis in order to establish the impact of any possible underestimation of the mortality risk after the 10-year time horizon. It noted that doubling of the mortality risk led to only very small changes in the results. The Committee therefore concluded that mortality effects beyond the 10-year time horizon had been reasonably accounted for in the model and that sufficient description of these methods had been made available to consultees.
The Committee considered comments from consultees that the population data on the distribution of BMD (T-score) were not appropriate. It noted the DSU response confirming that the UK epidemiological dataset from the Holt study had been correctly implemented in the Assessment Group's model, and that the assumptions about the normality of the distributions used were likely to favour treatment for women at risk of fracture. The Committee also noted that the particular UK epidemiological dataset used in the model had been originally suggested by consultees for this appraisal. The Committee concluded that the population data had been used appropriately in the model.
The Committee considered a comment from a consultee that using a single estimate of cost effectiveness for 5-year age groupings of women at risk of fracture could exclude women from being offered treatment. It noted that this identification method was a Committee decision, and that identification strategies based on other factors could make treatments less cost effective.
The Committee reviewed comments from a consultee that the application of the same disutility for the side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates. The Committee was aware that the side effects observed for strontium ranelate in the clinical trials did not include gastrointestinal effects, but did include an increased risk of VTE. Because the increased risk of VTE was not included in the Assessment Group's model, the Committee had agreed that it was appropriate to include a disutility equivalent to the bisphosphonate base-case side-effect disutility to take account of this adverse effect.
The Committee reviewed comments from consultees about model assumptions or inputs that the Committee had directed the Assessment Group to use. It noted that issues such as treatment compliance, discount rates, costs of fracture, utility values for vertebral fracture and side-effect profiles used in the model had been considered and agreed by the Committee and reported in the guidance. The Committee also agreed that it had considered identification strategies for women at risk of fracture and, noting the advice of clinical specialists, it had recommended that women should have their BMD assessed by DXA scanning, except in certain circumstances as defined in the guidance. The Committee concluded that views expressed by consultees on the choice of modelling assumptions, input parameters and risk identification strategy were not about the operation of the Assessment Group's model, but were about Committee decisions that had already been discussed during development of the guidance.
The Committee also considered the consultees' view that the FRAX tool provides a 'mechanism to compute cost-effectiveness' according to clinical risk factors and that each of the current recommendations covers a wide range of absolute risk values, depending on the individual risk factors involved. The Committee understood that the FRAX tool is not an economic model, but a tool to estimate fracture risk. The Committee acknowledged that the current set of recommendations involved necessary simplifications from the more complex algorithm used to develop the Assessment Group's model. It was also aware that a direct prediction of cost effectiveness from absolute fracture risk alone would be inappropriate (see section 4.3.48).
The Committee concluded that the Assessment Group had provided an executable economic model and had implemented the WHO algorithm (as supplied) correctly. The Committee agreed with the DSU's comments that alterations to the modelling approach, as suggested by consultees, would not lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The Committee confirmed that the model provided a suitable framework to allow it to make recommendations on the cost-effective use of treatment for women at risk of fracture. The Committee noted that assumptions used in the Assessment Group's model had been considered and agreed by the Committee in developing the guidance. It agreed that it would not be useful to request further analysis from the Assessment Group at this stage. The Committee further agreed that any exploration of how absolute fracture risk could be used in making treatment decisions would require a new assessment and appraisal. Therefore the Committee concluded that the recommendations based on the Assessment Group's model were appropriate, and that the recommendations should remain unchanged.
The Committee noted the comments from some consultees that the guidance should be reviewed soon because the price of some of the appraised drugs had changed. The Committee noted that any possible price reductions could be offset by the use of the currently applicable discount rate, and that any review should also take into consideration how NICE might assess diagnostic tools such as absolute fracture risk prediction tools.
T-scores were calculated according to trial-specific normative data, using a threshold of −3.0 or below, which is equivalent to a T-score of −2.4 or below when measured according to the standards subsequently adopted by the WHO. The latter classification is used throughout this guidance document.
The remit of the original osteoporosis guideline has since been amended; see Osteoporosis and Osteoporosis fragility fracture risk.# Recommendations for further research
Given the evidence that the benefits of one of the bisphosphonates (alendronate) may continue for several years after the end of treatment, the Committee recommends that research should be carried out to define the optimal duration of treatment with individual bisphosphonates.
The Committee recommends research into the long-term effects of bisphosphonates on bone quality, given the inhibitory effects on bone resorption of these drugs.# Review of guidance
The guidance on these technologies will be considered for review by the Guidance Executive as soon as the short clinical guideline on risk assessment has been published. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJanuary 2011
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{'Guidance': "This guidance relates only to treatments for the\xa0secondary prevention of fragility fractures in postmenopausal women who have osteoporosis and have sustained a clinically apparent osteoporotic fragility fracture. Osteoporosis is defined by a T-score of −2.5\xa0standard deviations (SD) or below on dual-energy X-ray absorptiometry (DXA) scanning. However, the diagnosis may be assumed in women aged 75\xa0years or older if the responsible clinician considers a DXA scan to be clinically inappropriate or unfeasible.\n\nThis guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered.\n\nThis guidance does not cover the following:\n\nThe use of raloxifene or teriparatide for the\xa0secondary prevention of osteoporotic fragility fractures in women with normal bone mineral density (BMD) or osteopenia (that is, women with a T-score between −1\xa0and −2.5\xa0SD below peak BMD).\n\nThe use of these drugs for the\xa0secondary prevention of osteoporotic fragility fractures in women who are on long-term systemic corticosteroid treatment.\n\nThis recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.\n\nThis recommendation has been replaced by the recommendations in the NICE technology appraisal guidance on bisphosphonates for treating osteoporosis.\n\nThe recommendation for strontium ranelate has been withdrawn because strontium ranelate is no longer marketed in the UK. Raloxifene is recommended as an alternative treatment option for the\xa0secondary prevention of osteoporotic fragility fractures in postmenopausal women:\n\nwho are unable to comply with the special instructions for the administration of alendronate and risedronate, or have a contraindication to or are intolerant of alendronate and risedronate (as defined in section\xa01.6) and\n\nwho also have a combination of T-score, age and number of independent clinical risk factors for fracture (see section\xa01.5) as indicated in the following table.\n\nT-scores (SD) at (or below) which raloxifene is recommended when alendronate and risedronate cannot be taken\n\n\n\nNumber\n of\n independent\n clinical\n risk\n factors\n for\n fracture\n (section\n 1.5)\n\nAge\n (years)\n\n\n\n\n\n\n\n–54\n\n– a\n\n−3.5\n\n−3.5\n\n–59\n\n−4.0\n\n−3.5\n\n−3.5\n\n–64\n\n−4.0\n\n−3.5\n\n−3.5\n\n–69\n\n−4.0\n\n−3.5\n\n−3.0\n\n–74\n\n−3.0\n\n−3.0\n\n−2.5\n\nor older\n\n−3.0\n\n−2.5\n\n−2.5\n\na Treatment with raloxifene is not recommended.\n\nIf a woman aged 75\xa0years or older who has one or more independent clinical risk factors for fracture or indicators of low BMD has not previously had her BMD measured, a DXA scan may not be required if the responsible clinician considers it to be clinically inappropriate or unfeasible.\n\nFor the purposes of this guidance, indicators of low BMD are low body mass index (defined as less than 22\xa0kg/m2), medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause.\n\nTeriparatide is recommended as an alternative treatment option for the\xa0secondary prevention of osteoporotic fragility fractures in postmenopausal women:\n\nwho are unable to take alendronate and risedronate, or have a contraindication to or are intolerant of alendronate and risedronate (as defined in section\xa01.6), or who have had an unsatisfactory response (as defined in section\xa01.8) to treatment with alendronate or risedronate and\n\nwho are 65\xa0years or older and have a T-score of –4.0\xa0SD or below, or a T-score of –3.5\xa0SD or below plus more than two fractures, or who are aged 55–64\xa0years and have a T-score of –4\xa0SD or below plus more than two fractures.\n\nFor the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4\xa0or more units per\xa0day, and rheumatoid arthritis.\n\nFor the purposes of this guidance, intolerance of alendronate or risedronate is defined as persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment, and that occurs even though the instructions for administration have been followed correctly.\n\nThe recommendation for strontium ranelate has been withdrawn because strontium ranelate is no longer marketed in the UK.\n\nFor the purposes of this guidance, an unsatisfactory response is defined as occurring when a woman has another fragility fracture despite adhering fully to treatment for 1\xa0year and there is evidence of a decline in BMD below her pre-treatment baseline.\n\nWomen who are currently receiving treatment with one of the drugs covered by this guidance, but for whom treatment would not have been recommended according to sections\xa01.1 to 1.4, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.\n\n T-score relates to the measurement of bone mineral density (BMD) using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) from peak BMD.\n\n Rheumatoid arthritis is also a medical condition indicative of low BMD.", 'Clinical need and practice': "Osteoporosis is a progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.\n\nBone formation exceeds bone resorption in youth, but by the third decade of life there is a gradual loss of bone mass. Osteoporosis is therefore usually an age-related disease. It can affect both sexes, but women are at greater risk because the decrease in oestrogen production after the menopause accelerates bone loss to a variable degree.\n\nThe World Health Organization (WHO) has established diagnostic criteria for osteoporosis based on the measurement of BMD, expressed as the T-score, which is the number of SD below the mean BMD of young adults at their peak bone mass:\n\nnormal BMD: T-score of −1\xa0SD or above\n\nosteopenia: T-score of between −1 and −2.5\xa0SD\n\nosteoporosis: T-score of −2.5\xa0SD or below\n\nestablished (severe) osteoporosis: T-score of −2.5\xa0SD or below with one or more associated fractures.\n\nT-score measurements vary depending on the site and method of investigation. Measurement of BMD using central (hip and/or spine) DXA scanning can estimate fracture risk.\n\nIt is estimated that more than 2\xa0million women have osteoporosis (that is, have a T-score of −2.5\xa0SD or below) in England and Wales. Osteoporosis is most common in older white women. After the menopause, the prevalence of osteoporosis increases markedly with age, from approximately 2% at 50\xa0years rising to more than 25% at 80\xa0years.\n\nFragility fracture is the clinically apparent and relevant outcome in osteoporosis (referred to as 'osteoporotic fragility fracture' in the following text). It is often referred to as a low-trauma fracture; that is, a fracture sustained as the result of a force equivalent to the force of a fall from a height equal to, or less than, that of an ordinary chair. In the absence of fracture, osteoporosis is asymptomatic and often remains undiagnosed. Osteoporotic fragility fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain and reduced quality of life.\n\nIn women aged over 50\xa0years, the lifetime risk of a vertebral fracture is estimated to be one in three, and that of hip fracture one in five. Postmenopausal women with an initial fracture are at substantially greater risk of subsequent fractures. For instance, a woman with a vertebral fracture has an increased relative risk (RR) of 4.4 for a further vertebral fracture, 2.3 for a hip fracture, and 1.4 for a wrist fracture.\n\nIt is estimated that annually there are 180,000 osteoporosis-related symptomatic fractures in England and Wales. Of these, 70,000 are hip fractures, 25,000 are clinical vertebral fractures, and 41,000 are wrist fractures.\n\nAfter a hip fracture, a high proportion of women are permanently unable to walk independently or to perform other activities of daily living and, consequently, many are unable to live independently. Hip fractures are also associated with increased mortality; estimates of the relative mortality risk vary from 2 to greater than 10 in the 12\xa0months following hip fracture. However, it is unclear to what extent this can be attributed to fracture alone as opposed to pre-existing comorbidity.\n\nVertebral fractures can be associated with curvature of the spine and loss of height and can result in pain, breathing difficulties, gastrointestinal problems and difficulties in performing activities of daily living. It is thought that the majority of vertebral fractures (50–70%) do not come to clinical attention. Vertebral fractures are also associated with increased mortality; UK-specific data indicate a 4.4-fold increase in mortality related to vertebral fracture. However, as with hip fractures, it is unclear to what extent this may be due to comorbidities.\n\nIn addition to increasing age and low BMD, other clinical factors have been associated with increased fracture risk. Some of these clinical risk factors are at least partly independent of BMD, and include parental history of hip fracture, alcohol intake of 4 or more units per\xa0day, long-term systemic use of corticosteroids (which is not covered in this guidance), and rheumatoid arthritis.\n\nFactors that are known to be indicators of low BMD include low body mass index (BMI) (defined as less than 22\xa0kg/m2), and medical conditions such as ankylosing spondylitis, Crohn's disease, conditions that result in prolonged immobility, and untreated premature menopause.", 'The technologies': "# Bisphosphonates: alendronate, etidronate and risedronate\n\nThe bisphosphonates alendronate, etidronate and risedronate are inhibitors of bone resorption and increase BMD by altering osteoclast activation and function.\n\nAlendronate is an oral bisphosphonate that has a UK marketing authorisation as a once-weekly preparation (70\xa0mg) for the treatment of postmenopausal osteoporosis. It also has a marketing authorisation at a daily dose of 10\xa0mg for the treatment of osteoporosis in postmenopausal women to prevent fractures. Non-proprietary alendronate (Teva UK) costs £4.12 for four 70\xa0mg tablets and £8.30 for twenty-eight 10\xa0mg tablets (excluding VAT; NHS Drug Tariff, 24 February 2008). At these prices the drug costs for 1\xa0year are £53.56 for once-weekly (70\xa0mg) tablets and £108.20 for daily (10\xa0mg) tablets. Proprietary alendronate (Fosamax; Merck Sharp & Dohme) is priced at £22.80 for four 70\xa0mg tablets and £23.12 for twenty-eight 10\xa0mg tablets (excluding VAT; 'British national formulary' [BNF] edition 54). At these prices, the drug costs for 1\xa0year are £296.40 for once-weekly (70\xa0mg) tablets and £301.39 for daily (10\xa0mg) tablets. Costs may vary in different settings because of negotiated procurement discounts.\n\nEtidronate (Didronel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation for the treatment of osteoporosis. The drug is administered in 90-day cycles, with each cycle consisting of etidronate (400\xa0mg/day) for 14\xa0days followed by calcium carbonate (1.25\xa0g/day) for the remaining 76\xa0days. The price per 90-day pack is £21.12 (excluding VAT; BNF 54), which equates to a\xa0yearly cost of £85.65. Costs may vary in different settings because of negotiated procurement discounts.\n\nRisedronate (Actonel; Procter & Gamble UK) is an oral bisphosphonate that has a UK marketing authorisation at a dosage of 5\xa0mg/day or 35\xa0mg/week for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures, and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Prices are £19.10 for twenty-eight 5\xa0mg tablets and £20.30 for four 35\xa0mg tablets (excluding VAT; BNF 54), which equates to\xa0yearly costs of £248.98 for the daily treatment or £264.63 for the once-weekly treatment. Costs may vary in different settings because of negotiated procurement discounts.\n\nGastrointestinal side effects are common with oral bisphosphonates. In people with oesophageal abnormalities and other factors that delay oesophageal transit or emptying, risedronate should be used cautiously and alendronate is contraindicated. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nBisphosphonates have relatively complex instructions for administration. Alendronate and risedronate must be taken with 200\xa0ml and 120\xa0ml of water, respectively. Before and immediately after administration patients should not eat or drink, and must remain upright for stipulated time periods. Etidronate should be taken with water at the midpoint of a 4-hour fast (that is, 2\xa0hours after and 2\xa0hours before food, vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium).\n\n# Selective oestrogen receptor modulator: raloxifene\n\nSelective oestrogen receptor modulators (SERMs) are drugs with selective activity in various organ systems, acting as weak oestrogen-receptor agonists in some systems and as oestrogen antagonists in others. The aim of treatment with SERMs is to maximise the beneficial effects of oestrogen on bone and to minimise the adverse effects on the breast and endometrium.\n\nRaloxifene (Evista; Eli Lilly) has marketing authorisation for the treatment of osteoporosis in postmenopausal women. The recommended dosage is 60\xa0mg/day. The prices of 28- and 84-tablet packs are £17.06 and £59.59, respectively (excluding VAT; BNF 54), which equate to\xa0yearly costs of £222.39 and £258.93, respectively. Costs may vary in different settings because of negotiated procurement discounts.\n\nRaloxifene is contraindicated in people with a history of venous thromboembolism (VTE), hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding or endometrial cancer. Raloxifene should not be co-administered with systemic oestrogens, and in patients with breast cancer it should not be used for osteoporosis treatment or prevention until treatment of the breast cancer, including adjuvant treatment, has been completed. Raloxifene is associated with an increased risk of venous thromboembolic events, particularly during the first 4\xa0months of treatment, which is similar to the reported risk associated with hormone replacement therapy. For full details of side effects and contraindications, see the summary of product characteristics.\n\n# Strontium ranelate\n\nStrontium ranelate (Protelos; Servier Laboratories) is a divalent strontium salt of ranelic acid (strontium is an element with properties similar to calcium). It is thought to have a dual effect on bone metabolism, increasing bone formation and decreasing bone resorption. It has a UK marketing authorisation for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. The recommended dose is one 2\xa0g sachet taken daily as a suspension in water. The price of a 28-sachet pack is £25.60 (excluding VAT; BNF 54), which equates to a\xa0yearly cost of £333.71. Costs may vary in different settings because of negotiated procurement discounts.\n\nThe absorption of strontium ranelate is reduced by food, milk and products derived from milk. It should therefore be administered between meals, ideally at bedtime and preferably at least 2\xa0hours after eating.\n\nThe summary of product characteristics states that strontium ranelate is not recommended in patients with severe renal impairment and that it should be used with caution in patients at increased risk of VTE. Treatment with strontium ranelate should be discontinued during treatment with oral tetracycline or quinolone antibiotics. For full details of side effects, drug interactions and contraindications, see the summary of product characteristics.\n\n# Parathyroid hormone: teriparatide\n\nTeriparatide (Forsteo; Eli Lilly & Company) is a recombinant fragment of human parathyroid hormone and, as an anabolic agent, it stimulates new formation of bone and increases resistance to fracture.\n\nTeriparatide has a marketing authorisation in the UK for the treatment of established osteoporosis in postmenopausal women. The recommended dose is 20\xa0micrograms administered once daily by subcutaneous injection in the thigh or abdomen. Patients taking teriparatide must receive training in the injection technique. At the time of appraisal, the maximum total duration of treatment was restricted, by the marketing authorisation, to 18\xa0months (see the summary of product characteristics for current information). The price of a 28-day pre-filled pen is £271.88 (excluding VAT; BNF\xa054), which equates to a\xa0yearly cost of £3544.15.\n\nParticular contraindications include pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget's disease of bone), unexplained elevations of alkaline phosphatase, and previous radiation treatment to the skeleton. For full details of side effects and contraindications, see the summary of product characteristics.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\n## Efficacy\n\nThe Assessment Group for this appraisal (School of Health and Related Research, University of Sheffield [ScHARR]) reviewed data from published randomised controlled trials (RCTs) in postmenopausal women in which fracture or health-related quality of life was an endpoint and where one of the six drugs of interest was compared with a relevant comparator, such as no treatment, placebo or one of the other included interventions. The majority of studies used placebo or no treatment as a control. Most studies ensured that women in all trial arms had normal calcium levels (that is, normal serum concentrations) or adequate supplementation, and some studies used additional dietary supplementation with vitamin D.\n\nFor this appraisal, reductions in RR associated with treatment were pooled regardless of the baseline BMD and fracture status of the participants in the studies. It was also assumed that these reductions in RR remained constant at all ages, although little evidence was available for the effectiveness of the drugs in women aged 80\xa0years or older.\n\nFor vertebral fractures, some studies used clinical (that is, symptomatic) fractures as their endpoint whereas others used fractures that were identified radiographically. Vertebral fractures identified radiographically, which are termed 'radiographic fractures' or 'morphometric fractures', include both symptomatic and asymptomatic fractures. There are different definitions of a vertebral radiographic fracture, but those definitions that require a 20% reduction in vertebral height are generally recognised as producing more reliable results than those that require a 15% reduction.\n\nFor non-vertebral fracture types, individual data on hip, leg, pelvis, wrist, hand, foot, rib and humerus fractures were sometimes provided, whereas some studies only presented data for all non-vertebral fractures grouped together.\n\nSixteen RCTs of alendronate in postmenopausal women were included in the assessment report: two studies in women with low or normal BMD; one in women with osteopenia; eight in women with osteopenia or osteoporosis; four in women with osteoporosis; and one in women with established osteoporosis. Overall, 15 studies compared alendronate with placebo or with no treatment. All the studies were conducted in women who had adequate levels of calcium, from either dietary intake or calcium supplementation.\n\nTwo studies, one comparing alendronate with oestrogen alone or with oestrogen and alendronate combined, and the other comparing alendronate with teriparatide, found no statistically significant differences between the groups in numbers of clinically apparent fractures of any type in women with osteoporosis. However, back pain was reported less frequently by women in the teriparatide group compared with women in the alendronate group (6% versus 19%, p\xa0=\xa00.012).\n\nIn addition to the 16 RCTs, a 2-year study demonstrated the equivalence of\xa0weekly and daily doses of alendronate, in terms of clinical fracture incidence and gastrointestinal adverse events. However, this study was not included in the analysis because it did not include the specified comparators.\n\nThe meta-analysis for alendronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.56 (95%\xa0confidence interval [CI] 0.46 to 0.68, four RCTs, n\xa0=\xa07039), an RR of hip fracture of 0.62 (95%\xa0CI 0.40 to 0.98, three RCTs, n\xa0=\xa07455), an RR of wrist fracture of 0.67 (95%\xa0CI 0.34 to 1.31, four RCTs, n\xa0=\xa07931) and an RR for other non-vertebral fractures of 0.81 (95%\xa0CI 0.68 to 0.97, six RCTs, n\xa0=\xa09973).\n\nA post-hoc analysis of data from the largest study on alendronate, the 'Fracture intervention trial' (FIT) RCT (non-vertebral fracture population), suggested that alendronate may be less effective at reducing fractures in women with T-scores above (that is, better than) −2.5\xa0SD than in women with osteoporosis. These results were not statistically significant.\n\nGastrointestinal adverse events, including nausea, dyspepsia, mild oesophagitis/gastritis and abdominal pain, were reported in at least one third of the participants in studies of alendronate. However, only one study found the increased frequency of these symptoms to be statistically significant relative to placebo. This is consistent with post-marketing studies that indicate that approximately one third of alendronate users experience gastrointestinal adverse events. To avoid oesophagitis, the summary of product characteristics now recommends that alendronate should be taken on rising for the\xa0day, with a full glass of water. It is possible that these instructions were not followed in all of the studies, particularly the earlier ones.\n\nPrescription-event monitoring studies in patients for whom alendronate was prescribed (n\xa0=\xa011,916) by GPs in England demonstrated a high incidence of dyspepsia, particularly in the first\xa0month of treatment. Consultations for dyspepsia ranged from 32.2 per 1000 patient-months in the first\xa0month of treatment to 10.9 per 1000 patient-months in\xa0months 2 to 6. Because these studies lacked a comparator, it is not possible to assess the extent to which these rates of upper gastrointestinal events may be above baseline levels in those not taking bisphosphonates.\n\nOne study reported health-related quality of life outcomes. At 12\xa0months there were statistically significant improvements in the alendronate group compared with the control group in scores for pain, social isolation, energy level and physical ability.\n\nTwelve RCTs of etidronate in postmenopausal women were reviewed: three studies in women with low-to-normal BMD; two in women with osteopenia or osteoporosis; one in women with osteoporosis; one in women with osteoporosis or established osteoporosis; and five in women with established osteoporosis. Four studies included active comparators, and eight compared etidronate with placebo or with no treatment (although in six of these, study participants in all arms received calcium, either alone or with vitamin D). Some studies did not use the exact treatment regimen that currently has a UK marketing authorisation (that is, 90-day cycles of etidronate 400\xa0mg/day for 14\xa0days, followed by calcium carbonate 1.25\xa0g/day for the remaining 76\xa0days). None of the studies reported health-related quality of life outcomes.\n\nThe meta-analysis of RCTs for etidronate relative to placebo carried out by the Assessment Group resulted in an RR of vertebral fracture of 0.40 (95%\xa0CI 0.20 to 0.83, three RCTs, n\xa0=\xa0341), an RR of hip fracture of 0.50 (95%\xa0CI 0.05 to 5.34, two RCTs, n\xa0=\xa0180), and an RR for other non-vertebral fractures of 1.04 (95%\xa0CI 0.64 to 1.69; four RCTs, n\xa0=\xa0410). There were no data for wrist fracture.\n\nAn observational study in a general practice setting in the UK reported on fracture rates in people with a diagnosis of osteoporosis who were receiving etidronate compared with those who were not taking a bisphosphonate. People taking etidronate had an RR of non-vertebral fracture of 0.80 (95%\xa0CI 0.70 to 0.92). The RR of hip fracture was 0.66 (95%\xa0CI 0.51 to 0.85) and that of wrist fracture was 0.81 (95%\xa0CI 0.58 to 1.14).\n\nHigher rates of gastrointestinal adverse effects were found in the etidronate groups of four RCTs, although the differences were not always statistically significant. However, non-RCT evidence and testimonies from clinical specialists and patient experts suggested that etidronate may be associated with fewer gastrointestinal adverse effects than other bisphosphonates.\n\nThe systematic review carried out by ScHARR in 2006 identified a cohort study conducted in the UK that indicated that etidronate may be associated with a much lower rate of upper gastrointestinal adverse effects than alendronate or risedronate.\n\nSeven RCTs of risedronate in postmenopausal women were reviewed: one study in women with normal BMD; one in women with osteopenia; one in women with osteopenia or osteoporosis; one in women with osteoporosis or specific risk factors for hip fracture, such as a recent fall; and three in women with established osteoporosis. All compared risedronate with placebo (although, with the exception of those in the normal BMD study, all women also received calcium) and none reported on health-related quality of life outcomes.\n\nThe meta-analysis for risedronate relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.61 (95%\xa0CI 0.50 to 0.75, three RCTs, n\xa0=\xa02301), an RR of hip fracture of 0.74 (95%\xa0CI 0.59 to 0.93, three RCTs, n\xa0=\xa011,770), an RR of wrist fracture of 0.68 (95%\xa0CI 0.43 to 1.08, two RCTs, n\xa0=\xa02439) and an RR for other non-vertebral fractures of 0.76 (95%\xa0CI 0.64 to 0.91, five RCTs, n\xa0=\xa012,399).\n\nIn all of the studies, rates of gastrointestinal adverse events were similar in the risedronate and placebo groups.\n\nPrescription-event monitoring studies in patients for whom risedronate was prescribed (n\xa0=\xa013,643) by GPs in England suggested a high incidence of dyspepsia, particularly in the first\xa0month of treatment. Consultations for dyspepsia ranged from 26.9 per 1000 patient-months in the first\xa0month of treatment to 8.1 per 1000 patient-months in\xa0months 2 to 6.\n\nA meta-analysis of pooled data from the alendronate and risedronate studies, carried out by ScHARR in 2006, resulted in an RR of vertebral fracture of 0.58 (95%\xa0CI 0.51 to 0.67, seven RCTs, n\xa0=\xa09340), an RR of hip fracture of 0.71 (95%\xa0CI 0.58 to 0.87, six RCTs, n\xa0=\xa019,233), an RR of wrist fracture of 0.69 (95%\xa0CI 0.45 to 1.05, six RCTs, n\xa0=\xa01037) and an RR for other non-vertebral fractures of 0.78 (95%\xa0CI 0.69 to 0.88, 11 RCTs, n\xa0=\xa022,372).\n\nThree RCTs of raloxifene in postmenopausal women were identified, but only two were included in the Assessment Group's meta-analysis: the largest study (the 'Multiple outcomes of raloxifene evaluation' [MORE] study) was carried out in women with osteoporosis, of whom 37% had a vertebral fracture at entry, and a smaller study was conducted in women with established osteoporosis. Both compared raloxifene with placebo (in both studies, women in both arms received calcium and vitamin D). Both studies examined raloxifene at dosages of 60\xa0mg/day (the dosage specified in the UK marketing authorisation for the treatment of postmenopausal osteoporosis) and 120\xa0mg/day. Neither reported on health-related quality of life outcomes. The mean age of women in the studies was 67–68\xa0years. The MORE study was extended further to assess fracture, breast cancer, and cardiovascular and uterine safety outcomes. A third study examined the additive effect of raloxifene compared with placebo in women with a femoral neck T-score of −2\xa0SD or below, with or without prior fracture, who were also receiving fluoride, calcium and vitamin D. Because of the use of fluoride as a co-intervention, these results were not included in the Assessment Group's meta-analysis.\n\nThe meta-analysis for raloxifene relative to placebo, carried out by the Assessment Group, resulted in an RR of vertebral fracture of 0.65 (95%\xa0CI 0.53 to 0.79, one RCT, n\xa0=\xa04551), an RR of hip fracture of 1.13 (95%\xa0CI 0.66 to 1.96, two RCTs, n\xa0=\xa06971), an RR of wrist fracture of 0.89 (95%\xa0CI 0.68 to 1.15, one RCT, n\xa0=\xa06828), and an RR for other non-vertebral fractures of 0.92 (95%\xa0CI 0.79 to 1.07, one RCT, n\xa0=\xa06828).\n\nThe most serious adverse effect associated with raloxifene was the approximately three-fold increased risk of VTE. Statistically significantly higher incidences of hot flushes, arthralgia, dizziness, leg cramps, influenza-like symptoms, endometrial cavity fluid, peripheral oedema and worsening diabetes were also found with raloxifene compared with placebo. The impact of raloxifene on cardiovascular disease is unclear, but there is evidence that it lowers serum concentrations of fibrinogen as well as both total and low-density lipoprotein (LDL) cholesterol levels (that is, serum concentrations) without increasing high-density lipoprotein (HDL) cholesterol.\n\nThe MORE study shows that raloxifene protects against breast cancer, with the RR at 4\xa0years for all types of breast cancer reported as 0.38 (95%\xa0CI 0.24 to 0.58), and that for invasive breast cancer as 0.28 (95%\xa0CI 0.17 to 0.46).\n\nThree RCTs of strontium ranelate in postmenopausal women were identified: one study in women with osteoporosis and two in women with osteoporosis or established osteoporosis. All three studies compared strontium ranelate with placebo, and provided calcium and vitamin D supplementation to ensure an adequate intake.\n\nThe Assessment Group reported the results of a published meta-analysis that gave an RR for vertebral fracture of 0.60 (95%\xa0CI 0.53 to 0.69, two RCTs, n\xa0=\xa06551) and an RR for all non-vertebral fractures (including wrist fracture) of 0.84 (95%\xa0CI 0.73 to 0.97, two RCTs, n\xa0=\xa06551). Efficacy in reducing the rate of hip fracture was established in one study; the RR for hip fracture in the whole study population was 0.85 (95%\xa0CI 0.61 to 1.19, one RCT, n\xa0=\xa04932). A post-hoc subgroup analysis in women aged 74\xa0or older with a T-score of −2.4\xa0SD resulted in an RR for hip fracture of 0.64 (95%\xa0CI 0.412 to 0.997, one RCT, n\xa0=\xa01977).\n\nIn general, strontium ranelate was not associated with an increased risk of adverse effects and for the most part adverse effects were mild and transient; nausea, diarrhoea and creatine kinase elevations were the most commonly reported. A serious adverse event associated with strontium ranelate treatment was an increased incidence (RR\xa0=\xa01.42) of VTE and pulmonary embolism. This finding has been investigated further with the extension of ongoing studies and by post-marketing surveillance.\n\nOne study published results on health-related quality of life outcomes. It reported that strontium ranelate had quality of life benefits compared with placebo, as assessed by the QUALIOST osteoporosis-specific questionnaire and by the general health perception score of the short form (SF)-36 general scale.\n\nThree RCTs of teriparatide in postmenopausal women were considered: one small study compared teriparatide with alendronate in women with osteoporosis (but was not targeted at women with fractures), and two were placebo-controlled (although study participants also received vitamin D either with calcium or with nutritional advice to ensure adequate calcium intake). The largest trial was conducted in women with established osteoporosis, and the other in women who either had established osteoporosis or had osteoporosis and had been receiving hormone replacement therapy for at least 2\xa0years.\n\nFor vertebral fractures (using a 20% reduction in vertebral height as the fracture definition) and grouped non-vertebral fractures in women with established osteoporosis, the largest placebo-controlled RCT found RRs of 0.35 (95%\xa0CI 0.22 to 0.55) and 0.65 (95%\xa0CI 0.43 to 0.98), respectively, in favour of teriparatide. When considered separately, the study did not demonstrate that teriparatide prevents hip and wrist fractures in women with established osteoporosis (RR for hip fractures 0.5; 95%\xa0CI 0.09 to 2.73; RR for wrist fractures 0.54; 95%\xa0CI 0.22 to 1.35). In this placebo-controlled trial, teriparatide reduced the incidence of new or worsened back pain reported as an adverse event.\n\nData from a follow-up observational study cited in the manufacturer's submission (published in abstract form or available as an unpublished manuscript only) suggest that 18\xa0months after the end of treatment with teriparatide there was a 41% reduction in vertebral fracture risk compared with placebo (p\xa0=\xa00.004). Further data from the same study 31\xa0months after the end of treatment with teriparatide suggest that proportionally fewer women who had received teriparatide reported non-vertebral fractures compared with those who had received placebo (13.3% in the placebo group; 8.5% in the 20\xa0micrograms/day teriparatide group; 7.3% in the 40\xa0micrograms/day teriparatide group; p\xa0=\xa00.03 for both treatment groups versus placebo). No information was given on vertebral fractures for the 31-month follow-up.\n\nThe study comparing 40\xa0micrograms/day teriparatide (twice the dose specified in the marketing authorisation) with 10\xa0mg/day alendronate found an RR of non-vertebral fracture in women with osteoporosis of 0.30 (95%\xa0CI 0.09 to 1.05). The study did not provide data on vertebral fractures. Back pain was reported less frequently in the teriparatide group (6% versus 19%, p\xa0=\xa00.012).\n\nNausea and headaches occurred more frequently with 40\xa0micrograms/day teriparatide in the main placebo-controlled trial. In the smaller placebo-controlled trial, a proportion of women taking teriparatide were reported to suffer mild discomfort at the injection site. A systematic review of parathyroid hormone reported that treatment in a small proportion of women was associated with hypercalcaemia.\n\n## Persistence and compliance\n\nData from 14 RCTs indicated that between 81% and 100% of patients persisted with bisphosphonates in the first\xa0year of treatment, with lower rates of persistence of between 51% and 89% in the third\xa0year of treatment (eight RCTs).\n\nA prescription-event monitoring study of patients for whom alendronate was prescribed (n\xa0=\xa011,916) by GPs in England indicated that 24% discontinued treatment within 1\xa0year. In a similar study of patients for whom risedronate was prescribed (n\xa0=\xa011,742) in primary care in England, 30% appeared to have discontinued treatment within 6\xa0months. In another 12 studies reviewed, persistence at 1\xa0year ranged from 16% to 90%.\n\nPaid claims data from the USA suggested that only 18% of women starting raloxifene treatment continued to take their medication uninterrupted, and an investigation of a pharmacy prescription database indicated that only 44% were continuing treatment at the end of\xa0year\xa02.\n\nCompliance data were reported for two RCTs of strontium ranelate and were similar in the strontium ranelate and placebo arms (ranging from 83% to 93%) at up to 3\xa0years.\n\nThe main placebo-controlled RCT reported that adherence with injections varied from 79% to 83% and that there were no statistically significant differences between the teriparatide and placebo groups. The smaller placebo-controlled trial found that, after 3\xa0years, 78% of women receiving teriparatide completed treatment, compared with 100% on placebo.\n\n## Acid-suppressive medication and fracture risk\n\nTwo cohort and two case–control studies reported on a potential relationship between acid-suppressive medication (proton pump inhibitors or histamine H2 receptor antagonists) and fracture risk. One of the case–control studies, which used the UK General Practice Research Database (GPRD), found that 1\xa0year or more of acid-suppressive medication was associated with an increase in fracture risk. The other case–control study reported a reduction of fracture risk associated with use of histamine H2 receptor antagonists, and that use of other acid-suppressive medication might increase fracture risk. Both studies, however, were unable to demonstrate convincingly that fracture risk was independent of underlying disease that might determine differences in fracture risk.\n\nA prospective cohort study excluded women taking medication for fracture prevention and reported an increase in non-vertebral fracture in those taking acid-suppressive medication compared with those who were not. Findings appeared similar for users of proton pump inhibitors or histamine H2 receptor antagonists, but differences in fracture risk were not statistically significant for those using proton pump inhibitors compared with those not using acid-suppressive medication. One large retrospective cohort study using the UK GPRD compared women taking acid-suppressive medication plus bisphosphonates with those taking bisphosphonates alone. This GPRD study reported an increase in fracture risk for some fracture sites with concomitant use of acid-suppressive medication and bisphosphonates, but a reduction in risk for other fracture sites. The information on patients included in this GPRD study was incomplete and details of adjustments for confounders were not reported. The two cohort studies were not fully published, and their analysis may have been prone to confounding.\n\n## Additional submission from the manufacturer of strontium ranelate\n\nFollowing the Court of Appeal Order of April 2010, NICE requested an additional submission from the manufacturer of strontium ranelate (Servier), setting out their views on the most appropriate estimate of strontium ranelate's efficacy in reducing the rate of hip fracture.\n\nServier explained that the pivotal phase III RCT (Treatment of Peripheral Osteoporosis Study [TROPOS]) was started before the increased regulatory emphasis on the prevention of hip fracture as a key measure of efficacy of treatments for osteoporosis (because of the significant morbidity associated with hip fracture). TROPOS had not been designed or powered to demonstrate the effect of strontium ranelate treatment on rates of hip fracture. In support of its application for regulatory approval of strontium ranelate, Servier was therefore asked by the European Medicines Agency (EMA) to investigate the efficacy of strontium ranelate in reducing the rate of hip fracture in a post-hoc subgroup analysis of TROPOS participants who met the definition of established osteoporosis (that is, a BMD T-score of −2.5 or below and one or more associated fractures). Instead of the requested subgroup, Servier provided the EMA with data for a different subgroup of trial participants whom they identified as being at high risk for hip fracture. This subgroup comprised women aged 74 or older who had a femoral T-score of −2.4 or below. This subgroup represented 42% of TROPOS participants and had an RR of hip fracture of 0.64 (95% CI 0.412 to 0.997).\n\nServier described the method used to identify this high-risk subgroup. The placebo arms of two RCTs (TROPOS and another trial designed to assess the efficacy of strontium ranelate in reducing vertebral fractures, Spinal Osteoporosis Therapeutic Intervention [SOTI]) were pooled and the influence on fracture rates of three of the main risk factors for fragility fracture – age, BMD and prior fracture – was explored. Servier found that, in the pooled placebo arms of these two RCTs, prior fracture had no effect on the rate of hip fracture, so this factor was not considered further. To select an age group in which the risk of hip fracture was elevated, Servier investigated various possible age cut-offs, and identified the age at which the difference in the rate of hip fracture between women older and younger than the cut-off was greatest. This process led to the selection of an age cut-off of 74\xa0years. Servier stated that this cut-off was consistent with epidemiological data, in particular a study by Donaldson et al. (1990), which Servier interpreted as showing a rising rate of hip fracture among women in the general population above the age of 74. The selected BMD cut-off was closely aligned to the WHO definition of osteoporosis (a T-score of −2.5 SD or below; see section 2.3). Servier emphasised that, having identified factors related to a high risk of hip fracture by screening the pooled data from the placebo arms of two RCTs, a single post-hoc analysis of the effect of strontium ranelate in this subgroup had been performed, without the need for multiple exploratory analyses of fracture risk reduction adopting different criteria for the subgroup selection.\n\nAfter Servier had submitted data on efficacy in its chosen subgroup to the EMA, the EMA requested further analyses to confirm the effect of strontium ranelate on the rate of hip fracture. Servier provided additional evidence, including data from longer follow-up periods and analyses of trial participants with demonstrated compliance to treatment. Servier indicated that this additional evidence supported the view that an RR of 0.64 is a valid estimate of the efficacy of strontium ranelate in reducing the rate of hip fracture.\n\nIn their additional submission to NICE following the Court of Appeal Order in April 2010, Servier also suggested a hypothesis for a possible increased effect of strontium ranelate in older women: most osteoporosis drugs work by reducing the loss of existing bone, but strontium ranelate also stimulates the creation of new bone. Because the creation of new bone is increasingly impaired as women age, Servier stated that it is possible that strontium ranelate is able to provide additional benefit to older women.\n\nServier argued that the RR of 0.64 derived from the post-hoc analysis of the high-risk subgroup should be used in cost-effectiveness analyses to quantify the effect of strontium ranelate in reducing the rate of hip fracture because, in its view, it represents a more robust estimate of efficacy than the RR for the whole trial population. Servier stated that, unlike the analysis of the whole trial population, the subgroup analysis was suitably powered to demonstrate the effect of strontium ranelate in reducing the rate of hip fracture. Because of this, in Servier's opinion, the estimate was statistically robust.\n\nServier's view was that the estimate derived from the high-risk subgroup could be assumed to apply to all women taking strontium ranelate, but it acknowledged issues surrounding extrapolation from the high-risk subgroup to a broader population. Servier therefore indicated that it might also be concluded that the RR of 0.64 could only be applied to a population corresponding to the high-risk subgroup.\n\n## Review of Servier's additional submission by the Decision Support Unit\n\nThe DSU was commissioned to review Servier's additional submission, and to comment on the scientific validity of the post-hoc subgroup analysis provided by Servier. The DSU advised that any set of data will show some variation in response to treatment across different subgroups simply by chance. The DSU explained that, because of this, the correct statistical procedure for establishing a subgroup of trial participants with a significantly different response to treatment is via a test for interaction (that is, a formal test, using regression methods, of the hypothesis that the effect is different in one group of participants from that observed in the rest of the trial population). The DSU noted that no such test had been reported by Servier.\n\nThe DSU stated that the method used by Servier to identify the high-risk subgroup (see section 4.1.45) was logically likely to yield an unduly large relative effect, and the DSU stated that this would lead to a biased estimate of RR. This was because the method used to identify the age cut-off to define the subgroup was 'data-dependent' – that is, most of the data that were used to define the subgroup (the rate of hip fracture in the placebo arm of TROPOS) were also used to estimate the efficacy of strontium ranelate in the selected subgroup. In this way, the rate of hip fracture in the placebo group was certain to be high, relative to other potential age cut-offs, with no guarantee that this was also the case in the strontium ranelate group. Therefore, the DSU stated that the estimate of RR derived from the subgroup was likely to be artificially inflated.\n\nThe DSU also noted that, whilst Servier indicated that there were epidemiological data to support the chosen age cut-off (see section 4.1.45), the study by Donaldson et al. (1990) suggested that the rate of hip fracture rises to a notable level after 75\xa0years of age, not\xa074.\n\nThe DSU advised that Servier's argument of enhanced statistical power in the subgroup analysis was incorrect. The DSU explained that, in an analysis of RR, statistical power is dependent on the number of events (in this case, hip fractures) and that choosing a smaller group of participants will tend to reduce, rather than increase, power unless the RR is markedly greater in that subgroup. Because of this, the DSU disagreed with Servier's claim that the subgroup analysis was 'fully powered'.\n\nThe DSU was asked to comment on the most appropriate approach, from a statistical viewpoint, to the use of data from the whole trial population of TROPOS and the high-risk subgroup, in determining the relative efficacy of strontium ranelate. The DSU responded that, if the relative effect were to be applied to women in the general population, an intention-to-treat analysis of all randomised trial participants would yield the most appropriate estimate of efficacy. The DSU also commented that, if more than one trial is available, a pooled analysis of RRs from the intention-to-treat data of all relevant trials would be preferable. A meta-analysis of the data from SOTI and TROPOS would have provided the most appropriate overall measure of efficacy.\n\nThe DSU also advised that even as an estimate of efficacy in the high-risk subgroup, the RR of 0.64 was likely to be too extreme because of the likelihood of selection bias arising from the way in which the subgroup had been identified (see section 4.1.51). The DSU also emphasised that, to estimate the cost effectiveness of strontium ranelate in a particular subgroup, it would not be sufficient simply to adopt an RR of hip fracture from that group. It would also be important to populate the rest of the economic decision model with evidence specific to the subgroup in question.\n\nNICE invited Servier to respond to the DSU's report. Servier provided a document reiterating its previous views that the subgroup analysis performed to evaluate the efficacy of strontium ranelate in reducing the rate of hip fracture was based on sound scientific principles and valid statistical methods. Servier did not respond to other specific issues raised in the DSU report.\n\n# Cost effectiveness\n\n## Manufacturers' models\n\nFor proprietary alendronate, compared with no treatment, the manufacturer's model provided an incremental cost-effectiveness ratio (ICER) of £3135 per quality-adjusted life\xa0year (QALY) gained for 70-year-old women with a T-score below −1.6\xa0SD. The manufacturer's results were more favourable than the results of Assessment Group's 2003 model. This could be because the manufacturer's model was not adjusted for baseline fracture prevalence, or because it used different utilities for vertebral fractures, different efficacy data, different risk groups and a longer time horizon.\n\nFor etidronate, compared with no treatment, the manufacturer's model provided an ICER of £18,634 per QALY gained for 70-year-old women with a T-score below −2.5\xa0SD. The manufacturer's model included morphometric vertebral fractures and corticosteroid use as risk factors for further fractures. It is unclear whether the manufacturer's ICER was for women with or without a prior osteoporotic fragility fracture.\n\nFor risedronate, compared with no treatment, the manufacturer provided data from two models. The ICER derived from the manufacturer's own model was £577 per QALY gained for women aged 74\xa0years. In the\xa0second model provided by the manufacturer, which was commissioned from an external body, the ICER was higher, varying from £35,800 per QALY gained in women aged 60\xa0years to £4800 per QALY gained in women aged 80\xa0years, for women with a prior vertebral osteoporotic fragility fracture and a T-score of −2.5\xa0SD. For women at slightly higher risk of fracture, the ICERs were £18,600 per QALY gained or less for all age groups. The ICER calculated using the manufacturer's own model was difficult to verify from the information given. The ICERs generated by the\xa0second model were more consistent with the figures provided by the Assessment Group's 2003 model, although they did differ somewhat. This may be because of different cost and RR inputs.\n\nFor raloxifene, compared with no treatment, the manufacturer provided data for different age groups and different risk levels. All of the analyses included the breast cancer benefits. It was not clear how the different risk levels were defined. The ICERs ranged from £12,000 to £22,000 per QALY gained, and were slightly more favourable than the Assessment Group's 2003 analysis, even when the Assessment Group included the breast cancer benefits. In the Assessment Group's 2003 model, the RR for the breast cancer effect was higher (0.38) than the RR for invasive breast cancer used in the manufacturer's model (0.28), and the breast cancer risk was adjusted for the association between low BMD and decreased risk of breast cancer. Additionally, the manufacturer's model was not adjusted for baseline fracture prevalence, and included different utilities for vertebral fractures, different efficacy data, different risk groups, and a longer time horizon than the Assessment Group's model.\n\nFor strontium ranelate, compared with no treatment, the manufacturer provided two models: one developed in-house and the other commissioned from an external body. The first model showed that, for women aged over 75\xa0years with previous fractures and a T-score of −2.5\xa0SD, strontium ranelate was cost-effective at a maximum acceptable incremental cost-effectiveness ratio of £30,000 per QALY gained. The results of this model were comparable with those generated by the Assessment Group's 2005 model. The\xa0second model resulted in an ICER of £6341 per QALY gained for 70-year-old women with a previous vertebral fracture and a T-score of −2.5\xa0SD, decreasing to £5002 per QALY gained in women aged 80\xa0years. The manufacturer's results were more favourable than the Assessment Group's 2005 results because different modelling assumptions were used. For example, fewer health-state transition possibilities were incorporated. Compared with the Assessment Group's model, the manufacturer's model used more favourable efficacy data for hip fracture from the post-hoc 'high-risk' subgroup of women (see sections 4.1.28 and 4.1.44 to 4.1.49), and slightly more favourable efficacy data for wrist and proximal humerus fracture. Higher hip-fracture costs were used in the manufacturer's model.\n\nFor teriparatide, compared with no treatment, the manufacturer provided ICERs for women aged 69\xa0years. For women with fractures that had occurred more than 6\xa0months previously (historical fracture), the ICER was £35,400 per QALY gained and for women with a more recent fracture the ICER was £28,863 per QALY gained. The manufacturer supplied additional economic analyses with ICERs of £18,845 and £12,106 per QALY gained for historical and recent fracture, respectively, based on changes to the assumptions of sustained efficacy for non-vertebral fractures and of the RR for specific risk groups. The manufacturer's model and the Assessment Group's 2003 model differed in a number of assumptions. The manufacturer's model was not adjusted for baseline fracture prevalence and used different utilities. The Assessment Group's 2003 model used more favourable assumptions on the duration of sustained efficacy after the end of treatment.\n\n## The Assessment Group's model\n\nThe Assessment Group provided a cost–utility model with two components (described in detail in the 2005 Strontium Ranelate Assessment Report). As a first step, the model calculated absolute fracture risk from the epidemiological literature on a number of independent clinical risk factors. These data were prepared under the auspices of the WHO and were provided for this appraisal under an academic-in-confidence agreement. As a\xa0second step, the model applied RR reductions for fracture taken from the meta-analysis described in section\xa04.1.22. A single estimate of efficacy was used for alendronate and risedronate based on pooled data for these two drugs. Following advice from the original Osteoporosis Guideline Development Group, it was assumed that RRs remained constant across all ages, T-scores and fracture status. The most recent analyses carried out by ScHARR were based on the price of non-proprietary alendronate in February 2008 (£53.56 per\xa0year for once-weekly 70\xa0mg tablets; £108.20 per\xa0year for daily 10\xa0mg tablets).\n\nAll osteoporotic fragility fractures in women aged 50\xa0years or older were included in the modelling. The RR for hip fracture was assumed to apply also to pelvis and other femoral fractures. The RR for non-vertebral fracture was assumed to apply also to proximal humerus, rib, sternum, scapula, tibia, fibula and wrist fractures. Where confidence intervals for RRs spanned unity, it was assumed that there was no effect of treatment, except in the case of strontium ranelate. In this case, an RR of 0.85 for hip fracture was used to acknowledge the effect reported in the high-risk subgroup of the study. The model used UK-specific epidemiological data on femoral neck BMD.\n\nThe model assumed an initial utility in the\xa0year of fracture and a higher utility in subsequent\xa0years. The time horizon for predicting morbidity was 10\xa0years, consisting of 5\xa0years of treatment with sustained efficacy plus 5\xa0years of linear decline to no effect. However, treatment-related decreases in mortality rate extended beyond the 10-year time horizon. For this, the life expectancy for a woman at the threshold T-score for osteoporosis was calculated from standard life tables, and any increase in mortality rate due to fracture would continue until death or an age of 110\xa0years. In the base case, vertebral-fracture utility was assumed to be lower than hip-fracture utility, and a sensitivity analysis was carried out in which the utility for vertebral fracture was assumed to be the same as that for hip fracture. The percentage of women assumed to move from community living to a nursing home following a hip fracture increased with increasing age. An age-dependent gradient of hip-fracture risk was used, and an association between vertebral or proximal humerus fracture and increased mortality in women with osteoporosis was included. No follow-up BMD scans were included in the model; this reflects current clinical practice in the UK.\n\nThe model included an assumption about the costs and disutility associated with treatment-related side effects for all drugs, based on the findings of prescription-event monitoring studies in patients treated with alendronate. For the base case, the model assumed 50% persistence with treatment. In addition to the base case, the Assessment Group undertook a number of sensitivity analyses using alternative assumptions, including: persistence with treatment (25% or 75% at 5\xa0years); reduction in the efficacy of the drugs at reducing the risk of fracture associated with risk factors other than age, prior fracture and low BMD to 0% or 50% (with a consequent upward adjustment of the RR for the risk factors of age, prior fracture and low BMD); disutility of vertebral fracture; updated fracture costs; and the disutility and costs of treatment-related side effects. It was assumed that women who experience bisphosphonate-related side effects had 91% of the utility of women who do not have such side effects. In the base case analysis for all of the drugs under consideration this was applied to 2.35% of women in the first treatment\xa0month and 0.35% of women thereafter and, in sensitivity analyses for bisphosphonates, to 24% of women in the first treatment\xa0month and 3.5% of women thereafter. In the case of strontium ranelate, the effect on VTE was not included in the model. Discount rates of 6% per\xa0year for costs and 1.5% per\xa0year for health benefits were applied, in accordance with NICE methods relevant to this appraisal.\n\nFor raloxifene, 4-year follow-up data from the MORE study were used, and it was assumed that women with low BMD have a lower breast cancer risk than women with normal BMD. The cost effectiveness was modelled excluding the breast cancer benefit, the risk of VTE and the effect on cardiovascular events.\n\nThe independent clinical risk factors for fracture used in the model were based on the data prepared under the auspices of the WHO (see section\xa04.2.7) and included BMI, prior fracture, previous or current use of corticosteroids, parental history of fracture, current smoking, alcohol intake of more than 2\xa0units per\xa0day, and rheumatoid arthritis. The study provided prevalence data for the different risk factors, and risk ratios for hip fracture and osteoporotic fracture for each risk factor, including T-score and age. Using these risk ratios, absolute risk of fracture was calculated.\n\nThe estimates of cost effectiveness were generated for different levels of absolute risk derived from a large number of combinations of T-score (in bands 0.5\xa0SD wide), age and number of independent clinical risk factors for fracture. For practical reasons relating to the number of potential combinations, single-point RRs of fracture, calculated from the log-normal efficacy distributions, were used in the model. Results were presented for population groups categorised according to age, T-score and number of independent clinical risk factors.\n\nWomen with a fracture who present to clinicians require a DXA scan for osteoporosis to be established. Therefore, the Assessment Group also estimated the impact of DXA scanning on the cost effectiveness of the drugs. This required both a calculation of the ICER for treatment, and a calculation of the distribution of risk assessment cost over the population who would benefit from treatment. A net-benefit approach was used to do this. The net-benefit approach is analogous to the more traditional cost per QALY gained approach, but also requires a value of willingness to pay (WTP) for an additional QALY gained. For the calculation of the net benefit of an intervention, the WTP is first multiplied by the incremental QALY gained associated with the intervention, then the incremental cost associated with the intervention is subtracted. For this appraisal, the total net benefit for each age group and DXA scanning approach was calculated by subtracting the cost of DXA scanning from the net benefit of treating all women who can be treated cost effectively.\n\nA stepped net-benefit approach was used to estimate, in reverse order, the cost effectiveness of risk assessment, DXA scanning and treatment of women with a prior fracture. Two WTP values, £20,000 or £30,000 per QALY gained, were applied in the modelling.\n\nStep 1. ICERs for treatment versus no treatment were calculated for each intervention for various combinations of age, T-score and number of independent clinical risk factors for fracture (see section\xa04.2.12). The net benefit of treatment per woman was calculated using the following formula: Net benefit\xa0=\xa0£30,000 (or £20,000)\xa0×\xa0incremental QALYs – incremental costs.For women for whom the ICER for treatment was more than £30,000 (or £20,000) per QALY gained, the net benefit was set to zero.\n\nStep 2. The net benefit per woman was multiplied by the number of women in the population estimated to fall within each combination of age, T-score and number of independent clinical risk factors for fracture (based on the data used to develop the algorithm prepared for the WHO). The net benefits for each group were then added together to give a total net benefit of treatment for women with no, one, two or three independent clinical risk factors within each age group.\n\nStep 3. The cost of DXA scanning all of the women in each age/independent clinical risk factor group was subtracted from the net benefit of treatment for that group (calculated as described in step 2). This provides the net benefit of treatment and DXA scanning for the group, assuming that the number of independent clinical risk factors is known. A positive net benefit indicates that DXA scanning of women in that age/independent clinical risk factor group and treating those groups of women in whom the ICER for treatment is £30,000 (or £20,000) or less provides an ICER for the entire strategy of less than £30,000 (or £20,000) per QALY gained.\n\nStep 4. When the resulting values of net benefit of treatment and scanning were negative they were set to zero. For each age group, the total net benefit of scanning and treatment was calculated by adding together the net benefits for each age/independent clinical risk factor group. The cost of opportunistic assessment for all women in this age group was then subtracted to give the net benefit of risk assessment, scanning and treatment. A positive net benefit indicates an ICER of less than £30,000 (or £20,000) per QALY gained for risk assessment, DXA scanning and treating women (at a specific T-score related to the ICER for treatment only) of that particular group. Cost per QALY gained data were presented for each strategy.\n\nFirst, the Assessment Group calculated ICERs (cost per QALY gained for alendronate compared with no treatment) without identification costs for all combinations of age, T-score and number of independent clinical risk factors for fracture. The cost per QALY gained, compared with no treatment, became more favourable with increasing age and number of independent clinical risk factors, and decreasing T-score (that is, with increasing annual absolute risk of fracture).\n\nThen, the Assessment Group presented the results of the economic analyses in the form of identification and treatment strategies (based on age, T-score and number of independent clinical risk factors for fracture) that resulted in an ICER of £30,000 or less (cost per QALY gained compared with no treatment). The analyses shown below included the following assumptions: persistence at 5\xa0years set to 50%; the efficacy of bisphosphonates on fracture risks associated with factors other than age, BMD and prior fracture status set to 50% of that observed for the total population in the trials (with a consequent upward adjustment of the RR associated with age, BMD and prior fracture); costs set to health resource group values including home-help costs; utility multiplier associated with vertebral fracture set to 0.792 in the first\xa0year of fracture and 0.909 in subsequent\xa0years (as for hip fracture); costs of bisphosphonate-related gastrointestinal symptoms incurred over 5\xa0years; utility multiplier associated with bisphosphonate-related gastrointestinal symptoms set to 0.91 (included utility losses for non-compliant patients); and alendronate at a cost of £53.56 or £108.20 per\xa0year.\n\nFor alendronate priced at £53.56 per\xa0year (once-weekly treatment), and when assuming that 24% of women in the first treatment\xa0month and 3.5% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate resulted in an ICER of less than £30,000 per QALY gained for all women aged 55\xa0years or older with confirmed osteoporosis (that is, a T-score of –2.5 SD), and for postmenopausal women aged 50–54\xa0years with confirmed osteoporosis and two independent clinical risk factors for fracture.\n\nIn a sensitivity analysis for alendronate priced at £53.56 per\xa0year (with other assumptions as in section 4.2.17 and 4.2.18), acid-suppressive medication was assumed to affect fracture risk. The data inputs for this were taken from one GPRD study (see section\xa04.1.41) and represent the midpoint values pooled for patients using acid-suppressive medication. This sensitivity analysis produced the following results:\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 55\xa0years resulted in an ICER of more than £30,000 per QALY gained.\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate resulted in an ICER of less than £30,000 per QALY gained for all women aged 65\xa0years or older with confirmed osteoporosis (that is, a T-score of –2.5 SD or below), for postmenopausal women aged 60–64\xa0years with confirmed osteoporosis and one independent clinical risk factor for fracture, and postmenopausal women aged 55–59\xa0years with confirmed osteoporosis and two independent clinical risk factors for fracture.The ICER for treatment with alendronate (but excluding identification costs) for a woman aged 60–64\xa0years with a T-score of −2.5 SD (using the assumptions described in sections 4.2.17 and 4.2.18) was £9005 per QALY gained without acid-suppressive medication and £21,656 per QALY gained with acid-suppressive medication. If this woman had an independent clinical risk factor for fracture, the ICERs would be £3969 per QALY gained without and £12,250 per QALY gained with acid-suppressive medication.\n\nFor alendronate priced at £108.20 per\xa0year (daily treatment), and when assuming that 24% of women were experiencing bisphosphonate-related side effects in the first treatment\xa0month and 3.5% of women thereafter, the model produced the following results:\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate in women younger than 55\xa0years resulted in an ICER of more than £30,000 per QALY gained.\n\nA strategy of risk assessment, DXA scanning and treatment with alendronate resulted in an ICER of less than £30,000 per QALY gained for women aged 65\xa0years or older with confirmed osteoporosis (that is a T-score of –2.5 SD or below), for postmenopausal women aged 60–64\xa0years with confirmed osteoporosis and one independent clinical risk factor for fracture, and for postmenopausal women aged 55–59\xa0years with confirmed osteoporosis and two independent clinical risk factors.\n\nRisedronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per\xa0year for alendronate); that is, these three drugs have a higher acquisition cost than alendronate, but are not more efficacious. Analyses were conducted as for alendronate (see section 4.2.17). For risedronate, base-case assumptions for bisphosphonate-related side effects were modelled; that is 2.35% of women in the first treatment\xa0month and 0.35% thereafter experienced side effects (see section 4.2.10). In addition a sensitivity analysis was performed, using the assumption that 24% of women in the first treatment\xa0month and 3.5% of women thereafter experienced bisphosphonate-related side effects. For raloxifene and strontium ranelate, base-case assumptions for side effects were used. In previous economic modelling and before the most recent price reduction for non-proprietary alendronate, etidronate's cost effectiveness was comparable to that of non-proprietary alendronate, but the calculations were based on a weaker clinical evidence base than for alendronate. Therefore the modelling for etidronate was not updated after the most recent price reduction for alendronate.\n\nFor risedronate, raloxifene, strontium ranelate and teriparatide, additional analyses were conducted to explore identification and treatment strategies that could be cost effective for these interventions when compared with no intervention. All results showed less favourable cost effectiveness than non-proprietary alendronate. For example, for women aged 55–59\xa0years with an independent clinical risk factor for fracture, the ICERs (without considering costs related to risk assessment and DXA scanning) for risedronate and strontium ranelate (each compared with no treatment) were more than £40,000 and £55,000 per QALY gained, respectively. For these two groups of women, treatment with\xa0weekly non-proprietary alendronate, including risk assessment and DXA scanning costs, resulted in an ICER of less than £30,000 per QALY gained.\n\nFurther analyses were carried out assuming\xa0second-line use; that is, costs for risk assessment or DXA scanning were excluded because BMD was assumed to be known from the first-line management.\n\nIn the economic modelling carried out for this appraisal in 2006, lower ages and higher T-scores resulted in ICERs of less than £30,000 per QALY gained for etidronate compared with risedronate; that is, etidronate was more cost effective than risedronate. Because of the concerns expressed about the weaker clinical evidence base for etidronate, the modelling for this bisphosphonate was not updated.\n\nFor risedronate in\xa0second-line use, when assuming that 2.35% of women in the first treatment\xa0month and 0.35% of women thereafter experienced bisphosphonate-related side effects, the model produced the following results:\n\nTreatment with risedronate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained. Including women aged 50–54\xa0years with no independent clinical risk factors for fracture increased the ICER to more than £30,000 per QALY gained.\n\nAge\n (years)\n\nNumber\n of\n independent\n clinical\n risk\n factors\n for\n fracture\n (section\n 1.5)\n\n\n\n\n\n\n\n–69\n\n– a\n\n−3.5\n\n−3.0\n\n–74\n\n−3.5\n\n−3.0\n\n−2.5\n\nor older\n\n−3.0\n\n−3.0\n\n−2.0b\n\na ICER more than £20,000 per QALY gained.\n\nb Women with osteopenia are not included in the guidance (see sections 1 and 4.3.6).\n\nFor strontium ranelate in\xa0second-line use, the model produced the following results:\n\nTreatment with strontium ranelate in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained. Including women aged 50–54\xa0years with no independent clinical risk factors for fracture increased the ICER to more than £30,000 per QALY gained.\n\nAge\n (years)\n\nNumber\n of\n independent\n clinical\n risk\n factors\n for\n fracture\n (section\n 1.5)\n\n\n\n\n\n\n\n–69\n\n– a\n\n−4.5\n\n−4.0\n\n–74\n\n−4.5\n\n−4.0\n\n−3.5\n\nor older\n\n−4.0\n\n−4.0\n\n−3.0\n\na ICER more than £20,000 per QALY gained\n\nFor raloxifene in\xa0second-line use, using base-case assumptions on side effects, the model produced the following results:\n\nTreatment with raloxifene in women younger than 70\xa0years resulted in an ICER of more than £30,000 per QALY gained.\n\nTreatment with raloxifene in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained.\n\n\n\nNumber\n of\n independent\n clinical\n risk\n factors\n for\n fracture\n (section\n 1.5)\n\nAge\n (years)\n\n\n\n\n\n\n\n–74\n\n−5.0\n\n−4.5\n\n−4.0\n\nor older\n\n−4.5\n\n−4.0\n\n−3.5\n\nFor teriparatide, the model produced the following results.\n\nTreatment with teriparatide in women who have the combinations of T-score, age and number of independent clinical risk factors for fracture indicated in the table below resulted in an ICER of less than £30,000 per QALY gained. Including women aged 50–54\xa0years with no independent clinical risk factors for fracture would increase the ICER to more than £30,000 per QALY gained.\n\n\n\nNumber\n of\n independent\n clinical\n risk\n factors\n for\n fracture\n (section\n 1.5)\n\nAge\n (years)\n\n\n\n\n\n\n\n–54\n\n– a\n\n−4.0\n\n−4.0\n\n–59\n\n−4.5\n\n−4.5\n\n−4.0\n\n–64\n\n−4.5\n\n−4.5\n\n−4.0\n\n–69\n\n−5.0\n\n−4.5\n\n−4.5\n\n–74\n\n−4.5\n\n−4.5\n\n−3.5\n\nor older\n\n−4.5\n\n−4.0\n\n−3.5\n\na ICER more than £30,000 per QALY gained\n\nIf it was assumed that acid-suppressive medication affects fracture risk, the ICER for treatment with risedronate (compared with no treatment, but excluding identification costs) for a woman aged 70\xa0years with a T-score of −3 SD increased from £12,273 to £17,848 per QALY gained (using base-case assumptions about side effects). The corresponding ICER for strontium ranelate was £28,026 per QALY gained compared with no treatment (using base-case assumptions about side effects). For a woman aged 70\xa0years with a T-score of −3.5 SD and one independent clinical risk factor for fracture, the ICER for risedronate increased from £3028 to £7688 per QALY gained when acid-suppressive medication was assumed to affect fracture risk (using base-case assumptions about side effects).The corresponding ICER for strontium ranelate was £14,986 per QALY gained compared with no treatment (using base-case assumptions about side effects).\n\n## Consultee comments on the Assessment Group's economic model\n\nFollowing the outcome of the judicial review and the court ruling of March 2009, NICE was able to offer the Assessment Group's executable economic model for consultation. Consultees and commentators who requested the model and returned the necessary confidentiality undertakings received a CD-ROM containing the executable version of the economic model, a document with instructions for running the model and a pro-forma for commenting on the model. Comments on the Assessment Group's model were received from Servier Laboratories (the manufacturer of strontium ranelate), the Bone Research Society (BRS), the National Osteoporosis Society (NOS) and the Society for Endocrinology. Comments received from each of these consultees are summarised in the sections below.\n\nThese four consultees expressed the view that the documentation provided with the Assessment Group's model was insufficient, that the model supplied to them was incomplete and that some inputs could not be altered. They also stated that the application of the fracture risk algorithm developed under the auspices of the WHO could not be assessed. They felt that the model could not be validated and that its validity had not been demonstrated in documents made available during development of the guidance.\n\nServier commented that the fracture risks entered in the Assessment Group's model differed from estimates that Servier calculated using the FRAX fracture risk calculation tool (see section 4.3.48 for further information about the FRAX tool). Servier commented that mortality risk associated with clinical risk factors had been omitted from the model. In Servier's opinion, these differences called into question whether the WHO fracture risk algorithm had been applied correctly in the Assessment Group's model.\n\nOther comments questioned the use of a fixed value for BMI in the model. Consultees commented that no clear explanation was provided of the rationale for the choice of BMI value, that a range of BMI values should have been used, and that the use of a fixed BMI value resulted in underestimation of the cost effectiveness of treatment for some women at risk of fracture.\n\nServier commented on the selection and weighting of the independent clinical risk factors for fracture used in the Assessment Group's model. Servier, BRS and NOS suggested that the risk associated with alcohol intake was incorrect in the model and that this would have adversely affected estimation of the cost\xa0effectiveness of treatment for women at risk of fracture. They suggested that a threshold alcohol intake of 3\xa0or\xa0more units per\xa0day, as used in the FRAX fracture risk calculation tool, should have been applied. They also stated that the Assessment Group's model and the guidance were inconsistent with each other, and that these differences resulted in the risk of fracture being underestimated in the model. Servier also noted that the Assessment Group's model gave an equal weighting to each of the independent clinical risk factors for fracture. Servier suggested that this was a less precise approach than that used in the FRAX tool, which used different weightings (some higher and some lower than those in the Assessment Group's model) for each fracture risk for specific risk factors. Servier stated that the FRAX tool assesses fracture risk and cost effectiveness more accurately and 'deals more fairly' with variation between women at risk of fracture. Servier also noted that one of the risk multipliers for fracture risk included in the Assessment Group's model was not consistent with that given in the assessment report.\n\nServier and NOS noted that the Assessment Group's model had a time horizon limited to 10\xa0years and criticised how mortality beyond 10\xa0years had been taken into account in the economic evaluation. Servier expressed the view that, as a consequence of this, the model was inaccurate and underestimated the cost effectiveness of treatment for women at risk of fracture. Servier also identified two values ('wristbonusat2.5' and 'phbonusat2.5', related to QALY calculations) that were included in the model, but not described in assessment reports.\n\nServier commented that using the same disutility for side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates.\n\nBRS and NOS thought that the proportion of women with low BMD in England and Wales was substantially underestimated in the Assessment Group's model. These consultees were also concerned that although both smoking and previous or current glucocorticoid (corticosteroid) use had been included as additional independent clinical risk factors for fracture in the Assessment Group's model, they were not defined as risk factors in the recommendations (see section 1.5). In addition, both consultees thought that interactions between several clinical risk factors were not incorporated in the model, thereby reducing the cost effectiveness of treatment for women at risk of fracture, especially younger women.\n\nAll four consultees commented on elements of the Assessment Group's economic evaluation that had been considered and agreed by the Appraisal Committee before it directed the Assessment Group to develop the economic model using specific assumptions. These Committee-directed assumptions included the compliance rate, costs associated with fracture, utility values used for vertebral fracture, and the strategy for identifying women at high risk. Servier also commented on the discount rates used in the model.\n\nServier reported that it had prepared a 'comparative' model which was run using assumptions similar to those in the Assessment Group's model. This model was referred to in a report to support the mathematical foundation of revised analyses discussed as part of Servier's comments on the Assessment Group's model. This report was made available to the Appraisal Committee to inform its consideration of comments by Servier on the DSU report (see below and section 4.3).\n\n## Decision Support Unit (DSU) report on consultee comments on the Assessment Group's economic model\n\nThe DSU was commissioned to review the comments from consultees on the Assessment Group's executable economic model and report to the Appraisal Committee. The DSU considered issues that were relevant to the economic model. Key issues were grouped under the common themes of model transparency and ability to assess its validity, methodology (approach) and model inputs.\n\nThe DSU assessed comments on the transparency and validity of the Assessment Group's model. With regard to the consultees' observation that some model inputs were fixed and that in their view the model provided for consultation was incomplete and not fully executable, the DSU confirmed that certain inputs were intentionally fixed and the ability to alter these inputs was not a feature of the model or necessary for some parameters with minimal uncertainty that are commonly fixed in other economic models. In response to comments on the consultees' inability to assess the application of the WHO algorithm, the DSU explained that the WHO algorithm itself was not embedded within the model. The DSU confirmed that absolute fracture risks were correctly calculated using the WHO algorithm before being entered into the model. The DSU noted that documentation had been provided to consultees in the form of publicly available reports and peer-reviewed manuscripts produced by the Assessment Group, and that instructions on the operation of the Assessment Group's model were also offered to consultees and commentators.\n\nWith regard to comments on the modelling approach adopted in the Assessment Group's model, the DSU responded by confirming that alcohol consumption of more than 2\xa0units per\xa0day was included in the model, and that the coefficients used in the model were consistent with the WHO algorithm (as supplied to the Assessment Group at the time the model was developed). The DSU also explored how the model considered corticosteroid-related fracture risk, and confirmed that corticosteroid use was included in the model and that the coefficient used for this risk factor was consistent with that calculated using the WHO algorithm. The DSU noted that the fracture risk of women using corticosteroids would have contributed to the overall fracture risk of the whole modelled population and thereby reduced the ICER associated with the treatment of all women at risk of fracture.\n\nThe DSU confirmed that each clinical risk factor for fracture was given equal weighting in the model. In response to consultee comments expressing the view that this was a less precise approach than that used in the FRAX tool, the DSU noted two points. Firstly, no individual risk calculation tool was publicly available when the model was developed.\xa0secondly, the DSU referred to the 2005 Strontium Ranelate Assessment Report, which compared suggested treatment thresholds (combinations of age, T-score and number of independent clinical risk factors for fracture) from the Assessment Group's model with treatment thresholds indicated by absolute fracture risk. The DSU suggested that the use of absolute fracture risk alone did not accurately predict cost effectiveness, and therefore would not provide a robust basis for the Committee's decision-making.\n\nConsultee comments on the modelling approach also addressed the time horizon and population data used and the grouping of age in 5-year bands. The DSU confirmed that the consequences of fracture were considered beyond 10\xa0years, and provided further explanation of the modelling approach. The DSU additionally undertook exploratory analyses of the impact of mortality after the 10-year time horizon and of incorporating mortality associated with vertebral fracture and proximal humerus fracture. They reported that the change in the results produced by the model was minimal when mortality risk beyond 10\xa0years was doubled. The DSU also confirmed that UK epidemiological data from a study by Holt et al. were used in the Assessment Group's model, and undertook an exploratory analysis around the assumptions of the distribution of T-scores used in the model. For some age bands modelled, the T-scores did not follow a statistically normal distribution, but the DSU noted that the assumption of a normal distribution made it more likely that treatments for women at risk of fracture would be judged to be cost effective. The DSU considered a comment on the calculation of cost-effectiveness estimates averaged for the 5-year age bands implemented in the model. It disagreed with the alternative suggested by the consultee and noted that the Committee had considered and agreed that initial identification by age band was a workable strategy for selecting women at risk of fracture in clinical practice. It also noted that alternative strategies (which did not use age bands) may in fact be more resource-consuming and less likely to be judged as cost effective.\n\nThe DSU reviewed consultee comments on inputs used in the Assessment Group's model. It confirmed that the WHO algorithm (as supplied) had been correctly implemented in the model to produce estimates of fracture risk for each T-score band. The DSU suggested that the differences in the estimates of fracture risk obtained using the FRAX fracture risk calculation tool and the Assessment Group's model did not necessarily suggest that the WHO algorithm had been incorrectly applied (see section 4.3.48), and that these differences could occur for a number of reasons. For example, the use of a midpoint age to represent an age band of 5\xa0years could lead to differences in estimates of fracture risk. The DSU confirmed that no increase in mortality associated with clinical risk factors was used in the model. The DSU suggested that inclusion of such mortality effects would be likely to increase the ICERs for women with those clinical risk factors. The DSU explained that this is because fewer QALY benefits would accrue in the model for women who die of causes related to risk factors. In response to a further comment from Servier, the DSU agreed that, for women without clinical risk factors, the inclusion of these mortality effects in the model may have the opposite effect (that is, a decrease in ICERs). Therefore the overall effect of including the increased mortality associated with clinical risk factors would be small.\n\nThe DSU also confirmed that a fixed value for BMI of 26\xa0kg/m2 was used in the Assessment Group's model. This was the mean BMI in the UK epidemiological dataset from the Holt study used in the model. In an exploratory analysis using the WHO algorithm, the DSU showed that using a BMI of 26\xa0kg/m2 resulted in higher estimated fracture risk than a BMI of 20 or 32\xa0kg/m2 when BMD is known, and this was confirmed by the estimates supplied by one consultee. The DSU suggested that the BMI value used in the model may favour treatment of women at risk of fracture compared with alternative BMI values. The DSU also pointed out that BMI is a weak predictor of fracture when BMD is known (as specified in the identification strategy in the guidance).\n\nThe DSU investigated the risk multipliers used for fracture risk in the Assessment Group's model and the consultee comment that interactions between clinical risk factors had been omitted. It confirmed that the risk multipliers used for fracture risk had been correctly calculated from the WHO algorithm and that all interactions between risk factors had been included. The DSU also noted that the inconsistency between one of the risk multipliers for fracture risk included in the Assessment Group's model compared with the assessment report was the result of a typographical error. Accordingly there was no impact on the results of the model.\n\nThe DSU did not respond in detail to comments on assumptions in the model that had already been documented and agreed by the Appraisal Committee and which were available to consultees and commentators earlier in the development of the appraisal guidance. The DSU did, however, list these issues in its report and cited where they had been considered by the Committee or had been available for comment during development of the guidance. Features of the economic evaluation previously discussed and agreed by the Committee included the following (the sections of this document where these points are covered are given in parentheses):\n\ndiscount rates used in model (4.2.10)\n\ntreatment compliance (4.2.10)\n\ncosts associated with fracture (4.2.17)\n\nstrategy for identifying women at high risk of fracture (4.2.17)\n\nutility values used for vertebral fracture (4.2.17 and 4.3.13)\n\nequal disutility for the side effects of strontium ranelate and bisphosphonates (4.2.10)\n\nsensitivity analyses on disutility (4.3.15).\n\nThe DSU concluded that, in its view, adequate documentation on the Assessment Group's model had been provided for consultees. It highlighted that the WHO algorithm used to generate estimates of fracture risk was not integrated within the Assessment Group's model; rather, the fracture risks derived from the algorithm were entered into the model. Comparisons with fracture risks derived using the FRAX fracture risk calculation tool were made by several consultees on the basis that the WHO algorithm supplied to the Assessment Group and the FRAX tool are assumed to be identical. The DSU could not verify these analyses without access to the FRAX algorithm. The DSU agreed that some parameters in the Assessment Group's model were fixed. These included those with minimal uncertainty, as well as those that are commonly fixed in other economic models. Sensitivity analyses conducted by the DSU suggested that none of the consultees' suggestions relating to the modelling approach would lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The DSU concluded that, in its view, no issues raised by consultees would either affect the validity of the Assessment Group's model or raise significant doubts about the appropriateness of using the model to inform the deliberations of the Committee.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alendronate, etidronate, risedronate, strontium ranelate, raloxifene and teriparatide, having considered evidence on the nature of osteoporosis and the value placed on the benefits of these drugs by women with the condition, those who represent them, and clinical specialists. It also considered the consultation comments received in response to the previous appraisal consultation documents, the extra analysis undertaken by ScHARR in November 2006 and February 2008, and comments received from consultees and commentators after an appeal against an earlier final appraisal determination was upheld in December 2007. Following the outcome of a judicial review and court ruling in March 2009, the Committee considered the comments received from consultees after release of the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report. It also took into account the effective use of NHS resources.\n\nThe Committee considered the extent to which NICE technology appraisal 87 should be updated in the light of the introduction of a new drug (strontium ranelate), new pricing for alendronate and etidronate, and new cost-effectiveness modelling developed as part of the technology appraisal on primary prevention.\n\nThe Committee considered the clinical effectiveness data for the bisphosphonates (alendronate, etidronate and risedronate), strontium ranelate, raloxifene and teriparatide. It noted that all these drugs have proven efficacy in reducing the incidence of vertebral fragility fractures in women with osteoporosis, but that there were differences between the drugs in the degree of certainty that treatment results in a reduction in hip fracture (considered a crucial goal in osteoporosis management). In the case of alendronate and risedronate, the Committee accepted that there was sufficiently robust evidence to suggest a reduction in hip-fracture risk. The Committee noted that the available RCTs for etidronate were of insufficient size to show statistically significant reductions in hip-fracture risk, but that observational data lent support to a reduction in hip-fracture risk.\n\nThe Committee noted that strontium ranelate was effective in preventing vertebral and non-vertebral fractures, and the drug resulted in a non-significant 15% reduction in hip-fracture risk. The Committee was also aware of the result of a post-hoc subgroup analysis showing a statistically significant reduction in the incidence of hip fractures in women aged 74\xa0or older who had a T-score of −2.4\xa0SD or below.\n\nThe Committee noted that the evidence for raloxifene showed an effect on risk of vertebral fractures, but did not show an effect on risk of hip fractures. In addition, there was evidence for a beneficial side effect of raloxifene on the incidence of breast cancer.\n\nThe Committee noted that teriparatide was effective in preventing vertebral and grouped non-vertebral fractures in women with osteoporosis who have had a fracture, compared with placebo. The Committee also considered the favourable findings for teriparatide from one head-to-head RCT of teriparatide and alendronate, and that it conferred relatively favourable back-pain relief. However, the Committee was concerned about the small size of the head-to-head study, the fact that the study was not targeted at women with fractures, and the high dose of teriparatide used. Therefore it considered that the evaluation of the overall advantages of teriparatide over bisphosphonates requires more research to establish relative clinical effectiveness.\n\nThe Committee did not consider it appropriate to make recommendations for the treatment of women on long-term corticosteroid treatment because this patient group is at greatly increased risk of fracture and therefore requires special consideration, particularly if they have had a prior fracture. The Appraisal Committee therefore felt that it would be disadvantageous for this group to be included in the current guidance.\n\nRecommendations for the treatment of women with osteopenia (T-score of between –1 and –2.5\xa0SD below peak BMD) were not made, for two reasons. Firstly, it was agreed after the scope was issued in 2002 that the outcome in this appraisal should be 'the prevention of osteoporotic fractures' and this has been understood by the Committee to be a fragility fracture experienced by women with osteoporosis, not osteopenia.\xa0Secondly, not all of the drugs under appraisal have a UK marketing authorisation for treatment of women with osteopenia.\n\nThe Committee noted that fracture risk is clearly related to age, low BMD and previous fracture. The Committee accepted that most other risk factors (see sections 2.11 and 2.12) were likely to be associated with an increased fracture risk. The Committee was concerned that there was not sufficient evidence for a proven treatment effect on fracture risk related to risk factors other than low BMD, age and prior fracture. The Committee therefore concluded that preventative drug treatment should be targeted at women whose absolute risk of fracture is driven by low BMD and age, and that the recommendations should be made on the basis of age and BMD in the form of T-scores below which treatment is recommended.\n\n## Cost-effectiveness modelling\n\nThe Committee acknowledged the efforts of the Assessment Group to build on the model used previously, particularly in using epidemiological data and a fracture risk algorithm developed under the auspices of the WHO to calculate transition probabilities and to model the identification approaches. The Committee concluded that the Assessment Group's model was likely to give the best estimates of cost effectiveness because it used data from a wide age range (age 50–75\xa0years or older), and was updated to use all osteoporotic fracture sites, more recent utility values, prevalence and risk-factor data, and an adjusted prevalence of fractures in the average population. Although the Assessment Group's model considered a shorter time period (10\xa0years for predicting morbidity, see section 4.2.9) than the manufacturers' models, the Committee thought that this was appropriate considering the age groups involved and the uncertainties around health effects over a longer period.\n\nThe Committee discussed the assumptions underpinning the economic modelling undertaken by the Assessment Group. It noted that the most recent modelling explored some of the uncertainties identified by the Committee surrounding the results of the previous modelling; these related to the costs and disutility associated with treatment-related side effects and to non-compliance or non-persistence with treatment in a proportion of patients. The Committee also noted the effect of the recent price reductions for non-proprietary alendronate (70\xa0mg\xa0weekly and 10\xa0mg daily doses) on the cost effectiveness of the drug.\n\nThe Committee considered the base-case assumptions and those used in additional analyses. The Committee noted that the costs associated with fractures used in the base-case analysis were those used in the original assessment report developed in 2003 and considered that these were likely to be outdated. The Committee agreed that costs based on health resource groups, including home-help costs, were likely to provide the most accurate reflection of the cost of fractures to the NHS and personal social services, and it decided to incorporate these costs into the base-case analysis.\n\nThe Committee considered the utility multiplier used in the base-case analysis for the first\xa0year after a vertebral fracture and noted that it was based on a hospitalised patient group and not on a typical group of patients with vertebral fractures. Consequently it was considerably lower than the utility value modelled for a hip fracture. Although the Committee acknowledged that vertebral fracture can lead to greatly reduced quality of life, it considered that its true value would not greatly outweigh the utility decrement associated with a hip fracture. Therefore, the Committee considered it reasonable to assume that the disutility in the first\xa0year after a vertebral fracture was equivalent to the disutility in the first\xa0year after a hip fracture and decided to include this assumption in the base-case analysis.\n\nThe Committee was not persuaded that the drugs under consideration had been unequivocally shown to reduce fracture risk that was attributable to risk factors not mediated through low BMD and age. The Committee concluded that the uncertainty surrounding the efficacy of the drugs on risk factors not mediated through low BMD and age should be factored into its decision-making by using an analysis that assumed 50% efficacy of the drugs on fractures associated with risk factors other than age and low BMD. Although the Committee recognised that 50% was necessarily an arbitrary figure, the use of either 0% or 100% was considered both extreme and less plausible. In the analysis accepted by the Committee, the assumption of 50% efficacy of the drugs on fracture risk associated with other risk factors was adjusted by using a correspondingly greater efficacy of the drugs on fractures associated with the key independent clinical risk factors (age, BMD and prior fracture).\n\nThe Committee considered the assumptions used in the modelling for the side effects of bisphosphonates, in which women who experience bisphosphonate-related side effects had 91% of the utility of women who did not have such side effects. In the base case, this was applied to 2.35% of patients in the first treatment\xa0month and 0.35% of patients thereafter. Taking into account the persistence data (sections\xa04.1.36 and 4.1.37) and the comments received from consultees and commentators that about 25–30% of women experience gastrointestinal side effects when first taking a bisphosphonate, the Committee agreed that it was important to consider the results of a sensitivity analysis assuming that 24% of women were experiencing bisphosphonate-related side effects in the first treatment\xa0month and 3.5% of women thereafter.\n\nThe Committee acknowledged that the modelling made assumptions necessary about the value of a QALY gained that could be considered an acceptable use of NHS resources. The Committee considered that women who have already sustained an osteoporotic fracture live with the pain and distress caused by the fracture. The Committee considered that women with an osteoporotic fracture constitute a different population from the primary prevention population and that there were some factors that justified considering a higher ICER range in line with the 'Guide to the methods of technology appraisal'.\n\nThe Committee discussed a number of concerns surrounding other issues that were not represented in the model but which may have had an impact on the cost-effectiveness estimates. These included: possible long-term adverse effects of bisphosphonates on the formation of new bone; the likelihood that DXA scanning outside a clinical trial environment would not be as effective as in the clinical trials; and the possibility that the proportion of women who experience side effects may exceed the model's base-case assumptions. Finally, the Committee noted that current discount rates used by the Treasury, the Department of Health and NICE result in a cost-effectiveness calculation less favourable to the drugs than the discount rates used in the analysis considered by the Committee. Although a quantitative analysis of the uncertainties surrounding all these issues was not available, the Committee agreed that, for first-line treatment with a bisphosphonate, these uncertainties could be collectively approximated through the sensitivity analysis for side effects (see section\xa04.3.15). The Committee was persuaded, however, that the results of the sensitivity analysis need only apply to first-line treatment with a bisphosphonate, because many of the factors that led to the adoption of the sensitivity analysis did not apply for\xa0second-line treatment.\n\n## Alendronate\n\nThe Committee considered the results of the economic model following the price reduction for non-proprietary alendronate, the newly included assumptions and the sensitivity analyses (see sections\xa04.3.9 to 4.3.15). The Committee agreed that, when considering the use of alendronate as a first-line treatment, the sensitivity analysis that captured the uncertainties in the economic model (see section\xa04.3.14) was the most appropriate. This led the Committee to conclude that alendronate (based on the price of £53.56 per\xa0year for once-weekly treatment) would be an appropriate use of NHS resources for\xa0secondary preventative treatment in postmenopausal women with fragility fractures and confirmed osteoporosis (that is, a T-score of –2.5\xa0SD or below). The Committee was advised by the clinical specialists from the original Guideline Development Group for the NICE clinical guideline on osteoporosis that, in women aged 75\xa0years or older with a prior fracture, a DXA scan may not be required if the responsible clinician considers it to be clinically inappropriate or unfeasible. This is because a very high proportion of these women would be likely to have a T-score of −2.5 SD or below.\n\nThe Committee noted that the prices of the different brands of alendronate vary greatly and concluded that alendronate should be prescribed on the basis of the lowest acquisition cost available.\n\n## Considerations for the other drugs under appraisal\n\nThe Committee noted that risedronate, etidronate, raloxifene and strontium ranelate were dominated by alendronate (based on the price of £53.56 per\xa0year for alendronate); that is, these drugs have a higher acquisition cost than alendronate, but are not more efficacious. The Committee was also aware that, for women for whom\xa0weekly non-proprietary alendronate could be recommended based on cost effectiveness, the ICERs for risedronate and strontium ranelate were very high, even without inclusion of identification costs (see examples in section 4.2.22).\n\nThe Committee considered an approach where the higher costs of risedronate, strontium ranelate and teriparatide were incorporated into the analysis by combining costs based on the estimated use of alendronate, risedronate and strontium ranelate and teriparatide. However, the overall cost effectiveness of such a combined approach for fracture prevention would be less favourable than that of alendronate. As a consequence, some women who would be eligible for treatment with alendronate as recommended in section\xa01.1 would not be offered treatment using such a combined approach. For this reason, the Committee did not consider the combined approach to be appropriate.\n\nThe Committee considered treatment options available for a woman who is intolerant to alendronate or unable to comply with instructions for administration despite reasonable measures to support continuation of alendronate treatment. The Committee noted that all other treatment options have higher acquisition costs and/or different effectiveness profiles, which would reduce the cost effectiveness of preventive treatment if these drugs were used. The Committee observed that the identification costs associated with finding women who could be cost-effectively treated with one of the other drugs would be negligible, because they would have already undergone an assessment and had a DXA scan in order to be assessed for first-line treatment with alendronate. Therefore, it agreed that the recommendations for this situation should be based on the modelling that excluded identification costs. The Committee also agreed that, when considering\xa0second-line or subsequent treatment, the base-case assumptions for side effects could be applied; that is, a 0.91 utility multiplier should be applied to 2.35% of patients in the first treatment\xa0month and 0.35% of patients thereafter.\n\nThe Committee considered women who cannot take alendronate because of a contraindication or a disability that prevents them from complying with the instructions for administration. Because such a contraindication or disability would be known before the risk assessment, this would comprise a first-line treatment situation, where identification costs are included. Alternative drugs become cost effective at a higher age and lower BMD in a first-line treatment situation, compared with a\xa0second-line treatment situation where identification costs are not included. However, such an approach was considered inappropriate by the Committee because it would unfairly disadvantage women who cannot take alendronate because of a contraindication or a disability. Therefore the Committee concluded that women who cannot take alendronate for these reasons should have access to alternative drugs in the same way as women who cannot tolerate alendronate (that is\xa0second-line treatment, where the analysis excluded identification and assessment costs).\n\nThe Committee concluded that risedronate could be recommended for women who are unable to comply with the special instructions for the administration of alendronate, or have a contraindication to or are intolerant of alendronate, and who have a T-score of –2.5\xa0SD or below plus a combination of age and number of independent clinical risk factors for fracture where treatment with risedronate resulted in an ICER of less than £30,000 per QALY gained without the consideration of identification costs, as outlined in section\xa04.2.25. The Committee agreed that in women aged 75\xa0years or older, where the T-score needed to make treatment cost-effective was −2.5 SD or below, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible (see section 4.3.18).\n\nHaving reviewed the evidence on independent clinical risk factors for fractures and the views of the clinical specialists, the Committee agreed that the appropriate independent clinical risk factors indicating an increased risk of fracture were: parental history of hip fracture, alcohol intake of 4\xa0or more units per\xa0day, and rheumatoid arthritis. The Committee noted that long-term systemic corticosteroid use is also a relevant clinical risk factor.\n\nThe Committee considered the cost effectiveness of etidronate, and noted that in previous modelling etidronate had a better cost-effectiveness profile than risedronate; since then there has been no change in the evidence base that would affect the relative position of these two drugs. In view of its concerns surrounding the clinical evidence base for etidronate, and taking into account the views of clinical specialists and consultees, the Committee decided that etidronate should not be recommended in preference to risedronate. However, the Committee agreed that guidance on the use of etidronate should be included in the recommendations, and concluded that etidronate can be recommended as an alternative treatment option for women who cannot take alendronate, as outlined for risedronate in section\xa04.3.24. In deciding between risedronate and etidronate, clinicians and patients need to balance the overall effectiveness profile of the drugs against their tolerability and adverse effects in individual patients.\n\nFollowing the Court of Appeal Order of April 2010, the Committee considered the clinical and cost effectiveness of strontium ranelate, focusing on the most appropriate estimate for the efficacy in reducing the rate of hip fracture. The Committee considered the additional submission from Servier (see sections 4.1.43 to 4.1.49), a report by the DSU (see sections 4.1.50 to 4.1.55) reviewing this new submission and Servier's response to the DSU report (see section 4.1.56). At its meeting on 20 October 2010, the Committee heard from representatives of Servier and a representative of the DSU.\n\nThe Committee first considered whether it was plausible that strontium ranelate has a greater or lesser relative benefit in any subgroup of the population for which it has a marketing authorisation (that is, whether a different RR for hip fracture could be assumed to apply to some women). The Committee was aware of the advice received from the original Osteoporosis Guideline Development Group that drugs for osteoporosis have constant RR reductions irrespective of age, BMD and prior fracture status (see section 4.2.7).\n\nThe Committee noted the DSU's advice that the correct statistical procedure for investigating if a subgroup of trial participants has a significantly different response to treatment is a test for interaction (see section 4.1.50). No test for interaction had been undertaken for the high-risk subgroup from TROPOS. The Committee also noted that it had not received evidence of a differential benefit, supported by a test for interaction, in any subgroup of any trial of osteoporosis drugs.\n\nThe Committee noted Servier's view that an age cut-off of 74\xa0years was justified by the epidemiological findings of Donaldson et al. (see section 4.1.45). It understood from the DSU that this paper suggests that the rate of hip fracture rises to a notable level after 75\xa0years of age (see section 4.1.52). The Committee also noted that Donaldson et al. state that the absolute risk of hip fracture increases 'steadily' with age: although women are at greater risk of hip fracture as they grow older, there is no particular age at which the risk jumps from low to high. The Committee therefore concluded that Donaldson et al.'s study did not provide support for the use of a specific age cut-off of 74\xa0years.\n\nThe Committee recognised the hypothesis advanced by Servier that there may be biological grounds for assuming an additional effect for strontium ranelate in older women (see section 4.1.47). However, it considered that it should be possible to demonstrate any such effect by statistical and biochemical tests, and it heard from Servier's representatives that no such evidence had been collected. The Committee concluded that a hypothesis alone, without supporting evidence, was insufficient to demonstrate a differential benefit for strontium ranelate in older women.\n\nFor these reasons, the Committee concluded that it could not justify discounting previous advice that drugs for osteoporosis are assumed to have the same relative effect regardless of age, BMD and prior fracture status. Therefore, it agreed that it was most appropriate for the cost-effectiveness model to rely on a single RR to quantify the effect of strontium ranelate in preventing hip fractures in all postmenopausal women with osteoporosis. As a result, the Committee did not concur with the view that it might choose to provide a specific recommendation only for women corresponding to the high-risk subgroup analysed by Servier, based on an assumption of differential effectiveness of strontium ranelate in those women.\n\nThe Committee then considered the value that represents the most appropriate estimate of effect (RR) for strontium ranelate in preventing hip fractures. It discussed Servier's view that the best estimate of effect for the whole population would be that observed in the high-risk subgroup – an RR of 0.64 (see section 4.1.48). The Committee emphasised that, in order to adopt this figure for the whole population, it would first need to be confident that it was a robust estimate of treatment effect. It discussed the process by which the high-risk subgroup had been selected by Servier. It noted that the pooled data from the placebo arms of TROPOS and SOTI had been screened to establish a subgroup at increased risk of hip fracture (see section 4.1.45). The Committee agreed with the DSU's advice that the method used to identify the age cut-off for the subgroup was 'data-dependent' and, therefore, the RR for strontium ranelate derived from this approach was likely to be inflated (see section 4.1.51).\n\nThe Committee also discussed whether it would be appropriate to use an RR derived from a subgroup of trial participants to quantify the effect of a drug in the whole population for which it has a marketing authorisation. It considered Servier's assertion that, in contrast to the whole trial population, the high-risk subgroup of TROPOS provided a statistically robust demonstration of the effect of strontium ranelate in preventing hip fractures (see section 4.1.48). It acknowledged that TROPOS did not include enough participants to demonstrate a statistically significant benefit for strontium ranelate in preventing hip fractures and that, because of this, it would be appropriate to consider using an estimate of effect that was more precise (that is, subject to less statistical uncertainty) than that derived from the whole trial population. The Committee accepted the DSU's advice that the precision of an RR is primarily influenced by the absolute number of observed events (in this case the absolute number of fractures), which would be greatest in the whole trial population. Additionally, it noted that the size of the groups – and, therefore, the rate of events – is important, so that, in theory, it is possible that an estimate of effect from a subgroup may be more statistically precise than the estimate from the whole trial population from which the subgroup is derived. However, in the case of TROPOS, the estimates from the subgroup and the whole trial population had 95% confidence intervals of very similar width. Therefore, the Committee did not accept that the RR in the subgroup was more precise than the RR in the whole trial population. As a result, the Committee concluded that there was no reason to assume that the subgroup analysis was any more statistically robust than the analysis of the whole trial population. The Committee also noted that it is incorrect to infer that one estimate is more accurate than another just because it achieved conventional standards of statistical significance whereas the other did not.\n\nTaking all this into account, the Committee decided that it would not be appropriate to adopt an RR of 0.64 in assessing the cost effectiveness of strontium ranelate, because the method for the subgroup selection was likely to favour strontium ranelate, and because the RR derived in this way was no more precise that the RR from the overall population.\n\nThe Committee further noted that when values derived from subgroups have been considered in NICE technology appraisals, the evidence has been used to inform specific recommendations applying only to groups of people with the same characteristics as those in the trial subgroup. The Committee reiterated its conclusion that it had not received unambiguous evidence of differential benefit from strontium ranelate in any particular group (see sections 4.3.27 to 4.3.32). The Committee was aware that, in order to make recommendations for cost-effective treatment to prevent fractures in postmenopausal women with osteoporosis, it was necessary to consider separate populations defined by age, T-score and independent clinical risk factors. However, these populations are defined because the absolute likelihood of fracture increases in the presence of these risk factors and not because of variations in the relative benefit of treatment.\n\nThe Committee next considered the possibility of adopting an RR of 1.00 to quantify the effect of strontium ranelate in reducing hip fractures. It noted that the 95% confidence interval around the RR from the whole TROPOS population spanned unity (the upper limit was greater than 1). This means that, at the 95% confidence level, the observed results could from a statistical point of view be interpreted as being consistent with strontium ranelate having no effect. The Committee noted that, when the other drugs within this appraisal had been associated with RRs with 95% confidence intervals spanning 1, the model had assumed no effect (RR\xa0=\xa01.00). Therefore, it might be considered consistent to apply the same logic to the estimation of the effectiveness of strontium ranelate. However, the Committee heard the DSU's advice that it is important to base cost-effectiveness analysis on the most plausible estimate for each parameter, with associated uncertainty explored in sensitivity analysis. The Committee also agreed with the DSU's view that the available evidence suggests that strontium ranelate is effective in reducing the risk of hip fracture. For these reasons, the Committee concluded that it would be inappropriate to assume that strontium ranelate has no effect on the incidence of hip fractures, and rejected the use of an RR of 1.00 in the model.\n\nFinally, the Committee discussed using an effect estimate of 0.85 – the RR of hip fracture observed in the whole TROPOS population. It noted the DSU's advice that, in the absence of a robust demonstration of differential benefit in one or more subgroup of a trial, it is most appropriate to rely on an intention-to-treat analysis of the whole trial population (see section 4.1.54). Having concluded that it had not seen evidence of a differential benefit for a specific subgroup in TROPOS, and having rejected the use of the alternative values 0.64 and 1.00 for the whole population, the Committee concluded it had no reason to depart from this principle. It therefore concluded that an RR of 0.85 represented the most appropriate estimate of effect for strontium ranelate in preventing hip fractures in postmenopausal women with osteoporosis. As a result, the Committee agreed that the Assessment Group had been correct to use an RR of 0.85 in its cost-effectiveness calculations to reflect the effect of strontium ranelate in reducing the rate of hip fractures (see section 4.2.8).\n\nThe Committee concluded that strontium ranelate can be recommended for women who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate, and who have a T-score of −2.5\xa0SD or below plus a combination of age and number of independent clinical risk factors for fracture where treatment with strontium ranelate resulted in an ICER of less than £30,000 per QALY gained, without the consideration of identification costs, as outlined in section\xa04.2.26. The Committee agreed that in women aged 75\xa0years or older, where the T-score needed to make treatment cost-effective was −2.5 SD or below, a DXA scan may not be required if the clinician considers it to be clinically inappropriate or unfeasible (see 4.3.18).\n\nThe Committee agreed a definition of alendronate, risedronate or etidronate intolerance as: persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment and that occurs even though the instructions for administration have been followed correctly.\n\nThe Committee discussed the reported benefits of raloxifene on breast cancer risk, and heard from the clinical specialists that the possibility of preventing vertebral fractures and breast cancer simultaneously could be attractive, particularly to younger postmenopausal women. The Committee also heard from the specialists that evidence on the effect of raloxifene in reducing cardiovascular risk is not considered to be robust and that there is some concern over the increased risk of VTE (see section\xa04.1.25).\n\nThe Committee noted that a higher proportion of the overall benefit associated with raloxifene was attributable to its effect on the prevention of breast cancer than to its effect on the prevention of osteoporotic fragility fractures. The Committee agreed that, in principle, the side effects of using a drug should be considered; however, there were a number of reasons why the Committee considered that the breast cancer benefit should not be the sole factor in deciding whether raloxifene is a cost-effective option for treatment for the\xa0secondary prevention of osteoporotic fragility fractures, as follows:\n\nFrom the evidence presented, raloxifene was not as effective as the bisphosphonates for treating osteoporosis.\n\nFull assessment of raloxifene's effect on the prevention of breast cancer and its cost effectiveness in this indication would require consideration of how it compares with other drugs that could be used for breast cancer prevention.\n\nThe Committee noted that\xa0second-line treatment with raloxifene did not result in ICERs lower than £30,000 per QALY gained for women younger than 70\xa0years, and for older women the T-scores at which ICERs were lower than £30,000 per QALY gained were very low. However, the Committee concluded that, the possible benefits in addition to fracture prevention meant that, in cases where women are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have contraindications to or are intolerant of alendronate and either risedronate or etidronate, raloxifene could be recommended for the same groups of women for whom treatment with strontium ranelate resulted in an ICER of less than £30,000 per QALY gained without the consideration of identification costs, as outlined in section\xa04.3.27. The Committee considered that in the younger women in these groups, raloxifene was a plausible choice. When deciding between strontium ranelate and raloxifene, clinicians and patients need to balance the overall proven effectiveness profile of these two drugs against their tolerability and other effects in individual patients.\n\nThe Committee noted the very high ICER for teriparatide when compared with pooled results for alendronate and risedronate in an analysis carried out by ScHARR before the latest price reduction for alendronate, and that there has been no change in the cost effectiveness evidence for teriparatide since. Noting the most recent modelling results for teriparatide, the Committee concluded that a change from the recommendations for teriparatide in NICE technology appraisal 87 for women aged 65\xa0years and older is not warranted. Furthermore, the Committee considered that the updated modelling indicated that women aged 55–64\xa0years who have a T score of –4\xa0SD or below and more than two fractures could be cost-effectively treated with teriparatide.\n\n## Women who cannot take alendronate\n\nThe Committee carefully considered the position of women who cannot take alendronate because of a condition which either makes alendronate contraindicated or which prevents individuals from complying with the instructions for administration for alendronate. In doing so the Committee noted that at least some women in this patient group were likely to be 'disabled' as defined by the Disability Discrimination Act 1995. The Committee was aware of its duties under that Act to avoid unlawful discrimination, to have due regard to the need to promote equality of opportunity for disabled people, and the need to take steps to take account of disabled people's disabilities, as well as its broader legal duties to ensure that its guidance is fair and reasonable.\n\nThe Committee noted that the drugs other than alendronate are cost effective only for patients at higher risk of fracture than the risk levels at which alendronate is cost effective. If these other drugs are recommended for use by patients who cannot take alendronate only when those patients meet the criteria at which these alternative drugs become cost effective, these patients will not receive preventative treatment unless they are at higher risk of fracture than the risk levels at which alendronate is recommended. The Committee therefore considered whether, for women who cannot receive alendronate, the other drugs should be recommended at the same risk levels as alendronate (that is using the criteria established as being cost effective for alendronate) in order to provide access to preventative treatment for all patients with the same level of risk. The Committee reviewed the ICERs for risedronate and strontium ranelate within the criteria established to be cost effective for alendronate. The Committee noted that the prices for risedronate and strontium ranelate are approximately five to six times higher than the price for non-proprietary\xa0weekly alendronate, and that the ICERs for these drugs compared with no treatment were very high. For example, the ICER for strontium ranelate for women aged 55–59\xa0years with an independent clinical risk factor for fracture was approximately £55,000 per QALY gained (see section 4.2.22). The Committee noted that strontium ranelate would be the most likely choice to be considered for women who are unable to comply with the instructions for administration of alendronate, because the instructions for administration of alendronate and risedronate are similar. The Committee took the view that recommending drugs other than alendronate using the same criteria as alendronate for women who cannot take alendronate would not be justified in this case because of the very high ICERs for the alternative drugs. In reaching this decision the Committee had regard to the fact that the impact of refusing the more favourable recommendation is that there is no generally recommended preventative treatment for a particular group of patients who are at the lower end of fracture risk for which treatment was considered, but that the alternative drugs are recommended when these patients are at higher risk of fracture.\n\nThe Committee considered that it is important to maximise the number of patients who are able to take alendronate. Some women will be unable to take alendronate in any circumstances because of contraindication, intolerance or inability to comply with the instructions for administration. However, some women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate would be able to receive the drug if they received assistance in taking it. The Committee concluded that all reasonable steps should be taken to provide women who have a disability that makes it difficult for them to comply with the instructions for administration of alendronate, with such practical support and assistance with administration (for example through district nurse visits or other home support services), as will enable them to take the drug.\n\n## FRAX fracture risk calculation tool\n\nThe Committee was aware of the availability of the FRAX internet-based tool, which can be used to calculate a 10-year absolute risk of fracture, developed under the auspices of the WHO. This assessment tool was based on the same epidemiological data that were used in the Assessment Group's model. However, the Committee was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX. Firstly, the Committee did not agree that all clinical risk factors included in the WHO algorithm were appropriate (see sections 4.2.12 and 4.3.9).\xa0Secondly, the Committee was aware that absolute fracture risk is not directly related to cost effectiveness, as outlined in the strontium ranelate assessment report issued in 2005. This is because absolute fracture risk is the total for all fracture sites, but different fracture sites have different impacts on quality of life, costs and mortality. Therefore, cost effectiveness is dependent on the contribution from each fracture site to the total fracture risk. Thirdly, the Committee had agreed that treatment benefit had not been proven for fracture risk associated with all independent clinical risk factors (section\xa04.3.9). Therefore, the Committee concluded that using a combination of T-score, age and number of independent clinical risk factors for fracture is more appropriate for defining treatment recommendations in this appraisal.\n\n## Evidence on use of acid suppressive medication and fracture risk\n\nThe Committee was made aware of data indicating that acid-suppressive medication leads to a small increase in fracture risk and that co-administration of acid-suppressive medication and bisphosphonates may lead to an increased fracture risk compared with bisphosphonate administration alone. The Committee was not persuaded by this evidence; it noted that the data are observational and have not been reported in full, and are different for different fracture sites and for different acid suppressors. Furthermore, the Committee was informed, during consultation, of analyses showing that acid-suppressive medication given in addition to risedronate did not increase fracture risk. The Committee concluded that caution should be exercised when considering the evidence about co-prescription of acid-suppressive medication and bisphosphonates.\n\nThe Committee noted sensitivity analyses that included the assumption of an increase in fracture risk for women for whom acid-suppressive medications are co-prescribed (see section 4.2.19). The analysis for treatment strategies did not decrease the T-scores at which the ICERs for alendronate fell below £30,000 to the T-scores established for strategies including strontium ranelate or raloxifene. The Committee also noted that the ICERs for treatment compared with no treatment for an individual woman with a relevant combination of age and T-score were not more favourable for strontium ranelate than for risedronate even if an effect of acid-suppressive medication was assumed. The Committee considered that the evidence for this effect was not sufficiently robust. However, it concluded that the relative positions of alendronate, risedronate and strontium ranelate would remain unchanged even if an effect of acid-suppressive medication was assumed. The Committee therefore concluded that it was not necessary to change its recommendations (section 1) to take account of acid-suppressive medication.\n\n## Calcium and vitamin D prerequisites for treatment\n\nThe Committee discussed the effect of calcium and vitamin D on the clinical effectiveness of the drugs considered. In the studies that formed the basis of this guidance, all participants were said to have adequate calcium and vitamin D levels. The Committee appreciated that the general population, particularly the elderly population, cannot be assumed to have an adequate dietary intake of calcium and vitamin D. It was also considered important to note that adequate levels (normal serum concentrations) of calcium and vitamin D are needed to ensure optimum effects of the treatments for osteoporosis. The Committee concluded that calcium and/or vitamin D supplementation should be provided unless clinicians are confident that women who receive treatment for osteoporosis have an adequate calcium intake and are vitamin D replete.\n\n## Consultation on the Assessment Group's economic model\n\nFollowing the outcome of the judicial review and the court ruling of March 2009, the Appraisal Committee considered the comments received from consultees on the Assessment Group's executable economic model, a report by the DSU reviewing these comments, and responses from the consultees to the DSU report.\n\nThe Committee considered the comments from consultees that the Assessment Group's model was not sufficiently transparent, lacked adequate documentation and could not be validated. It noted the number of consultations that took place during the appraisal guidance development, that the consultation documents had included descriptions of the model, and that assumptions and parameter values used had also been provided to consultees. The Committee was aware that instructions on how to run the model were released with the model and that consultees were able to run the model with changed input parameters. The Committee was satisfied with the exploration by the DSU of the functionality and validity of the model. The Committee noted that Servier stated that it had constructed its own economic model in order to validate the Assessment Group's model and to demonstrate the mathematical rationale to support its comments. The Committee noted that the results from Servier's model were very similar to those from the Assessment Group's model when similar assumptions and parameter inputs were used. The Committee was not persuaded by the consultees' doubt about the validity of the model, particularly since differences between the results obtained using Servier's model and the Assessment Group's model were largely because of differences in the assumptions used.\n\nThe Committee considered the comments from consultees that some inputs in the Assessment Group's model could not be changed and that it was unclear how fracture risk was calculated. The Committee noted that some of the fixed input parameters were inputs that do not need changing (such as the discount rate and standard mortality rates). Other fixed input values, such as the BMI and issues around the time horizon, were discussed separately (see sections 4.3.57 and 4.3.51 respectively). The Committee concluded that it was reasonable for some inputs in the model to be fixed. The Committee noted that fracture risks were calculated by the Assessment Group using the WHO algorithm in a separate spreadsheet and then entered into the model. It understood that the WHO algorithm itself was provided to the Assessment Group in 2005 as academic in confidence and that at that time NICE did not have permission from the owner of the algorithm to release it to consultees. The Committee understood that although the WHO fracture risk algorithm itself was not embedded in the economic model, the model could not be released because the algorithm could have been back-calculated from the fracture risks entered in the model and because the numbers of women with risk factors from the algorithm were included in the model.\n\nThe Committee considered the comments from consultees that the fracture risks entered into the model, calculated using the WHO algorithm, were different from fracture risks estimated using the FRAX tool. The Committee was aware that some differences could be because of the Assessment Group's use of midpoint ages in each 5-year age grouping. It also heard that the Assessment Group had verified the application of the WHO algorithm as provided in 2005, including all interactions between clinical risk factors, and was satisfied that the DSU had adequately assessed its application as being correct in the model. Because neither the DSU nor NICE has access to the algorithm used for the construction of the FRAX tool, the Committee was not in a position to comment further on differences between the two ways of estimating fracture risk. It concluded that differences between fracture risk estimates produced using the FRAX tool and those used in the Assessment Group's model were not in themselves a reason to doubt the correct use of the WHO algorithm within the Assessment Group's model.\n\nThe Committee considered the comments from consultees that mortality associated with clinical risk factors had been omitted from the Assessment Group's model, and noted the confirmation from the DSU that this was the case. It was persuaded that the inclusion of such additional mortality effects would increase the complexity of the model, and may increase the ICERs for the treatment of women with such clinical risk factors but decrease the ICERs for the treatment of women without such risk factors. The Committee agreed that the overall effect of including mortality associated with clinical risk factors in the model was unlikely to lead to a marked change in the overall results.\n\nThe Committee reviewed the consultee comments relating to the fixed BMI value of 26\xa0kg/m2 used in the Assessment Group's model. It noted the rationale for selecting this value (see section 4.2.46). It also noted that in the DSU's exploratory analysis using the WHO algorithm, no increase in fracture risk was identified for women with a higher or lower BMI when BMD was known. The Committee was aware of its recommendation to assess BMD in all women under the age of 75\xa0years for whom treatment is being considered, and noted that BMI is a weak predictor of fracture when BMD is known. Therefore the Committee concluded that the use of a fixed BMI value of 26\xa0kg/m2 did not lead to an unfavourable assessment of the cost effectiveness of the interventions.\n\nThe Committee considered comments from consultees that the fracture risk associated with alcohol consumption used in the model was incorrect. It noted that the DSU had determined that the WHO algorithm had been correctly implemented, and understood that alcohol consumption of more than 2\xa0units per\xa0day was included as a risk factor in the model. The Committee also noted that in its recommendations it had chosen to use a higher level of alcohol consumption in the risk identification strategy, because only alcohol consumption of 4\xa0or more units per\xa0day was identified as a statistically significant risk factor for fracture for women – the population considered in the guidance. The Committee also considered a consultee comment that stated that it was unclear whether smoking and corticosteroid use had been included in the model as risk factors. It noted that the DSU had determined that the WHO algorithm had been correctly implemented with regard to both smoking and corticosteroid use in the model. The Committee noted that the effect of smoking in women was not statistically significant when assessing risk of osteoporotic fractures taken as a whole. The Committee was therefore satisfied that risks associated with corticosteroids, smoking and alcohol consumption had been faithfully applied in the Assessment Group's model, and agreed that the levels of alcohol consumption and smoking that should be used in the risk identification strategy were a matter for the Committee to consider and determine. The Committee took the view that it is not appropriate to identify women at high risk of fracture on the basis of risks that were not statistically significant (such as smoking and consumption of fewer than 4\xa0units of alcohol per\xa0day) and that, in addition, the impact of these risk factors could arguably be approached by a strategy of smoking cessation and reducing alcohol consumption. The Committee noted comments from the consultees that the Assessment Group's model should have been amended to reflect the Committee's agreed inclusion of risk factors. However, the Committee took the pragmatic view that such amendments would have added unnecessarily to the mathematical complexity of an already complex clinical situation. It noted that women who had taken corticosteroids were included in the model and therefore contributed to the underlying fracture risk, with the effect of reducing the ICERs for the treatment of the population of women considered in the recommendations.\n\nThe Committee considered consultee comments that giving equal weighting to different clinical risk factors for fracture in the Assessment Group's model was inaccurate. The Committee considered the complex results presented originally in the 2005 Strontium Ranelate Assessment Report related to the inclusion of different risk factors and combinations of risk factors. The Committee noted that it had previously agreed that a clinically workable risk identification and treatment strategy should include the grouping of risk factors as the only practical way forward. At the time of the model's development, no individual risk calculation tool was available. Even if such a tool had been used in the development of the guidance, the prediction of cost effectiveness from overall absolute fracture risk alone, as suggested by consultees, would not be appropriate, for two reasons. Firstly, risk factors have different effects on different fracture types, and the cost effectiveness of treatment depends on the relative contributions of each risk factor to fracture risk. Secondly, the effectiveness of the drugs in reducing fracture risk was limited to only some of the clinical risk factors (age, T-score of −2.5\xa0SD or below and prior fracture). The Committee heard from the DSU that there was considerable uncertainty about the cost effectiveness of treating women based on absolute risk alone (see section 4.3.48). Therefore, the Committee concluded that, when developing the guidance, simplification of the model was justified to in order to produce workable recommendations.\n\nThe Committee reviewed a comment from a consultee that the methods used to model effects beyond 10\xa0years were not adequately described. It noted that the DSU confirmed that consequences beyond 10\xa0years were considered in the Assessment Group's model, and an expanded description of the methods used was provided in an annex to the DSU report. The Committee also noted that the DSU carried out a sensitivity analysis in order to establish the impact of any possible underestimation of the mortality risk after the 10-year time horizon. It noted that doubling of the mortality risk led to only very small changes in the results. The Committee therefore concluded that mortality effects beyond the 10-year time horizon had been reasonably accounted for in the model and that sufficient description of these methods had been made available to consultees.\n\nThe Committee considered comments from consultees that the population data on the distribution of BMD (T-score) were not appropriate. It noted the DSU response confirming that the UK epidemiological dataset from the Holt study had been correctly implemented in the Assessment Group's model, and that the assumptions about the normality of the distributions used were likely to favour treatment for women at risk of fracture. The Committee also noted that the particular UK epidemiological dataset used in the model had been originally suggested by consultees for this appraisal. The Committee concluded that the population data had been used appropriately in the model.\n\nThe Committee considered a comment from a consultee that using a single estimate of cost effectiveness for 5-year age groupings of women at risk of fracture could exclude women from being offered treatment. It noted that this identification method was a Committee decision, and that identification strategies based on other factors could make treatments less cost effective.\n\nThe Committee reviewed comments from a consultee that the application of the same disutility for the side effects associated with strontium ranelate and bisphosphonates was not correct, as the side effects of strontium ranelate are different from those of the bisphosphonates. The Committee was aware that the side effects observed for strontium ranelate in the clinical trials did not include gastrointestinal effects, but did include an increased risk of VTE. Because the increased risk of VTE was not included in the Assessment Group's model, the Committee had agreed that it was appropriate to include a disutility equivalent to the bisphosphonate base-case side-effect disutility to take account of this adverse effect.\n\nThe Committee reviewed comments from consultees about model assumptions or inputs that the Committee had directed the Assessment Group to use. It noted that issues such as treatment compliance, discount rates, costs of fracture, utility values for vertebral fracture and side-effect profiles used in the model had been considered and agreed by the Committee and reported in the guidance. The Committee also agreed that it had considered identification strategies for women at risk of fracture and, noting the advice of clinical specialists, it had recommended that women should have their BMD assessed by DXA scanning, except in certain circumstances as defined in the guidance. The Committee concluded that views expressed by consultees on the choice of modelling assumptions, input parameters and risk identification strategy were not about the operation of the Assessment Group's model, but were about Committee decisions that had already been discussed during development of the guidance.\n\nThe Committee also considered the consultees' view that the FRAX tool provides a 'mechanism to compute cost-effectiveness' according to clinical risk factors and that each of the current recommendations covers a wide range of absolute risk values, depending on the individual risk factors involved. The Committee understood that the FRAX tool is not an economic model, but a tool to estimate fracture risk. The Committee acknowledged that the current set of recommendations involved necessary simplifications from the more complex algorithm used to develop the Assessment Group's model. It was also aware that a direct prediction of cost effectiveness from absolute fracture risk alone would be inappropriate (see section 4.3.48).\n\nThe Committee concluded that the Assessment Group had provided an executable economic model and had implemented the WHO algorithm (as supplied) correctly. The Committee agreed with the DSU's comments that alterations to the modelling approach, as suggested by consultees, would not lead to significant improvements in the cost effectiveness of treatment for women at risk of fracture. The Committee confirmed that the model provided a suitable framework to allow it to make recommendations on the cost-effective use of treatment for women at risk of fracture. The Committee noted that assumptions used in the Assessment Group's model had been considered and agreed by the Committee in developing the guidance. It agreed that it would not be useful to request further analysis from the Assessment Group at this stage. The Committee further agreed that any exploration of how absolute fracture risk could be used in making treatment decisions would require a new assessment and appraisal. Therefore the Committee concluded that the recommendations based on the Assessment Group's model were appropriate, and that the recommendations should remain unchanged.\n\nThe Committee noted the comments from some consultees that the guidance should be reviewed soon because the price of some of the appraised drugs had changed. The Committee noted that any possible price reductions could be offset by the use of the currently applicable discount rate, and that any review should also take into consideration how NICE might assess diagnostic tools such as absolute fracture risk prediction tools.\n\n T-scores were calculated according to trial-specific normative data, using a threshold of −3.0 or below, which is equivalent to a T-score of −2.4 or below when measured according to the standards subsequently adopted by the WHO. The latter classification is used throughout this guidance document.\n\n The remit of the original osteoporosis guideline has since been amended; see Osteoporosis and Osteoporosis fragility fracture risk.", 'Recommendations for further research': 'Given the evidence that the benefits of one of the bisphosphonates (alendronate) may continue for several\xa0years after the end of treatment, the Committee recommends that research should be carried out to define the optimal duration of treatment with individual bisphosphonates.\n\nThe Committee recommends research into the long-term effects of bisphosphonates on bone quality, given the inhibitory effects on bone resorption of these drugs.', 'Review of guidance': 'The guidance on these technologies will be considered for review by the Guidance Executive as soon as the short clinical guideline on risk assessment has been published. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJanuary 2011'}
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https://www.nice.org.uk/guidance/ta161
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Evidence-based recommendations on raloxifene and teriparatide for preventing osteoporotic fragility fractures in postmenopausal women who have osteoporosis.
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4dd9a345329b46f2a2b18a6bf6ec9f1af9c53f0c
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nice
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Pancreatic cancer in adults: diagnosis and management
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Pancreatic cancer in adults: diagnosis and management
This guideline covers diagnosing and managing pancreatic cancer in adults aged 18 and over. It aims to improve care by ensuring quicker and more accurate diagnosis, and by specifying the most effective treatments for people depending on how advanced their cancer is.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diagnosis
## People with obstructive jaundice
For people with obstructive jaundice and suspected pancreatic cancer, offer a pancreatic protocol CT scan before draining the bile duct.
If the diagnosis is still unclear, offer fluorodeoxyglucose-positron emission tomography/CT (FDG‑PET/CT) and/or endoscopic ultrasound (EUS) with EUS‑guided tissue sampling.
Take a biliary brushing for cytology if:
endoscopic retrograde cholangiopancreatography (ERCP) is being used to relieve the biliary obstruction and
there is no tissue diagnosis.
## People without jaundice who have pancreatic abnormalities on imaging
Offer a pancreatic protocol CT scan to people with pancreatic abnormalities but no jaundice.
If the diagnosis is still unclear, offer FDG‑PET/CT and/or EUS with EUS‑guided tissue sampling.
If cytological or histological samples are needed, offer EUS with EUS‑guided tissue sampling.
## People with pancreatic cysts
Offer a pancreatic protocol CT scan or magnetic resonance cholangiopancreatography (MRI/MRCP) to people with pancreatic cysts. If more information is needed after one of these tests, offer the other one.
Refer people with any of these high-risk features for resection:
-bstructive jaundice with cystic lesions in the head of the pancreas
enhancing solid component in the cyst
a main pancreatic duct that is 10 mm diameter or larger.
Offer EUS after CT and MRI/MRCP if more information on the likelihood of malignancy is needed, or if it is not clear whether surgery is needed.
Consider fine-needle aspiration during EUS if more information on the likelihood of malignancy is needed.
When using fine-needle aspiration, perform carcinoembryonic antigen (CEA) assay in addition to cytology if there is sufficient sample.
For people with cysts that are thought to be malignant, follow the recommendations on staging.
## People with inherited high risk of pancreatic cancer
Ask people with pancreatic cancer if any of their first-degree relatives has had it. Address any concerns the person has about inherited risk.
Offer surveillance for pancreatic cancer to people with:
hereditary pancreatitis and a PRSS1 mutation
BRCA1, BRCA2, PALB2 or CDKN2A (p16) mutations, and one or more first-degree relatives with pancreatic cancer
Peutz–Jeghers syndrome.
Consider surveillance for pancreatic cancer for people with:
-r more first-degree relatives with pancreatic cancer, across 2 or more generations
Lynch syndrome (mismatch repair gene mutations) and any first-degree relatives with pancreatic cancer.
Consider an MRI/MRCP or EUS for pancreatic cancer surveillance in people without hereditary pancreatitis.
Consider a pancreatic protocol CT scan for pancreatic cancer surveillance in people with hereditary pancreatitis and a PRSS1 mutation.
Do not offer EUS to detect pancreatic cancer in people with hereditary pancreatitis.
# Specialist pancreatic multidisciplinary teams
A specialist pancreatic cancer multidisciplinary team should decide what care is needed, and involve the person with suspected or confirmed pancreatic cancer in the decision. Care should be delivered in partnership with local cancer units.
# Staging
For people with newly diagnosed pancreatic cancer who have not had a pancreatic protocol CT scan, offer a pancreatic protocol CT scan that includes the chest, abdomen and pelvis.
Offer fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to people with localised disease on CT who will be having cancer treatment (surgery, radiotherapy or systemic therapy).
If more information is needed to decide the person's clinical management, consider one or more of the following:
MRI, for suspected liver metastases
endoscopic ultrasound, if more information is needed for tumour and node staging
laparoscopy with laparoscopic ultrasound, for suspected small-volume peritoneal and/or liver metastases if resectional surgery is a possibility. See recommendation 1.2.1 on how care should be agreed and delivered.
# Psychological support
Throughout the person's pancreatic cancer care pathway, specifically assess the psychological impact of:
fatigue
pain
gastrointestinal symptoms (including changes to appetite)
nutrition
anxiety
depression.
Provide people and their family members or carers (as appropriate) with information and support to help them manage the psychological impact of pancreatic cancer on their lives and daily activities. This should be:
available on an ongoing basis
relevant to the stage of the person's condition
tailored to the person's needs.
For more guidance on providing information and support, see the NICE guideline on patient experience in adult NHS services.
# Pain management
Consider EUS-guided or image-guided percutaneous neurolytic coeliac plexus block to manage pain for people with pancreatic cancer who:
have uncontrolled pancreatic pain or
are experiencing unacceptable opioid adverse effects or
are receiving escalating doses of analgesics.
Do not offer thoracic splanchnicectomy to people with pancreatic cancer.
# Nutritional management
Offer enteric-coated pancreatin for people with unresectable pancreatic cancer.
Consider enteric-coated pancreatin before and after pancreatic cancer resection.
Do not use fish oils as a nutritional intervention to manage weight loss in people with unresectable pancreatic cancer.
For people who have had pancreatoduodenectomy and who have a functioning gut, offer early enteral nutrition (including oral and tube feeding) rather than parenteral nutrition.
For more guidance on nutrition support, see the NICE guideline on nutrition support in adults.
# Relieving biliary and duodenal obstruction
## Biliary obstruction
Offer resectional surgery rather than preoperative biliary drainage to people who:
have resectable pancreatic cancer and obstructive jaundice and
are well enough for the procedure and
are not enrolled in a clinical trial that requires preoperative biliary drainage.
During attempted resection for pancreatic cancer, consider surgical biliary bypass if the cancer is found to be unresectable.
If biliary drainage is needed in a person who has resectable pancreatic cancer and obstructive jaundice and is not yet fit enough for resectional surgery, offer endoscopically placed self‑expanding metal stents.
For people with suspected pancreatic cancer who may need their stent removed later on, consider endoscopically placed self-expanding fully covered metal stents.
Offer endoscopically placed self-expanding metal stents rather than surgical biliary bypass to people with unresectable pancreatic cancer.
## Duodenal obstruction
During attempted resection for head of pancreas cancer, consider prophylactic gastrojejunostomy if the cancer is found to be unresectable.
If possible, relieve symptomatic duodenal obstruction caused by unresectable pancreatic cancer.
When deciding between gastrojejunostomy and duodenal stent placement, consider gastrojejunostomy for people with a more favourable prognosis.
# Managing resectable and borderline resectable pancreatic cancer
## Neoadjuvant therapy
Only consider neoadjuvant therapy for people with borderline resectable pancreatic cancer as part of a clinical trial.
Only consider neoadjuvant therapy for people with resectable pancreatic cancer as part of a clinical trial.
## Surgery
For people having surgery for head of pancreas cancer, consider pylorus-preserving resection if the tumour can be adequately resected.
Consider standard lymphadenectomy, rather than extended lymphadenectomy for people having head of pancreas resection.
## Adjuvant treatment
Give people time to recover from surgery before starting adjuvant therapy. Start adjuvant therapy as soon as they are well enough to tolerate all 6 cycles.
Offer adjuvant gemcitabine plus capecitabine to people who have had sufficient time to recover after pancreatic cancer resection.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.
Consider adjuvant gemcitabine for people who are not well enough to tolerate combination chemotherapy.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.
## Follow-up for resected pancreatic cancer
For people who have had resection, offer ongoing specialist assessment and care to identify and manage any problems resulting from surgery.
For people who have new, unexplained or unresolved symptoms after treatment, provide access to specialist investigation and support services.
# Managing unresectable pancreatic cancer
## Locally advanced pancreatic cancer
Offer systemic combination chemotherapy to people with locally advanced pancreatic cancer who are well enough to tolerate it.
Consider gemcitabine for people with locally advanced pancreatic cancer who are not well enough to tolerate combination chemotherapy.
When using chemoradiotherapy, consider capecitabine as the radiosensitiser.
## Metastatic pancreatic cancer
Offer FOLFIRINOX to people with metastatic pancreatic cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.
Consider gemcitabine combination therapy for people who are not well enough to tolerate FOLFIRINOX. For guidance on combination therapy with gemcitabine and nab–paclitaxel, see NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer.In February 2018, this was an off-label use of many gemcitabine combination therapies. See NICE's information on prescribing medicines.
Offer gemcitabine to people who are not well enough to tolerate combination chemotherapy.
Consider oxaliplatin-based chemotherapy as second-line treatment for people who have not had first-line oxaliplatin.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.
Consider gemcitabine-based chemotherapy as second-line treatment for people whose cancer has progressed after first-line FOLFIRINOX.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.
For recommendations on venous thromboembolism prophylaxis for people with pancreatic cancer, see the NICE guideline on reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism in over 16s.
## Genomic biomarker-based treatment
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See our topic page on genomic biomarker-based cancer treatments.
# Terms used in this guideline
## Standard lymphadenectomy
As defined by Tol et al. (2014) Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)Tol et al. (2014) Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 156(3): 591–600# Context
Pancreatic cancer is the fifth most common cause of cancer death in the UK, with an annual incidence of nearly 9,600. On average, 23 people die each day from the disease. The UK has one of the worst survival rates in Europe, with average life expectancy on diagnosis just 4 to 6 months and a relative survival to 1 year of approximately 20%.
Only 3% of people survive for 5 years or longer. This figure has not improved much in over 40 years, and it is not yet clear how the more recent trend of increased surgery and adjuvant chemotherapy will affect survival.
Because of late diagnosis, only approximately 8% of people with pancreatic cancer are eligible for potentially curative surgery. However, people have up to a 30% chance of surviving 5 years if their tumour can be surgically removed and they have adjuvant chemotherapy.
The symptoms of pancreatic cancer are non-specific. One survey found that 40% of people diagnosed with pancreatic cancer in England had visited their GP 3 or more times before the diagnosis was made. Fifty per cent of people are diagnosed as an emergency in A&E. Even after diagnosis, there is evidence from the National Cancer Intelligence Network of wide variation in practice throughout England.
There are often delays in access to diagnosis and treatment (as highlighted in the NHS England Five Year Forward View), and this guideline will help to improve this.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Neoadjuvant therapy
Prospective randomised trials should be undertaken to compare preoperative (neoadjuvant) therapy with standard postoperative therapy in people with resectable pancreatic cancer.
## Why this is important
The survival rate of pancreatic cancer after surgical resection is very low, which suggests that most patients have metastatic disease at the time of surgery. In addition, complications of surgery may stop people from having adjuvant therapy. This makes neoadjuvant therapy an attractive option. However, the evidence for neoadjuvant therapy is limited and low quality. Using neoadjuvant therapy means delaying surgery, and it is possible that during this delay pancreatic cancer will progress and become unresectable in some people, negating any benefit of neoadjuvant therapy.
Research is needed to compare neoadjuvant treatments (which might be chemotherapy, radiotherapy or both) with surgery followed by adjuvant chemotherapy. The outcomes of interest are:
feasibility of delivering neoadjuvant treatment
feasibility of randomising patients
-bjective response rate of neoadjuvant therapy
R0 resection rate
surgical complications, length of hospital stay, mortality of surgery
delivery of planned treatment
disease-free survival and overall survival after surgery
quality of life, patient experience and patient-reported outcome measures.
# Cachexia interventions
A cohort study followed by phase 2 and 3 studies should be undertaken in people with pancreatic cancer and cachexia or pre-cachexia, to compare cachexia assessment methods and anti-cachexia interventions with standard care.
## Why this is important
Most people with advanced and metastatic pancreatic cancer also have cachexia. This causes severe reductions in their quality of life and is associated with reduced overall survival. Cachexia has 3 phases: pre‑cachexia, cachexia and refractory cachexia. The condition cannot be stopped by conventional nutritional support and leads to progressive functional impairment. Complete or partial reversal of cachexia would cause major improvements in quality of life, and potentially improve survival if people recover enough to have more effective cancer treatments. The outcomes of interest are:
prevention or reversal of cachexia
-verall survival
quality of life
pain relief
lean tissue mass
tolerance to treatment.
# Minimally invasive pancreatectomy
Prospective randomised trials should be undertaken to compare the effectiveness of minimally invasive pancreatectomy or pancreatoduodenectomy (laparoscopic or robotic) with open pancreatectomy or pancreatoduodenectomy in people with pancreatic cancer.
## Why this is important
Minimally invasive surgery is generally considered to be more acceptable to patients than open surgery. It has been introduced successfully for several other types of cancer and has been shown to improve quality of life. However, there is not enough evidence to determine whether minimally invasive surgery improves morbidity and mortality for people with pancreatic cancer, compared with open surgery. Prospective randomised trials are therefore needed in this area. The outcomes of interest are:
conversion rate to open surgery
R0 resection rate
lymph node yield
blood loss
duration of surgery
complications
need for critical care
length of hospital stay
time to return to normal activity
mortality of surgery
long-term survival after surgery
quality of life, patient experience and patient-reported outcome measures.
# Pain management
A randomised trial should be undertaken comparing early endoscopic ultrasound-guided neurolytic coeliac plexus (EUS‑guided NCP) interventions with on‑demand EUS‑guided NCP interventions in people with unresectable pancreatic cancer.
## Why this is important
There is a limited number of randomised trials in this area, and the methods used to perform NCP intervention are heterogeneous. It is not clear if early NCP intervention is superior to on‑demand NCP intervention in terms of the important outcomes for the patient and duration of effect of the procedure. On‑demand NCP intervention may benefit people with uncontrolled pain, people receiving escalating doses of analgesia, people experiencing unacceptable analgesic side effects, and others. However, people who receive early NCP intervention may not need on‑demand NCP intervention later on. Further research should clarify if the timing of the intervention confers any advantage. The outcomes of interest are:
reduction in pain
patient experience (including nutritional status)
health-related quality of life
adverse events
analgesic use
survival.
# Psychological support needs
A qualitative study should be undertaken to evaluate information and support interventions to address psychological needs at different points in the care pathway for people with pancreatic cancer.
## Why this is important
People with pancreatic cancer often have unmet psychological support needs that impact on their quality of life. These can be related to anxiety and depression, and to the psychological impact of fatigue, pain, gastrointestinal symptoms (particularly changes to appetite) and nutritional status. There has been very little research into the information and support interventions that would meet these needs. Research would help identify effective information and support interventions that would improve quality of life for people with pancreatic cancer and their family members or carers. Outcomes of interest are:
quality of life
psychological wellbeing
ability to carry out normal activities
patient experience and patient-reported outcome measures.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis\n\n## People with obstructive jaundice\n\nFor people with obstructive jaundice and suspected pancreatic cancer, offer a pancreatic protocol CT scan before draining the bile duct.\n\nIf the diagnosis is still unclear, offer fluorodeoxyglucose-positron emission tomography/CT (FDG‑PET/CT) and/or endoscopic ultrasound (EUS) with EUS‑guided tissue sampling.\n\nTake a biliary brushing for cytology if:\n\nendoscopic retrograde cholangiopancreatography (ERCP) is being used to relieve the biliary obstruction and\n\nthere is no tissue diagnosis.\n\n## People without jaundice who have pancreatic abnormalities on imaging\n\nOffer a pancreatic protocol CT scan to people with pancreatic abnormalities but no jaundice.\n\nIf the diagnosis is still unclear, offer FDG‑PET/CT and/or EUS with EUS‑guided tissue sampling.\n\nIf cytological or histological samples are needed, offer EUS with EUS‑guided tissue sampling.\n\n## People with pancreatic cysts\n\nOffer a pancreatic protocol CT scan or magnetic resonance cholangiopancreatography (MRI/MRCP) to people with pancreatic cysts. If more information is needed after one of these tests, offer the other one.\n\nRefer people with any of these high-risk features for resection:\n\nobstructive jaundice with cystic lesions in the head of the pancreas\n\nenhancing solid component in the cyst\n\na main pancreatic duct that is 10\xa0mm diameter or larger.\n\nOffer EUS after CT and MRI/MRCP if more information on the likelihood of malignancy is needed, or if it is not clear whether surgery is needed.\n\nConsider fine-needle aspiration during EUS if more information on the likelihood of malignancy is needed.\n\nWhen using fine-needle aspiration, perform carcinoembryonic antigen (CEA) assay in addition to cytology if there is sufficient sample.\n\nFor people with cysts that are thought to be malignant, follow the recommendations on staging.\n\n## People with inherited high risk of pancreatic cancer\n\nAsk people with pancreatic cancer if any of their first-degree relatives has had it. Address any concerns the person has about inherited risk.\n\nOffer surveillance for pancreatic cancer to people with:\n\nhereditary pancreatitis and a PRSS1 mutation\n\nBRCA1, BRCA2, PALB2 or CDKN2A (p16) mutations, and one or more first-degree relatives with pancreatic cancer\n\nPeutz–Jeghers syndrome.\n\nConsider surveillance for pancreatic cancer for people with:\n\nor more first-degree relatives with pancreatic cancer, across 2\xa0or more generations\n\nLynch syndrome (mismatch repair gene [MLH1, MSH2, MSH6 or PMS2] mutations) and any first-degree relatives with pancreatic cancer.\n\nConsider an MRI/MRCP or EUS for pancreatic cancer surveillance in people without hereditary pancreatitis.\n\nConsider a pancreatic protocol CT scan for pancreatic cancer surveillance in people with hereditary pancreatitis and a PRSS1 mutation.\n\nDo not offer EUS to detect pancreatic cancer in people with hereditary pancreatitis.\n\n# Specialist pancreatic multidisciplinary teams\n\nA specialist pancreatic cancer multidisciplinary team should decide what care is needed, and involve the person with suspected or confirmed pancreatic cancer in the decision. Care should be delivered in partnership with local cancer units.\n\n# Staging\n\nFor people with newly diagnosed pancreatic cancer who have not had a pancreatic protocol CT scan, offer a pancreatic protocol CT scan that includes the chest, abdomen and pelvis.\n\nOffer fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to people with localised disease on CT who will be having cancer treatment (surgery, radiotherapy or systemic therapy).\n\nIf more information is needed to decide the person's clinical management, consider one or more of the following:\n\nMRI, for suspected liver metastases\n\nendoscopic ultrasound, if more information is needed for tumour and node staging\n\nlaparoscopy with laparoscopic ultrasound, for suspected small-volume peritoneal and/or liver metastases if resectional surgery is a possibility. See recommendation\xa01.2.1 on how care should be agreed and delivered.\n\n# Psychological support\n\nThroughout the person's pancreatic cancer care pathway, specifically assess the psychological impact of:\n\nfatigue\n\npain\n\ngastrointestinal symptoms (including changes to appetite)\n\nnutrition\n\nanxiety\n\ndepression.\n\nProvide people and their family members or carers (as appropriate) with information and support to help them manage the psychological impact of pancreatic cancer on their lives and daily activities. This should be:\n\navailable on an ongoing basis\n\nrelevant to the stage of the person's condition\n\ntailored to the person's needs.\n\nFor more guidance on providing information and support, see the NICE guideline on patient experience in adult NHS services.\n\n# Pain management\n\nConsider EUS-guided or image-guided percutaneous neurolytic coeliac plexus block to manage pain for people with pancreatic cancer who:\n\nhave uncontrolled pancreatic pain or\n\nare experiencing unacceptable opioid adverse effects or\n\nare receiving escalating doses of analgesics.\n\nDo not offer thoracic splanchnicectomy to people with pancreatic cancer.\n\n# Nutritional management\n\nOffer enteric-coated pancreatin for people with unresectable pancreatic cancer.\n\nConsider enteric-coated pancreatin before and after pancreatic cancer resection.\n\nDo not use fish oils as a nutritional intervention to manage weight loss in people with unresectable pancreatic cancer.\n\nFor people who have had pancreatoduodenectomy and who have a functioning gut, offer early enteral nutrition (including oral and tube feeding) rather than parenteral nutrition.\n\nFor more guidance on nutrition support, see the NICE guideline on nutrition support in adults.\n\n# Relieving biliary and duodenal obstruction\n\n## Biliary obstruction\n\nOffer resectional surgery rather than preoperative biliary drainage to people who:\n\nhave resectable pancreatic cancer and obstructive jaundice and\n\nare well enough for the procedure and\n\nare not enrolled in a clinical trial that requires preoperative biliary drainage.\n\nDuring attempted resection for pancreatic cancer, consider surgical biliary bypass if the cancer is found to be unresectable.\n\nIf biliary drainage is needed in a person who has resectable pancreatic cancer and obstructive jaundice and is not yet fit enough for resectional surgery, offer endoscopically placed self‑expanding metal stents.\n\nFor people with suspected pancreatic cancer who may need their stent removed later on, consider endoscopically placed self-expanding fully covered metal stents.\n\nOffer endoscopically placed self-expanding metal stents rather than surgical biliary bypass to people with unresectable pancreatic cancer.\n\n## Duodenal obstruction\n\nDuring attempted resection for head of pancreas cancer, consider prophylactic gastrojejunostomy if the cancer is found to be unresectable.\n\nIf possible, relieve symptomatic duodenal obstruction caused by unresectable pancreatic cancer.\n\nWhen deciding between gastrojejunostomy and duodenal stent placement, consider gastrojejunostomy for people with a more favourable prognosis.\n\n# Managing resectable and borderline resectable pancreatic cancer\n\n## Neoadjuvant therapy\n\nOnly consider neoadjuvant therapy for people with borderline resectable pancreatic cancer as part of a clinical trial.\n\nOnly consider neoadjuvant therapy for people with resectable pancreatic cancer as part of a clinical trial.\n\n## Surgery\n\nFor people having surgery for head of pancreas cancer, consider pylorus-preserving resection if the tumour can be adequately resected.\n\nConsider standard lymphadenectomy, rather than extended lymphadenectomy for people having head of pancreas resection.\n\n## Adjuvant treatment\n\nGive people time to recover from surgery before starting adjuvant therapy. Start adjuvant therapy as soon as they are well enough to tolerate all 6\xa0cycles.\n\nOffer adjuvant gemcitabine plus capecitabine to people who have had sufficient time to recover after pancreatic cancer resection.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.\n\nConsider adjuvant gemcitabine for people who are not well enough to tolerate combination chemotherapy.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.\n\n## Follow-up for resected pancreatic cancer\n\nFor people who have had resection, offer ongoing specialist assessment and care to identify and manage any problems resulting from surgery.\n\nFor people who have new, unexplained or unresolved symptoms after treatment, provide access to specialist investigation and support services.\n\n# Managing unresectable pancreatic cancer\n\n## Locally advanced pancreatic cancer\n\nOffer systemic combination chemotherapy to people with locally advanced pancreatic cancer who are well enough to tolerate it.\n\nConsider gemcitabine for people with locally advanced pancreatic cancer who are not well enough to tolerate combination chemotherapy.\n\nWhen using chemoradiotherapy, consider capecitabine as the radiosensitiser.\n\n## Metastatic pancreatic cancer\n\nOffer FOLFIRINOX to people with metastatic pancreatic cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of\xa00 to\xa01.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.\n\nConsider gemcitabine combination therapy for people who are not well enough to tolerate FOLFIRINOX. For guidance on combination therapy with gemcitabine and nab–paclitaxel, see NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer.In February 2018, this was an off-label use of many gemcitabine combination therapies. See NICE's information on prescribing medicines.\n\nOffer gemcitabine to people who are not well enough to tolerate combination chemotherapy.\n\nConsider oxaliplatin-based chemotherapy as second-line treatment for people who have not had first-line oxaliplatin.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.\n\nConsider gemcitabine-based chemotherapy as second-line treatment for people whose cancer has progressed after first-line FOLFIRINOX.In February 2018, this was an off-label use. See NICE's information on prescribing medicines.\n\nFor recommendations on venous thromboembolism prophylaxis for people with pancreatic cancer, see the NICE guideline on reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism in over 16s.\n\n## Genomic biomarker-based treatment\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See our topic page on genomic biomarker-based cancer treatments.\n\n# Terms used in this guideline\n\n## Standard lymphadenectomy\n\nAs defined by Tol et al. (2014) Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)Tol et al. (2014) Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 156(3): 591–600", 'Context': 'Pancreatic cancer is the fifth most common cause of cancer death in the UK, with an annual incidence of nearly\xa09,600. On average, 23\xa0people die each day from the disease. The UK has one of the worst survival rates in Europe, with average life expectancy on diagnosis just 4\xa0to\xa06\xa0months and a relative survival to 1\xa0year of approximately\xa020%.\n\nOnly 3% of people survive for 5\xa0years or longer. This figure has not improved much in over 40\xa0years, and it is not yet clear how the more recent trend of increased surgery and adjuvant chemotherapy will affect survival.\n\nBecause of late diagnosis, only approximately 8% of people with pancreatic cancer are eligible for potentially curative surgery. However, people have up to a 30% chance of surviving 5\xa0years if their tumour can be surgically removed and they have adjuvant chemotherapy.\n\nThe symptoms of pancreatic cancer are non-specific. One survey found that 40% of people diagnosed with pancreatic cancer in England had visited their GP 3\xa0or more times before the diagnosis was made. Fifty per cent of people are diagnosed as an emergency in A&E. Even after diagnosis, there is evidence from the National Cancer Intelligence Network of wide variation in practice throughout England.\n\nThere are often delays in access to diagnosis and treatment (as highlighted in the NHS England Five Year Forward View), and this guideline will help to improve this.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Neoadjuvant therapy\n\nProspective randomised trials should be undertaken to compare preoperative (neoadjuvant) therapy with standard postoperative therapy in people with resectable pancreatic cancer.\n\n## Why this is important\n\nThe survival rate of pancreatic cancer after surgical resection is very low, which suggests that most patients have metastatic disease at the time of surgery. In addition, complications of surgery may stop people from having adjuvant therapy. This makes neoadjuvant therapy an attractive option. However, the evidence for neoadjuvant therapy is limited and low quality. Using neoadjuvant therapy means delaying surgery, and it is possible that during this delay pancreatic cancer will progress and become unresectable in some people, negating any benefit of neoadjuvant therapy.\n\nResearch is needed to compare neoadjuvant treatments (which might be chemotherapy, radiotherapy or both) with surgery followed by adjuvant chemotherapy. The outcomes of interest are:\n\nfeasibility of delivering neoadjuvant treatment\n\nfeasibility of randomising patients\n\nobjective response rate of neoadjuvant therapy\n\nR0 resection rate\n\nsurgical complications, length of hospital stay, mortality of surgery\n\ndelivery of planned treatment\n\ndisease-free survival and overall survival after surgery\n\nquality of life, patient experience and patient-reported outcome measures.\n\n# Cachexia interventions\n\nA cohort study followed by phase\xa02 and\xa03 studies should be undertaken in people with pancreatic cancer and cachexia or pre-cachexia, to compare cachexia assessment methods and anti-cachexia interventions with standard care.\n\n## Why this is important\n\nMost people with advanced and metastatic pancreatic cancer also have cachexia. This causes severe reductions in their quality of life and is associated with reduced overall survival. Cachexia has 3\xa0phases: pre‑cachexia, cachexia and refractory cachexia. The condition cannot be stopped by conventional nutritional support and leads to progressive functional impairment. Complete or partial reversal of cachexia would cause major improvements in quality of life, and potentially improve survival if people recover enough to have more effective cancer treatments. The outcomes of interest are:\n\nprevention or reversal of cachexia\n\noverall survival\n\nquality of life\n\npain relief\n\nlean tissue mass\n\ntolerance to treatment.\n\n# Minimally invasive pancreatectomy\n\nProspective randomised trials should be undertaken to compare the effectiveness of minimally invasive pancreatectomy or pancreatoduodenectomy (laparoscopic or robotic) with open pancreatectomy or pancreatoduodenectomy in people with pancreatic cancer.\n\n## Why this is important\n\nMinimally invasive surgery is generally considered to be more acceptable to patients than open surgery. It has been introduced successfully for several other types of cancer and has been shown to improve quality of life. However, there is not enough evidence to determine whether minimally invasive surgery improves morbidity and mortality for people with pancreatic cancer, compared with open surgery. Prospective randomised trials are therefore needed in this area. The outcomes of interest are:\n\nconversion rate to open surgery\n\nR0 resection rate\n\nlymph node yield\n\nblood loss\n\nduration of surgery\n\ncomplications\n\nneed for critical care\n\nlength of hospital stay\n\ntime to return to normal activity\n\nmortality of surgery\n\nlong-term survival after surgery\n\nquality of life, patient experience and patient-reported outcome measures.\n\n# Pain management\n\nA randomised trial should be undertaken comparing early endoscopic ultrasound-guided neurolytic coeliac plexus (EUS‑guided NCP) interventions with on‑demand EUS‑guided NCP interventions in people with unresectable pancreatic cancer.\n\n## Why this is important\n\nThere is a limited number of randomised trials in this area, and the methods used to perform NCP intervention are heterogeneous. It is not clear if early NCP intervention is superior to on‑demand NCP intervention in terms of the important outcomes for the patient and duration of effect of the procedure. On‑demand NCP intervention may benefit people with uncontrolled pain, people receiving escalating doses of analgesia, people experiencing unacceptable analgesic side effects, and others. However, people who receive early NCP intervention may not need on‑demand NCP intervention later on. Further research should clarify if the timing of the intervention confers any advantage. The outcomes of interest are:\n\nreduction in pain\n\npatient experience (including nutritional status)\n\nhealth-related quality of life\n\nadverse events\n\nanalgesic use\n\nsurvival.\n\n# Psychological support needs\n\nA qualitative study should be undertaken to evaluate information and support interventions to address psychological needs at different points in the care pathway for people with pancreatic cancer.\n\n## Why this is important\n\nPeople with pancreatic cancer often have unmet psychological support needs that impact on their quality of life. These can be related to anxiety and depression, and to the psychological impact of fatigue, pain, gastrointestinal symptoms (particularly changes to appetite) and nutritional status. There has been very little research into the information and support interventions that would meet these needs. Research would help identify effective information and support interventions that would improve quality of life for people with pancreatic cancer and their family members or carers. Outcomes of interest are:\n\nquality of life\n\npsychological wellbeing\n\nability to carry out normal activities\n\npatient experience and patient-reported outcome measures."}
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https://www.nice.org.uk/guidance/ng85
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This guideline covers diagnosing and managing pancreatic cancer in adults aged 18 and over. It aims to improve care by ensuring quicker and more accurate diagnosis, and by specifying the most effective treatments for people depending on how advanced their cancer is.
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38eb67602b1eb2242ad4b7abd6e765be353f465f
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nice
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Pirfenidone for treating idiopathic pulmonary fibrosis
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Pirfenidone for treating idiopathic pulmonary fibrosis
Evidence-based recommendations on pirfenidone (Esbriet) for idiopathic pulmonary fibrosis in adults.
# Recommendations
Pirfenidone is recommended as an option for treating idiopathic pulmonary fibrosis in adults only if:
the person has a forced vital capacity (FVC) between 50% and 80% predicted
the company provides pirfenidone with the discount agreed in the patient access scheme and
treatment is stopped if there is evidence of disease progression (an absolute decline of 10% or more in predicted FVC within any 12‑month period).
This recommendation is not intended to affect treatment with pirfenidone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Pirfenidone (Esbriet, Roche) is an oral immunosuppressant with anti-inflammatory and antifibrotic effects.
Marketing authorisation
Pirfenidone has a marketing authorisation in the UK for treating mild to moderate idiopathic pulmonary fibrosis in adults.
Adverse reactions
The summary of product characteristics states that the very common adverse reactions (affecting 1 in 10 or more people) associated with using pirfenidone are nausea, rash, diarrhoea, fatigue, dyspepsia, anorexia, headache and photosensitivity reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
The recommended dosage of pirfenidone is three 267‑mg capsules 3 times daily (that is, a total of 2,403 mg per day).
Price
The list price of pirfenidone is £501.92 for 63 capsules (excluding VAT; British national formulary online, accessed May 2016). This equates to a daily cost of £71.70. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pirfenidone, with the discount applied at the point of purchase or invoice. The level of discount is commercial in confidence. The Department of Health considered that the patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by Roche Products and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion
# Review objectives
The appraisal committee reviewed existing and new data on the clinical and cost effectiveness of pirfenidone, having considered evidence on the nature of idiopathic pulmonary fibrosis and the value placed on the benefits of pirfenidone by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee recognised that this appraisal reviewed NICE's previous technology appraisal guidance on pirfenidone to take into account new evidence relating to people with a forced vital capacity (FVC) above 80% predicted and to consider removing the stopping rule, that is, to no longer stop pirfenidone after an absolute decline of 10% or more in predicted FVC within any 12‑month period. The review considered the whole of pirfenidone's marketing authorisation.
# Current practice
The committee discussed the treatments for idiopathic pulmonary fibrosis in current NHS practice. The committee heard the clinical experts explain that they offer treatment with pirfenidone or nintedanib to people with an FVC between 50% and 80% predicted; this reflects NICE's previous technology appraisal guidance on pirfenidone and nintedanib for treating idiopathic pulmonary fibrosis. The clinical experts noted that they would offer best supportive care to people with an FVC above 80% predicted because NICE does not recommend pirfenidone or nintedanib in this population. The committee noted comments received during consultation that clinicians would like to offer active treatments to people with an FVC above 80% predicted. The committee concluded that the current treatment options are nintedanib and pirfenidone for people with an FVC between 50% and 80% predicted, and best supportive care for those with an FVC above 80% predicted.
The committee discussed the stopping rule included in NICE's previous technology appraisal guidance on pirfenidone and nintedanib, and how this is implemented in clinical practice. It heard from clinical experts that they follow this stopping rule, that is, stopping treatment if there is an absolute decline of 10% or more in predicted FVC within any 12‑month period, and that they often confirm the drop in percent predicted FVC with repeat testing. The committee heard from the clinical experts during the committee meeting and from the comments received during consultation about the limitations of using percent predicted FVC to assess lung function in people with idiopathic pulmonary fibrosis. It heard that the disease course varies, both between patients and over time. It heard that there were periods of relative stability interspersed with acute exacerbations, and that acute exacerbations are associated with permanently reduced lung function and an increased risk of dying. The committee noted that the clinical experts could not suggest a better way of objectively defining treatment success or failure than using percent predicted FVC. It noted the limitations of FVC but understood that, in clinical practice, the wider patient characteristics would be taken into account in interpreting percent predicted FVC.
# Comparators
The committee recalled that current NICE recommendations for treatment depend on percent predicted FVC, and discussed whether best supportive care or nintedanib were relevant comparators for pirfenidone. The committee was aware that nintedanib is recommended for a subgroup of the population, but recognised that the recommendation for nintedanib was based on the comparison of nintedanib with pirfenidone, rather than nintedanib with best supportive care. The committee therefore agreed it was more appropriate to compare pirfenidone with best supportive care and it did not consider the comparison with nintedanib further.
# Clinical effectiveness
The committee considered the clinical evidence presented by the company. It noted that the evidence came from 4 randomised double-blind placebo-controlled phase III trials (CAPACITY 1, CAPACITY 2, ASCEND and SP3) and other observational data:
The committee was aware that the results of SP3 and the CAPACITY trials were considered during NICE's previous technology appraisal of pirfenidone. It recognised that the new data presented by the company came from ASCEND, RECAP (an open label extension follow-up study of the CAPACITY trials) and observational data for best supportive care (the 'INOVA' registry).The committee noted that the primary end point in both ASCEND and the CAPACITY trials was the change in percent predicted FVC from baseline, and that this was after 52 weeks in ASCEND and after 72 weeks in CAPACITY 1 and 2.
The committee was aware that the company and the evidence review group (ERG) included data from ASCEND in their network meta-analyses with data from CAPACITY 1, CAPACITY 2 and SP3. It concluded that the trials included in the ERG's meta-analysis were appropriate.
The committee noted that the inclusion criteria of the trials differed with respect to percent predicted FVC: the CAPACITY trials recruited patients with an FVC above 50% predicted and without an upper limit. ASCEND recruited patients with an FVC between 50% and 90% predicted, and the SP3 trial did not specify the range, but reported an average baseline FVC of 77% predicted. The committee understood that most of the data presented by the company (92% of patients in ASCEND and the CAPACITY trials) came from patients with an FVC up to 90% predicted. The committee concluded that the trial evidence was most generalisable to people with an FVC of up to 90% predicted.
The committee discussed whether the populations in the pirfenidone trials reflected people with idiopathic pulmonary fibrosis in current NHS practice. It understood that only 25% of patients across ASCEND and the CAPACITY trials had an FVC above 80% predicted, compared with 36% to 41% in UK practice (as a proportion of people with an FVC above 50% predicted; estimates are based on data from the British Thoracic Society idiopathic pulmonary fibrosis registry and comments from the company at the committee meeting). The committee concluded that people with an FVC above 80% predicted were under-represented in the clinical trials.
The committee discussed the clinical effectiveness of pirfenidone. It was aware that in NICE's previous technology appraisal for pirfenidone the committee concluded that 'pirfenidone seemed to have a modest but measurable effect on slowing the decline in lung function'. The committee acknowledged that the company had provided new long-term and mature data in this appraisal, mainly relating to mortality, for patients with an FVC up to 90% predicted. The committee considered the results of the ERG's meta-analyses. It agreed that pirfenidone reduced disease progression compared with placebo. It also agreed that there was evidence that it may reduce mortality. It concluded that it had not seen anything to contradict the conclusion in NICE's previous technology appraisal. The committee concluded that pirfenidone is effective in people with an FVC between 50% and 90% predicted.
The committee discussed whether the effect of pirfenidone on slowing the decline in lung function may differ according to a person's baseline percent predicted FVC. It considered the evidence for people with an FVC above or below 80% predicted, noting that:
There was a smaller estimate of treatment effect at week 52 in the FVC above 80% predicted subgroup than in the FVC 80% predicted or less subgroup in each trial (between subgroups, these difference were not statistically significant).
In the CAPACITY 1 trial, the treatment effect at week 52 was no longer statistically significant when considering the FVC above 80% predicted group alone.
The results of the treatment-by-subgroup interaction tests from the company's analysis of covariance (ANCOVA) showed that there was no statistically significant difference in results between people with an FVC above 80% predicted at baseline and people with an FVC of 80% predicted or less (the p value varied between 0.20 and 0.78 depending on the clinical trial).
In an analysis using FVC data from only the CAPACITY trials (measured at week 72), the company's treatment-by-subgroup interaction test showed that there was no statistically significant difference in results between the 3 pre-defined subgroups in CAPACITY: predicted FVC at baseline of more than 80%; between 70% and 80%; and lower than 70% (p=0.35). The committee was aware of the company's opinion that the analysis with 3 subgroups was not as robust as the ANCOVA method.The committee observed that none of the studies were designed to determine the effectiveness of pirfenidone in people with FVC above 80% predicted, or to compare this group with those with an FVC between 50% and 80% predicted. The committee acknowledged the practical difficulties in designing studies to detect differences in outcomes between subgroups. The committee agreed to accept that pirfenidone has the same relative effectiveness in people with an FVC above 80% predicted and in people with an FVC of 80% predicted or less.
## Evidence on the stopping rule
The committee discussed whether or not to keep the stopping rule (stopping pirfenidone after disease progression, defined by an absolute decline of 10% or more in predicted FVC within any 12‑month period). It recalled that clinicians follow the rule in clinical practice (see section 4.3), however, it noted the consultation comments from professional groups that clinicians would like to continue treating people after disease progression because it may still be beneficial. The committee agreed that not all treatments are universally effective, and that stopping rules can improve the cost effectiveness of a technology by stopping treatment when it is no longer considered clinically effective.
The committee considered the company's post-hoc subgroup analyses of patients who continued pirfenidone after a decline in predicted FVC of 10% or more within any 12‑month period. These data showed that fewer people in the pirfenidone group (1 patient out of 24) experienced a further 10% decline in predicted FVC compared with those in the placebo group (15 patients out of 60; p=0.032). The committee was concerned with the results of this analysis because:
the sample size of 84 patients was small, meaning that decisions based on this subgroup are uncertain
the analysis broke the randomisation of the clinical trials
to test the hypothesis that people benefit from continuing pirfenidone treatment after disease progression, it would be more informative to compare people who do not stop pirfenidone after disease progression with people who do stop it after disease progression, rather than to compare people continuing pirfenidone after disease progression with people who had been randomised to placebo at baseline.The committee concluded that the company's evidence did not conclusively show that people continue to benefit from pirfenidone after disease progression. However, the committee recognised the comments from clinical experts that some patients may benefit after disease progression. It concluded it was appropriate to consider cost-effectiveness analyses with and without the stopping rule.
# Cost effectiveness
The committee considered the company's partitioned survival model, which had 3 mutually exclusive health states: progression-free, progressed and dead. The company's model assumed that the effectiveness of pirfenidone relative to best supportive care was the same regardless of a person's baseline percent predicted FVC. The committee considered this to be appropriate based on the data currently available (see section 4.9). The committee heard from the ERG that the company's model did not capture the progressive nature of idiopathic pulmonary fibrosis. The committee noted that the company, in choosing the model structure, made several clinically implausible assumptions. For example:
No relationship between time on treatment, time to disease progression (defined as a 10% decline in predicted FVC, a decline in 6‑minute walking distance of 50 metres or more, or death) and mortality. The committee agreed that these were likely to be linked, so it was not appropriate to model them independently.
Acute exacerbations were not explicitly connected to disease progression and mortality. Clinical experts advised that exacerbations had a substantial effect on quality of life and mortality. The committee agreed that the model may not fully represent the impact of idiopathic pulmonary fibrosis on patients.The committee had serious concerns about the company's model and understood that the ERG could address only some of the issues in its exploratory analyses. The committee noted that, in its response to the appraisal consultation document, the company did not provide new clinical evidence but did provide revised analyses with:
New parametric survival curves for mortality (see section 4.13 for discussion about the survival curves).
New assumptions around how long the benefits of treatment last (see section 4.14 for discussion about the time the benefits of treatment last).
A new subgroup with an FVC between 50% and 90% predicted.In its response to consultation, the company suggested that it based its model on mortality because of the data available and, in its view, increasing complexity would not improve the fit to available data on costs and utilities. The committee acknowledged the limitations in the data and concluded that the model could be used for its decision-making.
The committee discussed how the company estimated the potential long-term mortality benefit with pirfenidone over a patient's lifetime by extrapolating from relatively short trials. It noted that the choice of mortality parametric curve was a key driver of the cost-effectiveness results, and that the company estimated long-term mortality based on data from ASCEND, CAPACITY 1 CAPACITY 2 and RECAP. The committee agreed that this was appropriate. It noted that the company had modelled mortality using the Weibull distribution, and that the ERG had used the Gompertz distribution.
It heard from the ERG that, although the Weibull distribution fitted the observed data well, it predicted a lower probability of death for older people than in the general UK population; the ERG did not consider this to be clinically plausible.
The ERG considered that the Gompertz distribution also fitted the data well but provided more clinically plausible long-term estimates for mortality beyond the observed data.
In its response to the appraisal consultation document, the company adjusted the annual probability of death by age distribution in the UK population to show that the Weibull distribution did not predict a lower probability of death until the age of around 90 years. The company suggested that registry data (that is, the INOVA registry of people with idiopathic pulmonary fibrosis on best supportive care in the United States) supported the estimates of mortality using the Weibull rather than Gompertz distribution.
The ERG accepted that the adjustment addressed one of their concerns, but remained concerned that INOVA had a high proportion of censoring after 10 years (that is, people for whom there were no additional data).
The ERG acknowledged that there was uncertainty associated with the Gompertz distribution because it did not fit the data as well as the Weibull distribution, and advised the committee that both curves were plausible.
The committee agreed that the risk of death in people with idiopathic pulmonary fibrosis was likely to increase with length of time with the disease relative to the general population. With both the Gompertz and Weibull distributions, the risk of death increased with disease duration. The committee observed that, with the Weibull distribution, the risk of death for people with idiopathic pulmonary fibrosis increased more slowly than the risk of death over time in the general population. With the Gompertz distribution, the risk of death increased more rapidly with disease duration, above the risk of death over time in the general population. The committee agreed that the true risk of death of people with idiopathic pulmonary fibrosis might lie between the Weibull and Gompertz distributions, but closer to the Gompertz distribution.
The committee also considered the company's new analysis that used a weighted parametric survival curve based on a statistical test of model fit (that is, the Akaike information criterion). The committee agreed with the ERG that it did not consider the approach credible because it included curves (such as a log-logistic distribution) with limited clinical plausibility, and agreed that it was not appropriate.On balance, the committee acknowledged the company's different opinion on the choice of parametric survival curve and agreed to take the Weibull and Gompertz curves into account in its decision-making. However, the committee concluded that it was more plausible to use the Gompertz distribution to estimate mortality.
The committee discussed the company's modelling assumption that the mortality benefit of pirfenidone compared with best supportive care remains constant over a person's lifetime. It appreciated that the randomised trials were too short (that is, either 52 or 72 weeks) to provide evidence to support this assumption. The committee also noted that, although follow-up data for pirfenidone were collected for over 8 years in RECAP, there was no best supportive care group in the study and so no long-term relative effectiveness could be estimated from the study. The committee was also aware that the model was very sensitive to the assumptions around duration of treatment benefit. It heard from 1 clinical expert that the treatment benefit of pirfenidone was likely to be constant over a person's lifetime. The committee did not agree that this was plausible, based on advice from the ERG that the trials showed a reduction in treatment effect over time for mortality. In its response to the appraisal consultation document, the company used data from INOVA to support its argument that the treatment effect lasts for at least 8 years. The company provided a Kaplan–Meier plot and log-cumulative hazard plot for mortality based on data from the trials and INOVA. The committee noted that the log-cumulative hazard plots for pirfenidone and best supportive care were not parallel after 5 years. It determined that, although there was some maintained treatment effect, it was not constant. The committee concluded that the evidence did not justify assuming a constant mortality benefit for 8 years. It further concluded that it was reasonable to assume a constant benefit up to 5 years.
The committee discussed the population in the model. It recognised that the model was based on the pirfenidone clinical trials and therefore included fewer people with an FVC above 80% predicted than are seen in NHS clinical practice (see section 4.7). The committee considered whether the incremental cost-effectiveness ratios (ICERs) would be affected if the modelled population included a higher proportion of people with an FVC above 80% predicted, to better reflect NHS practice. It understood from the analyses presented that there was a consistent trend for higher ICERs in the population with an FVC above 80% predicted than in the population with an FVC between 50% and 80% predicted. For example, when assuming a 5‑year treatment effect and including the stopping rule, the ICER for pirfenidone compared with best supportive care was between:
£24,933 (Weibull) and £27,780 (Gompertz) per quality-adjusted life year (QALY) gained for people with an FVC between 50% and 80% predicted
£32,643 (Weibull) and £38,687 (Gompertz) per QALY gained for people with an FVC above 80% predicted.Therefore, the committee expected that the ICERs for the full population (specified in the marketing authorisation for pirfenidone) would be higher if the model included a higher proportion of people with an FVC above 80% predicted. The committee concluded that the current cost-effectiveness estimates for the full population are likely to be underestimated.
The committee discussed whether the company's model appropriately incorporated the treatment stopping rule. The ERG explained that ICERs including the stopping rule for pirfenidone would likely be biased in favour of pirfenidone when compared with best supportive care. This was because, in the model, the stopping rule reduced pirfenidone costs without affecting treatment outcomes. The committee had concluded that analyses including a stopping rule for pirfenidone would underestimate the ICER because of the model structure. However, at its third meeting, the committee heard from the company that analyses including a stopping rule would overestimate the ICERs in scenarios where the mortality benefit of pirfenidone is not constant over a person's lifetime. The company had not submitted any evidence to support its statement and therefore the committee could not draw a firm conclusion about whether reducing the duration of treatment benefit under- or overestimated the ICERs with a stopping rule. The committee concluded that all ICERs including the stopping rule for pirfenidone were associated with uncertainty.
# Cost-effectiveness results and conclusions
The committee considered the cost effectiveness of pirfenidone compared with best supportive care. The committee noted that, for the population specified in the marketing authorisation (people with 'mild to moderate' idiopathic pulmonary fibrosis, that is, people with an FVC above 50% predicted), the ICER (including the stopping rule) that most closely matched the committee's preferred assumptions was between £25,706 (Weibull) and £28,870 (Gompertz) per QALY gained when assuming a 5‑year treatment effect. The committee agreed that the estimate using the Gompertz survival curve was more plausible (see section 4.13). The committee then discussed the cost-effectiveness estimates for the group with an FVC between 50% and 90% predicted, because most of the data presented by the company was from this group (see section 4.6), noting that the ICERs were similar to those for the full population.
The committee recognised that, when above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources must take account of the degree of certainty around the ICER, the innovative nature of the technology and whether its benefits have been adequately captured in the model. The committee recalled that all of the ICERs were uncertain, noting that:
The modelled population did not include as many people with an FVC above 80% predicted as expected in NHS practice (see section 4.7 and section 4.15), and accounting for this may increase the ICER.
The impact of the stopping rule on the ICER was uncertain (see section 4.16).
There was still uncertainty about how long the survival benefit of pirfenidone would last; it could be less than 5 years (see section 4.14). The committee understood that the model was sensitive to this assumption, noting that the ICERs increased substantially, to around £58,000 per QALY gained, when assuming a 2-year treatment effect (including the stopping rule).The committee noted the company's suggestion that pirfenidone is associated with health-related benefits that cannot be adequately captured in the QALY calculation. These benefits include: a reduction in breathlessness; improved patient choice based on a different adverse event profile; improved NHS capacity by reducing inpatient stays attributed to acute exacerbations; and the effect on people of working age. The committee acknowledged that, although these aspects were important to people with idiopathic pulmonary fibrosis, it did not consider that any sizeable health-related benefits had been excluded from the economic model. Because of this, and the uncertainties in the ICERs, the committee concluded that pirfenidone could not be considered a cost-effective use of NHS resources for adults with mild to moderate idiopathic pulmonary fibrosis. It was aware that removing the stopping rule increased the ICERs and therefore did not consider estimates without the stopping rule for this population.
The committee then discussed whether there was a subgroup for whom pirfenidone could be recommended. The committee was aware that pirfenidone was associated with a lower ICER in populations with a lower FVC (see section 4.15). It recalled that treatment decisions based on percent predicted FVC are currently implemented in clinical practice (see section 4.2). The committee was aware that, in NICE's previous technology appraisal guidance, pirfenidone was regarded as cost effective for people with an FVC between 50% and 80% predicted if the company provided pirfenidone with the discount agreed in the patient access scheme. It noted that the company had presented analyses for this group. The ICER (including the stopping rule) that most closely matched the committee's preferred assumptions for pirfenidone compared with best supportive care was between £24,933 (Weibull) and £27,780 (Gompertz) per QALY gained when assuming a 5-year treatment effect. The committee agreed that these ICERs were also subject to uncertainty relating to the stopping rule and duration of survival benefit, and recalled its conclusion that no sizeable health-related benefits had been excluded from the economic model (see section 4.18). However, the committee understood that pirfenidone was considered a reasonably innovative treatment at the time of the previous appraisal because it was the first drug to improve outcomes in idiopathic pulmonary fibrosis without the long-term side effects of immunosuppressants. It agreed that it had not seen any clinical evidence contradictory to that considered in NICE's previous technology appraisal on pirfenidone (see section 4.8), and therefore it was not minded to change this recommendation and withdraw an existing treatment option for people with moderate disease, despite the relatively high ICERs. The committee concluded that the recommendations in NICE's previous technology appraisal guidance on pirfenidone remained appropriate for people with idiopathic pulmonary fibrosis with an FVC between 50% and 80% predicted.
The committee considered the cost effectiveness of removing the requirement to stop treatment if a person's predicted FVC drops by an absolute value of 10% in the population with an FVC between 50% and 80% predicted. The committee was aware that removing the stopping rule increased the ICERs. Having concluded that the ICER for pirfenidone in this group was high, and associated with uncertainty, when a stopping rule is included (see section 4.19), the committee concluded that pirfenidone could not be considered cost effective without the stopping rule.
# Potential equality issues
The committee noted the potential equality issue raised by consultees that restricting treatment based on percent predicted FVC could discriminate against:
minority ethnic groups, particularly people of south Asian family origin
disabled people who have difficulty standing straight because FVC is expressed as a percentage of the predicted normal value for a person of the same height
-lder people because the reference tables are derived from populations under the age of 70 years, but the average age of people with idiopathic pulmonary fibrosis is 72 years.The committee discussed these issues with the clinical experts, noting that:
The Global Lung Initiative has introduced equations to predict FVC values in minority ethnic groups and, when these equations were used, FVC values for these groups were comparable to the FVC values of people in clinical trials. Thus, when using the newer equations, people would not be denied treatment because of their ethnicity.
For people who cannot stand straight, their armspan (which estimates their height) can be used to calculate percent predicted FVC. Thus, when using this measure people would not be denied treatment because of their disability.
According to clinical experts, it is difficult to compare the predicted FVC values of older people with the FVC values of people in clinical trials because older people show a wide range of predicted FVC.The committee recognised the limitations of FVC but understood that, in clinical practice, wider patient characteristics would be taken into account when interpreting percent predicted FVC. It concluded that its recommendations did not discriminate against any groups of people protected by the Equality Act.
# The Pharmaceutical Price Regulation Scheme
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014 and, in particular, the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Summary of appraisal committee's key conclusions
TA504
Appraisal title: Pirfenidone for treating idiopathic pulmonary fibrosis
Section
Key conclusion
Pirfenidone continues to be recommended as an option for treating idiopathic pulmonary fibrosis in adults only if:
the person has a forced vital capacity (FVC) between 50% and 80% predicted
the company provides pirfenidone with the discount agreed in the patient access scheme and
treatment is stopped if there is evidence of disease progression (an absolute decline of 10% or more in predicted FVC within any 12-month period).
Pirfenidone could not be considered a cost-effective use of NHS resources for the population specified in the marketing authorisation (that is, adults with mild to moderate idiopathic pulmonary fibrosis) because the most plausible incremental cost-effectiveness ratio (ICER) for pirfenidone (including the stopping rule), of those presented, lay somewhere between about £25,700 and £28,900 per quality-adjusted life years (QALY) gained compared with best supportive care, and was associated with uncertainties that had the potential to substantially increase the ICER.
For people with an FVC between 50% and 80% predicted, the most plausible ICER (including the stopping rule) was also above £20,000 per QALY gained, and associated with uncertainties that had the potential to substantially increase the ICER. However, the committee agreed that it had not seen any clinical evidence to contradict the evidence considered in NICE's previous technology appraisal on pirfenidone so continued to recommend pirfenidone for this population.
to 4.20
Current practice
Clinical need of patients, including the availability of alternative treatments
The clinical experts noted that they would offer best supportive care to people with an FVC above 80% predicted. The committee concluded that the current treatment options are nintedanib and pirfenidone for people with an FVC between 50% and 80% predicted, and best supportive care for those with an FVC above 80% predicted.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee understood that pirfenidone was considered a reasonably innovative treatment at the time of the previous appraisal, but did not consider that any sizeable health-related benefits had been excluded from the economic model.
What is the position of the treatment in the pathway of care for the condition?
Pirfenidone has a marketing authorisation in the UK for treating mild to moderate idiopathic pulmonary fibrosis in adults.
Adverse reactions
The very common adverse reactions associated with using pirfenidone are nausea, rash, diarrhoea, fatigue, dyspepsia, anorexia, headache and photosensitivity reactions.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that the evidence came from 4 randomised double-blind placebo-controlled phase III trials (CAPACITY 1, CAPACITY 2, ASCEND and SP3) and other observational data.
Relevance to general clinical practice in the NHS
The committee concluded that people with an FVC above 80% predicted were under-represented in the clinical trials and that the trial evidence was most generalisable to people with an FVC of up to 90% predicted.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee agreed that pirfenidone reduced disease progression, and may reduce mortality, compared with placebo. The committee did not see anything to contradict the conclusion in NICE's previous technology appraisal and concluded that pirfenidone is effective in people with an FVC between 50% and 90% predicted.
How has the new clinical evidence that has emerged since the previous appraisal (TA282) influenced the current recommendations?
The changes to NICE's technology appraisal guidance 282 proposed by the company in light of new clinical data are not recommended, specifically:
removing the recommendation to stop pirfenidone if the disease progresses
expanding the population to include people with an FVC above 80% predicted.
Evidence for cost effectiveness
Availability and nature of evidence
The company provided a partitioned survival model which had 3 mutually exclusive health states: progression-free, progressed and dead.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee acknowledged the limitations in the data and concluded that the model could be used for its decision-making. The committee noted that there was no relationship between time on treatment, time to disease progression and mortality and that acute exacerbations were not connected to disease progression and mortality. There was uncertainty about how long the survival benefit of pirfenidone would last. All ICERs that included the stopping rule for pirfenidone were associated with uncertainty.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee did not consider that any sizeable health-related benefits had been excluded from the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
The committee concluded that the recommendations in NICE's previous technology appraisal guidance on pirfenidone (TA282) remained appropriate for people with idiopathic pulmonary fibrosis with an FVC between 50% and 80% predicted, even though the most plausible ICER for pirfenidone in this subgroup was relatively high.
What are the key drivers of cost effectiveness?
The estimate of long-term mortality benefit with pirfenidone over a patient's lifetime by extrapolating from relatively short trials
Whether or not pirfenidone is stopped after disease progression (the 'stopping rule').
to 4.14, 4.16
Most likely cost-effectiveness estimate (given as an ICER)
The most plausible ICER, of those presented, for pirfenidone compared with best supportive care in people with an FVC above 50% predicted ranged from £25,706 (Weibull) to £28,870 (Gompertz) per QALY gained when assuming a 5-year treatment effect (including the stopping rule). This was associated with uncertainties that had the potential to substantially increase the ICER.
For people with an FVC between 50% and 80% predicted, the most plausible ICER (including the stopping rule) was between £24,933 (Weibull) to £27,780 (Gompertz) per QALY gained, and was also associated with uncertainties that had the potential to substantially increase the ICER.
to 4.19
How has the new cost-effectiveness evidence that has emerged since the previous appraisal (TA282) influenced the current recommendations?
The committee concluded that the recommendations in NICE's previous technology appraisal guidance on pirfenidone (TA282) remained appropriate for people with idiopathic pulmonary fibrosis with an FVC between 50% and 80% predicted. The committee concluded that pirfenidone was not cost effective without the stopping rule in this group.
Additional factors taken into account
Patient access schemes (PPRS)
The committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee noted the potential equality issue raised by consultees, that restricting treatment based on percent predicted FVC could discriminate against minority ethnic people, older people and disabled people. The committee discussed these issues with the clinical experts and concluded that its recommendations did not discriminate against any groups of people protected by the Equality Act.
|
{'Recommendations': 'Pirfenidone is recommended as an option for treating idiopathic pulmonary fibrosis in adults only if:\n\nthe person has a forced vital capacity (FVC) between\xa050% and\xa080% predicted\n\nthe company provides pirfenidone with the discount agreed in the patient access scheme and\n\ntreatment is stopped if there is evidence of disease progression (an absolute decline of 10% or more in predicted FVC within any 12‑month period).\n\nThis recommendation is not intended to affect treatment with pirfenidone that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': 'Description of the technology\n\nPirfenidone (Esbriet, Roche) is an oral immunosuppressant with anti-inflammatory and antifibrotic effects.\n\nMarketing authorisation\n\nPirfenidone has a marketing authorisation in the UK for treating mild to moderate idiopathic pulmonary fibrosis in adults.\n\nAdverse reactions\n\nThe summary of product characteristics states that the very common adverse reactions (affecting 1\xa0in\xa010\xa0or more people) associated with using pirfenidone are nausea, rash, diarrhoea, fatigue, dyspepsia, anorexia, headache and photosensitivity reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dosage of pirfenidone is three 267‑mg capsules 3\xa0times daily (that is, a total of 2,403\xa0mg per day).\n\nPrice\n\nThe list price of pirfenidone is £501.92 for 63\xa0capsules (excluding VAT; British national formulary online, accessed May\xa02016). This equates to a daily cost of £71.70. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pirfenidone, with the discount applied at the point of purchase or invoice. The level of discount is commercial in confidence. The Department of Health considered that the patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Roche Products and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "# Review objectives\n\nThe appraisal committee reviewed existing and new data on the clinical and cost effectiveness of pirfenidone, having considered evidence on the nature of idiopathic pulmonary fibrosis and the value placed on the benefits of pirfenidone by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. The committee recognised that this appraisal reviewed NICE's previous technology appraisal guidance on pirfenidone to take into account new evidence relating to people with a forced vital capacity (FVC) above 80% predicted and to consider removing the stopping rule, that is, to no longer stop pirfenidone after an absolute decline of 10% or more in predicted FVC within any 12‑month period. The review considered the whole of pirfenidone's marketing authorisation.\n\n# Current practice\n\nThe committee discussed the treatments for idiopathic pulmonary fibrosis in current NHS practice. The committee heard the clinical experts explain that they offer treatment with pirfenidone or nintedanib to people with an FVC between 50% and 80% predicted; this reflects NICE's previous technology appraisal guidance on pirfenidone and nintedanib for treating idiopathic pulmonary fibrosis. The clinical experts noted that they would offer best supportive care to people with an FVC above 80% predicted because NICE does not recommend pirfenidone or nintedanib in this population. The committee noted comments received during consultation that clinicians would like to offer active treatments to people with an FVC above 80% predicted. The committee concluded that the current treatment options are nintedanib and pirfenidone for people with an FVC between 50% and 80% predicted, and best supportive care for those with an FVC above 80% predicted.\n\nThe committee discussed the stopping rule included in NICE's previous technology appraisal guidance on pirfenidone and nintedanib, and how this is implemented in clinical practice. It heard from clinical experts that they follow this stopping rule, that is, stopping treatment if there is an absolute decline of\xa010% or more in predicted FVC within any 12‑month period, and that they often confirm the drop in percent predicted FVC with repeat testing. The committee heard from the clinical experts during the committee meeting and from the comments received during consultation about the limitations of using percent predicted FVC to assess lung function in people with idiopathic pulmonary fibrosis. It heard that the disease course varies, both between patients and over time. It heard that there were periods of relative stability interspersed with acute exacerbations, and that acute exacerbations are associated with permanently reduced lung function and an increased risk of dying. The committee noted that the clinical experts could not suggest a better way of objectively defining treatment success or failure than using percent predicted FVC. It noted the limitations of FVC but understood that, in clinical practice, the wider patient characteristics would be taken into account in interpreting percent predicted FVC.\n\n# Comparators\n\nThe committee recalled that current NICE recommendations for treatment depend on percent predicted FVC, and discussed whether best supportive care or nintedanib were relevant comparators for pirfenidone. The committee was aware that nintedanib is recommended for a subgroup of the population, but recognised that the recommendation for nintedanib was based on the comparison of nintedanib with pirfenidone, rather than nintedanib with best supportive care. The committee therefore agreed it was more appropriate to compare pirfenidone with best supportive care and it did not consider the comparison with nintedanib further.\n\n# Clinical effectiveness\n\nThe committee considered the clinical evidence presented by the company. It noted that the evidence came from 4\xa0randomised double-blind placebo-controlled phase\xa0III trials (CAPACITY\xa01, CAPACITY\xa02, ASCEND and SP3) and other observational data:\n\nThe committee was aware that the results of SP3 and the CAPACITY trials were considered during NICE's previous technology appraisal of pirfenidone. It recognised that the new data presented by the company came from ASCEND, RECAP (an open label extension follow-up study of the CAPACITY trials) and observational data for best supportive care (the 'INOVA' registry).The committee noted that the primary end point in both ASCEND and the CAPACITY trials was the change in percent predicted FVC from baseline, and that this was after 52\xa0weeks in ASCEND and after 72\xa0weeks in CAPACITY\xa01 and\xa02.\n\nThe committee was aware that the company and the evidence review group (ERG) included data from ASCEND in their network meta-analyses with data from CAPACITY\xa01, CAPACITY\xa02 and SP3. It concluded that the trials included in the ERG's meta-analysis were appropriate.\n\nThe committee noted that the inclusion criteria of the trials differed with respect to percent predicted FVC: the CAPACITY trials recruited patients with an FVC above 50% predicted and without an upper limit. ASCEND recruited patients with an FVC between 50% and 90% predicted, and the SP3 trial did not specify the range, but reported an average baseline FVC of 77% predicted. The committee understood that most of the data presented by the company (92% of patients in ASCEND and the CAPACITY trials) came from patients with an FVC up to 90% predicted. The committee concluded that the trial evidence was most generalisable to people with an FVC of up to 90% predicted.\n\nThe committee discussed whether the populations in the pirfenidone trials reflected people with idiopathic pulmonary fibrosis in current NHS practice. It understood that only 25% of patients across ASCEND and the CAPACITY trials had an FVC above 80% predicted, compared with 36% to 41% in UK practice (as a proportion of people with an FVC above 50% predicted; estimates are based on data from the British Thoracic Society idiopathic pulmonary fibrosis registry and comments from the company at the committee meeting). The committee concluded that people with an FVC above 80% predicted were under-represented in the clinical trials.\n\nThe committee discussed the clinical effectiveness of pirfenidone. It was aware that in NICE's previous technology appraisal for pirfenidone the committee concluded that 'pirfenidone seemed to have a modest but measurable effect on slowing the decline in lung function'. The committee acknowledged that the company had provided new long-term and mature data in this appraisal, mainly relating to mortality, for patients with an FVC up to 90% predicted. The committee considered the results of the ERG's meta-analyses. It agreed that pirfenidone reduced disease progression compared with placebo. It also agreed that there was evidence that it may reduce mortality. It concluded that it had not seen anything to contradict the conclusion in NICE's previous technology appraisal. The committee concluded that pirfenidone is effective in people with an FVC between 50% and 90% predicted.\n\nThe committee discussed whether the effect of pirfenidone on slowing the decline in lung function may differ according to a person's baseline percent predicted FVC. It considered the evidence for people with an FVC above or below 80% predicted, noting that:\n\nThere was a smaller estimate of treatment effect at week\xa052 in the FVC above 80% predicted subgroup than in the FVC 80% predicted or less subgroup in each trial (between subgroups, these difference were not statistically significant).\n\nIn the CAPACITY\xa01 trial, the treatment effect at week\xa052 was no longer statistically significant when considering the FVC above 80% predicted group alone.\n\nThe results of the treatment-by-subgroup interaction tests from the company's analysis of covariance (ANCOVA) showed that there was no statistically significant difference in results between people with an FVC above 80% predicted at baseline and people with an FVC of 80% predicted or less (the p\xa0value varied between 0.20 and 0.78 depending on the clinical trial).\n\nIn an analysis using FVC data from only the CAPACITY trials (measured at week\xa072), the company's treatment-by-subgroup interaction test showed that there was no statistically significant difference in results between the 3\xa0pre-defined subgroups in CAPACITY: predicted FVC at baseline of more than 80%; between 70% and 80%; and lower than 70% (p=0.35). The committee was aware of the company's opinion that the analysis with 3\xa0subgroups was not as robust as the ANCOVA method.The committee observed that none of the studies were designed to determine the effectiveness of pirfenidone in people with FVC above 80% predicted, or to compare this group with those with an FVC between 50% and 80% predicted. The committee acknowledged the practical difficulties in designing studies to detect differences in outcomes between subgroups. The committee agreed to accept that pirfenidone has the same relative effectiveness in people with an FVC above 80% predicted and in people with an FVC of 80% predicted or less.\n\n## Evidence on the stopping rule\n\nThe committee discussed whether or not to keep the stopping rule (stopping pirfenidone after disease progression, defined by an absolute decline of\xa010% or more in predicted FVC within any 12‑month period). It recalled that clinicians follow the rule in clinical practice (see section\xa04.3), however, it noted the consultation comments from professional groups that clinicians would like to continue treating people after disease progression because it may still be beneficial. The committee agreed that not all treatments are universally effective, and that stopping rules can improve the cost effectiveness of a technology by stopping treatment when it is no longer considered clinically effective.\n\nThe committee considered the company's post-hoc subgroup analyses of patients who continued pirfenidone after a decline in predicted FVC of 10% or more within any 12‑month period. These data showed that fewer people in the pirfenidone group (1\xa0patient out of\xa024) experienced a further 10% decline in predicted FVC compared with those in the placebo group (15\xa0patients out of\xa060; p=0.032). The committee was concerned with the results of this analysis because:\n\nthe sample size of 84\xa0patients was small, meaning that decisions based on this subgroup are uncertain\n\nthe analysis broke the randomisation of the clinical trials\n\nto test the hypothesis that people benefit from continuing pirfenidone treatment after disease progression, it would be more informative to compare people who do not stop pirfenidone after disease progression with people who do stop it after disease progression, rather than to compare people continuing pirfenidone after disease progression with people who had been randomised to placebo at baseline.The committee concluded that the company's evidence did not conclusively show that people continue to benefit from pirfenidone after disease progression. However, the committee recognised the comments from clinical experts that some patients may benefit after disease progression. It concluded it was appropriate to consider cost-effectiveness analyses with and without the stopping rule.\n\n# Cost effectiveness\n\nThe committee considered the company's partitioned survival model, which had 3\xa0mutually exclusive health states: progression-free, progressed and dead. The company's model assumed that the effectiveness of pirfenidone relative to best supportive care was the same regardless of a person's baseline percent predicted FVC. The committee considered this to be appropriate based on the data currently available (see section\xa04.9). The committee heard from the ERG that the company's model did not capture the progressive nature of idiopathic pulmonary fibrosis. The committee noted that the company, in choosing the model structure, made several clinically implausible assumptions. For example:\n\nNo relationship between time on treatment, time to disease progression (defined as a 10% decline in predicted FVC, a decline in 6‑minute walking distance of 50\xa0metres or more, or death) and mortality. The committee agreed that these were likely to be linked, so it was not appropriate to model them independently.\n\nAcute exacerbations were not explicitly connected to disease progression and mortality. Clinical experts advised that exacerbations had a substantial effect on quality of life and mortality. The committee agreed that the model may not fully represent the impact of idiopathic pulmonary fibrosis on patients.The committee had serious concerns about the company's model and understood that the ERG could address only some of the issues in its exploratory analyses. The committee noted that, in its response to the appraisal consultation document, the company did not provide new clinical evidence but did provide revised analyses with:\n\nNew parametric survival curves for mortality (see section\xa04.13 for discussion about the survival curves).\n\nNew assumptions around how long the benefits of treatment last (see section\xa04.14 for discussion about the time the benefits of treatment last).\n\nA new subgroup with an FVC between 50% and 90% predicted.In its response to consultation, the company suggested that it based its model on mortality because of the data available and, in its view, increasing complexity would not improve the fit to available data on costs and utilities. The committee acknowledged the limitations in the data and concluded that the model could be used for its decision-making.\n\nThe committee discussed how the company estimated the potential long-term mortality benefit with pirfenidone over a patient's lifetime by extrapolating from relatively short trials. It noted that the choice of mortality parametric curve was a key driver of the cost-effectiveness results, and that the company estimated long-term mortality based on data from ASCEND, CAPACITY\xa01 CAPACITY\xa02 and RECAP. The committee agreed that this was appropriate. It noted that the company had modelled mortality using the Weibull distribution, and that the ERG had used the Gompertz distribution.\n\nIt heard from the ERG that, although the Weibull distribution fitted the observed data well, it predicted a lower probability of death for older people than in the general UK population; the ERG did not consider this to be clinically plausible.\n\nThe ERG considered that the Gompertz distribution also fitted the data well but provided more clinically plausible long-term estimates for mortality beyond the observed data.\n\nIn its response to the appraisal consultation document, the company adjusted the annual probability of death by age distribution in the UK population to show that the Weibull distribution did not predict a lower probability of death until the age of around 90\xa0years. The company suggested that registry data (that is, the INOVA registry of people with idiopathic pulmonary fibrosis on best supportive care in the United States) supported the estimates of mortality using the Weibull rather than Gompertz distribution.\n\nThe ERG accepted that the adjustment addressed one of their concerns, but remained concerned that INOVA had a high proportion of censoring after 10\xa0years (that is, people for whom there were no additional data).\n\nThe ERG acknowledged that there was uncertainty associated with the Gompertz distribution because it did not fit the data as well as the Weibull distribution, and advised the committee that both curves were plausible.\n\nThe committee agreed that the risk of death in people with idiopathic pulmonary fibrosis was likely to increase with length of time with the disease relative to the general population. With both the Gompertz and Weibull distributions, the risk of death increased with disease duration. The committee observed that, with the Weibull distribution, the risk of death for people with idiopathic pulmonary fibrosis increased more slowly than the risk of death over time in the general population. With the Gompertz distribution, the risk of death increased more rapidly with disease duration, above the risk of death over time in the general population. The committee agreed that the true risk of death of people with idiopathic pulmonary fibrosis might lie between the Weibull and Gompertz distributions, but closer to the Gompertz distribution.\n\nThe committee also considered the company's new analysis that used a weighted parametric survival curve based on a statistical test of model fit (that is, the Akaike information criterion). The committee agreed with the ERG that it did not consider the approach credible because it included curves (such as a log-logistic distribution) with limited clinical plausibility, and agreed that it was not appropriate.On balance, the committee acknowledged the company's different opinion on the choice of parametric survival curve and agreed to take the Weibull and Gompertz curves into account in its decision-making. However, the committee concluded that it was more plausible to use the Gompertz distribution to estimate mortality.\n\nThe committee discussed the company's modelling assumption that the mortality benefit of pirfenidone compared with best supportive care remains constant over a person's lifetime. It appreciated that the randomised trials were too short (that is, either 52\xa0or 72\xa0weeks) to provide evidence to support this assumption. The committee also noted that, although follow-up data for pirfenidone were collected for over 8\xa0years in RECAP, there was no best supportive care group in the study and so no long-term relative effectiveness could be estimated from the study. The committee was also aware that the model was very sensitive to the assumptions around duration of treatment benefit. It heard from 1\xa0clinical expert that the treatment benefit of pirfenidone was likely to be constant over a person's lifetime. The committee did not agree that this was plausible, based on advice from the ERG that the trials showed a reduction in treatment effect over time for mortality. In its response to the appraisal consultation document, the company used data from INOVA to support its argument that the treatment effect lasts for at least 8\xa0years. The company provided a Kaplan–Meier plot and log-cumulative hazard plot for mortality based on data from the trials and INOVA. The committee noted that the log-cumulative hazard plots for pirfenidone and best supportive care were not parallel after 5\xa0years. It determined that, although there was some maintained treatment effect, it was not constant. The committee concluded that the evidence did not justify assuming a constant mortality benefit for 8\xa0years. It further concluded that it was reasonable to assume a constant benefit up to 5\xa0years.\n\nThe committee discussed the population in the model. It recognised that the model was based on the pirfenidone clinical trials and therefore included fewer people with an FVC above 80% predicted than are seen in NHS clinical practice (see section\xa04.7). The committee considered whether the incremental cost-effectiveness ratios (ICERs) would be affected if the modelled population included a higher proportion of people with an FVC above 80% predicted, to better reflect NHS practice. It understood from the analyses presented that there was a consistent trend for higher ICERs in the population with an FVC above 80% predicted than in the population with an FVC between 50% and 80% predicted. For example, when assuming a 5‑year treatment effect and including the stopping rule, the ICER for pirfenidone compared with best supportive care was between:\n\n£24,933 (Weibull) and £27,780 (Gompertz) per quality-adjusted life year (QALY) gained for people with an FVC between 50% and 80% predicted\n\n£32,643 (Weibull) and £38,687 (Gompertz) per QALY gained for people with an FVC above 80% predicted.Therefore, the committee expected that the ICERs for the full population (specified in the marketing authorisation for pirfenidone) would be higher if the model included a higher proportion of people with an FVC above 80% predicted. The committee concluded that the current cost-effectiveness estimates for the full population are likely to be underestimated.\n\nThe committee discussed whether the company's model appropriately incorporated the treatment stopping rule. The ERG explained that ICERs including the stopping rule for pirfenidone would likely be biased in favour of pirfenidone when compared with best supportive care. This was because, in the model, the stopping rule reduced pirfenidone costs without affecting treatment outcomes. The committee had concluded that analyses including a stopping rule for pirfenidone would underestimate the ICER because of the model structure. However, at its third meeting, the committee heard from the company that analyses including a stopping rule would overestimate the ICERs in scenarios where the mortality benefit of pirfenidone is not constant over a person's lifetime. The company had not submitted any evidence to support its statement and therefore the committee could not draw a firm conclusion about whether reducing the duration of treatment benefit under- or overestimated the ICERs with a stopping rule. The committee concluded that all ICERs including the stopping rule for pirfenidone were associated with uncertainty.\n\n# Cost-effectiveness results and conclusions\n\nThe committee considered the cost effectiveness of pirfenidone compared with best supportive care. The committee noted that, for the population specified in the marketing authorisation (people with 'mild to moderate' idiopathic pulmonary fibrosis, that is, people with an FVC above 50% predicted), the ICER (including the stopping rule) that most closely matched the committee's preferred assumptions was between £25,706 (Weibull) and £28,870 (Gompertz) per QALY gained when assuming a 5‑year treatment effect. The committee agreed that the estimate using the Gompertz survival curve was more plausible (see section\xa04.13). The committee then discussed the cost-effectiveness estimates for the group with an FVC between 50% and 90% predicted, because most of the data presented by the company was from this group (see section\xa04.6), noting that the ICERs were similar to those for the full population.\n\nThe committee recognised that, when above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources must take account of the degree of certainty around the ICER, the innovative nature of the technology and whether its benefits have been adequately captured in the model. The committee recalled that all of the ICERs were uncertain, noting that:\n\nThe modelled population did not include as many people with an FVC above 80% predicted as expected in NHS practice (see section\xa04.7 and section\xa04.15), and accounting for this may increase the ICER.\n\nThe impact of the stopping rule on the ICER was uncertain (see section\xa04.16).\n\nThere was still uncertainty about how long the survival benefit of pirfenidone would last; it could be less than 5\xa0years (see section\xa04.14). The committee understood that the model was sensitive to this assumption, noting that the ICERs increased substantially, to around £58,000 per QALY gained, when assuming a 2-year treatment effect (including the stopping rule).The committee noted the company's suggestion that pirfenidone is associated with health-related benefits that cannot be adequately captured in the QALY calculation. These benefits include: a reduction in breathlessness; improved patient choice based on a different adverse event profile; improved NHS capacity by reducing inpatient stays attributed to acute exacerbations; and the effect on people of working age. The committee acknowledged that, although these aspects were important to people with idiopathic pulmonary fibrosis, it did not consider that any sizeable health-related benefits had been excluded from the economic model. Because of this, and the uncertainties in the ICERs, the committee concluded that pirfenidone could not be considered a cost-effective use of NHS resources for adults with mild to moderate idiopathic pulmonary fibrosis. It was aware that removing the stopping rule increased the ICERs and therefore did not consider estimates without the stopping rule for this population.\n\nThe committee then discussed whether there was a subgroup for whom pirfenidone could be recommended. The committee was aware that pirfenidone was associated with a lower ICER in populations with a lower FVC (see section\xa04.15). It recalled that treatment decisions based on percent predicted FVC are currently implemented in clinical practice (see section 4.2). The committee was aware that, in NICE's previous technology appraisal guidance, pirfenidone was regarded as cost effective for people with an FVC between 50% and 80% predicted if the company provided pirfenidone with the discount agreed in the patient access scheme. It noted that the company had presented analyses for this group. The ICER (including the stopping rule) that most closely matched the committee's preferred assumptions for pirfenidone compared with best supportive care was between £24,933 (Weibull) and £27,780 (Gompertz) per QALY gained when assuming a 5-year treatment effect. The committee agreed that these ICERs were also subject to uncertainty relating to the stopping rule and duration of survival benefit, and recalled its conclusion that no sizeable health-related benefits had been excluded from the economic model (see section\xa04.18). However, the committee understood that pirfenidone was considered a reasonably innovative treatment at the time of the previous appraisal because it was the first drug to improve outcomes in idiopathic pulmonary fibrosis without the long-term side effects of immunosuppressants. It agreed that it had not seen any clinical evidence contradictory to that considered in NICE's previous technology appraisal on pirfenidone (see section\xa04.8), and therefore it was not minded to change this recommendation and withdraw an existing treatment option for people with moderate disease, despite the relatively high ICERs. The committee concluded that the recommendations in NICE's previous technology appraisal guidance on pirfenidone remained appropriate for people with idiopathic pulmonary fibrosis with an FVC between 50% and 80% predicted.\n\nThe committee considered the cost effectiveness of removing the requirement to stop treatment if a person's predicted FVC drops by an absolute value of 10% in the population with an FVC between 50% and 80% predicted. The committee was aware that removing the stopping rule increased the ICERs. Having concluded that the ICER for pirfenidone in this group was high, and associated with uncertainty, when a stopping rule is included (see section\xa04.19), the committee concluded that pirfenidone could not be considered cost effective without the stopping rule.\n\n# Potential equality issues\n\nThe committee noted the potential equality issue raised by consultees that restricting treatment based on percent predicted FVC could discriminate against:\n\nminority ethnic groups, particularly people of south Asian family origin\n\ndisabled people who have difficulty standing straight because FVC is expressed as a percentage of the predicted normal value for a person of the same height\n\nolder people because the reference tables are derived from populations under the age of 70\xa0years, but the average age of people with idiopathic pulmonary fibrosis is 72\xa0years.The committee discussed these issues with the clinical experts, noting that:\n\nThe Global Lung Initiative has introduced equations to predict FVC values in minority ethnic groups and, when these equations were used, FVC values for these groups were comparable to the FVC values of people in clinical trials. Thus, when using the newer equations, people would not be denied treatment because of their ethnicity.\n\nFor people who cannot stand straight, their armspan (which estimates their height) can be used to calculate percent predicted FVC. Thus, when using this measure people would not be denied treatment because of their disability.\n\nAccording to clinical experts, it is difficult to compare the predicted FVC values of older people with the FVC values of people in clinical trials because older people show a wide range of predicted FVC.The committee recognised the limitations of FVC but understood that, in clinical practice, wider patient characteristics would be taken into account when interpreting percent predicted FVC. It concluded that its recommendations did not discriminate against any groups of people protected by the Equality Act.\n\n# The Pharmaceutical Price Regulation Scheme\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014 and, in particular, the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA504\n\nAppraisal title: Pirfenidone for treating idiopathic pulmonary fibrosis\n\nSection\n\nKey conclusion\n\nPirfenidone continues to be recommended as an option for treating idiopathic pulmonary fibrosis in adults only if:\n\nthe person has a forced vital capacity (FVC) between 50% and 80% predicted\n\nthe company provides pirfenidone with the discount agreed in the patient access scheme and\n\ntreatment is stopped if there is evidence of disease progression (an absolute decline of 10% or more in predicted FVC within any 12-month period).\n\n\n\nPirfenidone could not be considered a cost-effective use of NHS resources for the population specified in the marketing authorisation (that is, adults with mild to moderate idiopathic pulmonary fibrosis) because the most plausible incremental cost-effectiveness ratio (ICER) for pirfenidone (including the stopping rule), of those presented, lay somewhere between about £25,700 and £28,900 per quality-adjusted life years (QALY) gained compared with best supportive care, and was associated with uncertainties that had the potential to substantially increase the ICER.\n\nFor people with an FVC between 50% and 80% predicted, the most plausible ICER (including the stopping rule) was also above £20,000 per QALY gained, and associated with uncertainties that had the potential to substantially increase the ICER. However, the committee agreed that it had not seen any clinical evidence to contradict the evidence considered in NICE's previous technology appraisal on pirfenidone so continued to recommend pirfenidone for this population.\n\nto 4.20\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe clinical experts noted that they would offer best supportive care to people with an FVC above 80% predicted. The committee concluded that the current treatment options are nintedanib and pirfenidone for people with an FVC between 50% and 80% predicted, and best supportive care for those with an FVC above 80% predicted.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee understood that pirfenidone was considered a reasonably innovative treatment at the time of the previous appraisal, but did not consider that any sizeable health-related benefits had been excluded from the economic model.\n\n, 4.19\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nPirfenidone has a marketing authorisation in the UK for treating mild to moderate idiopathic pulmonary fibrosis in adults.\n\n\n\nAdverse reactions\n\nThe very common adverse reactions associated with using pirfenidone are nausea, rash, diarrhoea, fatigue, dyspepsia, anorexia, headache and photosensitivity reactions.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee noted that the evidence came from 4\xa0randomised double-blind placebo-controlled phase\xa0III trials (CAPACITY\xa01, CAPACITY\xa02, ASCEND and SP3) and other observational data.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that people with an FVC above 80% predicted were under-represented in the clinical trials and that the trial evidence was most generalisable to people with an FVC of up to 90% predicted.\n\n, 4.7\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee agreed that pirfenidone reduced disease progression, and may reduce mortality, compared with placebo. The committee did not see anything to contradict the conclusion in NICE's previous technology appraisal and concluded that pirfenidone is effective in people with an FVC between 50% and 90% predicted.\n\n\n\nHow has the new clinical evidence that has emerged since the previous appraisal (TA282) influenced the current recommendations?\n\nThe changes to NICE's technology appraisal guidance\xa0282 proposed by the company in light of new clinical data are not recommended, specifically:\n\nremoving the recommendation to stop pirfenidone if the disease progresses\n\nexpanding the population to include people with an FVC above 80% predicted.\n\n, 4.1\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company provided a partitioned survival model which had 3 mutually exclusive health states: progression-free, progressed and dead.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee acknowledged the limitations in the data and concluded that the model could be used for its decision-making. The committee noted that there was no relationship between time on treatment, time to disease progression and mortality and that acute exacerbations were not connected to disease progression and mortality. There was uncertainty about how long the survival benefit of pirfenidone would last. All ICERs that included the stopping rule for pirfenidone were associated with uncertainty.\n\n, 4.14, 4.16\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee did not consider that any sizeable health-related benefits had been excluded from the economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee concluded that the recommendations in NICE's previous technology appraisal guidance on pirfenidone (TA282) remained appropriate for people with idiopathic pulmonary fibrosis with an FVC between 50% and 80% predicted, even though the most plausible ICER for pirfenidone in this subgroup was relatively high.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe estimate of long-term mortality benefit with pirfenidone over a patient's lifetime by extrapolating from relatively short trials\n\nWhether or not pirfenidone is stopped after disease progression (the 'stopping rule').\n\nto 4.14, 4.16\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe most plausible ICER, of those presented, for pirfenidone compared with best supportive care in people with an FVC above 50% predicted ranged from £25,706 (Weibull) to £28,870 (Gompertz) per QALY gained when assuming a 5-year treatment effect (including the stopping rule). This was associated with uncertainties that had the potential to substantially increase the ICER.\n\nFor people with an FVC between 50% and 80% predicted, the most plausible ICER (including the stopping rule) was between £24,933 (Weibull) to £27,780 (Gompertz) per QALY gained, and was also associated with uncertainties that had the potential to substantially increase the ICER.\n\nto 4.19\n\nHow has the new cost-effectiveness evidence that has emerged since the previous appraisal (TA282) influenced the current recommendations?\n\nThe committee concluded that the recommendations in NICE's previous technology appraisal guidance on pirfenidone (TA282) remained appropriate for people with idiopathic pulmonary fibrosis with an FVC between 50% and 80% predicted. The committee concluded that pirfenidone was not cost effective without the stopping rule in this group.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe committee concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee noted the potential equality issue raised by consultees, that restricting treatment based on percent predicted FVC could discriminate against minority ethnic people, older people and disabled people. The committee discussed these issues with the clinical experts and concluded that its recommendations did not discriminate against any groups of people protected by the Equality Act.\n\n"}
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https://www.nice.org.uk/guidance/ta504
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Evidence-based recommendations on pirfenidone (Esbriet) for idiopathic pulmonary fibrosis in adults.
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24d4655ad05f26671fb88b28af620efafd806bf9
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nice
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Intrabeam radiotherapy system for adjuvant treatment of early breast cancer
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Intrabeam radiotherapy system for adjuvant treatment of early breast cancer
Evidence-based recommendations on using Intrabeam radiotherapy during breast-conserving surgery in adults.
# Recommendations
The Intrabeam radiotherapy system is not recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgical removal of the tumour.
Use of the Intrabeam radiotherapy system is recommended only using machines that are already available and in conjunction with NHS England specified clinical governance, data collection and submission arrangements.
The procedure should only be carried out by clinicians with specific training in the use of the Intrabeam radiotherapy system.
Patient selection for Intrabeam radiotherapy should be done by a multidisciplinary team experienced in the management of early invasive breast cancer, which includes both breast surgeons and clinical oncologists.
Clinicians wishing to undertake Intrabeam radiotherapy should take the following actions:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainties about the procedure and inform them about alternative treatment options.
Provide patients with NICE's written information on the evidence of the risks and benefits of the range of treatment options available as an aid to shared decision-making.# The technology
Description of the technology
The Intrabeam radiotherapy system (Carl Zeiss UK) is a mobile irradiation system. It is designed to deliver a single dose of targeted low-energy radiation (X‑rays) directly to the tumour bed, while limiting the exposure of healthy tissue to radiation. Because it delivers low energy radiation, it can be used in an ordinary operating theatre at the time of surgery. The Intrabeam radiotherapy system provides a source of 50 kV energy from a spherical applicator of between 1.5 cm and 5.0 cm diameter. The applicator is sutured to the tumour bed so that breast tissue at risk of local recurrence receives the prescribed dose while skin and deeper structures are protected. Radiation is delivered over 20 to 30 minutes.
CE marking
The Intrabeam radiotherapy system was granted a CE (Conformité Européene) mark in 1999 for use in radiotherapy.
Intrabeam can be used as an intraoperative radiotherapy system given as the sole treatment or as a boost treatment followed by external beam radiotherapy (EBRT). When intraoperative radiotherapy is given as a boost treatment with Intrabeam and followed by EBRT, there is no need for further external boost treatment. Six NHS centres in the UK have used Intrabeam for adjuvant treatment of early breast cancer.
Adverse reactions
Adverse reactions are mostly related to wound-related complications and radiotherapy-related complications.
Recommended dose and schedule
The surface of the tumour bed typically receives a single fraction of 20 grays, which attenuates to 5 grays to 7 grays at a depth of 1 cm.
Price
The cost of the Intrabeam radiotherapy system (including the spherical applicators) is £435,000 (excluding VAT, Carl Zeiss UK personal notification). The company estimates that device maintenance and servicing costs are about £35,000 per year. Costs may vary in different settings because of negotiated procurement discounts.# Evidence
The appraisal committee (section 7) considered evidence from a number of sources. See the committee papers, for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of the Intrabeam radiotherapy system, having considered evidence on the nature of early invasive breast cancer and the value placed on the benefits of the Intrabeam radiotherapy system by people with the condition, those who represent them and clinical experts. It also took into account the effective use of NHS resources.
# The management of early invasive breast cancer
The committee heard from the clinical experts that usual clinical practice in the NHS is to give adjuvant radiotherapy to people with early invasive breast cancer after successful breast-conserving surgery (that is, removal of the tumour with clear margins). This is given by external beam radiotherapy (EBRT) using a linear accelerator delivering 40 grays in 15 fractions over 3 weeks in line with NICE's clinical guideline on early and locally advanced breast cancer (CG80). The committee heard from the clinical experts that there was some variation in clinical practice, with some oncologists recommending EBRT over 5 weeks but that, in general, most oncologists would recommend EBRT in line with CG80. An additional external radiotherapy boost dose to the site of the excised tumour lasting a further 1 week to 2 weeks could be offered to people with a higher risk of local recurrence. The committee noted comments from professional groups and also heard from the clinical experts that radiotherapy is constantly evolving. It also noted that there are several ongoing trials investigating, for example, whether the course of radiotherapy could be reduced from 3 weeks to 1 week, or whether radiotherapy is needed at all for patients considered to be at low risk of recurrence. The clinical experts suggested that the results of these trials may influence future clinical practice in the UK. The committee understood that clinical practice is evolving and that the delivery and use of external radiotherapy may change in the future, moving towards a more targeted approach in which patients have treatment based on their individual risks. The committee noted that Intrabeam could be used at the time of surgery as an alternative to postoperative treatment with EBRT. It also noted that, if adverse histological features are identified in the cancer cells at final pathology after treatment with Intrabeam, and subsequent EBRT is recommended, a further external boost dose would not be needed.
# Potential benefits of Intrabeam
The committee noted that Intrabeam delivers a single dose of targeted low energy (X‑ray) radiation to the tumour bed. It can be used in an operating theatre as a single treatment at the same time as the surgery to remove the primary tumour. Patients at low risk of recurrence do not receive any further radiotherapy. However the committee was aware that patients with a higher risk of recurrence (for example, histopathology showing invasive lobular carcinoma, extensive intraductal component, node involvement, and close margins) may go on to receive an additional course of EBRT. For patients having EBRT, treatment can only begin after the surgical wound has healed and takes several weeks of daily therapy to complete. Intrabeam also has the theoretical advantage of having the source of radiation directly applied to the tumour bed. However, the committee heard from the clinical experts that there are now techniques allowing clinical oncologists to more accurately target the dose with EBRT, such as using clips during surgery to mark the site of the tumour. Although there is a risk of clips moving within the cavity, EBRT has evolved and is generally considered to be accurate for targeting the tumour site. The committee noted comments from professional groups that the main aim of radiotherapy after surgical removal of the tumour is to prevent local recurrence. A clinical expert confirmed that local recurrence is not related to an increased risk of metastatic disease or mortality in people with low-risk early breast cancer, such as those included in a randomised trial of breast cancer surgery with or without subsequent EBRT: the PRIME II study. This study included women aged 65 years or older with tumours no bigger than 3 cm that had not spread to the lymph nodes and that were hormone-receptor positive. All the patients received adjuvant hormone treatment. If there is local recurrence after breast-conserving surgery and EBRT, this is usually treated by mastectomy. However, for some patients, brachytherapy may be a suitable breast-conserving treatment instead of mastectomy. If there is recurrence after treatment with Intrabeam, further breast-conserving surgery and EBRT still remain a theoretical treatment option. The committee also heard from the patient expert that Intrabeam could be used when EBRT is unsuitable or not possible, for example, for those patients who are unable to raise their arm. The committee understood from the clinical experts that people for whom EBRT was not a suitable treatment would currently be offered mastectomy, and that Intrabeam might be an appropriate option for them. The committee concluded that Intrabeam, given at the same time as surgery, provided a potential advantage in delivering radiotherapy in direct contact with the tumour bed, and also represented an alternative treatment option for people for whom EBRT is not suitable, although for those people with a higher risk of recurrence an additional course of EBRT may still be required.
The committee heard from the patient expert that the psychological burden of breast cancer is high for patients and their families. The patient expert explained that, when a patient is diagnosed with breast cancer, the thought of many radiotherapy sessions over a number of weeks can cause emotional stress and anxiety and is highly disruptive to daily living. The patient may need to stop working and face substantial travel costs, which can have a considerable financial and emotional impact on the patient and their family. The committee also heard from the patient expert that some patients who live a long distance from a radiotherapy centre may need to stay away from their home to be able to complete the course of radiotherapy. The patient and clinical experts highlighted that the time between diagnosis and the end of treatment is much reduced with Intrabeam compared with EBRT. This is because the patient has the treatment at the same time as surgery and, for most people, no further treatment is needed. The patient expert also considered that Intrabeam does not have the adverse effects that are associated with EBRT such as local tenderness, breast pain, swelling and reduced range of movement. However, the committee also heard from clinical experts that the adverse effects of EBRT are mainly fatigue and that only a few patients have radiosensitivity, which can cause swelling and weeping of the breast. The patient and the company expert stated that Intrabeam is associated with better cosmetic outcomes than EBRT, and that changes in breast appearance and texture can be avoided or reduced with Intrabeam. The patient expert highlighted that cosmetic outcomes have a big effect on patients' quality of life. However the committee heard differing opinions from the clinical experts as to whether the cosmetic outcome from Intrabeam is superior to modern EBRT because the cosmetic outcomes with EBRT have improved substantially in recent years. The committee heard from the clinical experts that breast fibrosis is more common with EBRT than with Intrabeam, but that both treatments are associated with a substantial increase in the occurrence of fibrosis in the breast. The committee noted comments from the company and patient groups stating that treatment with EBRT is associated with potential long-term damage to other organs including the heart, and that treatment with Intrabeam would reduce the radiation dose to adjacent tissues. However, a clinical expert stated that the radiation dose to the heart with modern EBRT is not clinically significant. The committee concluded that patients generally tolerate EBRT well, with good outcomes, but that avoiding multiple radiotherapy sessions by having a single treatment with Intrabeam at the same time as surgery would be considered a major advantage by some patients.
# Clinical effectiveness
## The TARGIT‑A trial
The committee discussed the clinical evidence presented for Intrabeam, which came from a randomised trial comparing Intrabeam with EBRT (TARGIT‑A). The committee had a number of concerns with the trial; it noted several comments received from professional and patient groups, and comments made by the assessment group, highlighting concerns about the robustness of the trial and its generalisability to NHS clinical practice. The committee noted that in TARGIT‑A, EBRT was delivered in an average of 23 fractions, longer than the 15 fractions delivered in established clinical practice in the NHS. The radiation doses administered with EBRT also ranged from 40 grays to 56 grays in TARGIT‑A, whereas established clinical practice in the NHS is a dose of 40 grays. The committee also noted comments from professional groups highlighting that quality control of EBRT was not reported in some centres, and may have shown considerable variation internationally. The clinical experts stated that it is not possible to predict what effect the variation in dose may have had on the results of the trial. Only 6 of the 33 centres participating in the trial were in the UK. The committee concluded that some doubt remains about the generalisability of the trial results to NHS clinical practice.
## Length of follow-up in the TARGIT‑A trial
The committee noted comments received from professional and patient groups that the length of follow-up in the trial was too short to reliably demonstrate the clinical effectiveness of Intrabeam compared with EBRT for the incidence of local recurrence. Median follow-up in the trial was 2 years and 5 months and only 35% of the patients had 5‑year follow-up at the time of the analysis. The committee heard from the clinical experts that longer follow-up, usually of at least 5 years, is needed for clinicians to feel confident about data on local recurrence. A clinical expert noted that this is the approach being followed for reporting the results of ongoing trials that are investigating whether the course of radiotherapy could be reduced from 3 weeks to 1 week, or whether radiotherapy is needed at all for some patients considered to have low risk of recurrence. The committee also noted comments from consultation on its preliminary recommendations that questioned the reliability of the data presented and suggested that the data are too immature to be the basis of firm recommendations. The committee heard from the TARGIT‑A investigators that median follow-up in the trial is currently 4 years, and that complete follow-up and publication of final results is not yet known. The committee was aware of the large debate in the medical community about TARGIT‑A, in which opposite views have been raised about the importance of mature follow-up, trial governance and the interpretation of the results. The committee concluded that the results of TARGIT‑A should be interpreted with caution because the length of follow-up is less than 5 years for the full trial population.
## Subgroups in the TARGIT‑A trial
The committee noted that TARGIT‑A included a pre-pathology group (that is, treatment with Intrabeam was delivered at the same time as surgical removal of the tumour) and a post-pathology group (that is, treatment with Intrabeam was delayed and provided after a second surgical procedure to re-open the wound), and that this stratification was included as a protocol amendment. A clinical expert commented that this stratification was included because of centre preferences. Some trial centres gave Intrabeam only at a second operation after pathology results were available. The committee noted that the rate of local recurrence in the post-pathology group was higher than in the pre-pathology group, and that the company stated that non-inferiority for local recurrence had not been established in the post-pathology group. The committee also noted that, because of these results, the company suggested focusing only on the pre-pathology group and that the assessment group had also focused on this group to develop its economic model. The committee heard from a clinical expert that there were plausible reasons for worse results with Intrabeam when the treatment was delivered post pathology. At a second operation there could be scar tissue or seroma present, and targeting the exact tumour bed would be more difficult. The committee concluded that it was reasonable to consider treatment with Intrabeam only at the time of primary surgical removal of the tumour.
## The non-inferiority margin in TARGIT‑A
The committee noted that TARGIT‑A was a non-inferiority trial, and that the primary end point was local recurrence in the conserved breast. The committee heard from the company that there were no differences in the rate of local recurrence in this group compared with the rest of the trial population. The committee considered the low rates of local recurrence, which had so far been demonstrated in both arms of the trial: 1.1% for EBRT and 2.1% for Intrabeam in the pre-pathology group. The committee noted that the pre-specified non-inferiority margin at 5 years for the absolute difference of local recurrence between treatment groups was 2.5%. The committee heard from the clinical experts that this was based on an estimated rate of 5‑year local recurrence of 6% in the EBRT group. The committee noted that the non-inferiority margin is normally estimated based on the expected hazard ratio rather than on an estimated rate in the control group and an absolute difference in rates between groups. It considered that the pre-trial estimated 5‑year rate of 6% for local recurrence, on which the non-inferiority margin was based, is higher than the current expected rate of local recurrence in people having treatment with EBRT. The committee also noted that patients in the trial had a relatively good prognosis and low risk of local recurrence and heard from the clinical experts that, since 2000, when patients were first recruited into the trial, the 5‑year local recurrence rate with EBRT has decreased to much lower than 6%. The committee also noted that, when assessing non-inferiority, the point estimate alone is not sufficient. The confidence interval (CI) around the point estimate should also be considered and compared with the pre-specified non-inferiority margin. The committee noted that, in their response to the committee's request, the TARGIT‑A investigators quantified the difference in the Kaplan–Meier estimates of local recurrence, and its 95% CI, using 2 different methods. The committee also noted that the integrated difference method presented by the investigators: is not commonly used; provided more favourable results for Intrabeam; and was not pre-specified in the TARGIT‑A protocol. It further noted that, because the non-inferiority margin was based on the absolute difference in local recurrence, the same margin could not be used for assessing non-inferiority if the integrated difference method were to be accepted. The committee considered that difference in Kaplan–Meier estimates of local recurrence and its 95% CI calculated using the conventional method were more appropriate. It noted that, using this method, the absolute difference between 5‑year Kaplan–Meier estimates for local recurrence in the pre-pathology group was 1% and the 95% CI was −0.68 to 2.68. On the currently available evidence, the committee concluded that there was no statistical reason for using a different method to assess whether Intrabeam is non-inferior to EBRT.
## Local recurrence rates
The committee acknowledged that the rate of local recurrence in TARGIT‑A was low in both treatment groups, and that longer follow-up of patients is needed to provide more long-term data and less uncertain results. The committee noted that the CI around the absolute difference in local recurrence at 5 years is wide, and that the upper end of the interval is higher than the pre-specified non-inferiority margin (absolute difference 1%; 95% CI −0.68 to 2.68). The committee considered that the criterion for non-inferiority was not appropriately defined. This meant that the trial was underpowered and the results could not be considered robust enough to determine whether Intrabeam is non-inferior to EBRT in terms of local recurrence. The committee therefore concluded that the non-inferiority of Intrabeam compared with EBRT in terms of local recurrence is unproven. However, it acknowledged that the recurrence rates reported in the Intrabeam group could be considered low in absolute terms and, based on the evidence available so far, not out of line with current recurrence rates with EBRT in the NHS. The committee noted that the trial investigators stated that there have been 15 additional local recurrence events in the pre-pathology group since the analysis was done. But, because data were blinded, it is not possible to know which treatment group these events occurred in. The committee concluded that, although complete follow-up is needed to reduce the uncertainty around the results, the absolute number of local recurrences was still low. The committee expressed disappointment that the trial results remained blinded because this meant the technology appraisal was done without access to the latest data, or a date when this would be available.
## Overall survival results from TARGIT‑A
The committee noted that the number of breast cancer deaths was higher in the Intrabeam group compared with the EBRT group, although the difference was not statistically significant. The committee also noted that there were fewer non-breast cancer deaths in the Intrabeam group compared with the EBRT group and that this difference was statistically significant. The committee noted the assessment group's considerations and the comments received on the assessment group's report from professional groups and the company on the difference in overall survival between the 2 treatment groups in TARGIT‑A. It understood that the assessment group had reported that the difference in overall survival was based on a small number of events and that it did not consider that there was an excess of deaths in the EBRT group, but rather a shortfall of deaths in the Intrabeam group occurring by chance. The committee noted that the assessment group had compared the non-breast cancer mortality data from the EBRT group with the annual all-cause mortality probabilities obtained from the Office of National Statistics data and found that they were similar. The committee acknowledged that caution is needed when comparing international trial data (such as data from TARGIT‑A) and country-specific data (such as data from the Office of National Statistics in the UK). The committee also noted comments received from professional groups and the company suggesting that the assessment group's conclusion on the difference in non-breast cancer death between treatment groups occurring by chance was erroneous and that whole breast radiation is associated with cardiac toxicity, which can increase the subsequent rate of ischaemic cardiac events. The committee heard from a clinical expert that the mean radiation dose to the heart was not provided in the TARGIT‑A publication and that the mean dose to the heart delivered with EBRT in clinical practice in the NHS is minimal. Therefore it is highly unlikely that the difference in non-breast cancer deaths between treatment groups in TARGIT‑A could be explained by an increased risk of cardiovascular death related to EBRT. The committee heard from clinical experts and noted comments from professional groups suggesting that it is not possible to draw any conclusions from TARGIT‑A in terms of an overall survival benefit with Intrabeam compared with EBRT. The committee agreed that, because the patient baseline characteristics in the trial did not include cardiovascular risk factors, it is not possible to confirm that there is an overall survival benefit with Intrabeam compared with EBRT.
## The relative benefits and risks of Intrabeam
The committee considered the clinical evidence available for Intrabeam, taking into account the advantages of the technology that were highlighted by the patient expert. The committee noted that the clinical evidence for Intrabeam is immature and associated with considerable uncertainty. It acknowledged that Intrabeam has not been proven to be non-inferior to EBRT and could have a higher risk of local recurrence. The committee understood that some patients are willing to accept a higher risk of local recurrence as long as the absolute risk remains low and the treatment has other benefits that they consider important (see sections 4.2 and 4.3). The patient expert highlighted that patient choice should be based on an informed discussion between the patient and clinician, and that it is really important that patients understand all the benefits and risks associated with the technology. They noted that many patients make their decisions based on their personal circumstances and not necessarily based on the possibility of a future event in the long term. The clinical experts agreed that patient choice is important and the patient should be fully and clearly informed when making their decision. The committee heard from a clinical expert and noted comments from professional groups highlighting that patient choice needs to be based on high-quality evidence with adequate follow-up, which Intrabeam currently lacks. The committee concluded that there are benefits with Intrabeam that are very important to patients, particularly those associated with length of treatment and quality of life. It acknowledged its previous conclusion that, although complete follow-up is needed to reduce uncertainty around the results, the absolute number of local recurrences is still low (see section 4.7).
# Cost effectiveness
The committee considered the cost-effectiveness evidence presented for Intrabeam compared with EBRT. It noted that both the company and the assessment group focused on the pre-pathology group of TARGIT‑A to develop their economic models. The committee noted that the results from both the company's and the assessment group's models estimated that the quality-adjusted life year (QALY) difference between Intrabeam and EBRT was very small. This was despite Intrabeam being associated with slightly more QALYs than EBRT in the company's model and being associated with fewer QALYs than EBRT in the assessment group's model. The committee also noted that the results from both the company's and the assessment group's models indicated that Intrabeam provided some cost savings compared with EBRT. However, these savings were higher in the company's model than in the assessment group's model. The committee also noted that the assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use the best way to incorporate this into the economic modelling is not clear. The committee noted that section 5.5.8 of the NICE guide to the methods of technology appraisal (2013) states that, if introduction of the technology needs changes in infrastructure, costs and savings should be included in the analysis. Section 5.12.6 of the guide states that, if savings are anticipated, the extent to which these finances can actually be realised should be specified. The committee debated whether the costs for Intrabeam and linear accelerator equipment should be included in the same way in the economic model (that is, including the capital costs of equipment for both technologies), or whether only the tariff cost associated with each technology should be included. The committee considered that, if the capital cost of EBRT were included in the economic model, the cost savings associated with Intrabeam compared with EBRT would be greater. The committee agreed that both the company and the assessment group estimated the costs of Intrabeam treatment as lower than EBRT, but it concluded that the size of the cost savings was uncertain.
## Uncertainty in the cost-effectiveness analyses
The committee agreed with its previous conclusion that the clinical effectiveness of Intrabeam compared with EBRT remains considerably uncertain (see section 4.8 and section 4.9). The committee noted the results from the assessment group's probabilistic sensitivity analysis, which also showed extreme uncertainty in the model results. It noted that the point estimate of the incremental cost-effectiveness ratio (ICER) for Intrabeam is associated with lower costs and fewer QALYs compared with EBRT. The committee considered that, based on the high degree of uncertainty in the cost-effectiveness analysis, it was not possible to state the most plausible ICER for Intrabeam compared with EBRT. It concluded that Intrabeam was associated with slightly lower costs and fewer QALYs than EBRT.
# Conclusions
The committee discussed whether, based on the evidence available, it was reasonable to recommend Intrabeam for routine commissioning in the NHS in England. It considered that the clinical- and cost-effectiveness evidence for Intrabeam remained uncertain. The committee noted its previous conclusions that, even if the length of follow-up of patients in TARGIT‑A had been longer, the quality of the trial and particularly its generalisability to NHS clinical practice would still not have provided conclusive evidence to establish the relative clinical and cost effectiveness of Intrabeam compared with EBRT as delivered in the NHS. The committee also noted that the rate of local recurrence with Intrabeam may be higher than with EBRT. However, it took into account that Intrabeam may provide benefits that some patients would consider substantial and that there are some patients who could particularly benefit from Intrabeam, such as people for whom EBRT is not suitable. The committee recognised its role of not recommending treatments for routine use if the benefits to patients are unproven, or if the treatments are not cost effective, in line with section 6.1.2 of the guide to the methods of technology appraisal (2013). However, it understood that, to have the benefits of Intrabeam, some patients may be willing to accept a treatment that may be associated with a higher risk of local recurrence. It noted several benefits highlighted by the patient and clinical experts in terms of improving patients' quality of life, which could not be captured in the QALY calculation. It also noted that, although non-inferiority for Intrabeam compared with EBRT was unproven for local recurrence, the rates of recurrence in the Intrabeam group in the pre-pathology group were low. The committee understood the concerns raised by the clinical experts and the comments from professional groups that it is crucial to offer informed choice in clinical practice. The committee accepted that individual patient preference is important and agreed with the patient and clinical experts that patients should be fully informed of the evidence and treatment options available. The committee concluded that, given the difficulty in interpreting the evidence (particularly when specialist clinicians do not agree), patient selection for Intrabeam radiotherapy, if made available, should be done by multidisciplinary teams experienced in managing early invasive breast cancer including breast surgeons, clinical oncologists and radiotherapy physics experts in brachytherapy. The committee agreed that clinicians wishing to carry out Intrabeam radiotherapy should ensure that patients understand the uncertainties about the procedure, and inform them about alternative treatment options. It also agreed that patients should be given written information, from NICE, on the evidence of the risks and benefits of all available treatment options to help with shared decision-making.
The committee understood that, if treatment with Intrabeam became widespread, considerable investment in equipment would be needed. However, if Intrabeam results were subsequently found to be unfavourable, this would be associated with irrecoverable costs to the NHS and potentially with overall worse outcomes at a population level. However, the option of localised single treatment with Intrabeam is welcomed by patients and, if its clinical and cost effectiveness can be confirmed, it could be beneficial for both patients and the NHS. Taking these factors into account, the committee considered that it is a technology worthy of further evaluation. The committee concluded that, because of the uncertainty in the evidence available, the Intrabeam radiotherapy system cannot be recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgery to remove the tumour.
The committee heard from the clinical experts that there are 6 Intrabeam devices in the UK, which were used in TARGIT‑A but are not all being used at the moment. The committee considered that, given these existing resources, including staff trained in using Intrabeam, it would be reasonable to continue to use those devices that are available until further data is collected. The committee understood that there is considerable pressure on the existing NHS infrastructure for providing radiotherapy. As demand continues to rise the NHS will have to make further investment in new radiotherapy resources, taking into account emerging evidence on optimum pathways of care. The committee considered that collecting information about all patients having treatment with Intrabeam at a national level will allow the evidence from TARGIT‑A to mature while further data are collected in the NHS in a carefully controlled manner. The committee therefore concluded that it can only recommend the use of the Intrabeam radiotherapy system using only machines that are already available and only in conjunction with NHS England specified clinical governance, data collection and submission arrangements. These providers will also be required to comply with any NHS England service specifications pertaining to the delivery of intra-operative radiotherapy.
The committee recommended that further data collection in the NHS should include, as a minimum, a national collection of data from all patients having the Intrabeam radiotherapy system for adjuvant treatment of early invasive breast cancer in the NHS and it be recorded in the national radiotherapy dataset. Clinicians should audit, review and document clinical outcomes (described in section 6) locally, and consider the relationship between outcomes and patients' characteristics.
The committee discussed the technical requirements for Intrabeam and noted comments received from professional groups. It heard from the clinical experts that, although staff training is needed for Intrabeam, this will not necessarily mean there will be an increase in the number of staff or staff time, rather a change in their responsibilities and duties. The committee agreed with the clinical experts and concluded that the Intrabeam radiotherapy system should only be used by clinicians with specific training in its use.
# Equalities issues
The committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. A committee member raised the question of whether there is the potential for some patients to be disadvantaged by the recommendations, if they lack the capacity to understand the information provided by the clinician and to make an informed choice (such as people with learning disabilities or communication difficulties). The committee considered that patients would not be disadvantaged by the recommendations, providing that clinicians act in the interest of their patients, in line with their usual responsibilities, and tailor their explanation to each patient's level of understanding, and discuss the risks and benefits with the patient's carers when applicable. The committee concluded that there was no need to alter or add to its recommendations.
# Summary of appraisal committee's key conclusions
TA501
Appraisal title: Intrabeam radiotherapy system for adjuvant treatment of early breast cancer
Section
Key conclusion
The Intrabeam radiotherapy system is not recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgical removal of the tumour.
Use of the Intrabeam radiotherapy system is recommended only using machines that are already available and in conjunction with NHS England specified clinical governance, data collection and submission arrangements.
The procedure should only be carried out by clinicians with specific training in the use of the Intrabeam radiotherapy system.
Patient selection for Intrabeam radiotherapy should be done by a multidisciplinary team experienced in the management of early invasive breast cancer, which includes both breast surgeons and clinical oncologists.
Clinicians wishing to undertake Intrabeam radiotherapy should take the following actions:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainties about the procedure and inform them about alternative treatment options.
Provide patients with NICE's written information on the evidence of the risks and benefits of the range of treatment options available as an aid to shared decision-making.
to 1.5
Current practice
Clinical need of patients, including the availability of alternative treatments
Intrabeam could be used when external beam radiotherapy (EBRT) is unsuitable or not possible, for example, for those patients who are unable to raise their arm. People for whom EBRT is not a suitable treatment are currently offered mastectomy, and Intrabeam might be an appropriate option for them.
Patients generally tolerate EBRT well, with good outcomes, but avoiding multiple radiotherapy sessions by having a single treatment with Intrabeam at the same time as surgery would be considered a major advantage by some patients.
The technology
Proposed benefits of the technology
How innovative is the technology/are the technologies in its/their potential to make a significant and substantial impact on health-related benefits?
The committee concluded that Intrabeam, given at the same time as surgery, provided a potential advantage in delivering radiotherapy in direct contact with the tumour bed, and also represented an alternative treatment option for people for whom EBRT is not suitable or not possible.
What is the position of the treatment(s) in the pathway of care for the condition?
Usual clinical practice in the NHS is to give adjuvant radiotherapy to people with early breast cancer after successful breast-conserving surgery (that is, removal of the tumour with clear margins). This is given by external beam radiotherapy (EBRT). An additional external radiotherapy boost dose to the site of the excised tumour lasting a further 1 week to 2 weeks could be offered to people with a higher risk of local recurrence.
Intrabeam delivers a single dose of targeted low energy (X-ray) radiation to the tumour bed and can be used in an operating theatre as a single treatment at the same time as surgery to remove the primary tumour.
Adverse reactions
Adverse reactions are mostly related to wound-related and radiotherapy-related complications.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
A randomised trial comparing Intrabeam with EBRT (TARGIT‑A). It was a non-inferiority trial and the primary end point was local recurrence in the conserved breast.
Length of follow-up in the trial was too short to reliably show the clinical effectiveness of Intrabeam compared with EBRT for the incidence of local recurrence.
The committee noted that the clinical evidence for Intrabeam was immature and associated with considerable uncertainty. It acknowledged that Intrabeam had not been proven to be non-inferior to EBRT and could be associated with a higher risk of local recurrence.
Relevance to general clinical practice in the NHS
In TARGIT‑A, EBRT was delivered in an average of 23 fractions, longer than the 15 fractions delivered in established clinical practice in the NHS. The radiation doses administered with EBRT also ranged from 40 grays to 56 grays in TARGIT‑A, whereas established clinical practice in the NHS is a dose of 40 grays. Comments from professional groups highlighted that quality control of EBRT was not reported in some centres, and there may have been considerable variation internationally. The committee concluded that some doubt remained about the generalisability of the trial data to NHS clinical practice.
Uncertainties generated by the evidence
The committee noted that the clinical evidence for Intrabeam was immature and associated with considerable uncertainty. It acknowledged that Intrabeam had not been proven to be non-inferior to EBRT and could be associated with a higher risk of local recurrence.
It was not possible to confirm that there is an overall survival benefit with Intrabeam compared with EBRT.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
TARGIT‑A included a pre-pathology group (that is, treatment with Intrabeam was delivered at the same time as surgical removal of the tumour) and a post-pathology group (that is, treatment with Intrabeam was delayed and provided after a second surgical procedure to re-open the wound). The rate of local recurrence in the post-pathology group was higher than in the pre-pathology group, and the company stated that non-inferiority for local recurrence had not been established in the post-pathology group. The committee concluded that it was reasonable to consider treatment with Intrabeam only at the time of primary surgical removal of the tumour.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee considered the low rates of local recurrence that had so far been shown in both arms of the trial: 1.1% for EBRT and 2.1% for Intrabeam in the pre-pathology group. It noted that the pre-specified non-inferiority margin at 5 years for the absolute difference of local recurrence between treatment groups was 2.5%. The clinical experts stated that this was based on an estimated rate of a 5‑year local recurrence of 6% in the EBRT group. The committee considered that the difference in Kaplan–Meier estimates of local recurrence was 1% and the 95% CI was −0.68 to 2.68.
Evidence for cost effectiveness
Availability and nature of evidence
Both the company and the assessment group focused on the pre-pathology group of TARGIT‑A to develop their economic models.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use, the best way to incorporate this into the economic modelling is not clear. The committee debated whether the costs for Intrabeam and linear accelerator equipment should be included in the same way in the economic model (that is, including the capital costs of equipment for both technologies) or whether only the tariff cost associated with each technology should be included. The committee considered that, if the capital cost of EBRT had been included in the economic model, the cost savings associated with Intrabeam compared with EBRT would have been greater.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee concluded that there are benefits of Intrabeam that are very important to patients, particularly those associated with length of treatment and quality of life.
The committee understood that, to have the benefits of Intrabeam, some patients may be willing to accept a treatment that may be associated with a higher risk of local recurrence. It noted several benefits highlighted by the patient expert and clinical experts in terms of improving patients' quality of life, which could not be captured in the quality-adjusted life year (QALY) calculation.
Are there specific groups of people for whom the technology is particularly cost effective?
Only the pre-pathology group of patients was considered.
What are the key drivers of cost effectiveness?
The results from both the company's and the assessment group's models estimated that the QALY difference between Intrabeam and EBRT was very small. This was despite Intrabeam being associated with slightly more QALYs than EBRT in the company's model and being associated with fewer QALYs than EBRT in the assessment group's model. The results from both the company's and the assessment group's models indicated that Intrabeam provided some cost savings compared with EBRT. However, these savings were higher in the company's model than in the assessment group's model. The assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use the best way to incorporate this into the economic modelling is not clear.
Most likely cost-effectiveness estimate (given as an ICER)
The results from both the company's and the assessment group's models estimated that the QALY difference between Intrabeam and EBRT was very small.
The committee considered that, based on the high degree of uncertainty in the cost-effectiveness analysis, it was not possible to state the most plausible incremental cost-effectiveness ratio (ICER) for Intrabeam compared with EBRT. It concluded that Intrabeam was associated with slightly lower costs and fewer QALYs than EBRT.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
A committee member raised the question of whether there is the potential for some patients to be disadvantaged if they lack the capacity to understand the information provided by the clinician and to make an informed choice (such as people with learning disabilities or communication difficulties). The committee considered that patients would not be disadvantaged by the recommendations, providing that clinicians act in the interest of their patients, in line with their usual responsibilities, and tailor their explanation to each patient's level of understanding, and discuss the risks and benefits with the patient's carers when applicable.
# Recommendations for further data collection
Clinicians should enter details about all patients who choose to have the Intrabeam radiotherapy system for adjuvant treatment of early invasive breast cancer during breast-conserving surgical removal of the tumour in the NHS onto a national register. They should audit, review and document clinical outcomes locally, and consider the relationship between outcomes and patients' characteristics.
The data and clinical outcomes to be collected include:
histology of the cancer and patients' characteristics including: type, size and grade of the tumour; side of the body affected; lymph node status; oestrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 status; and age of the patient
local recurrence
treatment after local recurrence
metastatic disease
disease-free survival
-verall survival
adverse effects of treatment
health-related quality of life (including EQ‑5D).
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{'Recommendations': "The Intrabeam radiotherapy system is not recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgical removal of the tumour.\n\nUse of the Intrabeam radiotherapy system is recommended only using machines that are already available and in conjunction with NHS England specified clinical governance, data collection and submission arrangements.\n\nThe procedure should only be carried out by clinicians with specific training in the use of the Intrabeam radiotherapy system.\n\nPatient selection for Intrabeam radiotherapy should be done by a multidisciplinary team experienced in the management of early invasive breast cancer, which includes both breast surgeons and clinical oncologists.\n\nClinicians wishing to undertake Intrabeam radiotherapy should take the following actions:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainties about the procedure and inform them about alternative treatment options.\n\nProvide patients with NICE's written information on the evidence of the risks and benefits of the range of treatment options available as an aid to shared decision-making.", 'The technology': 'Description of the technology\n\nThe Intrabeam radiotherapy system (Carl Zeiss UK) is a mobile irradiation system. It is designed to deliver a single dose of targeted low-energy radiation (X‑rays) directly to the tumour bed, while limiting the exposure of healthy tissue to radiation. Because it delivers low energy radiation, it can be used in an ordinary operating theatre at the time of surgery. The Intrabeam radiotherapy system provides a source of 50\xa0kV energy from a spherical applicator of between 1.5\xa0cm and 5.0\xa0cm diameter. The applicator is sutured to the tumour bed so that breast tissue at risk of local recurrence receives the prescribed dose while skin and deeper structures are protected. Radiation is delivered over 20\xa0to 30\xa0minutes.\n\nCE marking\n\nThe Intrabeam radiotherapy system was granted a CE (Conformité Européene) mark in 1999 for use in radiotherapy.\n\nIntrabeam can be used as an intraoperative radiotherapy system given as the sole treatment or as a boost treatment followed by external beam radiotherapy (EBRT). When intraoperative radiotherapy is given as a boost treatment with Intrabeam and followed by EBRT, there is no need for further external boost treatment. Six NHS centres in the UK have used Intrabeam for adjuvant treatment of early breast cancer.\n\nAdverse reactions\n\nAdverse reactions are mostly related to wound-related complications and radiotherapy-related complications.\n\nRecommended dose and schedule\n\nThe surface of the tumour bed typically receives a single fraction of 20\xa0grays, which attenuates to 5\xa0grays to 7\xa0grays at a depth of 1\xa0cm.\n\nPrice\n\nThe cost of the Intrabeam radiotherapy system (including the spherical applicators) is £435,000 (excluding VAT, Carl Zeiss UK personal notification). The company estimates that device maintenance and servicing costs are about £35,000 per year. Costs may vary in different settings because of negotiated procurement discounts.', 'Evidence': 'The appraisal committee (section\xa07) considered evidence from a number of sources. See the committee papers, for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of the Intrabeam radiotherapy system, having considered evidence on the nature of early invasive breast cancer and the value placed on the benefits of the Intrabeam radiotherapy system by people with the condition, those who represent them and clinical experts. It also took into account the effective use of NHS resources.\n\n# The management of early invasive breast cancer\n\nThe committee heard from the clinical experts that usual clinical practice in the NHS is to give adjuvant radiotherapy to people with early invasive breast cancer after successful breast-conserving surgery (that is, removal of the tumour with clear margins). This is given by external beam radiotherapy (EBRT) using a linear accelerator delivering 40\xa0grays in 15\xa0fractions over 3\xa0weeks in line with NICE's clinical guideline on early and locally advanced breast cancer (CG80). The committee heard from the clinical experts that there was some variation in clinical practice, with some oncologists recommending EBRT over 5\xa0weeks but that, in general, most oncologists would recommend EBRT in line with CG80. An additional external radiotherapy boost dose to the site of the excised tumour lasting a further 1\xa0week to 2\xa0weeks could be offered to people with a higher risk of local recurrence. The committee noted comments from professional groups and also heard from the clinical experts that radiotherapy is constantly evolving. It also noted that there are several ongoing trials investigating, for example, whether the course of radiotherapy could be reduced from 3\xa0weeks to 1\xa0week, or whether radiotherapy is needed at all for patients considered to be at low risk of recurrence. The clinical experts suggested that the results of these trials may influence future clinical practice in the UK. The committee understood that clinical practice is evolving and that the delivery and use of external radiotherapy may change in the future, moving towards a more targeted approach in which patients have treatment based on their individual risks. The committee noted that Intrabeam could be used at the time of surgery as an alternative to postoperative treatment with EBRT. It also noted that, if adverse histological features are identified in the cancer cells at final pathology after treatment with Intrabeam, and subsequent EBRT is recommended, a further external boost dose would not be needed.\n\n# Potential benefits of Intrabeam\n\nThe committee noted that Intrabeam delivers a single dose of targeted low energy (X‑ray) radiation to the tumour bed. It can be used in an operating theatre as a single treatment at the same time as the surgery to remove the primary tumour. Patients at low risk of recurrence do not receive any further radiotherapy. However the committee was aware that patients with a higher risk of recurrence (for example, histopathology showing invasive lobular carcinoma, extensive intraductal component, node involvement, and close margins) may go on to receive an additional course of EBRT. For patients having EBRT, treatment can only begin after the surgical wound has healed and takes several weeks of daily therapy to complete. Intrabeam also has the theoretical advantage of having the source of radiation directly applied to the tumour bed. However, the committee heard from the clinical experts that there are now techniques allowing clinical oncologists to more accurately target the dose with EBRT, such as using clips during surgery to mark the site of the tumour. Although there is a risk of clips moving within the cavity, EBRT has evolved and is generally considered to be accurate for targeting the tumour site. The committee noted comments from professional groups that the main aim of radiotherapy after surgical removal of the tumour is to prevent local recurrence. A clinical expert confirmed that local recurrence is not related to an increased risk of metastatic disease or mortality in people with low-risk early breast cancer, such as those included in a randomised trial of breast cancer surgery with or without subsequent EBRT: the PRIME II study. This study included women aged 65\xa0years or older with tumours no bigger than 3\xa0cm that had not spread to the lymph nodes and that were hormone-receptor positive. All the patients received adjuvant hormone treatment. If there is local recurrence after breast-conserving surgery and EBRT, this is usually treated by mastectomy. However, for some patients, brachytherapy may be a suitable breast-conserving treatment instead of mastectomy. If there is recurrence after treatment with Intrabeam, further breast-conserving surgery and EBRT still remain a theoretical treatment option. The committee also heard from the patient expert that Intrabeam could be used when EBRT is unsuitable or not possible, for example, for those patients who are unable to raise their arm. The committee understood from the clinical experts that people for whom EBRT was not a suitable treatment would currently be offered mastectomy, and that Intrabeam might be an appropriate option for them. The committee concluded that Intrabeam, given at the same time as surgery, provided a potential advantage in delivering radiotherapy in direct contact with the tumour bed, and also represented an alternative treatment option for people for whom EBRT is not suitable, although for those people with a higher risk of recurrence an additional course of EBRT may still be required.\n\nThe committee heard from the patient expert that the psychological burden of breast cancer is high for patients and their families. The patient expert explained that, when a patient is diagnosed with breast cancer, the thought of many radiotherapy sessions over a number of weeks can cause emotional stress and anxiety and is highly disruptive to daily living. The patient may need to stop working and face substantial travel costs, which can have a considerable financial and emotional impact on the patient and their family. The committee also heard from the patient expert that some patients who live a long distance from a radiotherapy centre may need to stay away from their home to be able to complete the course of radiotherapy. The patient and clinical experts highlighted that the time between diagnosis and the end of treatment is much reduced with Intrabeam compared with EBRT. This is because the patient has the treatment at the same time as surgery and, for most people, no further treatment is needed. The patient expert also considered that Intrabeam does not have the adverse effects that are associated with EBRT such as local tenderness, breast pain, swelling and reduced range of movement. However, the committee also heard from clinical experts that the adverse effects of EBRT are mainly fatigue and that only a few patients have radiosensitivity, which can cause swelling and weeping of the breast. The patient and the company expert stated that Intrabeam is associated with better cosmetic outcomes than EBRT, and that changes in breast appearance and texture can be avoided or reduced with Intrabeam. The patient expert highlighted that cosmetic outcomes have a big effect on patients' quality of life. However the committee heard differing opinions from the clinical experts as to whether the cosmetic outcome from Intrabeam is superior to modern EBRT because the cosmetic outcomes with EBRT have improved substantially in recent years. The committee heard from the clinical experts that breast fibrosis is more common with EBRT than with Intrabeam, but that both treatments are associated with a substantial increase in the occurrence of fibrosis in the breast. The committee noted comments from the company and patient groups stating that treatment with EBRT is associated with potential long-term damage to other organs including the heart, and that treatment with Intrabeam would reduce the radiation dose to adjacent tissues. However, a clinical expert stated that the radiation dose to the heart with modern EBRT is not clinically significant. The committee concluded that patients generally tolerate EBRT well, with good outcomes, but that avoiding multiple radiotherapy sessions by having a single treatment with Intrabeam at the same time as surgery would be considered a major advantage by some patients.\n\n# Clinical effectiveness\n\n## The TARGIT‑A trial\n\nThe committee discussed the clinical evidence presented for Intrabeam, which came from a randomised trial comparing Intrabeam with EBRT (TARGIT‑A). The committee had a number of concerns with the trial; it noted several comments received from professional and patient groups, and comments made by the assessment group, highlighting concerns about the robustness of the trial and its generalisability to NHS clinical practice. The committee noted that in TARGIT‑A, EBRT was delivered in an average of 23\xa0fractions, longer than the 15\xa0fractions delivered in established clinical practice in the NHS. The radiation doses administered with EBRT also ranged from 40\xa0grays to 56\xa0grays in TARGIT‑A, whereas established clinical practice in the NHS is a dose of 40\xa0grays. The committee also noted comments from professional groups highlighting that quality control of EBRT was not reported in some centres, and may have shown considerable variation internationally. The clinical experts stated that it is not possible to predict what effect the variation in dose may have had on the results of the trial. Only 6\xa0of the 33\xa0centres participating in the trial were in the UK. The committee concluded that some doubt remains about the generalisability of the trial results to NHS clinical practice.\n\n## Length of follow-up in the TARGIT‑A trial\n\nThe committee noted comments received from professional and patient groups that the length of follow-up in the trial was too short to reliably demonstrate the clinical effectiveness of Intrabeam compared with EBRT for the incidence of local recurrence. Median follow-up in the trial was 2\xa0years and 5\xa0months and only 35% of the patients had 5‑year follow-up at the time of the analysis. The committee heard from the clinical experts that longer follow-up, usually of at least 5\xa0years, is needed for clinicians to feel confident about data on local recurrence. A clinical expert noted that this is the approach being followed for reporting the results of ongoing trials that are investigating whether the course of radiotherapy could be reduced from 3\xa0weeks to 1\xa0week, or whether radiotherapy is needed at all for some patients considered to have low risk of recurrence. The committee also noted comments from consultation on its preliminary recommendations that questioned the reliability of the data presented and suggested that the data are too immature to be the basis of firm recommendations. The committee heard from the TARGIT‑A investigators that median follow-up in the trial is currently 4\xa0years, and that complete follow-up and publication of final results is not yet known. The committee was aware of the large debate in the medical community about TARGIT‑A, in which opposite views have been raised about the importance of mature follow-up, trial governance and the interpretation of the results. The committee concluded that the results of TARGIT‑A should be interpreted with caution because the length of follow-up is less than 5\xa0years for the full trial population.\n\n## Subgroups in the TARGIT‑A trial\n\nThe committee noted that TARGIT‑A included a pre-pathology group (that is, treatment with Intrabeam was delivered at the same time as surgical removal of the tumour) and a post-pathology group (that is, treatment with Intrabeam was delayed and provided after a second surgical procedure to re-open the wound), and that this stratification was included as a protocol amendment. A clinical expert commented that this stratification was included because of centre preferences. Some trial centres gave Intrabeam only at a second operation after pathology results were available. The committee noted that the rate of local recurrence in the post-pathology group was higher than in the pre-pathology group, and that the company stated that non-inferiority for local recurrence had not been established in the post-pathology group. The committee also noted that, because of these results, the company suggested focusing only on the pre-pathology group and that the assessment group had also focused on this group to develop its economic model. The committee heard from a clinical expert that there were plausible reasons for worse results with Intrabeam when the treatment was delivered post pathology. At a second operation there could be scar tissue or seroma present, and targeting the exact tumour bed would be more difficult. The committee concluded that it was reasonable to consider treatment with Intrabeam only at the time of primary surgical removal of the tumour.\n\n## The non-inferiority margin in TARGIT‑A\n\nThe committee noted that TARGIT‑A was a non-inferiority trial, and that the primary end point was local recurrence in the conserved breast. The committee heard from the company that there were no differences in the rate of local recurrence in this group compared with the rest of the trial population. The committee considered the low rates of local recurrence, which had so far been demonstrated in both arms of the trial: 1.1% for EBRT and 2.1% for Intrabeam in the pre-pathology group. The committee noted that the pre-specified non-inferiority margin at 5\xa0years for the absolute difference of local recurrence between treatment groups was 2.5%. The committee heard from the clinical experts that this was based on an estimated rate of 5‑year local recurrence of 6% in the EBRT group. The committee noted that the non-inferiority margin is normally estimated based on the expected hazard ratio rather than on an estimated rate in the control group and an absolute difference in rates between groups. It considered that the pre-trial estimated 5‑year rate of 6% for local recurrence, on which the non-inferiority margin was based, is higher than the current expected rate of local recurrence in people having treatment with EBRT. The committee also noted that patients in the trial had a relatively good prognosis and low risk of local recurrence and heard from the clinical experts that, since 2000, when patients were first recruited into the trial, the 5‑year local recurrence rate with EBRT has decreased to much lower than 6%. The committee also noted that, when assessing non-inferiority, the point estimate alone is not sufficient. The confidence interval (CI) around the point estimate should also be considered and compared with the pre-specified non-inferiority margin. The committee noted that, in their response to the committee's request, the TARGIT‑A investigators quantified the difference in the Kaplan–Meier estimates of local recurrence, and its 95% CI, using 2\xa0different methods. The committee also noted that the integrated difference method presented by the investigators: is not commonly used; provided more favourable results for Intrabeam; and was not pre-specified in the TARGIT‑A protocol. It further noted that, because the non-inferiority margin was based on the absolute difference in local recurrence, the same margin could not be used for assessing non-inferiority if the integrated difference method were to be accepted. The committee considered that difference in Kaplan–Meier estimates of local recurrence and its 95% CI calculated using the conventional method were more appropriate. It noted that, using this method, the absolute difference between 5‑year Kaplan–Meier estimates for local recurrence in the pre-pathology group was 1% and the 95% CI was −0.68 to 2.68. On the currently available evidence, the committee concluded that there was no statistical reason for using a different method to assess whether Intrabeam is non-inferior to EBRT.\n\n## Local recurrence rates\n\nThe committee acknowledged that the rate of local recurrence in TARGIT‑A was low in both treatment groups, and that longer follow-up of patients is needed to provide more long-term data and less uncertain results. The committee noted that the CI around the absolute difference in local recurrence at 5\xa0years is wide, and that the upper end of the interval is higher than the pre-specified non-inferiority margin (absolute difference 1%; 95% CI −0.68 to 2.68). The committee considered that the criterion for non-inferiority was not appropriately defined. This meant that the trial was underpowered and the results could not be considered robust enough to determine whether Intrabeam is non-inferior to EBRT in terms of local recurrence. The committee therefore concluded that the non-inferiority of Intrabeam compared with EBRT in terms of local recurrence is unproven. However, it acknowledged that the recurrence rates reported in the Intrabeam group could be considered low in absolute terms and, based on the evidence available so far, not out of line with current recurrence rates with EBRT in the NHS. The committee noted that the trial investigators stated that there have been 15\xa0additional local recurrence events in the pre-pathology group since the analysis was done. But, because data were blinded, it is not possible to know which treatment group these events occurred in. The committee concluded that, although complete follow-up is needed to reduce the uncertainty around the results, the absolute number of local recurrences was still low. The committee expressed disappointment that the trial results remained blinded because this meant the technology appraisal was done without access to the latest data, or a date when this would be available.\n\n## Overall survival results from TARGIT‑A\n\nThe committee noted that the number of breast cancer deaths was higher in the Intrabeam group compared with the EBRT group, although the difference was not statistically significant. The committee also noted that there were fewer non-breast cancer deaths in the Intrabeam group compared with the EBRT group and that this difference was statistically significant. The committee noted the assessment group's considerations and the comments received on the assessment group's report from professional groups and the company on the difference in overall survival between the 2\xa0treatment groups in TARGIT‑A. It understood that the assessment group had reported that the difference in overall survival was based on a small number of events and that it did not consider that there was an excess of deaths in the EBRT group, but rather a shortfall of deaths in the Intrabeam group occurring by chance. The committee noted that the assessment group had compared the non-breast cancer mortality data from the EBRT group with the annual all-cause mortality probabilities obtained from the Office of National Statistics data and found that they were similar. The committee acknowledged that caution is needed when comparing international trial data (such as data from TARGIT‑A) and country-specific data (such as data from the Office of National Statistics in the UK). The committee also noted comments received from professional groups and the company suggesting that the assessment group's conclusion on the difference in non-breast cancer death between treatment groups occurring by chance was erroneous and that whole breast radiation is associated with cardiac toxicity, which can increase the subsequent rate of ischaemic cardiac events. The committee heard from a clinical expert that the mean radiation dose to the heart was not provided in the TARGIT‑A publication and that the mean dose to the heart delivered with EBRT in clinical practice in the NHS is minimal. Therefore it is highly unlikely that the difference in non-breast cancer deaths between treatment groups in TARGIT‑A could be explained by an increased risk of cardiovascular death related to EBRT. The committee heard from clinical experts and noted comments from professional groups suggesting that it is not possible to draw any conclusions from TARGIT‑A in terms of an overall survival benefit with Intrabeam compared with EBRT. The committee agreed that, because the patient baseline characteristics in the trial did not include cardiovascular risk factors, it is not possible to confirm that there is an overall survival benefit with Intrabeam compared with EBRT.\n\n## The relative benefits and risks of Intrabeam\n\nThe committee considered the clinical evidence available for Intrabeam, taking into account the advantages of the technology that were highlighted by the patient expert. The committee noted that the clinical evidence for Intrabeam is immature and associated with considerable uncertainty. It acknowledged that Intrabeam has not been proven to be non-inferior to EBRT and could have a higher risk of local recurrence. The committee understood that some patients are willing to accept a higher risk of local recurrence as long as the absolute risk remains low and the treatment has other benefits that they consider important (see sections\xa04.2 and\xa04.3). The patient expert highlighted that patient choice should be based on an informed discussion between the patient and clinician, and that it is really important that patients understand all the benefits and risks associated with the technology. They noted that many patients make their decisions based on their personal circumstances and not necessarily based on the possibility of a future event in the long term. The clinical experts agreed that patient choice is important and the patient should be fully and clearly informed when making their decision. The committee heard from a clinical expert and noted comments from professional groups highlighting that patient choice needs to be based on high-quality evidence with adequate follow-up, which Intrabeam currently lacks. The committee concluded that there are benefits with Intrabeam that are very important to patients, particularly those associated with length of treatment and quality of life. It acknowledged its previous conclusion that, although complete follow-up is needed to reduce uncertainty around the results, the absolute number of local recurrences is still low (see section\xa04.7).\n\n# Cost effectiveness\n\nThe committee considered the cost-effectiveness evidence presented for Intrabeam compared with EBRT. It noted that both the company and the assessment group focused on the pre-pathology group of TARGIT‑A to develop their economic models. The committee noted that the results from both the company's and the assessment group's models estimated that the quality-adjusted life year (QALY) difference between Intrabeam and EBRT was very small. This was despite Intrabeam being associated with slightly more QALYs than EBRT in the company's model and being associated with fewer QALYs than EBRT in the assessment group's model. The committee also noted that the results from both the company's and the assessment group's models indicated that Intrabeam provided some cost savings compared with EBRT. However, these savings were higher in the company's model than in the assessment group's model. The committee also noted that the assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use the best way to incorporate this into the economic modelling is not clear. The committee noted that section\xa05.5.8 of the NICE guide to the methods of technology appraisal (2013) states that, if introduction of the technology needs changes in infrastructure, costs and savings should be included in the analysis. Section\xa05.12.6 of the guide states that, if savings are anticipated, the extent to which these finances can actually be realised should be specified. The committee debated whether the costs for Intrabeam and linear accelerator equipment should be included in the same way in the economic model (that is, including the capital costs of equipment for both technologies), or whether only the tariff cost associated with each technology should be included. The committee considered that, if the capital cost of EBRT were included in the economic model, the cost savings associated with Intrabeam compared with EBRT would be greater. The committee agreed that both the company and the assessment group estimated the costs of Intrabeam treatment as lower than EBRT, but it concluded that the size of the cost savings was uncertain.\n\n## Uncertainty in the cost-effectiveness analyses\n\nThe committee agreed with its previous conclusion that the clinical effectiveness of Intrabeam compared with EBRT remains considerably uncertain (see section\xa04.8 and section\xa04.9). The committee noted the results from the assessment group's probabilistic sensitivity analysis, which also showed extreme uncertainty in the model results. It noted that the point estimate of the incremental cost-effectiveness ratio (ICER) for Intrabeam is associated with lower costs and fewer QALYs compared with EBRT. The committee considered that, based on the high degree of uncertainty in the cost-effectiveness analysis, it was not possible to state the most plausible ICER for Intrabeam compared with EBRT. It concluded that Intrabeam was associated with slightly lower costs and fewer QALYs than EBRT.\n\n# Conclusions\n\nThe committee discussed whether, based on the evidence available, it was reasonable to recommend Intrabeam for routine commissioning in the NHS in England. It considered that the clinical- and cost-effectiveness evidence for Intrabeam remained uncertain. The committee noted its previous conclusions that, even if the length of follow-up of patients in TARGIT‑A had been longer, the quality of the trial and particularly its generalisability to NHS clinical practice would still not have provided conclusive evidence to establish the relative clinical and cost effectiveness of Intrabeam compared with EBRT as delivered in the NHS. The committee also noted that the rate of local recurrence with Intrabeam may be higher than with EBRT. However, it took into account that Intrabeam may provide benefits that some patients would consider substantial and that there are some patients who could particularly benefit from Intrabeam, such as people for whom EBRT is not suitable. The committee recognised its role of not recommending treatments for routine use if the benefits to patients are unproven, or if the treatments are not cost effective, in line with section\xa06.1.2 of the guide to the methods of technology appraisal (2013). However, it understood that, to have the benefits of Intrabeam, some patients may be willing to accept a treatment that may be associated with a higher risk of local recurrence. It noted several benefits highlighted by the patient and clinical experts in terms of improving patients' quality of life, which could not be captured in the QALY calculation. It also noted that, although non-inferiority for Intrabeam compared with EBRT was unproven for local recurrence, the rates of recurrence in the Intrabeam group in the pre-pathology group were low. The committee understood the concerns raised by the clinical experts and the comments from professional groups that it is crucial to offer informed choice in clinical practice. The committee accepted that individual patient preference is important and agreed with the patient and clinical experts that patients should be fully informed of the evidence and treatment options available. The committee concluded that, given the difficulty in interpreting the evidence (particularly when specialist clinicians do not agree), patient selection for Intrabeam radiotherapy, if made available, should be done by multidisciplinary teams experienced in managing early invasive breast cancer including breast surgeons, clinical oncologists and radiotherapy physics experts in brachytherapy. The committee agreed that clinicians wishing to carry out Intrabeam radiotherapy should ensure that patients understand the uncertainties about the procedure, and inform them about alternative treatment options. It also agreed that patients should be given written information, from NICE, on the evidence of the risks and benefits of all available treatment options to help with shared decision-making.\n\nThe committee understood that, if treatment with Intrabeam became widespread, considerable investment in equipment would be needed. However, if Intrabeam results were subsequently found to be unfavourable, this would be associated with irrecoverable costs to the NHS and potentially with overall worse outcomes at a population level. However, the option of localised single treatment with Intrabeam is welcomed by patients and, if its clinical and cost effectiveness can be confirmed, it could be beneficial for both patients and the NHS. Taking these factors into account, the committee considered that it is a technology worthy of further evaluation. The committee concluded that, because of the uncertainty in the evidence available, the Intrabeam radiotherapy system cannot be recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgery to remove the tumour.\n\nThe committee heard from the clinical experts that there are 6\xa0Intrabeam devices in the UK, which were used in TARGIT‑A but are not all being used at the moment. The committee considered that, given these existing resources, including staff trained in using Intrabeam, it would be reasonable to continue to use those devices that are available until further data is collected. The committee understood that there is considerable pressure on the existing NHS infrastructure for providing radiotherapy. As demand continues to rise the NHS will have to make further investment in new radiotherapy resources, taking into account emerging evidence on optimum pathways of care. The committee considered that collecting information about all patients having treatment with Intrabeam at a national level will allow the evidence from TARGIT‑A to mature while further data are collected in the NHS in a carefully controlled manner. The committee therefore concluded that it can only recommend the use of the Intrabeam radiotherapy system using only machines that are already available and only in conjunction with NHS England specified clinical governance, data collection and submission arrangements. These providers will also be required to comply with any NHS England service specifications pertaining to the delivery of intra-operative radiotherapy.\n\nThe committee recommended that further data collection in the NHS should include, as a minimum, a national collection of data from all patients having the Intrabeam radiotherapy system for adjuvant treatment of early invasive breast cancer in the NHS and it be recorded in the national radiotherapy dataset. Clinicians should audit, review and document clinical outcomes (described in section\xa06) locally, and consider the relationship between outcomes and patients' characteristics.\n\nThe committee discussed the technical requirements for Intrabeam and noted comments received from professional groups. It heard from the clinical experts that, although staff training is needed for Intrabeam, this will not necessarily mean there will be an increase in the number of staff or staff time, rather a change in their responsibilities and duties. The committee agreed with the clinical experts and concluded that the Intrabeam radiotherapy system should only be used by clinicians with specific training in its use.\n\n# Equalities issues\n\nThe committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. A committee member raised the question of whether there is the potential for some patients to be disadvantaged by the recommendations, if they lack the capacity to understand the information provided by the clinician and to make an informed choice (such as people with learning disabilities or communication difficulties). The committee considered that patients would not be disadvantaged by the recommendations, providing that clinicians act in the interest of their patients, in line with their usual responsibilities, and tailor their explanation to each patient's level of understanding, and discuss the risks and benefits with the patient's carers when applicable. The committee concluded that there was no need to alter or add to its recommendations.\n\n# Summary of appraisal committee's key conclusions\n\nTA501\n\nAppraisal title: Intrabeam radiotherapy system for adjuvant treatment of early breast cancer\n\nSection\n\nKey conclusion\n\nThe Intrabeam radiotherapy system is not recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgical removal of the tumour.\n\nUse of the Intrabeam radiotherapy system is recommended only using machines that are already available and in conjunction with NHS England specified clinical governance, data collection and submission arrangements.\n\nThe procedure should only be carried out by clinicians with specific training in the use of the Intrabeam radiotherapy system.\n\nPatient selection for Intrabeam radiotherapy should be done by a multidisciplinary team experienced in the management of early invasive breast cancer, which includes both breast surgeons and clinical oncologists.\n\nClinicians wishing to undertake Intrabeam radiotherapy should take the following actions:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainties about the procedure and inform them about alternative treatment options.\n\nProvide patients with NICE's written information on the evidence of the risks and benefits of the range of treatment options available as an aid to shared decision-making.\n\nto 1.5\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nIntrabeam could be used when external beam radiotherapy (EBRT) is unsuitable or not possible, for example, for those patients who are unable to raise their arm. People for whom EBRT is not a suitable treatment are currently offered mastectomy, and Intrabeam might be an appropriate option for them.\n\n\n\nPatients generally tolerate EBRT well, with good outcomes, but avoiding multiple radiotherapy sessions by having a single treatment with Intrabeam at the same time as surgery would be considered a major advantage by some patients.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology/are the technologies in its/their potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that Intrabeam, given at the same time as surgery, provided a potential advantage in delivering radiotherapy in direct contact with the tumour bed, and also represented an alternative treatment option for people for whom EBRT is not suitable or not possible.\n\n\n\nWhat is the position of the treatment(s) in the pathway of care for the condition?\n\nUsual clinical practice in the NHS is to give adjuvant radiotherapy to people with early breast cancer after successful breast-conserving surgery (that is, removal of the tumour with clear margins). This is given by external beam radiotherapy (EBRT). An additional external radiotherapy boost dose to the site of the excised tumour lasting a further 1\xa0week to 2\xa0weeks could be offered to people with a higher risk of local recurrence.\n\n\n\nIntrabeam delivers a single dose of targeted low energy (X-ray) radiation to the tumour bed and can be used in an operating theatre as a single treatment at the same time as surgery to remove the primary tumour.\n\n\n\nAdverse reactions\n\nAdverse reactions are mostly related to wound-related and radiotherapy-related complications.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nA randomised trial comparing Intrabeam with EBRT (TARGIT‑A). It was a non-inferiority trial and the primary end point was local recurrence in the conserved breast.\n\n, 4.7\n\nLength of follow-up in the trial was too short to reliably show the clinical effectiveness of Intrabeam compared with EBRT for the incidence of local recurrence.\n\n\n\nThe committee noted that the clinical evidence for Intrabeam was immature and associated with considerable uncertainty. It acknowledged that Intrabeam had not been proven to be non-inferior to EBRT and could be associated with a higher risk of local recurrence.\n\n\n\nRelevance to general clinical practice in the NHS\n\nIn TARGIT‑A, EBRT was delivered in an average of 23\xa0fractions, longer than the 15\xa0fractions delivered in established clinical practice in the NHS. The radiation doses administered with EBRT also ranged from 40\xa0grays to 56\xa0grays in TARGIT‑A, whereas established clinical practice in the NHS is a dose of 40\xa0grays. Comments from professional groups highlighted that quality control of EBRT was not reported in some centres, and there may have been considerable variation internationally. The committee concluded that some doubt remained about the generalisability of the trial data to NHS clinical practice.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that the clinical evidence for Intrabeam was immature and associated with considerable uncertainty. It acknowledged that Intrabeam had not been proven to be non-inferior to EBRT and could be associated with a higher risk of local recurrence.\n\n\n\nIt was not possible to confirm that there is an overall survival benefit with Intrabeam compared with EBRT.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nTARGIT‑A included a pre-pathology group (that is, treatment with Intrabeam was delivered at the same time as surgical removal of the tumour) and a post-pathology group (that is, treatment with Intrabeam was delayed and provided after a second surgical procedure to re-open the wound). The rate of local recurrence in the post-pathology group was higher than in the pre-pathology group, and the company stated that non-inferiority for local recurrence had not been established in the post-pathology group. The committee concluded that it was reasonable to consider treatment with Intrabeam only at the time of primary surgical removal of the tumour.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee considered the low rates of local recurrence that had so far been shown in both arms of the trial: 1.1% for EBRT and 2.1% for Intrabeam in the pre-pathology group. It noted that the pre-specified non-inferiority margin at 5\xa0years for the absolute difference of local recurrence between treatment groups was 2.5%. The clinical experts stated that this was based on an estimated rate of a 5‑year local recurrence of 6% in the EBRT group. The committee considered that the difference in Kaplan–Meier estimates of local recurrence was 1% and the 95% CI was −0.68 to 2.68.\n\n, 4.8\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nBoth the company and the assessment group focused on the pre-pathology group of TARGIT‑A to develop their economic models.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use, the best way to incorporate this into the economic modelling is not clear. The committee debated whether the costs for Intrabeam and linear accelerator equipment should be included in the same way in the economic model (that is, including the capital costs of equipment for both technologies) or whether only the tariff cost associated with each technology should be included. The committee considered that, if the capital cost of EBRT had been included in the economic model, the cost savings associated with Intrabeam compared with EBRT would have been greater.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee concluded that there are benefits of Intrabeam that are very important to patients, particularly those associated with length of treatment and quality of life.\n\n\n\nThe committee understood that, to have the benefits of Intrabeam, some patients may be willing to accept a treatment that may be associated with a higher risk of local recurrence. It noted several benefits highlighted by the patient expert and clinical experts in terms of improving patients' quality of life, which could not be captured in the quality-adjusted life year (QALY) calculation.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nOnly the pre-pathology group of patients was considered.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe results from both the company's and the assessment group's models estimated that the QALY difference between Intrabeam and EBRT was very small. This was despite Intrabeam being associated with slightly more QALYs than EBRT in the company's model and being associated with fewer QALYs than EBRT in the assessment group's model. The results from both the company's and the assessment group's models indicated that Intrabeam provided some cost savings compared with EBRT. However, these savings were higher in the company's model than in the assessment group's model. The assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use the best way to incorporate this into the economic modelling is not clear.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe results from both the company's and the assessment group's models estimated that the QALY difference between Intrabeam and EBRT was very small.\n\nThe committee considered that, based on the high degree of uncertainty in the cost-effectiveness analysis, it was not possible to state the most plausible incremental cost-effectiveness ratio (ICER) for Intrabeam compared with EBRT. It concluded that Intrabeam was associated with slightly lower costs and fewer QALYs than EBRT.\n\n, 4.12\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nA committee member raised the question of whether there is the potential for some patients to be disadvantaged if they lack the capacity to understand the information provided by the clinician and to make an informed choice (such as people with learning disabilities or communication difficulties). The committee considered that patients would not be disadvantaged by the recommendations, providing that clinicians act in the interest of their patients, in line with their usual responsibilities, and tailor their explanation to each patient's level of understanding, and discuss the risks and benefits with the patient's carers when applicable.\n\n", 'Recommendations for further data collection': "Clinicians should enter details about all patients who choose to have the Intrabeam radiotherapy system for adjuvant treatment of early invasive breast cancer during breast-conserving surgical removal of the tumour in the NHS onto a national register. They should audit, review and document clinical outcomes locally, and consider the relationship between outcomes and patients' characteristics.\n\nThe data and clinical outcomes to be collected include:\n\nhistology of the cancer and patients' characteristics including: type, size and grade of the tumour; side of the body affected; lymph node status; oestrogen receptor status; progesterone receptor status; human epidermal growth factor receptor\xa02 status; and age of the patient\n\nlocal recurrence\n\ntreatment after local recurrence\n\nmetastatic disease\n\ndisease-free survival\n\noverall survival\n\nadverse effects of treatment\n\nhealth-related quality of life (including EQ‑5D)."}
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https://www.nice.org.uk/guidance/ta501
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Evidence-based recommendations on using Intrabeam radiotherapy during breast-conserving surgery in adults.
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9f5f64860adff2f61fe7c1b7e7e33e33f7ad20f1
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nice
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Ibrutinib for treating relapsed or refractory mantle cell lymphoma
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Ibrutinib for treating relapsed or refractory mantle cell lymphoma
Evidence-based recommendations on ibrutinib (Imbruvica) for treating relapsed or refractory mantle cell lymphoma in adults.
# Recommendations
Ibrutinib is recommended as an option for treating relapsed or refractory mantle cell lymphoma in adults, only if:
they have had only 1 previous line of therapy and
the company provides ibrutinib with the discount agreed in the commercial access agreement with NHS England.
This recommendation is not intended to affect treatment with ibrutinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Ibrutinib (Imbruvica, Janssen) inhibits a protein called Bruton's tyrosine kinase, stopping B-cell (lymphocyte) proliferation and promoting cell death.
Marketing authorisation
Ibrutinib has a marketing authorisation in the UK for the treatment of adults 'with relapsed or refractory mantle cell lymphoma'.
Adverse reactions
The most common adverse reactions associated with ibrutinib include diarrhoea, musculoskeletal pain, upper respiratory tract infection, haemorrhage, bruising, rash, and nausea. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Ibrutinib is taken orally (4×140‑mg capsules) once daily, until the disease progresses or there is unacceptable toxicity.
Price
Ibrutinib is available at the list price of £4,599.00 for 90×140‑mg capsules (£51.10 per capsule) and £6,132.00 for 120×140‑mg capsules (£51.10 per capsule; excluding VAT, British national formulary June 2016). The pricing arrangement considered during guidance development was a patient access scheme agreed with the Department of Health that applied to all indications for ibrutinib. The company subsequently agreed a commercial access agreement with NHS England that replaced the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.# Evidence
The appraisal committee (section 6) considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of ibrutinib, having considered evidence on the nature of relapsed or refractory mantle cell lymphoma and the value placed on the benefits of ibrutinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical effectiveness
## Clinical management of relapsed or refractory mantle cell lymphoma
The committee heard from the clinical expert that the most common first‑line options for treating mantle cell lymphoma are rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP), or rituximab in combination with bendamustine. These are followed by 2 years of rituximab maintenance treatment. The committee understood that there is no accepted standard of care for treating relapsed or refractory mantle cell lymphoma, and that a range of chemotherapy regimens are used. It heard from the clinical expert that these often contain rituximab, even though many people will have had rituximab as part of first-line and maintenance treatment. The clinical expert highlighted that as many as 22 different treatments are used in the UK for treating relapsed or refractory mantle cell lymphoma. The choice of treatment largely depends on the availability of drugs and clinician's choice, because there is no treatment regimen that has been shown to be the most effective in this setting. The clinical expert also commented that temsirolimus, the comparator in the main ibrutinib study (RAY), is not used in the UK because it is considered to be of low efficacy despite being licensed for this indication. The committee concluded that there is no standard of care for treating relapsed or refractory mantle cell lymphoma in England, and that treatment tends to combine rituximab with a range of chemotherapy options. It also concluded that temsirolimus is not relevant to UK clinical practice.
## Clinical need of patients with mantle cell lymphoma
The committee noted that mantle cell lymphoma is an aggressive form of non‑Hodgkin's lymphoma and in some cases can be associated with debilitating symptoms. There are very high rates of relapse after initial treatment, and a huge effect on quality of life. The committee heard from the patient and clinical experts that ibrutinib is already widely used in clinical practice because of its previous availability through the Cancer Drugs Fund, and is welcomed by patients because it is highly effective compared with existing treatments and extremely well tolerated with very few adverse reactions. It is taken orally and people value this highly because it can be taken in the privacy of their own home and reduces the need for hospital visits. It can be used by older and frail people and, unlike current chemotherapy options, patients do not usually need additional treatments to counter adverse reactions. For these reasons, the patient experts considered that ibrutinib is a life-transforming drug that results in a step change in the quality of life of patients with relapsed or refractory mantle cell lymphoma and their families and carers, allowing many to participate in general day-to-day activities, and very quickly return to their normal life. The committee concluded that the availability of an effective oral therapy with a manageable adverse-reaction profile is highly valued by patients and addresses a high unmet need among people with relapsed or refractory mantle cell lymphoma.
## Overview of ibrutinib studies
The committee noted that the evidence on the clinical effectiveness of ibrutinib came from 1 randomised controlled trial (RAY) and 2 single-arm studies (SPARK and PCYC‑1104). It considered that RAY is not strictly relevant to NHS practice because temsirolimus, the comparator treatment in the trial, is not routinely used in the UK. It noted the absence of any trials comparing ibrutinib with any comparator defined in the NICE scope. It also noted that all 3 studies were open label, which made them potentially prone to bias, although it accepted that the studies addressed potential measurement bias by using an independent review committee to evaluate the primary outcome. The committee concluded that the studies were of a reasonable quality but were limited by the lack of a comparison against a treatment used in UK clinical practice.
## Clinical evidence – trial results
The committee noted that at median follow-up of 20 months, median progression-free survival in RAY was statistically significantly longer for ibrutinib compared with temsirolimus (14.6 months compared with 6.2 months; hazard ratio 0.43; 95% confidence interval 0.32 to 0.58; p<0.0001). At the time of the first appraisal committee meeting the overall-survival data from RAY were immature and median overall survival had not yet been reached in the ibrutinib arm, indicating that more than 50% of patients were still alive. The committee noted that the crossover of 23% of patients in the temsirolimus arm to the ibrutinib arm could confound the overall-survival results, which could also be confounded by the use of subsequent anticancer systemic therapies in both arms (31.7% of patients in the ibrutinib arm and 58.2% of patients in the temsirolimus arm). Following consultation on the appraisal consultation document, the committee considered updated RAY data submitted by the company, with a median follow‐up of 39 months. It noted that the results were consistent with the earlier data and that median overall survival had now been reached (30.3 months for ibrutinib compared with 23.5 months for temsirolimus; HR 0.74; 95% CI 0.54 to 1.02). The committee concluded that the results from RAY suggest that ibrutinib significantly improves progression-free survival compared with temsirolimus. But the overall-survival benefits remain uncertain, despite the availability of more mature data, because of potential confounding from crossover and the use of further anticancer therapies.
The committee considered that the results from the 2 single-arm trials were generally supportive of the results from RAY, although it noted that the overall-response rates and progression-free survival were slightly lower in the single-arm trials than in the ibrutinib arm of RAY. It concluded that it was appropriate to pool the results from the 3 studies to give a larger patient population, given the general lack of evidence for treating relapsed or refractory mantle cell lymphoma with ibrutinib.
## Indirect comparison
The committee noted that in the absence of any direct trial evidence for ibrutinib against a comparator reflective of current UK clinical practice, the company did an indirect treatment comparison using results from RAY and from the OPTIMAL study (Hess, 2009) that compared temsirolimus with clinician's choice of single-agent chemotherapy. The indirect treatment comparison compared ibrutinib against clinician's choice of single-agent chemotherapy in OPTIMAL, using temsirolimus as the common comparator. The committee noted that the company adjusted the treatment effect of chemotherapy, as estimated from the indirect comparison, to take into account the additional effect of adding rituximab (R‑chemo). This adjustment used data on the benefit of R‑chemo compared with single-agent chemotherapy from the Haematological Malignancy Research Network (HMRN) audit of 118 patients with mantle cell lymphoma that had been treated with first-line therapy. The committee understood that this resulted in a progression-free survival hazard ratio for ibrutinib compared with R‑chemo of 0.28 (representing a 72% reduction in the risk of disease progression with ibrutinib compared with R‑chemo).
The committee acknowledged the limitations of the indirect comparison that were highlighted by both the company and the evidence review group (ERG), such as differences in the patient populations in OPTIMAL and RAY. It also noted that the HMRN audit did not specifically relate to patients with relapsed or refractory mantle cell lymphoma. It also understood that the ERG did not agree with the company's 2‑stage approach to estimating treatment effects for ibrutinib compared with R‑chemo, and that the ERG had done a separate analysis based on a single‑stage approach using a random effects network meta-analysis instead of fixed effects. This resulted in a hazard ratio for progression-free survival of 0.27 (HR 0.27; 95% credible interval 0.06 to 1.26), similar to the company's estimate of 0.28. However, the committee noted that because of concerns about the evidence used to inform the indirect comparisons, the ERG considered that the results of both analyses should be interpreted with caution. The committee also noted that the company's alternative approach to estimating the effectiveness of ibrutinib compared with R‑chemo (that is, assuming that temsirolimus has equal efficacy to R‑chemo based on the results from RAY) produced a less-favourable hazard ratio of 0.43. The committee concluded that there is considerable uncertainty associated with the indirect comparisons and that the benefit of ibrutinib compared with R‑chemo is unclear, although it accepted that the available evidence and experience from clinical practice strongly suggest that ibrutinib is more effective.
## Subgroups
The committee discussed the efficacy results for subgroups of patients, based on the number of previous lines of therapy. It noted that the results suggest greater efficacy in patients who had ibrutinib after only 1 previous line of therapy, compared with 2 or more therapies. The clinical expert also stated that ibrutinib is particularly beneficial after the first relapse. The committee considered the updated RAY data, which have a median follow‐up of 39 months. These provide further evidence of a greater benefit of ibrutinib when taken after only 1 previous line of therapy. Updated median overall survival was 42.1 months for ibrutinib and 27.0 months for temsirolimus in the 1 previous therapy subgroup, compared with 22.1 months and 17.0 months respectively after 2 or more therapies. The committee understood that the data were potentially confounded by crossover of patients in the temsirolimus arm to the ibrutinib arm (39% in the 1 previous therapy subgroup). It was also concerned that the subgroups were defined post hoc. However, the committee noted responses to the appraisal consultation document from professional groups. These state that evidence from clinical practice supports the RAY results, and that earlier use of ibrutinib in relapsed or refractory disease is the most beneficial. The committee concluded that the evidence from RAY and clinical experience suggest that ibrutinib is most effective in people who have had only 1 previous line of therapy.
# Cost effectiveness
## The company's model and the ERG's exploratory analyses
The committee noted that the company had developed a Markov model comparing ibrutinib with R‑chemo, comprising 3 states (pre-progression, post-progression and death), and that this approach had been used in previous NICE appraisals. The committee was aware that overall-survival data from the ibrutinib studies were not directly extrapolated but were modelled using progression-free-survival data from the pooled ibrutinib dataset. The committee considered that the company's approach is appropriate given the immaturity of the overall-survival data at the time of the modelling.
The committee considered the ERG's critique of the company's model. It noted the ERG's comments that the company's Markov approach imposed structural constraints, which did not make the best use of the trial data on survival, and that the overall survival predicted by the model did not provide a good visual fit to the observed Kaplan–Meier survival curve from the trials. The committee understood that the ERG favoured a partitioned survival model using overall-survival data for ibrutinib directly from the trials rather than using progression-free survival, and had explored the effect of using this approach in an exploratory analysis (set B). The committee examined the ERG's set B exploratory analysis but was concerned that the partitioned survival approach resulted in efficacy estimates for R‑chemo that were higher than those for ibrutinib, giving higher quality-adjusted life year (QALY) gains for R‑chemo than ibrutinib. By contrast, it heard from the clinical expert that experience has shown that ibrutinib is more effective than R‑chemo for treating relapsed or refractory mantle cell lymphoma. This is partly because relapsed or refractory disease will already have been treated with R‑chemo and rituximab maintenance therapy, which will become progressively less effective with further relapse. The committee concluded that the results of the partitioned survival analysis are not clinically plausible, acknowledging the ERG's comments that they are associated with major uncertainty because they used the outputs of a highly uncertain meta-analysis.
The committee re-examined the company's Markov approach, which it considered led to more plausible results (incremental QALYs for ibrutinib compared with R‑chemo ranging from 0.82 to 1.87 depending on the scenario), although it acknowledged the considerable uncertainty associated with these estimates. The committee noted that in the company's base-case analysis, incorporating the updated patient access scheme, the incremental cost-effectiveness ratio (ICER) for ibrutinib compared with R‑chemo was £62,650 per QALY gained. It also noted that the company carried out a range of scenario analyses to test the assumptions in the model. These included estimating the effectiveness of ibrutinib compared with R‑chemo using temsirolimus as a proxy for R‑chemo. The committee noted that this scenario used the efficacy data from RAY and resulted in an estimated ICER for ibrutinib compared with R‑chemo of £69,142 per QALY gained. The committee also noted that the ICER was above £59,000 per QALY gained in all but 1 of the scenarios presented by the company. In that 1 scenario, the company applied a hazard ratio to post-progression survival for R‑chemo. This was adjusted to be as close as possible to the anticipated survival based on the results of the HMRN audit (that is, 8.4 months for patients on second-line treatment). This resulted in an ICER of £49,849 per QALY gained. However, the committee understood that time-to-event estimates for progression-free survival and post-progression survival for ibrutinib were taken from the 1 previous therapy subgroup, and therefore that the analysis reflects this subgroup.
The ERG did a set of exploratory analyses (set A) that made adjustments to some of the parameter values in the company's model. These mostly resulted in a lower ICER for ibrutinib compared with R‑chemo than that estimated by the company. However, the committee was minded not to accept the results of the ERG's amendments because these represented the extreme (lowest) end of the ERG's wide estimate of possible ICERs, depending on the model and parameters used. The committee concluded that the ICERs presented by the company for the whole population of people with relapsed or refractory mantle cell lymphoma, incorporating the confidential patient access scheme for ibrutinib, are above the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).
The committee recognised the high clinical need of people with mantle cell lymphoma and that ibrutinib has several benefits including oral administration, manageable adverse reactions and low toxicity. It therefore considered that ibrutinib is a step change in managing relapsed or refractory mantle cell lymphoma. However, it did not consider that any additional health-related benefits, that had not been captured fully in the QALY calculation, would be enough to lower the ICER for the whole population to within the range normally considered cost effective.
The committee recalled its earlier conclusion that trial evidence and clinical experience suggest that ibrutinib is most effective in people who have had only 1 previous line of therapy (see section 4.8). It therefore considered whether ibrutinib could be considered cost effective in this group of patients. It noted that the company's ICER of £49,849 per QALY gained may be a conservative estimate because updated trial data from RAY suggest that the model underestimates survival for this subgroup. The committee also noted that overall survival in RAY may have been confounded by the crossover of 39% of people from the temsirolimus arm to the ibrutinib arm. The committee concluded that the most plausible ICER in this group of patients is likely to be lower than the company's estimate of £49,848 per QALY gained.
# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It accepted that ibrutinib is indicated for people with a short life expectancy, noting that the estimates presented for people with relapsed or refractory mantle cell lymphoma ranged from 5.2 months to 9.7 months. It also accepted that there is enough evidence to indicate that ibrutinib offers an extension to life of at least an additional 3 months, compared with current NHS treatment. The committee concluded that ibrutinib met all the criteria to be considered a life-extending end-of-life treatment.
Taking all the evidence and uncertainties together, and given the extra weight applied to QALYs at the end of life, the committee concluded that the company's ICERs for the whole population of people with relapsed or refractory mantle cell lymphoma are above the range normally considered to be a cost-effective use of NHS resources. However, the committee concluded that ibrutinib is a cost-effective use of NHS resources for people who have had only 1 previous line of therapy, and that ibrutinib can be recommended for use in this group of people.
# Potential equality issues
The committee noted the potential equality issue raised by the company and patient groups that ibrutinib would offer an alternative to less effective but better tolerated chemotherapy agents for older or frailer people. It also noted the issue raised that oral administration allows an effective treatment option for people without access or transport to an infusion unit and significantly reduces multiple hospital visits. The committee acknowledged that access to ibrutinib may enhance treatment in these groups of people.
# Pharmaceutical Price Regulation Scheme (PPRS) 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Summary of appraisal committee's key conclusions
TA502
Appraisal title: Ibrutinib for treating relapsed or refractory mantle cell lymphoma
Section
Key conclusion
Ibrutinib is recommended as an option for treating relapsed or refractory mantle cell lymphoma in adults, only if:
they have had only 1 previous line of therapy and
the company provides ibrutinib with the discount agreed in the commercial access agreement.
The committee concluded that the incremental cost-effectiveness ratios (ICERs) presented by the company for the whole population of people with relapsed or refractory mantle cell lymphoma, incorporating the updated confidential patient access scheme for ibrutinib, are above the range normally considered a cost‑effective use of NHS resources (that is, £20,000 to £30,000 per quality-adjusted life year gained).
The committee noted that the evidence from trials and clinical experience suggest that ibrutinib is most effective in people who have had only 1 previous line of therapy. It concluded that ibrutinib is a cost-effective use of NHS resources for this subgroup.
The committee concluded that ibrutinib met all the criteria to be considered a life-extending end-of-life treatment.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee concluded that the availability of an effective oral therapy with a manageable adverse-reaction profile is highly valued by people, and addresses a high unmet need for people with relapsed or refractory mantle cell lymphoma.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee accepted that ibrutinib has several benefits for people including oral administration, manageable adverse reactions and low toxicity. The committee concluded that ibrutinib could be considered a step change in managing relapsed or refractory mantle cell lymphoma.
What is the position of the treatment in the pathway of care for the condition?
Ibrutinib has a marketing authorisation in the UK for the treatment of adults 'with relapsed or refractory mantle cell lymphoma'.
Adverse reactions
The committee understood that ibrutinib is extremely well tolerated with very few adverse reactions.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee understood that the clinical evidence for ibrutinib came from 1 randomised controlled trial (RAY), in which ibrutinib was compared with temsirolimus, and 2 single-arm studies (SPARK and PCYC‑1104). The committee concluded that the studies were of a reasonable quality but were limited by the lack of a comparison against a treatment used in UK clinical practice.
Relevance to general clinical practice in the NHS
The committee considered that RAY was not strictly relevant to NHS practice because temsirolimus, the comparator treatment in the trial, is not routinely used in the UK.
Uncertainties generated by the evidence
The committee concluded that the overall-survival benefits from RAY were uncertain because of the crossover of many patients in the temsirolimus arm to the ibrutinib arm, and the use of further anticancer systemic therapies in both arms.
The committee was aware that there is considerable uncertainty associated with the indirect comparisons and that the size of the benefit of ibrutinib compared with R‑chemo is unclear.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee recognised that trial evidence and clinical experience suggest that ibrutinib is most effective in people who have had only 1 previous line of therapy.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee concluded that the results from RAY suggest that ibrutinib significantly improves progression-free survival compared with temsirolimus. The committee considered that the results from the 2 single-arm studies are generally supportive of the results from RAY. It concluded that it is appropriate to pool the results from the 3 studies to give a larger patient population, given the general lack of evidence for treating relapsed or refractory mantle cell lymphoma with ibrutinib.
Evidence for cost effectiveness
Availability and nature of evidence
The company developed a Markov model, comparing ibrutinib with R‑chemo, with 3 states (pre-progression, post-progression and death). The committee was aware that overall-survival data from the ibrutinib studies were not directly extrapolated but were modelled using progression-free survival data from the pooled ibrutinib dataset. It concluded that the company's approach is appropriate, given the immaturity of the overall-survival data at the time of the modelling.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee understood that the evidence review group (ERG) favoured a partitioned survival model using overall-survival data directly from the trials rather than using progression-free survival, and had explored the effect of using this approach. However, the committee concluded that the results of the partitioned survival analysis are not clinically plausible, acknowledging the ERG's comments that they are associated with major uncertainty because they used the outputs of a highly uncertain meta-analysis.
The committee considered that the company's Markov approach led to more plausible results, although it acknowledged the considerable uncertainty associated with these estimates. It concluded that the company's ICERs for the whole population of people with relapsed or refractory mantle cell lymphoma, incorporating the confidential patient access scheme for ibrutinib, are above the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee noted that ibrutinib has several benefits for people including oral administration, manageable adverse reactions and low toxicity. It therefore considered that ibrutinib is a step change in managing relapsed or refractory mantle cell lymphoma. However, it did not consider that any additional health-related benefits that had not been captured fully in the QALY calculation would be enough to lower the ICER to within the range normally considered cost effective.
Are there specific groups of people for whom the technology is particularly cost effective?
The committee concluded that ibrutinib is a cost-effective use of NHS resources for the subgroup of people who have had only 1 previous line of therapy.
What are the key drivers of cost effectiveness?
The committee was aware that in all but 1 of the scenarios presented by the company, the ICER was above £59,000 per QALY gained.
Most likely cost-effectiveness estimate (given as an ICER)
The committee concluded that the most plausible ICER for the 1 previous therapy subgroup is likely to be lower than the company's estimate of £49,848 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The company agreed a patient access scheme with the Department of Health that applied to all indications for ibrutinib. The level of the discount increased during the appraisal and was commercial in confidence. The company subsequently agreed a commercial access agreement with NHS England that replaced the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.
End-of-life considerations
The committee concluded that ibrutinib met all the criteria to be considered a life-extending end-of-life treatment.
Equalities considerations and social value judgements
The committee acknowledged that access to ibrutinib may enhance treatment for older, frailer people by offering an alternative to less effective but better tolerated chemotherapy for these people. It also acknowledged that oral administration allows an effective treatment option for people without local access or transport to an infusion unit.
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{'Recommendations': 'Ibrutinib is recommended as an option for treating relapsed or refractory mantle cell lymphoma in adults, only if:\n\nthey have had only 1\xa0previous line of therapy and\n\nthe company provides ibrutinib with the discount agreed in the commercial access agreement with NHS England.\n\nThis recommendation is not intended to affect treatment with ibrutinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nIbrutinib (Imbruvica, Janssen) inhibits a protein called Bruton's tyrosine kinase, stopping B-cell (lymphocyte) proliferation and promoting cell death.\n\nMarketing authorisation\n\nIbrutinib has a marketing authorisation in the UK for the treatment of adults 'with relapsed or refractory mantle cell lymphoma'.\n\nAdverse reactions\n\nThe most common adverse reactions associated with ibrutinib include diarrhoea, musculoskeletal pain, upper respiratory tract infection, haemorrhage, bruising, rash, and nausea. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nIbrutinib is taken orally (4×140‑mg capsules) once daily, until the disease progresses or there is unacceptable toxicity.\n\nPrice\n\nIbrutinib is available at the list price of £4,599.00 for 90×140‑mg capsules (£51.10 per capsule) and £6,132.00 for 120×140‑mg capsules (£51.10 per capsule; excluding VAT, British national formulary [BNF] June 2016). The pricing arrangement considered during guidance development was a patient access scheme agreed with the Department of Health that applied to all indications for ibrutinib. The company subsequently agreed a commercial access agreement with NHS England that replaced the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of ibrutinib, having considered evidence on the nature of relapsed or refractory mantle cell lymphoma and the value placed on the benefits of ibrutinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\n## Clinical management of relapsed or refractory mantle cell lymphoma\n\nThe committee heard from the clinical expert that the most common first‑line options for treating mantle cell lymphoma are rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R‑CHOP), or rituximab in combination with bendamustine. These are followed by 2\xa0years of rituximab maintenance treatment. The committee understood that there is no accepted standard of care for treating relapsed or refractory mantle cell lymphoma, and that a range of chemotherapy regimens are used. It heard from the clinical expert that these often contain rituximab, even though many people will have had rituximab as part of first-line and maintenance treatment. The clinical expert highlighted that as many as 22\xa0different treatments are used in the UK for treating relapsed or refractory mantle cell lymphoma. The choice of treatment largely depends on the availability of drugs and clinician's choice, because there is no treatment regimen that has been shown to be the most effective in this setting. The clinical expert also commented that temsirolimus, the comparator in the main ibrutinib study (RAY), is not used in the UK because it is considered to be of low efficacy despite being licensed for this indication. The committee concluded that there is no standard of care for treating relapsed or refractory mantle cell lymphoma in England, and that treatment tends to combine rituximab with a range of chemotherapy options. It also concluded that temsirolimus is not relevant to UK clinical practice.\n\n## Clinical need of patients with mantle cell lymphoma\n\nThe committee noted that mantle cell lymphoma is an aggressive form of non‑Hodgkin's lymphoma and in some cases can be associated with debilitating symptoms. There are very high rates of relapse after initial treatment, and a huge effect on quality of life. The committee heard from the patient and clinical experts that ibrutinib is already widely used in clinical practice because of its previous availability through the Cancer Drugs Fund, and is welcomed by patients because it is highly effective compared with existing treatments and extremely well tolerated with very few adverse reactions. It is taken orally and people value this highly because it can be taken in the privacy of their own home and reduces the need for hospital visits. It can be used by older and frail people and, unlike current chemotherapy options, patients do not usually need additional treatments to counter adverse reactions. For these reasons, the patient experts considered that ibrutinib is a life-transforming drug that results in a step change in the quality of life of patients with relapsed or refractory mantle cell lymphoma and their families and carers, allowing many to participate in general day-to-day activities, and very quickly return to their normal life. The committee concluded that the availability of an effective oral therapy with a manageable adverse-reaction profile is highly valued by patients and addresses a high unmet need among people with relapsed or refractory mantle cell lymphoma.\n\n## Overview of ibrutinib studies\n\nThe committee noted that the evidence on the clinical effectiveness of ibrutinib came from 1\xa0randomised controlled trial (RAY) and 2\xa0single-arm studies (SPARK and PCYC‑1104). It considered that RAY is not strictly relevant to NHS practice because temsirolimus, the comparator treatment in the trial, is not routinely used in the UK. It noted the absence of any trials comparing ibrutinib with any comparator defined in the NICE scope. It also noted that all 3\xa0studies were open label, which made them potentially prone to bias, although it accepted that the studies addressed potential measurement bias by using an independent review committee to evaluate the primary outcome. The committee concluded that the studies were of a reasonable quality but were limited by the lack of a comparison against a treatment used in UK clinical practice.\n\n## Clinical evidence – trial results\n\nThe committee noted that at median follow-up of 20\xa0months, median progression-free survival in RAY was statistically significantly longer for ibrutinib compared with temsirolimus (14.6\xa0months compared with 6.2\xa0months; hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.32 to 0.58; p<0.0001). At the time of the first appraisal committee meeting the overall-survival data from RAY were immature and median overall survival had not yet been reached in the ibrutinib arm, indicating that more than 50% of patients were still alive. The committee noted that the crossover of 23% of patients in the temsirolimus arm to the ibrutinib arm could confound the overall-survival results, which could also be confounded by the use of subsequent anticancer systemic therapies in both arms (31.7% of patients in the ibrutinib arm and 58.2% of patients in the temsirolimus arm). Following consultation on the appraisal consultation document, the committee considered updated RAY data submitted by the company, with a median follow‐up of 39\xa0months. It noted that the results were consistent with the earlier data and that median overall survival had now been reached (30.3\xa0months for ibrutinib compared with 23.5\xa0months for temsirolimus; HR 0.74; 95% CI 0.54 to 1.02). The committee concluded that the results from RAY suggest that ibrutinib significantly improves progression-free survival compared with temsirolimus. But the overall-survival benefits remain uncertain, despite the availability of more mature data, because of potential confounding from crossover and the use of further anticancer therapies.\n\nThe committee considered that the results from the 2\xa0single-arm trials were generally supportive of the results from RAY, although it noted that the overall-response rates and progression-free survival were slightly lower in the single-arm trials than in the ibrutinib arm of RAY. It concluded that it was appropriate to pool the results from the 3\xa0studies to give a larger patient population, given the general lack of evidence for treating relapsed or refractory mantle cell lymphoma with ibrutinib.\n\n## Indirect comparison\n\nThe committee noted that in the absence of any direct trial evidence for ibrutinib against a comparator reflective of current UK clinical practice, the company did an indirect treatment comparison using results from RAY and from the OPTIMAL study (Hess, 2009) that compared temsirolimus with clinician's choice of single-agent chemotherapy. The indirect treatment comparison compared ibrutinib against clinician's choice of single-agent chemotherapy in OPTIMAL, using temsirolimus as the common comparator. The committee noted that the company adjusted the treatment effect of chemotherapy, as estimated from the indirect comparison, to take into account the additional effect of adding rituximab (R‑chemo). This adjustment used data on the benefit of R‑chemo compared with single-agent chemotherapy from the Haematological Malignancy Research Network (HMRN) audit of 118\xa0patients with mantle cell lymphoma that had been treated with first-line therapy. The committee understood that this resulted in a progression-free survival hazard ratio for ibrutinib compared with R‑chemo of 0.28 (representing a 72% reduction in the risk of disease progression with ibrutinib compared with R‑chemo).\n\nThe committee acknowledged the limitations of the indirect comparison that were highlighted by both the company and the evidence review group (ERG), such as differences in the patient populations in OPTIMAL and RAY. It also noted that the HMRN audit did not specifically relate to patients with relapsed or refractory mantle cell lymphoma. It also understood that the ERG did not agree with the company's 2‑stage approach to estimating treatment effects for ibrutinib compared with R‑chemo, and that the ERG had done a separate analysis based on a single‑stage approach using a random effects network meta-analysis instead of fixed effects. This resulted in a hazard ratio for progression-free survival of 0.27 (HR 0.27; 95% credible interval 0.06 to 1.26), similar to the company's estimate of 0.28. However, the committee noted that because of concerns about the evidence used to inform the indirect comparisons, the ERG considered that the results of both analyses should be interpreted with caution. The committee also noted that the company's alternative approach to estimating the effectiveness of ibrutinib compared with R‑chemo (that is, assuming that temsirolimus has equal efficacy to R‑chemo based on the results from RAY) produced a less-favourable hazard ratio of 0.43. The committee concluded that there is considerable uncertainty associated with the indirect comparisons and that the benefit of ibrutinib compared with R‑chemo is unclear, although it accepted that the available evidence and experience from clinical practice strongly suggest that ibrutinib is more effective.\n\n## Subgroups\n\nThe committee discussed the efficacy results for subgroups of patients, based on the number of previous lines of therapy. It noted that the results suggest greater efficacy in patients who had ibrutinib after only 1\xa0previous line of therapy, compared with 2\xa0or\xa0more therapies. The clinical expert also stated that ibrutinib is particularly beneficial after the first relapse. The committee considered the updated RAY data, which have a median follow‐up of 39\xa0months. These provide further evidence of a greater benefit of ibrutinib when taken after only 1\xa0previous line of therapy. Updated median overall survival was 42.1\xa0months for ibrutinib and 27.0\xa0months for temsirolimus in the 1\xa0previous therapy subgroup, compared with 22.1\xa0months and 17.0\xa0months respectively after 2\xa0or more therapies. The committee understood that the data were potentially confounded by crossover of patients in the temsirolimus arm to the ibrutinib arm (39% in the 1\xa0previous therapy subgroup). It was also concerned that the subgroups were defined post hoc. However, the committee noted responses to the appraisal consultation document from professional groups. These state that evidence from clinical practice supports the RAY results, and that earlier use of ibrutinib in relapsed or refractory disease is the most beneficial. The committee concluded that the evidence from RAY and clinical experience suggest that ibrutinib is most effective in people who have had only 1\xa0previous line of therapy.\n\n# Cost effectiveness\n\n## The company's model and the ERG's exploratory analyses\n\nThe committee noted that the company had developed a Markov model comparing ibrutinib with R‑chemo, comprising 3\xa0states (pre-progression, post-progression and death), and that this approach had been used in previous NICE appraisals. The committee was aware that overall-survival data from the ibrutinib studies were not directly extrapolated but were modelled using progression-free-survival data from the pooled ibrutinib dataset. The committee considered that the company's approach is appropriate given the immaturity of the overall-survival data at the time of the modelling.\n\nThe committee considered the ERG's critique of the company's model. It noted the ERG's comments that the company's Markov approach imposed structural constraints, which did not make the best use of the trial data on survival, and that the overall survival predicted by the model did not provide a good visual fit to the observed Kaplan–Meier survival curve from the trials. The committee understood that the ERG favoured a partitioned survival model using overall-survival data for ibrutinib directly from the trials rather than using progression-free survival, and had explored the effect of using this approach in an exploratory analysis (set\xa0B). The committee examined the ERG's set\xa0B exploratory analysis but was concerned that the partitioned survival approach resulted in efficacy estimates for R‑chemo that were higher than those for ibrutinib, giving higher quality-adjusted life year (QALY) gains for R‑chemo than ibrutinib. By contrast, it heard from the clinical expert that experience has shown that ibrutinib is more effective than R‑chemo for treating relapsed or refractory mantle cell lymphoma. This is partly because relapsed or refractory disease will already have been treated with R‑chemo and rituximab maintenance therapy, which will become progressively less effective with further relapse. The committee concluded that the results of the partitioned survival analysis are not clinically plausible, acknowledging the ERG's comments that they are associated with major uncertainty because they used the outputs of a highly uncertain meta-analysis.\n\nThe committee re-examined the company's Markov approach, which it considered led to more plausible results (incremental QALYs for ibrutinib compared with R‑chemo ranging from 0.82 to 1.87 depending on the scenario), although it acknowledged the considerable uncertainty associated with these estimates. The committee noted that in the company's base-case analysis, incorporating the updated patient access scheme, the incremental cost-effectiveness ratio (ICER) for ibrutinib compared with R‑chemo was £62,650 per QALY gained. It also noted that the company carried out a range of scenario analyses to test the assumptions in the model. These included estimating the effectiveness of ibrutinib compared with R‑chemo using temsirolimus as a proxy for R‑chemo. The committee noted that this scenario used the efficacy data from RAY and resulted in an estimated ICER for ibrutinib compared with R‑chemo of £69,142 per QALY gained. The committee also noted that the ICER was above £59,000 per QALY gained in all but 1\xa0of the scenarios presented by the company. In that 1\xa0scenario, the company applied a hazard ratio to post-progression survival for R‑chemo. This was adjusted to be as close as possible to the anticipated survival based on the results of the HMRN audit (that is, 8.4\xa0months for patients on second-line treatment). This resulted in an ICER of £49,849 per QALY gained. However, the committee understood that time-to-event estimates for progression-free survival and post-progression survival for ibrutinib were taken from the 1\xa0previous therapy subgroup, and therefore that the analysis reflects this subgroup.\n\nThe ERG did a set of exploratory analyses (set\xa0A) that made adjustments to some of the parameter values in the company's model. These mostly resulted in a lower ICER for ibrutinib compared with R‑chemo than that estimated by the company. However, the committee was minded not to accept the results of the ERG's amendments because these represented the extreme (lowest) end of the ERG's wide estimate of possible ICERs, depending on the model and parameters used. The committee concluded that the ICERs presented by the company for the whole population of people with relapsed or refractory mantle cell lymphoma, incorporating the confidential patient access scheme for ibrutinib, are above the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).\n\nThe committee recognised the high clinical need of people with mantle cell lymphoma and that ibrutinib has several benefits including oral administration, manageable adverse reactions and low toxicity. It therefore considered that ibrutinib is a step change in managing relapsed or refractory mantle cell lymphoma. However, it did not consider that any additional health-related benefits, that had not been captured fully in the QALY calculation, would be enough to lower the ICER for the whole population to within the range normally considered cost effective.\n\nThe committee recalled its earlier conclusion that trial evidence and clinical experience suggest that ibrutinib is most effective in people who have had only 1\xa0previous line of therapy (see section\xa04.8). It therefore considered whether ibrutinib could be considered cost effective in this group of patients. It noted that the company's ICER of £49,849 per QALY gained may be a conservative estimate because updated trial data from RAY suggest that the model underestimates survival for this subgroup. The committee also noted that overall survival in RAY may have been confounded by the crossover of 39% of people from the temsirolimus arm to the ibrutinib arm. The committee concluded that the most plausible ICER in this group of patients is likely to be lower than the company's estimate of £49,848 per QALY gained.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It accepted that ibrutinib is indicated for people with a short life expectancy, noting that the estimates presented for people with relapsed or refractory mantle cell lymphoma ranged from 5.2\xa0months to 9.7\xa0months. It also accepted that there is enough evidence to indicate that ibrutinib offers an extension to life of at least an additional 3\xa0months, compared with current NHS treatment. The committee concluded that ibrutinib met all the criteria to be considered a life-extending end-of-life treatment.\n\nTaking all the evidence and uncertainties together, and given the extra weight applied to QALYs at the end of life, the committee concluded that the company's ICERs for the whole population of people with relapsed or refractory mantle cell lymphoma are above the range normally considered to be a cost-effective use of NHS resources. However, the committee concluded that ibrutinib is a cost-effective use of NHS resources for people who have had only 1\xa0previous line of therapy, and that ibrutinib can be recommended for use in this group of people.\n\n# Potential equality issues\n\nThe committee noted the potential equality issue raised by the company and patient groups that ibrutinib would offer an alternative to less effective but better tolerated chemotherapy agents for older or frailer people. It also noted the issue raised that oral administration allows an effective treatment option for people without access or transport to an infusion unit and significantly reduces multiple hospital visits. The committee acknowledged that access to ibrutinib may enhance treatment in these groups of people.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA502\n\nAppraisal title: Ibrutinib for treating relapsed or refractory mantle cell lymphoma\n\nSection\n\nKey conclusion\n\nIbrutinib is recommended as an option for treating relapsed or refractory mantle cell lymphoma in adults, only if:\n\nthey have had only 1 previous line of therapy and\n\nthe company provides ibrutinib with the discount agreed in the commercial access agreement.\n\nThe committee concluded that the incremental cost-effectiveness ratios (ICERs) presented by the company for the whole population of people with relapsed or refractory mantle cell lymphoma, incorporating the updated confidential patient access scheme for ibrutinib, are above the range normally considered a cost‑effective use of NHS resources (that is, £20,000 to £30,000 per quality-adjusted life year [QALY] gained).\n\nThe committee noted that the evidence from trials and clinical experience suggest that ibrutinib is most effective in people who have had only 1\xa0previous line of therapy. It concluded that ibrutinib is a cost-effective use of NHS resources for this subgroup.\n\nThe committee concluded that ibrutinib met all the criteria to be considered a life-extending end-of-life treatment.\n\n, 4.12, 4.8, 4.15\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee concluded that the availability of an effective oral therapy with a manageable adverse-reaction profile is highly valued by people, and addresses a high unmet need for people with relapsed or refractory mantle cell lymphoma.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee accepted that ibrutinib has several benefits for people including oral administration, manageable adverse reactions and low toxicity. The committee concluded that ibrutinib could be considered a step change in managing relapsed or refractory mantle cell lymphoma.\n\n, 4.16\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nIbrutinib has a marketing authorisation in the UK for the treatment of adults 'with relapsed or refractory mantle cell lymphoma'.\n\n\n\nAdverse reactions\n\nThe committee understood that ibrutinib is extremely well tolerated with very few adverse reactions.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee understood that the clinical evidence for ibrutinib came from 1\xa0randomised controlled trial (RAY), in which ibrutinib was compared with temsirolimus, and 2\xa0single-arm studies (SPARK and PCYC‑1104). The committee concluded that the studies were of a reasonable quality but were limited by the lack of a comparison against a treatment used in UK clinical practice.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee considered that RAY was not strictly relevant to NHS practice because temsirolimus, the comparator treatment in the trial, is not routinely used in the UK.\n\n\n\nUncertainties generated by the evidence\n\nThe committee concluded that the overall-survival benefits from RAY were uncertain because of the crossover of many patients in the temsirolimus arm to the ibrutinib arm, and the use of further anticancer systemic therapies in both arms.\n\nThe committee was aware that there is considerable uncertainty associated with the indirect comparisons and that the size of the benefit of ibrutinib compared with R‑chemo is unclear.\n\n, 4.7\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee recognised that trial evidence and clinical experience suggest that ibrutinib is most effective in people who have had only 1 previous line of therapy.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that the results from RAY suggest that ibrutinib significantly improves progression-free survival compared with temsirolimus. The committee considered that the results from the 2 single-arm studies are generally supportive of the results from RAY. It concluded that it is appropriate to pool the results from the 3\xa0studies to give a larger patient population, given the general lack of evidence for treating relapsed or refractory mantle cell lymphoma with ibrutinib.\n\n, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company developed a Markov model, comparing ibrutinib with R‑chemo, with 3\xa0states (pre-progression, post-progression and death). The committee was aware that overall-survival data from the ibrutinib studies were not directly extrapolated but were modelled using progression-free survival data from the pooled ibrutinib dataset. It concluded that the company's approach is appropriate, given the immaturity of the overall-survival data at the time of the modelling.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee understood that the evidence review group (ERG) favoured a partitioned survival model using overall-survival data directly from the trials rather than using progression-free survival, and had explored the effect of using this approach. However, the committee concluded that the results of the partitioned survival analysis are not clinically plausible, acknowledging the ERG's comments that they are associated with major uncertainty because they used the outputs of a highly uncertain meta-analysis.\n\nThe committee considered that the company's Markov approach led to more plausible results, although it acknowledged the considerable uncertainty associated with these estimates. It concluded that the company's ICERs for the whole population of people with relapsed or refractory mantle cell lymphoma, incorporating the confidential patient access scheme for ibrutinib, are above the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).\n\n, 4.11, 4.12\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that ibrutinib has several benefits for people including oral administration, manageable adverse reactions and low toxicity. It therefore considered that ibrutinib is a step change in managing relapsed or refractory mantle cell lymphoma. However, it did not consider that any additional health-related benefits that had not been captured fully in the QALY calculation would be enough to lower the ICER to within the range normally considered cost effective.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee concluded that ibrutinib is a cost-effective use of NHS resources for the subgroup of people who have had only 1 previous line of therapy.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee was aware that in all but 1\xa0of the scenarios presented by the company, the ICER was above £59,000 per QALY gained.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that the most plausible ICER for the 1 previous therapy subgroup is likely to be lower than the company's estimate of £49,848 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company agreed a patient access scheme with the Department of Health that applied to all indications for ibrutinib. The level of the discount increased during the appraisal and was commercial in confidence. The company subsequently agreed a commercial access agreement with NHS England that replaced the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.\n\n, 4.11\n\nEnd-of-life considerations\n\nThe committee concluded that ibrutinib met all the criteria to be considered a life-extending end-of-life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nThe committee acknowledged that access to ibrutinib may enhance treatment for older, frailer people by offering an alternative to less effective but better tolerated chemotherapy for these people. It also acknowledged that oral administration allows an effective treatment option for people without local access or transport to an infusion unit.\n\n"}
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https://www.nice.org.uk/guidance/ta502
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Evidence-based recommendations on ibrutinib (Imbruvica) for treating relapsed or refractory mantle cell lymphoma in adults.
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f0690ef3a189faaa39e963c98c215323e33576c7
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nice
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Fulvestrant for untreated locally advanced or metastatic oestrogen-receptor positive breast cancer
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Fulvestrant for untreated locally advanced or metastatic oestrogen-receptor positive breast cancer
Evidence-based recommendations on fulvestrant (Faslodex) for treating locally advanced or metastatic (secondary), oestrogen-receptor positive breast cancer in postmenopausal women who have not had endocrine therapy before.
# Recommendations
Fulvestrant is not recommended, within its marketing authorisation, for treating locally advanced or metastatic oestrogen-receptor positive breast cancer in postmenopausal women who have not had endocrine therapy before.
This recommendation is not intended to affect treatment with fulvestrant that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made this recommendation
People with untreated disease are first offered an aromatase inhibitor, either anastrozole or letrozole. These drugs are considered to be similarly effective. Tamoxifen is used for women in whom an aromatase inhibitor is not tolerated or is contraindicated. Fulvestrant is a further treatment option that may have additional benefits for some women. However, the final results on overall survival from the FALCON trial are not available yet, so it is unclear whether fulvestrant will extend overall survival compared with aromatase inhibitors.
Because of the uncertainty in the clinical evidence, the cost effectiveness of fulvestrant compared with existing treatments is highly uncertain. However, it is likely to be above the range normally considered a cost-effective use of NHS resources, so fulvestrant cannot be recommended.# Information about fulvestrant
Marketing authorisation
Fulvestrant (Faslodex, AstraZeneca) is indicated for 'the treatment of oestrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women:
not previously treated with endocrine therapy (licence extension under appraisal) or
with disease relapse on or after adjuvant antioestrogen therapy, or disease progression on antioestrogen therapy' (appraised in NICE technology appraisal guidance on fulvestrant for the treatment of locally advanced or metastatic breast cancer).
Recommended dose and schedule
The recommended dosage is 500 mg intramuscularly into the buttocks as 2×5‑ml injections (1 in each buttock) on days 1, 15 and 29, and then once monthly (until disease progression).
Price
A pack of 2×5‑ml (50 mg/ml) prefilled syringes costs £522.41 (NHS indicative price, British national formulary online, August 2017). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Current management
## Aromatase inhibitors are standard care but further effective treatments are needed
The clinical expert explained that advanced or metastatic breast cancer without high-volume visceral disease or another indication for immediate chemotherapy is generally treated first-line with an aromatase inhibitor (anastrozole or letrozole). For a few people, tamoxifen may be more appropriate, for example, when aromatase inhibitors are not tolerated because of side effects such as arthralgia or gastrointestinal symptoms. The committee heard that current treatments are effective in providing a temporary improvement and delaying disease progression. However, more effective treatments that delay the need for chemotherapy and extend survival are needed. The committee concluded that aromatase inhibitors are the first-line treatment for endocrine-naive advanced or metastatic oestrogen-receptor positive breast cancer, but that further effective treatments are needed.
## Anastrozole and letrozole are considered to have a class effect
The committee was aware from past appraisals for advanced breast cancer that letrozole and anastrozole are considered to have a class effect. In addition, the clinical expert confirmed that multiple trials show that these agents are indistinguishable in terms of clinical effectiveness and toxicity. Therefore, the committee concluded that it is appropriate to consider anastrozole and letrozole as equivalent.
# New treatment options
## Fulvestrant is a further treatment option that may have additional benefits for some people
The committee heard from a patient expert who had previously had various treatments, including anastrozole, fulvestrant and chemotherapy. The patient expert explained that prolonging survival is of primary importance, but that quality of life is also important. Her experience was that quality of life and general wellbeing were very good while taking either fulvestrant or anastrozole. However, she found that chemotherapy was much harder to cope with and was much more detrimental to quality of life. She also explained that intramuscular injections with fulvestrant can be painful but this may be related to the competency of the person giving them, and a monthly injection may be preferable to daily tablets (such as aromatase inhibitors) for some people. For example, some people find swallowing tablets very difficult. The clinical expert noted that monthly injections may improve compliance, particularly for some vulnerable patients. The clinical expert explained that fulvestrant would ideally be used in place of an aromatase inhibitor for first-line treatment in patients within the licensed population, because of the progression-free survival gain seen in the trials. They explained that treatment would be started in hospital but it could then be delivered in primary care for convenience, although ongoing specialist supervision would be needed to monitor response. The committee acknowledged that fulvestrant provides a further treatment option that may have additional benefits for some people.
# Direct comparison with anastrozole
## Evidence from FALCON is more relevant than FIRST
The company presented direct head-to-head evidence comparing fulvestrant with anastrozole from 2 randomised-controlled trials:
FIRST: an open-label non-inferiority study
FALCON: a double-blind superiority study.The committee noted that investigators and patients were not blinded to treatment allocation in FIRST, potentially leading to bias, whereas FALCON was a double-blind trial. There were also important differences in the baseline characteristics of the patients in FIRST compared with the licensed population, which called into question the generalisability of the trial population to clinical practice in England. The committee noted that the indication specified in the marketing authorisation is for postmenopausal women who have not previously had endocrine therapy, but around 25% of patients in FIRST had had endocrine therapy before (including aromatase inhibitors). Also, about 19% of patients in FIRST had human epidermal growth receptor 2 (HER2)-positive disease and 35% had an unknown HER2 status. The committee understood from the clinical expert that people with HER2-positive disease usually have HER2-targeted therapies such as trastuzumab. In contrast, the FALCON trial had no patients with HER2-positive disease and none had had endocrine therapy before. Therefore, the committee concluded that the FALCON data are more applicable to the evaluation of the clinical effectiveness of fulvestrant than the FIRST data because:
the trial population directly reflects the licence (that is, postmenopausal women with endocrine-naive, oestrogen-receptor positive disease)
the double-blind trial design reduces the likelihood of bias.
## There is a gain in progression-free survival with fulvestrant but this is less in FALCON than in the FIRST trial
The FIRST trial collected data on time-to-progression rather than progression-free survival. However, the committee noted comments from the ERG that the definition of time-to-progression was very similar to that of progression-free survival so they can be considered comparable. It noted that the hazard ratio (HR) for progression or death was greater in FIRST than in FALCON (HR 0.66 in FIRST; HR 0.80 in FALCON). The difference between the fulvestrant and anastrozole arms in the median time to event was 10.3 months in FIRST compared with 2.8 months in FALCON. The committee accepted that the progression-free survival results from FALCON show modest improvement compared with anastrozole, but it stated that the results in FIRST should be interpreted with caution because of concerns about the trial (see section 3.4).
## Final overall-survival benefit with fulvestrant is uncertain
The overall-survival data from FALCON are immature (31% of events reached) and mature data are not expected until the end of 2019. An overall-survival benefit had been shown in FIRST (HR for death 0.70, 95% confidence interval 0.50 to 0.98, and a difference between the fulvestrant and anastrozole arms in median survival of 5.7 months). However, the committee noted that these results should be interpreted cautiously because they may not be generalisable to the licensed population (see section 3.4). In FIRST, the median overall-survival benefit was much shorter than the progression-free survival (5.7 months compared with 10.3 months). The committee was concerned that if an overall-survival benefit is shown in FALCON, it could be considerably lower than seen in FIRST, given that the progression-free survival was much shorter in FALCON than FIRST (2.8 months compared with 10.3 months; see section 3.5). The committee concluded that it is unclear whether, and by how much, fulvestrant would extend overall survival compared with anastrozole. It noted that mature data from FALCON, which is better matched to the licensed indication than FIRST, are needed.
# Indirect treatment comparison with letrozole and tamoxifen
## PO25 should be removed from the analysis and equal efficacy of anastrozole and letrozole should be assumed
The company carried out an indirect treatment comparison comparing fulvestrant with letrozole and tamoxifen. This included 3 studies in addition to FIRST and FALCON: NORTH AMERICAN and TARGET (anastrozole compared with tamoxifen); and PO25 (letrozole compared with tamoxifen). The committee noted comments from the ERG that it preferred to exclude PO25 from the network because it could not obtain patient-level data from it and the results were compromised by about a 50% crossover after progression. The committee therefore questioned whether the trial should be included in the analysis. It understood that PO25 was incorporated to allow a comparison between fulvestrant and letrozole. However, it recalled its earlier conclusion that letrozole and anastrozole have equivalent clinical effectiveness (see section 3.2) and so concluded that PO25 should be removed from the analysis.
## The results of the indirect treatment comparison for overall survival are highly uncertain
The company applied the inclusion and exclusion criteria from FALCON to the included studies to 'match' the trial population in FALCON. This meant that the company derived a subgroup from the included studies to create a homogenous population. The ERG commented that this approach reduced the sample size of the comparator studies and broke randomisation in all the studies except for FALCON. Although FALCON excluded people with HER2-positive disease, it was unclear whether people with HER2-positive disease in the NORTH AMERICAN and TARGET studies (for a comparison with tamoxifen) had been excluded. The company commented that older trials would not necessarily have included HER2 testing because it was not routinely carried out at the time of enrolment. The committee considered whether the advantages of reducing heterogeneity outweighed the disadvantages of reducing the number of patients included in the analysis and breaking randomisation, but was not persuaded it was and so questioned the reliability of the results. Following consultation, the committee noted the company's view that the 'matched' analysis was a robust estimator of efficacy given the heterogeneity in the trial populations. The company stated that the analysis did not break randomisation, the relative treatment effects were consistent with published trial data and the baseline characteristics remained balanced in the matched subgroups. The ERG acknowledged that the baseline characteristics of the matched and whole trial populations were similar. However, it stated that stratification of the initial randomisation on the baseline characteristics used for matching would be the only way to avoid breaking randomisation. The company presented an updated indirect treatment comparison using intention-to-treat data from the included studies, instead of 'matching' the trial populations to FALCON. The committee agreed that the results of the indirect comparison did not appear to have been distorted by the matching process. However, it remained concerned that the results for overall survival are highly uncertain, because mature data from FALCON were not available for inclusion in the analysis.
# Survival extrapolations
## Overall-survival projections are highly uncertain
The committee considered that the partitioned survival cost-effectiveness model presented by the company is acceptable for decision-making. It considered the parametric survival curves for extrapolating progression-free and overall survival, which were estimated from the indirect treatment comparison. It noted that the company chose generalised gamma distributions for progression-free survival and Weibull distributions for overall survival, based on clinical plausibility and statistical fit, and applied these to fulvestrant and all the comparators. The committee was satisfied with the choice of parametric survival curves because the projections seem consistent with clinical expert opinion. However, it was concerned that the data from FALCON were immature, and noted comments that much of the data used for the projection of overall survival were from FIRST. The committee recalled that the results from FIRST may not be generalisable to the licensed population (see section 3.4), and that the final overall-survival benefit from FALCON is highly uncertain (see section 3.6). Therefore, it concluded that the projections for overall survival are highly uncertain.
# Utility values used in the model
## The utility values are not in line with other appraisals, but are not critical to the cost-effectiveness analysis
The company derived utility values directly from FALCON using the EQ‑5D questionnaire (progression-free survival 0.75; progressed disease 0.69). The ERG commented that using EQ‑5D from the trial is consistent with the NICE reference case. The committee noted that the value for progressed disease was higher than those used in past appraisals. The company acknowledged this and presented a scenario analysis using lower values. The committee noted that alternative utility values for progressed disease had little effect on the cost-effectiveness results, and did not pursue this issue further.
# Cost-effectiveness estimate
## The main area of uncertainty in the cost-effectiveness analysis is the projected overall-survival benefit
The committee noted that the initial incremental cost-effectiveness ratios (ICERs) presented by the company for fulvestrant compared with anastrozole and tamoxifen (based on the company's indirect treatment comparison that 'matched' the trial populations to FALCON) were about £34,100 and £22,500 per quality-adjusted life year (QALY) gained respectively. The ERG did an exploratory base-case analysis that changed the assumptions on resource use, setting for the administration for fulvestrant and use of subsequent therapies. The ERG also assumed equal efficacy for letrozole and anastrozole (excluding PO25 from the indirect comparison). The committee noted that these changes had very little impact on the ICERs for fulvestrant (about £33,500 and £23,700 per QALY gained, compared with anastrozole and tamoxifen respectively). However, it concluded that the main area of uncertainty in the cost-effectiveness analysis is the projected overall-survival benefit.
## Fulvestrant is not a cost-effective use of NHS resources compared with aromatase inhibitors
The committee noted that the overall-survival projection for fulvestrant was mostly based on data from FIRST, which it had concluded was less relevant for its decision-making than FALCON (see sections 3.4 and 3.9). It also questioned the validity of the modelled results because the predicted difference in median survival between the fulvestrant and anastrozole arms was about 8.3 months in the model, whereas in FIRST it was 5.7 months (see section 3.6). It also noted the considerable uncertainty in the final cost-effectiveness estimates because of immature overall-survival data from FALCON. It was uncertain whether, and by how much, fulvestrant would extend survival compared with anastrozole in the licensed population (see section 3.6). It therefore considered the ERG's scenario analyses that explored the effect of different predictions of overall survival on the ICERs. Lowering the estimate of the overall-survival gain for fulvestrant compared with anastrozole (to the equivalent of assuming an HR of 0.82 and 0.88, instead of 0.77 in the company's base case) increased the ICER to about £40,800 and £52,400 per QALY gained respectively. When the HR was assumed to be 1 (that is, fulvestrant was assumed to have no overall-survival benefit over anastrozole), the ICERs increased to above £200,000 per QALY gained. The committee concluded that the results are very sensitive to changes in the predicted overall-survival gain used for fulvestrant, and that the base-case results are highly uncertain. It considered that the base-case estimate is likely to be optimistic, being based on a projected median overall-survival benefit of 8.3 months, when the median difference in progression-free survival in FALCON was only 2.8 months and the overall-survival benefit is unknown. Following consultation, the company presented confidential ICERs based on a proposed alternative pricing assumption. However, the committee agreed that the revised base-case estimates remain highly uncertain and may substantially overestimate the cost effectiveness of fulvestrant. It concluded that further survival data from FALCON are needed in order to produce robust estimates of the cost effectiveness of fulvestrant. The committee appreciated that some patients would welcome this alternative treatment option, but at present it cannot recommend fulvestrant as a cost-effective use of NHS resources for postmenopausal women with untreated, locally advanced or metastatic oestrogen-receptor positive breast cancer.
## Fulvestrant is not a cost-effective use of NHS resources for people in whom aromatase inhibitors are not tolerated or are contraindicated
The committee considered the ICERs for fulvestrant compared with tamoxifen. It noted that the ICERs estimated by both the company and the ERG were in the range of £20,000 to £30,000 per QALY gained. The committee referred to section 6.3.3 of NICE's guide to the methods of technology appraisal. This states that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of the technology as an effective use of NHS resources take into account a number of factors including the degree of certainty around the ICER. The committee considered that the ICERs are highly uncertain because of the immaturity of the overall-survival data (the key driver of the results; see section 3.12). It noted that, in the ERG's scenario analysis that explored the effect of different predictions of overall-survival benefit, the ICERs vary from about £24,400 to £39,000 per QALY gained. The committee also noted the company's updated confidential ICERs, based on the proposed alternative pricing assumption. However, it concluded that the ICERs remain highly uncertain because of the immaturity of the overall-survival data used in the indirect comparison. Therefore, fulvestrant cannot be recommended as a cost-effective use of NHS resources for postmenopausal women who have untreated, locally advanced or metastatic oestrogen-receptor positive breast cancer.
# Conclusion
## It is unclear whether, and by how much, fulvestrant would extend overall survival compared with aromatase inhibitors
The committee concluded that the FALCON trial, which directly compared fulvestrant with anastrozole, was superior to the FIRST trial because the population is more relevant and it has less potential for bias. It noted that, for FALCON, the progression-free survival results are modest and the overall-survival data are immature. The committee was therefore unclear whether, and by how much, fulvestrant would extend overall survival compared with anastrozole.
## Fulvestrant is not a cost-effective use of NHS resources compared with aromatase inhibitors or when aromatase inhibitors are not suitable
The overall-survival benefit for fulvestrant compared with existing treatments is highly uncertain, and could affect the estimates of cost effectiveness for fulvestrant compared with existing treatments. More survival data from FALCON are needed in order to produce robust estimates of cost effectiveness. Therefore, fulvestrant cannot be recommended as a cost-effective use of NHS resources for postmenopausal women who have untreated, locally advanced or metastatic oestrogen-receptor positive breast cancer.
|
{'Recommendations': 'Fulvestrant is not recommended, within its marketing authorisation, for treating locally advanced or metastatic oestrogen-receptor positive breast cancer in postmenopausal women who have not had endocrine therapy before.\n\nThis recommendation is not intended to affect treatment with fulvestrant that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made this recommendation\n\nPeople with untreated disease are first offered an aromatase inhibitor, either anastrozole or letrozole. These drugs are considered to be similarly effective. Tamoxifen is used for women in whom an aromatase inhibitor is not tolerated or is contraindicated. Fulvestrant is a further treatment option that may have additional benefits for some women. However, the final results on overall survival from the FALCON trial are not available yet, so it is unclear whether fulvestrant will extend overall survival compared with aromatase inhibitors.\n\nBecause of the uncertainty in the clinical evidence, the cost effectiveness of fulvestrant compared with existing treatments is highly uncertain. However, it is likely to be above the range normally considered a cost-effective use of NHS resources, so fulvestrant cannot be recommended.', 'Information about fulvestrant': "Marketing authorisation\n\nFulvestrant (Faslodex, AstraZeneca) is indicated for 'the treatment of oestrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women:\n\nnot previously treated with endocrine therapy (licence extension under appraisal) or\n\nwith disease relapse on or after adjuvant antioestrogen therapy, or disease progression on antioestrogen therapy' (appraised in NICE technology appraisal guidance on fulvestrant for the treatment of locally advanced or metastatic breast cancer).\n\nRecommended dose and schedule\n\nThe recommended dosage is 500\xa0mg intramuscularly into the buttocks as 2×5‑ml injections (1\xa0in each buttock) on days\xa01, 15 and\xa029, and then once monthly (until disease progression).\n\nPrice\n\nA pack of 2×5‑ml (50\xa0mg/ml) prefilled syringes costs £522.41 (NHS indicative price, British national formulary online, August\xa02017). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Current management\n\n## Aromatase inhibitors are standard care but further effective treatments are needed\n\nThe clinical expert explained that advanced or metastatic breast cancer without high-volume visceral disease or another indication for immediate chemotherapy is generally treated first-line with an aromatase inhibitor (anastrozole or letrozole). For a few people, tamoxifen may be more appropriate, for example, when aromatase inhibitors are not tolerated because of side effects such as arthralgia or gastrointestinal symptoms. The committee heard that current treatments are effective in providing a temporary improvement and delaying disease progression. However, more effective treatments that delay the need for chemotherapy and extend survival are needed. The committee concluded that aromatase inhibitors are the first-line treatment for endocrine-naive advanced or metastatic oestrogen-receptor positive breast cancer, but that further effective treatments are needed.\n\n## Anastrozole and letrozole are considered to have a class effect\n\nThe committee was aware from past appraisals for advanced breast cancer that letrozole and anastrozole are considered to have a class effect. In addition, the clinical expert confirmed that multiple trials show that these agents are indistinguishable in terms of clinical effectiveness and toxicity. Therefore, the committee concluded that it is appropriate to consider anastrozole and letrozole as equivalent.\n\n# New treatment options\n\n## Fulvestrant is a further treatment option that may have additional benefits for some people\n\nThe committee heard from a patient expert who had previously had various treatments, including anastrozole, fulvestrant and chemotherapy. The patient expert explained that prolonging survival is of primary importance, but that quality of life is also important. Her experience was that quality of life and general wellbeing were very good while taking either fulvestrant or anastrozole. However, she found that chemotherapy was much harder to cope with and was much more detrimental to quality of life. She also explained that intramuscular injections with fulvestrant can be painful but this may be related to the competency of the person giving them, and a monthly injection may be preferable to daily tablets (such as aromatase inhibitors) for some people. For example, some people find swallowing tablets very difficult. The clinical expert noted that monthly injections may improve compliance, particularly for some vulnerable patients. The clinical expert explained that fulvestrant would ideally be used in place of an aromatase inhibitor for first-line treatment in patients within the licensed population, because of the progression-free survival gain seen in the trials. They explained that treatment would be started in hospital but it could then be delivered in primary care for convenience, although ongoing specialist supervision would be needed to monitor response. The committee acknowledged that fulvestrant provides a further treatment option that may have additional benefits for some people.\n\n# Direct comparison with anastrozole\n\n## Evidence from FALCON is more relevant than FIRST\n\nThe company presented direct head-to-head evidence comparing fulvestrant with anastrozole from 2\xa0randomised-controlled trials:\n\nFIRST: an open-label non-inferiority study\n\nFALCON: a double-blind superiority study.The committee noted that investigators and patients were not blinded to treatment allocation in FIRST, potentially leading to bias, whereas FALCON was a double-blind trial. There were also important differences in the baseline characteristics of the patients in FIRST compared with the licensed population, which called into question the generalisability of the trial population to clinical practice in England. The committee noted that the indication specified in the marketing authorisation is for postmenopausal women who have not previously had endocrine therapy, but around 25% of patients in FIRST had had endocrine therapy before (including aromatase inhibitors). Also, about 19% of patients in FIRST had human epidermal growth receptor\xa02 (HER2)-positive disease and 35% had an unknown HER2 status. The committee understood from the clinical expert that people with HER2-positive disease usually have HER2-targeted therapies such as trastuzumab. In contrast, the FALCON trial had no patients with HER2-positive disease and none had had endocrine therapy before. Therefore, the committee concluded that the FALCON data are more applicable to the evaluation of the clinical effectiveness of fulvestrant than the FIRST data because:\n\nthe trial population directly reflects the licence (that is, postmenopausal women with endocrine-naive, oestrogen-receptor positive disease)\n\nthe double-blind trial design reduces the likelihood of bias.\n\n## There is a gain in progression-free survival with fulvestrant but this is less in FALCON than in the FIRST trial\n\nThe FIRST trial collected data on time-to-progression rather than progression-free survival. However, the committee noted comments from the ERG that the definition of time-to-progression was very similar to that of progression-free survival so they can be considered comparable. It noted that the hazard ratio (HR) for progression or death was greater in FIRST than in FALCON (HR\xa00.66 in FIRST; HR\xa00.80 in FALCON). The difference between the fulvestrant and anastrozole arms in the median time to event was 10.3\xa0months in FIRST compared with 2.8\xa0months in FALCON. The committee accepted that the progression-free survival results from FALCON show modest improvement compared with anastrozole, but it stated that the results in FIRST should be interpreted with caution because of concerns about the trial (see section\xa03.4).\n\n## Final overall-survival benefit with fulvestrant is uncertain\n\nThe overall-survival data from FALCON are immature (31% of events reached) and mature data are not expected until the end of\xa02019. An overall-survival benefit had been shown in FIRST (HR for death 0.70, 95% confidence interval [CI] 0.50 to 0.98, and a difference between the fulvestrant and anastrozole arms in median survival of 5.7\xa0months). However, the committee noted that these results should be interpreted cautiously because they may not be generalisable to the licensed population (see section\xa03.4). In FIRST, the median overall-survival benefit was much shorter than the progression-free survival (5.7\xa0months compared with 10.3\xa0months). The committee was concerned that if an overall-survival benefit is shown in FALCON, it could be considerably lower than seen in FIRST, given that the progression-free survival was much shorter in FALCON than FIRST (2.8\xa0months compared with 10.3\xa0months; see section\xa03.5). The committee concluded that it is unclear whether, and by how much, fulvestrant would extend overall survival compared with anastrozole. It noted that mature data from FALCON, which is better matched to the licensed indication than FIRST, are needed.\n\n# Indirect treatment comparison with letrozole and tamoxifen\n\n## PO25 should be removed from the analysis and equal efficacy of anastrozole and letrozole should be assumed\n\nThe company carried out an indirect treatment comparison comparing fulvestrant with letrozole and tamoxifen. This included 3\xa0studies in addition to FIRST and FALCON: NORTH AMERICAN and TARGET (anastrozole compared with tamoxifen); and PO25 (letrozole compared with tamoxifen). The committee noted comments from the ERG that it preferred to exclude PO25 from the network because it could not obtain patient-level data from it and the results were compromised by about a 50% crossover after progression. The committee therefore questioned whether the trial should be included in the analysis. It understood that PO25 was incorporated to allow a comparison between fulvestrant and letrozole. However, it recalled its earlier conclusion that letrozole and anastrozole have equivalent clinical effectiveness (see section\xa03.2) and so concluded that PO25 should be removed from the analysis.\n\n## The results of the indirect treatment comparison for overall survival are highly uncertain\n\nThe company applied the inclusion and exclusion criteria from FALCON to the included studies to 'match' the trial population in FALCON. This meant that the company derived a subgroup from the included studies to create a homogenous population. The ERG commented that this approach reduced the sample size of the comparator studies and broke randomisation in all the studies except for FALCON. Although FALCON excluded people with HER2-positive disease, it was unclear whether people with HER2-positive disease in the NORTH AMERICAN and TARGET studies (for a comparison with tamoxifen) had been excluded. The company commented that older trials would not necessarily have included HER2 testing because it was not routinely carried out at the time of enrolment. The committee considered whether the advantages of reducing heterogeneity outweighed the disadvantages of reducing the number of patients included in the analysis and breaking randomisation, but was not persuaded it was and so questioned the reliability of the results. Following consultation, the committee noted the company's view that the 'matched' analysis was a robust estimator of efficacy given the heterogeneity in the trial populations. The company stated that the analysis did not break randomisation, the relative treatment effects were consistent with published trial data and the baseline characteristics remained balanced in the matched subgroups. The ERG acknowledged that the baseline characteristics of the matched and whole trial populations were similar. However, it stated that stratification of the initial randomisation on the baseline characteristics used for matching would be the only way to avoid breaking randomisation. The company presented an updated indirect treatment comparison using intention-to-treat data from the included studies, instead of 'matching' the trial populations to FALCON. The committee agreed that the results of the indirect comparison did not appear to have been distorted by the matching process. However, it remained concerned that the results for overall survival are highly uncertain, because mature data from FALCON were not available for inclusion in the analysis.\n\n# Survival extrapolations\n\n## Overall-survival projections are highly uncertain\n\nThe committee considered that the partitioned survival cost-effectiveness model presented by the company is acceptable for decision-making. It considered the parametric survival curves for extrapolating progression-free and overall survival, which were estimated from the indirect treatment comparison. It noted that the company chose generalised gamma distributions for progression-free survival and Weibull distributions for overall survival, based on clinical plausibility and statistical fit, and applied these to fulvestrant and all the comparators. The committee was satisfied with the choice of parametric survival curves because the projections seem consistent with clinical expert opinion. However, it was concerned that the data from FALCON were immature, and noted comments that much of the data used for the projection of overall survival were from FIRST. The committee recalled that the results from FIRST may not be generalisable to the licensed population (see section\xa03.4), and that the final overall-survival benefit from FALCON is highly uncertain (see section\xa03.6). Therefore, it concluded that the projections for overall survival are highly uncertain.\n\n# Utility values used in the model\n\n## The utility values are not in line with other appraisals, but are not critical to the cost-effectiveness analysis\n\nThe company derived utility values directly from FALCON using the EQ‑5D questionnaire (progression-free survival\xa00.75; progressed disease\xa00.69). The ERG commented that using EQ‑5D from the trial is consistent with the NICE reference case. The committee noted that the value for progressed disease was higher than those used in past appraisals. The company acknowledged this and presented a scenario analysis using lower values. The committee noted that alternative utility values for progressed disease had little effect on the cost-effectiveness results, and did not pursue this issue further.\n\n# Cost-effectiveness estimate\n\n## The main area of uncertainty in the cost-effectiveness analysis is the projected overall-survival benefit\n\nThe committee noted that the initial incremental cost-effectiveness ratios (ICERs) presented by the company for fulvestrant compared with anastrozole and tamoxifen (based on the company's indirect treatment comparison that 'matched' the trial populations to FALCON) were about £34,100 and £22,500 per quality-adjusted life year (QALY) gained respectively. The ERG did an exploratory base-case analysis that changed the assumptions on resource use, setting for the administration for fulvestrant and use of subsequent therapies. The ERG also assumed equal efficacy for letrozole and anastrozole (excluding PO25 from the indirect comparison). The committee noted that these changes had very little impact on the ICERs for fulvestrant (about £33,500 and £23,700 per QALY gained, compared with anastrozole and tamoxifen respectively). However, it concluded that the main area of uncertainty in the cost-effectiveness analysis is the projected overall-survival benefit.\n\n## Fulvestrant is not a cost-effective use of NHS resources compared with aromatase inhibitors\n\nThe committee noted that the overall-survival projection for fulvestrant was mostly based on data from FIRST, which it had concluded was less relevant for its decision-making than FALCON (see sections\xa03.4 and\xa03.9). It also questioned the validity of the modelled results because the predicted difference in median survival between the fulvestrant and anastrozole arms was about 8.3\xa0months in the model, whereas in FIRST it was 5.7\xa0months (see section\xa03.6). It also noted the considerable uncertainty in the final cost-effectiveness estimates because of immature overall-survival data from FALCON. It was uncertain whether, and by how much, fulvestrant would extend survival compared with anastrozole in the licensed population (see section\xa03.6). It therefore considered the ERG's scenario analyses that explored the effect of different predictions of overall survival on the ICERs. Lowering the estimate of the overall-survival gain for fulvestrant compared with anastrozole (to the equivalent of assuming an HR of 0.82 and 0.88, instead of 0.77 in the company's base case) increased the ICER to about £40,800 and £52,400 per QALY gained respectively. When the HR was assumed to be\xa01 (that is, fulvestrant was assumed to have no overall-survival benefit over anastrozole), the ICERs increased to above £200,000 per QALY gained. The committee concluded that the results are very sensitive to changes in the predicted overall-survival gain used for fulvestrant, and that the base-case results are highly uncertain. It considered that the base-case estimate is likely to be optimistic, being based on a projected median overall-survival benefit of 8.3\xa0months, when the median difference in progression-free survival in FALCON was only 2.8\xa0months and the overall-survival benefit is unknown. Following consultation, the company presented confidential ICERs based on a proposed alternative pricing assumption. However, the committee agreed that the revised base-case estimates remain highly uncertain and may substantially overestimate the cost effectiveness of fulvestrant. It concluded that further survival data from FALCON are needed in order to produce robust estimates of the cost effectiveness of fulvestrant. The committee appreciated that some patients would welcome this alternative treatment option, but at present it cannot recommend fulvestrant as a cost-effective use of NHS resources for postmenopausal women with untreated, locally advanced or metastatic oestrogen-receptor positive breast cancer.\n\n## Fulvestrant is not a cost-effective use of NHS resources for people in whom aromatase inhibitors are not tolerated or are contraindicated\n\nThe committee considered the ICERs for fulvestrant compared with tamoxifen. It noted that the ICERs estimated by both the company and the ERG were in the range of £20,000 to £30,000 per QALY gained. The committee referred to section\xa06.3.3 of NICE's guide to the methods of technology appraisal. This states that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of the technology as an effective use of NHS resources take into account a number of factors including the degree of certainty around the ICER. The committee considered that the ICERs are highly uncertain because of the immaturity of the overall-survival data (the key driver of the results; see section\xa03.12). It noted that, in the ERG's scenario analysis that explored the effect of different predictions of overall-survival benefit, the ICERs vary from about £24,400 to £39,000 per QALY gained. The committee also noted the company's updated confidential ICERs, based on the proposed alternative pricing assumption. However, it concluded that the ICERs remain highly uncertain because of the immaturity of the overall-survival data used in the indirect comparison. Therefore, fulvestrant cannot be recommended as a cost-effective use of NHS resources for postmenopausal women who have untreated, locally advanced or metastatic oestrogen-receptor positive breast cancer.\n\n# Conclusion\n\n## It is unclear whether, and by how much, fulvestrant would extend overall survival compared with aromatase inhibitors\n\nThe committee concluded that the FALCON trial, which directly compared fulvestrant with anastrozole, was superior to the FIRST trial because the population is more relevant and it has less potential for bias. It noted that, for FALCON, the progression-free survival results are modest and the overall-survival data are immature. The committee was therefore unclear whether, and by how much, fulvestrant would extend overall survival compared with anastrozole.\n\n## Fulvestrant is not a cost-effective use of NHS resources compared with aromatase inhibitors or when aromatase inhibitors are not suitable\n\nThe overall-survival benefit for fulvestrant compared with existing treatments is highly uncertain, and could affect the estimates of cost effectiveness for fulvestrant compared with existing treatments. More survival data from FALCON are needed in order to produce robust estimates of cost effectiveness. Therefore, fulvestrant cannot be recommended as a cost-effective use of NHS resources for postmenopausal women who have untreated, locally advanced or metastatic oestrogen-receptor positive breast cancer."}
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https://www.nice.org.uk/guidance/ta503
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Evidence-based recommendations on fulvestrant (Faslodex) for treating locally advanced or metastatic (secondary), oestrogen-receptor positive breast cancer in postmenopausal women who have not had endocrine therapy before.
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be34f6874ba74572456a73b6abcc7620f8ec6d71
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nice
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Sore throat (acute): antimicrobial prescribing
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Sore throat (acute): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute sore throat. It aims to limit antibiotic use and reduce antimicrobial resistance. Acute sore throat is often caused by a virus, lasts for about a week, and most people get better without antibiotics. Withholding antibiotics rarely leads to complications.
# Recommendations
# Managing acute sore throat
## All people with acute sore throat
Be aware that:
acute sore throat (including pharyngitis and tonsillitis) is self‑limiting and often triggered by a viral infection of the upper respiratory tract
symptoms can last for around 1 week, but most people will get better within this time without antibiotics, regardless of cause (bacteria or virus).
Assess and manage children under 5 who present with fever as outlined in the NICE guideline on fever in under 5s.
Use FeverPAIN or Centor criteria to identify people who are more likely to benefit from an antibiotic and manage in line with recommendations 1.1.4 to 1.1.13.
Give advice about:
the usual course of acute sore throat (can last around 1 week)
managing symptoms, including pain, fever and dehydration, with self-care (see the recommendations on self-care).
Reassess at any time if symptoms worsen rapidly or significantly, taking account of:
alternative diagnoses such as scarlet fever or glandular fever
any symptoms or signs suggesting a more serious illness or condition
previous antibiotic use, which may lead to resistant organisms.
## People who are unlikely to benefit from an antibiotic (FeverPAIN score of 0 or 1, or Centor score of 0, 1 or 2):
Do not offer an antibiotic prescription.
As well as the general advice in recommendation 1.1.4, give advice about:
an antibiotic not being needed
seeking medical help if symptoms worsen rapidly or significantly, do not start to improve after 1 week, or the person becomes systemically very unwell.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on no antibiotic.
Full details of the evidence and the committee's discussion are in the evidence review.
## People who may be more likely to benefit from an antibiotic (FeverPAIN score of 2 or 3)
Consider no antibiotic prescription with advice (see recommendation 1.1.7) or a back-up antibiotic prescription (see recommendation 1.3.1 for choice of antibiotic), taking account of:
evidence that antibiotics make little difference to how long symptoms last (on average, they shorten symptoms by about 16 hours)
evidence that most people feel better after 1 week, with or without antibiotics
the unlikely event of complications if antibiotics are withheld
possible adverse effects, particularly diarrhoea and nausea.
When a back-up antibiotic prescription is given, as well as the general advice in recommendation 1.1.4, give advice about:
an antibiotic not being needed immediately
using the back-up prescription if symptoms do not start to improve within 3 to 5 days or if they worsen rapidly or significantly at any time
seeking medical help if symptoms worsen rapidly or significantly or the person becomes systemically very unwell.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on no antibiotic and back-up antibiotics.
Full details of the evidence and the committee's discussion are in the evidence review.
## People who are most likely to benefit from an antibiotic (FeverPAIN score of 4 or 5, or Centor score of 3 or 4)
Consider an immediate antibiotic prescription (see recommendation 1.3.1 for choice of antibiotic), or a back-up antibiotic prescription with advice (see recommendation 1.1.9), taking account of:
the unlikely event of complications if antibiotics are withheld
possible adverse effects, particularly diarrhoea and nausea.
When an immediate antibiotic prescription is given, as well as the general advice in recommendation 1.1.4, give advice about seeking medical help if symptoms worsen rapidly or significantly or the person becomes systemically very unwell.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on back-up antibiotics and choice of antibiotic.
Full details of the evidence and the committee's discussion are in the evidence review.
## People who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high-risk of complications
Offer an immediate antibiotic prescription (see recommendation 1.3.1 for choice of antibiotic) with advice (see recommendation 1.1.11).
Refer people to hospital if they have acute sore throat associated with any of the following:
a severe systemic infection (see the NICE guideline on sepsis)
severe suppurative complications (such as quinsy or cellulitis, parapharyngeal abscess or retropharyngeal abscess or Lemierre syndrome).
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic.
Full details of the evidence and the committee's discussion are in the evidence review.
# Self-care
## All people with acute sore throat
Consider paracetamol for pain or fever, or if preferred and suitable, ibuprofen.
Advise about the adequate intake of fluids.
Explain that some adults may wish to try medicated lozenges containing either a local anaesthetic, a non-steroidal anti-inflammatory drug (NSAID) or an antiseptic. However, they may only help to reduce pain by a small amount.
Be aware that no evidence was found on non-medicated lozenges, mouthwashes, or local anaesthetic mouth spray used on its own.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.
Full details of the evidence and committee's discussion are in the evidence review.
# Choice of antibiotic
When prescribing an antibiotic for acute sore throat:
follow table 1 for adults aged 18 years and over
follow table 2 for children and young people under 18 years.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic
Phenoxymethylpenicillin:
mg four times a day or 1,000 mg twice a day for 5 to 10 days
Five days may be enough for symptomatic cure; but a 10-day course may increase the chance of microbiological cure
Alternative first choice for penicillin allergy or intolerance (for people who are not pregnant)
Clarithromycin:
mg to 500 mg twice a day for 5 days
Alternative first choice for penicillin allergy in pregnancy
Erythromycin:
mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic
Phenoxymethylpenicillin:
month to 11 months, 62.5 mg four times a day or 125 mg twice a day for 5 to 10 days
year to 5 years, 125 mg four times a day or 250 mg twice a day for 5 to 10 days
years to 11 years, 250 mg four times a day or 500 mg twice a day for 5 to 10 days
years to 17 years, 500 mg four times a day or 1,000 mg twice a day for 5 to 10 days
Five days may be enough for symptomatic cure; but a 10-day course may increase the chance of microbiological cure
Alternative first choice for penicillin allergy or intolerance (for people who are not pregnant)
Clarithromycin:
month to 11 years:Under 8 kg, 7.5 mg/kg twice a day for 5 days
kg to 11 kg, 62.5 mg twice a day for 5 days
kg to 19 kg, 125 mg twice a day for 5 days
kg to 29 kg, 187.5 mg twice a day for 5 days
kg to 40 kg, 250 mg twice a day for 5 days
years to 17 years, 250 mg to 500 mg twice a day for 5 days
Alternative first choice for penicillin allergy in pregnancy
Erythromycin:
years to 17 years, 250 mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
See the BNF for children for appropriate use and dosing in specific populations, for example hepatic impairment and renal impairment.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.
For a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic choice and antibiotic course length.
Full details of the evidence and committee's discussion are in the evidence review.# Summary of the evidence
# Self-care
## Oral analgesia
Overall aspirin, paracetamol and diclofenac potassium (not available to buy over the counter) were all more effective than placebo at reducing pain and fever in adults with sore throat associated with an upper respiratory tract infection. This was based on low to moderate quality evidence from 3 randomised controlled trials (RCTs) (Eccles et al. 2003, Gehanno et al. 2003 and Voelker et al. 2016).
Overall, adverse events for aspirin, paracetamol and diclofenac potassium in the 3 RCTs did not appear to be significantly different from placebo (very low to low quality evidence), although adverse events were poorly reported. Another RCT that assessed safety outcomes (Moore et al. 2002) found significantly higher rates of adverse events with aspirin compared with ibuprofen (low quality evidence).
Diclofenac is associated with higher cardiovascular risk than other non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Risk is similar to that with selective COX‑2 inhibitors. Naproxen and low-dose ibuprofen (1,200 mg daily or less in adults) are considered to have the most favourable cardiovascular safety profiles (Medicines and Healthcare products Regulatory Agency Drug Safety Update on NSAIDs, October 2012). Of the non‑selective NSAIDs, low-dose ibuprofen has the lowest gastrointestinal risk (MHRA Drug Safety Update on NSAIDS and coxibs, December 2007).
## Medicated lozenges
Medicated lozenges containing benzocaine, hexylresorcinol or flurbiprofen may help to reduce pain compared with placebo in adults. This was based on low to moderate quality evidence from 6 RCTs (Watson et al. 2000, Benrimoj et al. 2001, Blagden et al. 2001, Chrubasik et al. 2012, McNally et al. 2012 and Schachtel et al. 2014). However, the absolute improvements in pain score were small.
Few adverse events were reported in the RCTs with benzocaine lozenges or hexylresorcinol lozenges. Adverse events occurred in 30% to 50% of people using flurbiprofen lozenges, including taste disturbances, numbness, dry mouth and nausea.
## Throat sprays
Chlorhexidine plus benzydamine combination throat spray (not available in the UK) significantly reduced pain symptoms by day 7 compared with placebo in adults who were also taking phenoxymethylpenicillin. This was based on high quality evidence from an RCT (Cingi et al. 2011). The absolute improvements in symptom score were small and the clinical relevance is not clear.
Local adverse events, including numbness and taste disturbances, were common (moderate quality evidence).
No systematic reviews or RCTs of local anaesthetic mouth sprays (without an antiseptic) were identified.
## Other interventions
No systematic reviews or RCTs of non-medicated lozenges or mouthwashes were identified.
Based on evidence, experience and safety data the committee agreed that it was reasonable to consider paracetamol (first-line) or ibuprofen for self-care of pain or fever associated with acute sore throat. Although no studies were identified on paracetamol and ibuprofen in children with sore throat, the committee noted that these medicines have well-established efficacy and safety profiles for managing pain and fever in children.
Based on evidence and experience, the committee agreed that people may wish to try self-care with medicated lozenges (containing a local anaesthetic, an NSAID or an antiseptic agent) to help reduce pain in acute sore throat, but should be told that the benefit is likely to be small.
Based on evidence and experience, the committee agreed that it is unclear whether throat sprays containing an antiseptic plus a local anaesthetic help symptoms. Furthermore, the combination product used in the study is not available in the UK.
The committee agreed that prescribers should be aware that no evidence was found on non-medicated lozenges, mouthwashes or local anaesthetic mouth sprays (without an antiseptic).
The committee was aware of the potential benefits of avoiding GP appointments if people access self-care and seek advice from other health professionals, particularly their community pharmacist, rather than making an appointment to see their GP. The committee agreed that community pharmacists are often more accessible to people than GPs to offer advice.
# Corticosteroids
Corticosteroids (oral or intramuscular) significantly increased the number of adults and children with no pain at 24 and 48 hours (number needed to treat 4 ; high quality evidence) and significantly reduced the time to pain resolution by about 14 hours (low quality evidence), compared with placebo. This was based on a systematic review of RCTs (Hayward et al. 2012). There were no significant differences between corticosteroids and placebo in recurrence or relapse of symptoms, or in the number of days missed from work or school (low to moderate quality evidence). All people in the studies were also treated with antibiotics.
A single dose of dexamethasone given to adults who did not need an immediate antibiotic prescription did not increase the proportion of people with resolution of symptoms at 24 hours, although a significant difference was seen at 48 hours. This was based on moderate quality evidence from an RCT (Hayward et al. 2017).
There was no difference in adverse events for people taking corticosteroids compared with placebo, although reporting of adverse events was incomplete. The RCTs were not large enough to identify rare adverse events associated with corticosteroids.
## Committee discussions on corticosteroids
The committee noted that most studies of corticosteroids were carried out in accident and emergency departments and included people with more severe symptoms.
The committee noted that the studies did not report on the long-term safety of corticosteroids and the risks of recurrent treatment. No studies compared corticosteroids with analgesia.
The committee agreed that sore throat is a self-limiting illness and there are concerns about the safety of corticosteroids and the risks of recurrent treatment. The committee noted that there are safer alternatives and agreed not to recommend corticosteroids for managing acute sore throat.
# No antibiotic
In most cases, acute sore throat is a self-limiting infection, often caused by a viral infection, and most people will not need an antibiotic. Group A beta‑haemolytic streptococcus (GABHS) is the most common bacterial pathogen in sore throat (European Society for Clinical Microbiology and Infectious Diseases sore throat guideline ), isolated in approximately 20% of cases (Kronman et al. 2014).
Complications of sore throat caused by a GABHS infection are generally rare in adults and children. Complications can be suppurative (including quinsy , acute otitis media and acute sinusitis) or non-suppurative (including acute rheumatic fever and acute glomerulonephritis; European Society for Clinical Microbiology and Infectious Diseases Sore Throat Guideline ).
## Efficacy of antibiotics
With antibiotics, significantly more people with acute sore throat were symptom free at days 3 and 7 compared with placebo. At day 3, 51% were symptom free with antibiotics compared with 34% with placebo (NNT 6 ). At day 7, most people in both groups were symptom free (87% versus 82%, NNT 21 ). This was based on low quality evidence from a systematic review and meta-analysis of RCTs and quasi-RCTs (Spinks et al. 2013). Overall, antibiotics shortened the duration of symptoms by about 16 hours over 7 days.
Subgroup analyses suggest antibiotics are more effective in people with a throat swab positive for GABHS. The NNT with antibiotics compared with placebo to prevent 1 person with a negative throat swab having a sore throat on day 3 was 7 (range 5 to 12), with an NNT of about 4 (range 4 to 5) for people with a throat swab positive for GABHS (low to moderate quality evidence).
The overall incidence of suppurative complications, including acute otitis media, acute sinusitis and quinsy (peri-tonsillar abscess), was low and based on data from older studies, mostly conducted in the 1950s. These studies found that antibiotics significantly reduced the incidence of acute otitis media and acute sinusitis within 14 days, and quinsy (peri-tonsillar abscess) within 2 months, compared with placebo (low to high quality evidence). Based on the complication rates from studies conducted after 1975, Spinks et al. (2013) estimated that 200 people would need to be treated with antibiotics to prevent 1 case of acute otitis media.
Rheumatic fever was reported only in RCTs published before 1961, and the authors noted that the incidence has continued to decline in western societies since then. Results from these early studies found that antibiotics reduced acute rheumatic fever by more than two-thirds compared with placebo (low quality evidence).
There was no statistically significant reduction in acute glomerulonephritis in people taking antibiotics, although it was difficult to detect a significant reduction because the absolute rates of this complication were low (less than 0.1%; very low quality evidence).
## Safety of antibiotics
Allergic reactions to penicillins occur in 1 to 10% of people and anaphylactic reactions occur in less than 0.05%. People with a history of atopic allergy (for example, asthma, eczema and hay fever) are at a higher risk of anaphylactic reactions to penicillins. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin). See the NICE guideline on drug allergy: diagnosis and management for more information.
Antibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE Clinical Knowledge Summary : diarrhoea – antibiotic associated).
Adverse effects were not reported by Spinks et al. (2013) because of inconsistencies in reporting these effects in the RCTs.
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
# Back-up antibiotics
A back-up antibiotic prescription (either patient-led collection or delayed collection) or no antibiotic prescription was as effective as an immediate antibiotic prescription for reducing duration and severity of symptoms in people with pharyngitis. This was based on moderate quality evidence from 1 RCT in adults (de la Poza Abad et al. 2016).
Immediate antibiotics were significantly more effective than back-up antibiotics for improving fever, pain and malaise in some RCTs from a systematic review (Spurling et al. 2013), whereas there was no difference between groups in other RCTs (low to moderate quality evidence).
Across the RCT and systematic review there was generally no difference in adverse events between an immediate antibiotic prescription strategy and a back-up antibiotic prescription or no prescription strategy (very low to moderate quality evidence).
# Identifying people more likely to benefit from antibiotics
Targeted use of antibiotics using the FeverPAIN clinical scoring system improved symptoms on days 2 to 4 (to a statistically but possibly not clinically meaningful amount) and reduced antibiotic use, compared with a back-up antibiotic prescribing strategy alone. This was based on low to moderate quality evidence from an open-label RCT (Little et al. 2013). People in the group with a low FeverPAIN score (0 or 1 points) were not offered an antibiotic. People with a moderate FeverPAIN score (2 or 3 points) were offered a back-up prescription, and people with a high FeverPAIN score (4 points or more) were offered an immediate antibiotic prescription. The additional use of rapid antigen tests for GABHS in people with a high FeverPAIN score had no clear advantage over using FeverPAIN score alone.
## Committee discussions on no antibiotics, back-up antibiotics and identifying people more likely to benefit from antibiotics
Based on evidence and experience, the committee agreed that acute sore throat is a self-limiting infection, and most people will get better within a week without antibiotic treatment. Based on evidence and experience, the committee agreed that complications are rare in adults and children, and the committee noted the adverse effects associated with antibiotic use.
The committee agreed that prescribers need to weigh up the small clinical benefits from antibiotics against their potential to cause adverse effects.
Based on evidence and experience, the committee agreed that no or back-up antibiotic prescribing was as effective as immediate antibiotic prescribing for people with acute sore throat. A back-up antibiotic prescription could be used if symptoms deteriorate rapidly or significantly, or do not improve within the next 3 to 5 days.
The committee discussed the clinical scoring systems available to help identify people with acute sore throat who may be more likely to benefit from antibiotics. The committee noted that FeverPAIN and Centor criteria have not been validated in a UK population.
The committee was aware that the FeverPAIN criteria were developed in a UK primary care setting in 2013 and have not been assessed in children under 3 years. External validation has not been carried out, but the criteria have been tested in an RCT setting.
The FeverPAIN scoring tool can help prescribers to determine if a person's sore throat is more likely to benefit from antibiotics. The scoring tool includes the FeverPAIN criteria plus additional parameters to help prescribers determine the severity of the sore throat. The additional parameters do not affect the overall FeverPAIN score. The committee was aware that the tool may help prescribers implement FeverPAIN criteria in practice and supports shared decision-making in consultations with people.
The committee noted that the Centor criteria were developed in the US in an emergency department setting in 1981 and has only been assessed in an adult population. The committee was aware that the previous NICE guideline on upper respiratory tract infections used Centor criteria. FeverPAIN criteria were not available at the time this guideline was published.
The committee noted that a FeverPAIN score of 4 or 5 is thought to be associated with a 62 to 65% probability of having a bacterial infection, which is slightly higher than the 32 to 56% probability associated with a Centor score of 3 or 4. The committee was aware that using FeverPAIN in preference to Centor may increase the use of back-up antibiotic prescribing. However, the committee discussed that if more back-up antibiotic prescribing strategies are implemented the overall use of antibiotics may reduce, assuming that around two‑thirds of people will not collect (and take) the antibiotics.
The committee acknowledged the recommendation in the previous NICE guideline on upper respiratory tract infections for a no or back-up antibiotic prescribing strategy in acute sore throat, with an immediate antibiotic prescribing strategy also an option for people with an acute sore throat when 3 or more Centor criteria are present.
The committee discussed FeverPAIN scores of 4 or 5, or Centor scores of 3 or 4. In some cases people may have these scores but may have milder symptoms. To ensure people with milder and improving symptoms are not issued an immediate antibiotic prescription the committee used its expertise and agreed that a back-up prescription may also be appropriate for this group of people. Withholding antibiotics is unlikely to lead to complications.
The committee discussed FeverPAIN scores of 0 or 1, or Centor scores of 0, 1 or 2. The committee was aware that the previous NICE guideline on upper respiratory tract infections recommended either a no antibiotic or a back-up antibiotic prescribing strategy for people with these Centor scores. However, based on evidence, experience and the principles of antimicrobial stewardship the committee recommended a no antibiotic prescribing strategy for this group.
The committee was aware that FeverPAIN criteria had not been tested in populations under 3 years and that the Centor criteria were developed in an adult population. However, the committee, using its experience, advised that young children (under 3 years) are unlikely to present with sore throat symptoms alone. Prescribers should follow the NICE guideline on fever in under 5s to assess and manage fever in this population.
The committee agreed that there is currently uncertainty about which scoring tool is more effective in a UK population. They noted that both criteria are used in clinical practice and that using a scoring tool is preferential to not using any tool. The committee concluded that either FeverPAIN or Centor criteria should be used to identify people with acute sore throat who may be more likely to benefit from antibiotics.
# Antibiotic choice
There were no major differences in clinical effectiveness between classes of antibiotics, including penicillins, cephalosporins, macrolides, and sulfonamides in adults and children with GABHS-positive sore throat. This was based on very low to moderate quality evidence from 2 systematic reviews and meta-analyses of RCTs (Altamimi et al. 2012 and van Driel et al. 2016). Statistically significant differences were seen for some comparisons but the absolute differences between antibiotic classes was small.
There was no significant difference in adverse events for cephalosporins, macrolides or sulfonamides compared with phenoxymethylpenicillin in 1 systematic review (van Driel et al. 2016). The other systematic review Altamimi et al. 2012) found that a shorter course of late-generation (broader spectrum) antibiotics was associated with significantly more adverse events compared with a 10‑day course of phenoxymethylpenicillin.
## Frequency of antibiotic dosing
Twice daily dosing of phenoxymethylpenicillin was as effective as 3 or 4 times daily dosing for microbiological cure in adults and children with GABHS-positive sore throat. This was based on low quality evidence from 1 systematic review and meta-analysis of RCTs (Lan and Colford 2000). Once-daily dosing was significantly less effective than 3 or 4 times daily dosing of phenoxymethylpenicillin (low quality evidence).
The committee discussed that, generally, if an antibiotic is needed to treat an infection that is not life threatening, narrow-spectrum antibiotics should be used as the first choice. Indiscriminate use of broad-spectrum antibiotics is undesirable because it creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. For infections that are not life threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective. Based on evidence, clinical experience and resistance data, the committee agreed to recommend phenoxymethylpenicillin as the first-choice antibiotic. This is a narrow-spectrum penicillin with the lowest risk of causing resistance.
The committee discussed whether amoxicillin would be a suitable alternative to phenoxymethylpenicillin to support medicines adherence. However, it was aware of evidence that the risk of resistance to amoxicillin is significantly increased in urinary isolates of Escherichia coli following a course of amoxicillin. These effects are greatest in the first month after use, but are detectable for up to 12 months. Also, if the sore throat is due to glandular fever, the BNF states that erythematous rashes are common in people with glandular fever who take amoxicillin.
The committee discussed the systematic review by Lan and Colford (2000) that suggested twice-daily dosing was as effective as four times daily dosing. The committee noted that four times daily dosing was the standard dose frequency for phenoxymethylpenicillin and the dose used most frequently in the included studies. The committee noted that this is low quality evidence, using data from only 6 studies and used bacteriological cure at follow-up as an efficacy outcome (rather than a patient-oriented outcome).
The committee discussed the benefits and harms of using twice daily dosing of phenoxymethylpenicillin. Twice daily dosing would support medicines adherence in those people who may struggle to take 4 doses at 6‑hourly intervals before food, such as children at school. The committee was concerned that if a twice daily dose was used, phenoxymethylpenicillin levels may fall below the minimum inhibitory concentration. However, they also discussed that streptococci are highly sensitive to phenoxymethylpenicillin, and that antibiotic penetration in sore throat tissue is good, therefore even small concentrations of antibiotic will treat the infection.
Based on evidence and clinical experience, the committee agreed that if phenoxymethylpenicillin was prescribed, twice daily or four times a day dosing could be used, providing the same total daily dose was given.
Based on evidence, clinical experience and resistance data, the committee agreed to recommend clarithromycin as the alternative first-choice antibiotic for use in penicillin allergy or for phenoxymethylpenicillin intolerance. In pregnancy, erythromycin was recommended if there is true penicillin allergy. Both are macrolides, given at usual doses.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
Based on the evidence that there are no major differences in clinical effectiveness between classes of antibiotics, the committee used its experience to agree that the choice should largely be driven by minimising the risk of resistance.
# Antibiotic course length
In people with GABHS-positive sore throat, treatment with phenoxymethylpenicillin for 5 to 7 days had significantly lower microbiological cure rates compared with 10 days treatment (NNT 13 ). This was based on low quality evidence from 1 systematic review and meta-analysis of RCTs (Falagas et al. 2008).
There were no significant differences between 5 to 7 days treatment with phenoxymethylpenicillin compared with 10 days treatment, in the rate of relapse or recurrence (very low quality evidence).
The studies that compared different course lengths of phenoxymethylpenicillin treatment did not report on adverse events.
## Committee discussions on antibiotic course length
The committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.
The committee noted that most studies involving clarithromycin or erythromycin used a 5‑day course, whereas, most studies involving phenoxymethylpenicillin used a 10‑day course.
The committee noted that no studies were identified that compared 10‑day and 5‑day courses of phenoxymethylpenicillin given at the current recommended dose (500 mg four times daily). However, the committee was aware from its experience that many people do not complete a 10‑day course.
Based on evidence, the committee recognised that microbiological cure may be better with a 10‑day course of phenoxymethylpenicillin compared with a 5‑ or 7‑day course, although there were no differences in relapse or recurrence. They agreed that, in situations where bacterial eradication is not specifically needed, and where symptomatic cure is the goal, if a decision to prescribe an antibiotic is made, a shorter course of phenoxymethylpenicillin may be sufficient. However, in situations where there is recurrent infection, a 10‑day course may increase the likelihood of microbiological cure.
Based on evidence, clinical experience and resistance data, the committee agreed that when an antibiotic was appropriate, a 5- to 10‑day course of phenoxymethylpenicillin was needed.
The committee was aware that bottles of phenoxymethylpenicillin suspension expire within 7 days once reconstituted and a second bottle would be needed to complete a 10‑day course. Prescribing a 7‑day course may help with medicines adherence.
A 5-day course of clarithromycin or erythromycin (which is preferred in pregnancy) is an alternative for people with penicillin allergy or intolerance. This course length takes into account the overall efficacy and safety evidence for antibiotics, and minimises the risk of resistance.
See the full evidence review for more information.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing or longer treatment duration (for example, antibiotics). See the NICE guideline on medicines adherence.
# Resource implications
Respiratory tract infections, including acute sore throat, are a common reason for consultations in primary care, and therefore are a common reason for potential antibiotic prescribing. In a 2011 survey of UK primary care (Gulliford et al. 2014), consultations for 'sore throat' accounted for 27% of all consultations for respiratory tract infections, and the median practice issued an antibiotic prescription for 60% of these.
There is potential for resource savings if a no antibiotic or a back-up antibiotic prescription strategy is used. One open-label RCT (de la Poza Abad et al. 2016) found significantly lower rates of antibiotic collection in the delayed collection prescription group (26.0%, p<0.001) and patient-led back-up prescription group (34.7%, p<0.001) compared with the immediate prescription group (89.1%, low quality evidence).
Recommended antibiotics are all available as generic formulations, see the Drug Tariff for costs.# Terms used in the guideline
People with a sore throat caused by streptococcal bacteria are more likely to benefit from antibiotics. FeverPAIN or Centor criteria are clinical scoring tools that can help to identify the people in whom this is more likely.
# FeverPAIN criteria
Fever (during previous 24 hours)
Purulence (pus on tonsils)
Attend rapidly (within 3 days after onset of symptoms)
Severely Inflamed tonsils
No cough or coryza (inflammation of mucus membranes in the nose)
Each of the FeverPAIN criteria score 1 point (maximum score of 5). Higher scores suggest more severe symptoms and likely bacterial (streptococcal) cause. A score of 0 or 1 is thought to be associated with a 13 to 18% likelihood of isolating streptococcus. A score of 2 or 3 is thought to be associated with a 34 to 40% likelihood of isolating streptococcus. A score of 4 or 5 is thought to be associated with a 62 to 65% likelihood of isolating streptococcus.
# Centor criteria
Tonsillar exudate
Tender anterior cervical lymphadenopathy or lymphadenitis
History of fever (over 38 degrees Celsius)
Absence of cough
Each of the Centor criteria score 1 point (maximum score of 4). A score of 0, 1 or 2 is thought to be associated with a 3 to 17% likelihood of isolating streptococcus. A score of 3 or 4 is thought to be associated with a 32 to 56% likelihood of isolating streptococcus.
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{'Recommendations': "# Managing acute sore throat\n\n## All people with acute sore throat\n\nBe aware that:\n\nacute sore throat (including pharyngitis and tonsillitis) is self‑limiting and often triggered by a viral infection of the upper respiratory tract\n\nsymptoms can last for around 1\xa0week, but most people will get better within this time without antibiotics, regardless of cause (bacteria or virus).\n\nAssess and manage children under 5 who present with fever as outlined in the NICE guideline on fever in under 5s.\n\nUse FeverPAIN or Centor criteria to identify people who are more likely to benefit from an antibiotic and manage in line with recommendations 1.1.4 to 1.1.13.\n\nGive advice about:\n\nthe usual course of acute sore throat (can last around 1\xa0week)\n\nmanaging symptoms, including pain, fever and dehydration, with self-care (see the recommendations on self-care).\n\nReassess at any time if symptoms worsen rapidly or significantly, taking account of:\n\nalternative diagnoses such as scarlet fever or glandular fever\n\nany symptoms or signs suggesting a more serious illness or condition\n\nprevious antibiotic use, which may lead to resistant organisms.\n\n## People who are unlikely to benefit from an antibiotic (FeverPAIN score of 0 or 1, or Centor score of 0, 1 or 2):\n\nDo not offer an antibiotic prescription.\n\nAs well as the general advice in recommendation 1.1.4, give advice about:\n\nan antibiotic not being needed\n\nseeking medical help if symptoms worsen rapidly or significantly, do not start to improve after 1\xa0week, or the person becomes systemically very unwell.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on no antibiotic.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n## People who may be more likely to benefit from an antibiotic (FeverPAIN score of 2 or 3)\n\nConsider no antibiotic prescription with advice (see recommendation 1.1.7) or a back-up antibiotic prescription (see recommendation 1.3.1 for choice of antibiotic), taking account of:\n\nevidence that antibiotics make little difference to how long symptoms last (on average, they shorten symptoms by about 16\xa0hours)\n\nevidence that most people feel better after 1\xa0week, with or without antibiotics\n\nthe unlikely event of complications if antibiotics are withheld\n\npossible adverse effects, particularly diarrhoea and nausea.\n\nWhen a back-up antibiotic prescription is given, as well as the general advice in recommendation 1.1.4, give advice about:\n\nan antibiotic not being needed immediately\n\nusing the back-up prescription if symptoms do not start to improve within 3 to 5\xa0days or if they worsen rapidly or significantly at any time\n\nseeking medical help if symptoms worsen rapidly or significantly or the person becomes systemically very unwell.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on no antibiotic and back-up antibiotics.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n## People who are most likely to benefit from an antibiotic (FeverPAIN score of 4 or 5, or Centor score of 3 or 4)\n\nConsider an immediate antibiotic prescription (see recommendation 1.3.1 for choice of antibiotic), or a back-up antibiotic prescription with advice (see recommendation 1.1.9), taking account of:\n\nthe unlikely event of complications if antibiotics are withheld\n\npossible adverse effects, particularly diarrhoea and nausea.\n\nWhen an immediate antibiotic prescription is given, as well as the general advice in recommendation 1.1.4, give advice about seeking medical help if symptoms worsen rapidly or significantly or the person becomes systemically very unwell.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on back-up antibiotics and choice of antibiotic.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n## People who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high-risk of complications\n\nOffer an immediate antibiotic prescription (see recommendation 1.3.1 for choice of antibiotic) with advice (see recommendation 1.1.11).\n\nRefer people to hospital if they have acute sore throat associated with any of the following:\n\na severe systemic infection (see the NICE guideline on sepsis)\n\nsevere suppurative complications (such as quinsy [peri-tonsillar abscess] or cellulitis, parapharyngeal abscess or retropharyngeal abscess or Lemierre syndrome).\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on choice of antibiotic.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Self-care\n\n## All people with acute sore throat\n\nConsider paracetamol for pain or fever, or if preferred and suitable, ibuprofen.\n\nAdvise about the adequate intake of fluids.\n\nExplain that some adults may wish to try medicated lozenges containing either a local anaesthetic, a non-steroidal anti-inflammatory drug (NSAID) or an antiseptic. However, they may only help to reduce pain by a small amount.\n\nBe aware that no evidence was found on non-medicated lozenges, mouthwashes, or local anaesthetic mouth spray used on its own.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on self-care.\n\nFull details of the evidence and committee's discussion are in the evidence review.\n\n# Choice of antibiotic\n\nWhen prescribing an antibiotic for acute sore throat:\n\nfollow table\xa01 for adults aged 18\xa0years and over\n\nfollow table\xa02 for children and young people under 18\xa0years.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic\n\nPhenoxymethylpenicillin:\n\nmg four times a day or 1,000\xa0mg twice a day for 5\xa0to 10\xa0days\n\n\n\nFive days may be enough for symptomatic cure; but a 10-day course may increase the chance of microbiological cure\n\nAlternative first choice for penicillin allergy or intolerance (for people who are not pregnant)\n\nClarithromycin:\n\nmg to 500\xa0mg twice a day for 5\xa0days\n\nAlternative first choice for penicillin allergy in pregnancy\n\nErythromycin:\n\nmg to 500\xa0mg four times a day or 500\xa0mg to 1,000\xa0mg twice a day for 5\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic\n\nPhenoxymethylpenicillin:\n\nmonth to 11\xa0months, 62.5\xa0mg four times a day or 125\xa0mg twice a day for 5\xa0to 10\xa0days\n\nyear to 5\xa0years, 125\xa0mg four times a day or 250\xa0mg twice a day for 5\xa0to 10\xa0days\n\nyears to 11\xa0years, 250\xa0mg four times a day or 500\xa0mg twice a day for 5\xa0to 10\xa0days\n\nyears to 17\xa0years, 500\xa0mg four times a day or 1,000\xa0mg twice a day for 5\xa0to 10\xa0days\n\nFive\xa0days may be enough for symptomatic cure; but a 10-day course may increase the chance of microbiological cure\n\nAlternative first choice for penicillin allergy or intolerance (for people who are not pregnant)\n\nClarithromycin:\n\nmonth to 11\xa0years:Under 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg twice a day for 5\xa0days\n\nAlternative first choice for penicillin allergy in pregnancy\n\nErythromycin:\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day or 500\xa0mg to 1,000\xa0mg twice a day for 5\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example hepatic impairment and renal impairment.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age.\n\nFor a short explanation of why the committee made these recommendations, see the evidence and committee discussion on antibiotic choice and antibiotic course length.\n\nFull details of the evidence and committee's discussion are in the evidence review.", 'Summary of the evidence': "# Self-care\n\n## Oral analgesia\n\nOverall aspirin, paracetamol and diclofenac potassium (not available to buy over the counter) were all more effective than placebo at reducing pain and fever in adults with sore throat associated with an upper respiratory tract infection. This was based on low to moderate quality evidence from 3\xa0randomised controlled trials (RCTs) (Eccles et al. 2003, Gehanno et al. 2003 and Voelker et al. 2016).\n\nOverall, adverse events for aspirin, paracetamol and diclofenac potassium in the 3\xa0RCTs did not appear to be significantly different from placebo (very low to low quality evidence), although adverse events were poorly reported. Another RCT that assessed safety outcomes (Moore et al. 2002) found significantly higher rates of adverse events with aspirin compared with ibuprofen (low quality evidence).\n\nDiclofenac is associated with higher cardiovascular risk than other non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Risk is similar to that with selective COX‑2 inhibitors. Naproxen and low-dose ibuprofen (1,200\xa0mg daily or less in adults) are considered to have the most favourable cardiovascular safety profiles (Medicines and Healthcare products Regulatory Agency [MHRA] Drug Safety Update on NSAIDs, October 2012). Of the non‑selective NSAIDs, low-dose ibuprofen has the lowest gastrointestinal risk (MHRA Drug Safety Update on NSAIDS and coxibs, December 2007).\n\n## Medicated lozenges\n\nMedicated lozenges containing benzocaine, hexylresorcinol or flurbiprofen may help to reduce pain compared with placebo in adults. This was based on low to moderate quality evidence from 6\xa0RCTs (Watson et al. 2000, Benrimoj et al. 2001, Blagden et al. 2001, Chrubasik et al. 2012, McNally et al. 2012 and Schachtel et al. 2014). However, the absolute improvements in pain score were small.\n\nFew adverse events were reported in the RCTs with benzocaine lozenges or hexylresorcinol lozenges. Adverse events occurred in 30% to 50% of people using flurbiprofen lozenges, including taste disturbances, numbness, dry mouth and nausea.\n\n## Throat sprays\n\nChlorhexidine plus benzydamine combination throat spray (not available in the UK) significantly reduced pain symptoms by day\xa07 compared with placebo in adults who were also taking phenoxymethylpenicillin. This was based on high quality evidence from an RCT (Cingi et al. 2011). The absolute improvements in symptom score were small and the clinical relevance is not clear.\n\nLocal adverse events, including numbness and taste disturbances, were common (moderate quality evidence).\n\nNo systematic reviews or RCTs of local anaesthetic mouth sprays (without an antiseptic) were identified.\n\n## Other interventions\n\nNo systematic reviews or RCTs of non-medicated lozenges or mouthwashes were identified.\n\nBased on evidence, experience and safety data the committee agreed that it was reasonable to consider paracetamol (first-line) or ibuprofen for self-care of pain or fever associated with acute sore throat. Although no studies were identified on paracetamol and ibuprofen in children with sore throat, the committee noted that these medicines have well-established efficacy and safety profiles for managing pain and fever in children.\n\nBased on evidence and experience, the committee agreed that people may wish to try self-care with medicated lozenges (containing a local anaesthetic, an NSAID or an antiseptic agent) to help reduce pain in acute sore throat, but should be told that the benefit is likely to be small.\n\nBased on evidence and experience, the committee agreed that it is unclear whether throat sprays containing an antiseptic plus a local anaesthetic help symptoms. Furthermore, the combination product used in the study is not available in the UK.\n\nThe committee agreed that prescribers should be aware that no evidence was found on non-medicated lozenges, mouthwashes or local anaesthetic mouth sprays (without an antiseptic).\n\nThe committee was aware of the potential benefits of avoiding GP appointments if people access self-care and seek advice from other health professionals, particularly their community pharmacist, rather than making an appointment to see their GP. The committee agreed that community pharmacists are often more accessible to people than GPs to offer advice.\n\n# Corticosteroids\n\nCorticosteroids (oral or intramuscular) significantly increased the number of adults and children with no pain at 24 and 48\xa0hours (number needed to treat [NNT] 4 [range 3 to 6]; high quality evidence) and significantly reduced the time to pain resolution by about 14\xa0hours (low quality evidence), compared with placebo. This was based on a systematic review of RCTs (Hayward et al. 2012). There were no significant differences between corticosteroids and placebo in recurrence or relapse of symptoms, or in the number of days missed from work or school (low to moderate quality evidence). All people in the studies were also treated with antibiotics.\n\nA single dose of dexamethasone given to adults who did not need an immediate antibiotic prescription did not increase the proportion of people with resolution of symptoms at 24\xa0hours, although a significant difference was seen at 48\xa0hours. This was based on moderate quality evidence from an RCT (Hayward et al. 2017).\n\nThere was no difference in adverse events for people taking corticosteroids compared with placebo, although reporting of adverse events was incomplete. The RCTs were not large enough to identify rare adverse events associated with corticosteroids.\n\n## Committee discussions on corticosteroids\n\nThe committee noted that most studies of corticosteroids were carried out in accident and emergency departments and included people with more severe symptoms.\n\nThe committee noted that the studies did not report on the long-term safety of corticosteroids and the risks of recurrent treatment. No studies compared corticosteroids with analgesia.\n\nThe committee agreed that sore throat is a self-limiting illness and there are concerns about the safety of corticosteroids and the risks of recurrent treatment. The committee noted that there are safer alternatives and agreed not to recommend corticosteroids for managing acute sore throat.\n\n# No antibiotic\n\nIn most cases, acute sore throat is a self-limiting infection, often caused by a viral infection, and most people will not need an antibiotic. Group\xa0A beta‑haemolytic streptococcus (GABHS) is the most common bacterial pathogen in sore throat (European Society for Clinical Microbiology and Infectious Diseases sore throat guideline ), isolated in approximately 20% of cases (Kronman et al. 2014).\n\nComplications of sore throat caused by a GABHS infection are generally rare in adults and children. Complications can be suppurative (including quinsy [peri-tonsillar abscess], acute otitis media and acute sinusitis) or non-suppurative (including acute rheumatic fever and acute glomerulonephritis; European Society for Clinical Microbiology and Infectious Diseases Sore Throat Guideline ).\n\n## Efficacy of antibiotics\n\nWith antibiotics, significantly more people with acute sore throat were symptom free at days 3 and 7 compared with placebo. At day\xa03, 51% were symptom free with antibiotics compared with 34% with placebo (NNT 6 [range 5 to 7]). At day\xa07, most people in both groups were symptom free (87% versus 82%, NNT 21 [range 14 to 49]). This was based on low quality evidence from a systematic review and meta-analysis of RCTs and quasi-RCTs (Spinks et al. 2013). Overall, antibiotics shortened the duration of symptoms by about 16\xa0hours over 7\xa0days.\n\nSubgroup analyses suggest antibiotics are more effective in people with a throat swab positive for GABHS. The NNT with antibiotics compared with placebo to prevent 1\xa0person with a negative throat swab having a sore throat on day\xa03 was 7 (range 5 to 12), with an NNT of about 4 (range 4 to 5) for people with a throat swab positive for GABHS (low to moderate quality evidence).\n\nThe overall incidence of suppurative complications, including acute otitis media, acute sinusitis and quinsy (peri-tonsillar abscess), was low and based on data from older studies, mostly conducted in the 1950s. These studies found that antibiotics significantly reduced the incidence of acute otitis media and acute sinusitis within 14\xa0days, and quinsy (peri-tonsillar abscess) within 2\xa0months, compared with placebo (low to high quality evidence). Based on the complication rates from studies conducted after 1975, Spinks et al. (2013) estimated that 200 people would need to be treated with antibiotics to prevent 1 case of acute otitis media.\n\nRheumatic fever was reported only in RCTs published before 1961, and the authors noted that the incidence has continued to decline in western societies since then. Results from these early studies found that antibiotics reduced acute rheumatic fever by more than two-thirds compared with placebo (low quality evidence).\n\nThere was no statistically significant reduction in acute glomerulonephritis in people taking antibiotics, although it was difficult to detect a significant reduction because the absolute rates of this complication were low (less than 0.1%; very low quality evidence).\n\n## Safety of antibiotics\n\nAllergic reactions to penicillins occur in 1 to 10% of people and anaphylactic reactions occur in less than 0.05%. People with a history of atopic allergy (for example, asthma, eczema and hay fever) are at a higher risk of anaphylactic reactions to penicillins. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin). See the NICE guideline on drug allergy: diagnosis and management for more information.\n\nAntibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE Clinical Knowledge Summary [CKS]: diarrhoea – antibiotic associated).\n\nAdverse effects were not reported by Spinks et al. (2013) because of inconsistencies in reporting these effects in the RCTs.\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\n# Back-up antibiotics\n\nA back-up antibiotic prescription (either patient-led collection or delayed collection) or no antibiotic prescription was as effective as an immediate antibiotic prescription for reducing duration and severity of symptoms in people with pharyngitis. This was based on moderate quality evidence from 1\xa0RCT in adults (de la Poza Abad et al. 2016).\n\nImmediate antibiotics were significantly more effective than back-up antibiotics for improving fever, pain and malaise in some RCTs from a systematic review (Spurling et al. 2013), whereas there was no difference between groups in other RCTs (low to moderate quality evidence).\n\nAcross the RCT and systematic review there was generally no difference in adverse events between an immediate antibiotic prescription strategy and a back-up antibiotic prescription or no prescription strategy (very low to moderate quality evidence).\n\n# Identifying people more likely to benefit from antibiotics\n\nTargeted use of antibiotics using the FeverPAIN clinical scoring system improved symptoms on days 2 to 4 (to a statistically but possibly not clinically meaningful amount) and reduced antibiotic use, compared with a back-up antibiotic prescribing strategy alone. This was based on low to moderate quality evidence from an open-label RCT (Little et al. 2013). People in the group with a low FeverPAIN score (0 or 1\xa0points) were not offered an antibiotic. People with a moderate FeverPAIN score (2 or 3\xa0points) were offered a back-up prescription, and people with a high FeverPAIN score (4\xa0points or more) were offered an immediate antibiotic prescription. The additional use of rapid antigen tests for GABHS in people with a high FeverPAIN score had no clear advantage over using FeverPAIN score alone.\n\n## Committee discussions on no antibiotics, back-up antibiotics and identifying people more likely to benefit from antibiotics\n\nBased on evidence and experience, the committee agreed that acute sore throat is a self-limiting infection, and most people will get better within a week without antibiotic treatment. Based on evidence and experience, the committee agreed that complications are rare in adults and children, and the committee noted the adverse effects associated with antibiotic use.\n\nThe committee agreed that prescribers need to weigh up the small clinical benefits from antibiotics against their potential to cause adverse effects.\n\nBased on evidence and experience, the committee agreed that no or back-up antibiotic prescribing was as effective as immediate antibiotic prescribing for people with acute sore throat. A back-up antibiotic prescription could be used if symptoms deteriorate rapidly or significantly, or do not improve within the next 3 to 5\xa0days.\n\nThe committee discussed the clinical scoring systems available to help identify people with acute sore throat who may be more likely to benefit from antibiotics. The committee noted that FeverPAIN and Centor criteria have not been validated in a UK population.\n\nThe committee was aware that the FeverPAIN criteria were developed in a UK primary care setting in 2013 and have not been assessed in children under 3\xa0years. External validation has not been carried out, but the criteria have been tested in an RCT setting.\n\nThe FeverPAIN scoring tool can help prescribers to determine if a person's sore throat is more likely to benefit from antibiotics. The scoring tool includes the FeverPAIN criteria plus additional parameters to help prescribers determine the severity of the sore throat. The additional parameters do not affect the overall FeverPAIN score. The committee was aware that the tool may help prescribers implement FeverPAIN criteria in practice and supports shared decision-making in consultations with people.\n\nThe committee noted that the Centor criteria were developed in the US in an emergency department setting in 1981 and has only been assessed in an adult population. The committee was aware that the previous NICE guideline on upper respiratory tract infections used Centor criteria. FeverPAIN criteria were not available at the time this guideline was published.\n\nThe committee noted that a FeverPAIN score of 4 or 5 is thought to be associated with a 62\xa0to 65% probability of having a bacterial infection, which is slightly higher than the 32\xa0to 56% probability associated with a Centor score of 3 or 4. The committee was aware that using FeverPAIN in preference to Centor may increase the use of back-up antibiotic prescribing. However, the committee discussed that if more back-up antibiotic prescribing strategies are implemented the overall use of antibiotics may reduce, assuming that around two‑thirds of people will not collect (and take) the antibiotics.\n\nThe committee acknowledged the recommendation in the previous NICE guideline on upper respiratory tract infections for a no or back-up antibiotic prescribing strategy in acute sore throat, with an immediate antibiotic prescribing strategy also an option for people with an acute sore throat when 3 or more Centor criteria are present.\n\nThe committee discussed FeverPAIN scores of 4 or 5, or Centor scores of 3 or 4. In some cases people may have these scores but may have milder symptoms. To ensure people with milder and improving symptoms are not issued an immediate antibiotic prescription the committee used its expertise and agreed that a back-up prescription may also be appropriate for this group of people. Withholding antibiotics is unlikely to lead to complications.\n\nThe committee discussed FeverPAIN scores of 0 or 1, or Centor scores of 0, 1 or 2. The committee was aware that the previous NICE guideline on upper respiratory tract infections recommended either a no antibiotic or a back-up antibiotic prescribing strategy for people with these Centor scores. However, based on evidence, experience and the principles of antimicrobial stewardship the committee recommended a no antibiotic prescribing strategy for this group.\n\nThe committee was aware that FeverPAIN criteria had not been tested in populations under 3\xa0years and that the Centor criteria were developed in an adult population. However, the committee, using its experience, advised that young children (under 3\xa0years) are unlikely to present with sore throat symptoms alone. Prescribers should follow the NICE guideline on fever in under 5s to assess and manage fever in this population.\n\nThe committee agreed that there is currently uncertainty about which scoring tool is more effective in a UK population. They noted that both criteria are used in clinical practice and that using a scoring tool is preferential to not using any tool. The committee concluded that either FeverPAIN or Centor criteria should be used to identify people with acute sore throat who may be more likely to benefit from antibiotics.\n\n# Antibiotic choice\n\nThere were no major differences in clinical effectiveness between classes of antibiotics, including penicillins, cephalosporins, macrolides, and sulfonamides in adults and children with GABHS-positive sore throat. This was based on very low to moderate quality evidence from 2 systematic reviews and meta-analyses of RCTs (Altamimi et al. 2012 and van Driel et al. 2016). Statistically significant differences were seen for some comparisons but the absolute differences between antibiotic classes was small.\n\nThere was no significant difference in adverse events for cephalosporins, macrolides or sulfonamides compared with phenoxymethylpenicillin in 1 systematic review (van Driel et al. 2016). The other systematic review Altamimi et al. 2012) found that a shorter course of late-generation (broader spectrum) antibiotics was associated with significantly more adverse events compared with a 10‑day course of phenoxymethylpenicillin.\n\n## Frequency of antibiotic dosing\n\nTwice daily dosing of phenoxymethylpenicillin was as effective as 3 or 4 times daily dosing for microbiological cure in adults and children with GABHS-positive sore throat. This was based on low quality evidence from 1 systematic review and meta-analysis of RCTs (Lan and Colford 2000). Once-daily dosing was significantly less effective than 3 or 4 times daily dosing of phenoxymethylpenicillin (low quality evidence).\n\nThe committee discussed that, generally, if an antibiotic is needed to treat an infection that is not life threatening, narrow-spectrum antibiotics should be used as the first choice. Indiscriminate use of broad-spectrum antibiotics is undesirable because it creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. For infections that are not life threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective. Based on evidence, clinical experience and resistance data, the committee agreed to recommend phenoxymethylpenicillin as the first-choice antibiotic. This is a narrow-spectrum penicillin with the lowest risk of causing resistance.\n\nThe committee discussed whether amoxicillin would be a suitable alternative to phenoxymethylpenicillin to support medicines adherence. However, it was aware of evidence that the risk of resistance to amoxicillin is significantly increased in urinary isolates of Escherichia coli following a course of amoxicillin. These effects are greatest in the first month after use, but are detectable for up to 12\xa0months. Also, if the sore throat is due to glandular fever, the BNF states that erythematous rashes are common in people with glandular fever who take amoxicillin.\n\nThe committee discussed the systematic review by Lan and Colford (2000) that suggested twice-daily dosing was as effective as four times daily dosing. The committee noted that four times daily dosing was the standard dose frequency for phenoxymethylpenicillin and the dose used most frequently in the included studies. The committee noted that this is low quality evidence, using data from only 6\xa0studies and used bacteriological cure at follow-up as an efficacy outcome (rather than a patient-oriented outcome).\n\nThe committee discussed the benefits and harms of using twice daily dosing of phenoxymethylpenicillin. Twice daily dosing would support medicines adherence in those people who may struggle to take 4\xa0doses at 6‑hourly intervals before food, such as children at school. The committee was concerned that if a twice daily dose was used, phenoxymethylpenicillin levels may fall below the minimum inhibitory concentration. However, they also discussed that streptococci are highly sensitive to phenoxymethylpenicillin, and that antibiotic penetration in sore throat tissue is good, therefore even small concentrations of antibiotic will treat the infection.\n\nBased on evidence and clinical experience, the committee agreed that if phenoxymethylpenicillin was prescribed, twice daily or four times a day dosing could be used, providing the same total daily dose was given.\n\nBased on evidence, clinical experience and resistance data, the committee agreed to recommend clarithromycin as the alternative first-choice antibiotic for use in penicillin allergy or for phenoxymethylpenicillin intolerance. In pregnancy, erythromycin was recommended if there is true penicillin allergy. Both are macrolides, given at usual doses.\n\nThe committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nBased on the evidence that there are no major differences in clinical effectiveness between classes of antibiotics, the committee used its experience to agree that the choice should largely be driven by minimising the risk of resistance.\n\n# Antibiotic course length\n\nIn people with GABHS-positive sore throat, treatment with phenoxymethylpenicillin for 5 to 7\xa0days had significantly lower microbiological cure rates compared with 10\xa0days treatment (NNT 13 [range 8 to 37]). This was based on low quality evidence from 1 systematic review and meta-analysis of RCTs (Falagas et al. 2008).\n\nThere were no significant differences between 5 to 7\xa0days treatment with phenoxymethylpenicillin compared with 10\xa0days treatment, in the rate of relapse or recurrence (very low quality evidence).\n\nThe studies that compared different course lengths of phenoxymethylpenicillin treatment did not report on adverse events.\n\n## Committee discussions on antibiotic course length\n\nThe committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed to reduce the risk of antimicrobial resistance and minimise the risk of adverse effects.\n\nThe committee noted that most studies involving clarithromycin or erythromycin used a 5‑day course, whereas, most studies involving phenoxymethylpenicillin used a 10‑day course.\n\nThe committee noted that no studies were identified that compared 10‑day and 5‑day courses of phenoxymethylpenicillin given at the current recommended dose (500\xa0mg four times daily). However, the committee was aware from its experience that many people do not complete a 10‑day course.\n\nBased on evidence, the committee recognised that microbiological cure may be better with a 10‑day course of phenoxymethylpenicillin compared with a 5‑ or 7‑day course, although there were no differences in relapse or recurrence. They agreed that, in situations where bacterial eradication is not specifically needed, and where symptomatic cure is the goal, if a decision to prescribe an antibiotic is made, a shorter course of phenoxymethylpenicillin may be sufficient. However, in situations where there is recurrent infection, a 10‑day course may increase the likelihood of microbiological cure.\n\nBased on evidence, clinical experience and resistance data, the committee agreed that when an antibiotic was appropriate, a 5- to 10‑day course of phenoxymethylpenicillin was needed.\n\nThe committee was aware that bottles of phenoxymethylpenicillin suspension expire within 7\xa0days once reconstituted and a second bottle would be needed to complete a 10‑day course. Prescribing a 7‑day course may help with medicines adherence.\n\nA 5-day course of clarithromycin or erythromycin (which is preferred in pregnancy) is an alternative for people with penicillin allergy or intolerance. This course length takes into account the overall efficacy and safety evidence for antibiotics, and minimises the risk of resistance.\n\nSee the full evidence review for more information.", 'Other considerations': "# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing or longer treatment duration (for example, antibiotics). See the NICE guideline on medicines adherence.\n\n# Resource implications\n\nRespiratory tract infections, including acute sore throat, are a common reason for consultations in primary care, and therefore are a common reason for potential antibiotic prescribing. In a 2011 survey of UK primary care (Gulliford et al. 2014), consultations for 'sore throat' accounted for 27% of all consultations for respiratory tract infections, and the median practice issued an antibiotic prescription for 60% of these.\n\nThere is potential for resource savings if a no antibiotic or a back-up antibiotic prescription strategy is used. One open-label RCT (de la Poza Abad et al. 2016) found significantly lower rates of antibiotic collection in the delayed collection prescription group (26.0%, p<0.001) and patient-led back-up prescription group (34.7%, p<0.001) compared with the immediate prescription group (89.1%, low quality evidence).\n\nRecommended antibiotics are all available as generic formulations, see the Drug Tariff for costs.", 'Terms used in the guideline': 'People with a sore throat caused by streptococcal bacteria are more likely to benefit from antibiotics. FeverPAIN or Centor criteria are clinical scoring tools that can help to identify the people in whom this is more likely.\n\n# FeverPAIN criteria\n\nFever (during previous 24\xa0hours)\n\nPurulence (pus on tonsils)\n\nAttend rapidly (within 3\xa0days after onset of symptoms)\n\nSeverely Inflamed tonsils\n\nNo cough or coryza (inflammation of mucus membranes in the nose)\n\nEach of the FeverPAIN criteria score 1 point (maximum score of 5). Higher scores suggest more severe symptoms and likely bacterial (streptococcal) cause. A score of 0 or 1 is thought to be associated with a 13\xa0to 18% likelihood of isolating streptococcus. A score of 2 or 3 is thought to be associated with a 34\xa0to 40% likelihood of isolating streptococcus. A score of 4 or 5 is thought to be associated with a 62\xa0to 65% likelihood of isolating streptococcus.\n\n# Centor criteria\n\nTonsillar exudate\n\nTender anterior cervical lymphadenopathy or lymphadenitis\n\nHistory of fever (over 38 degrees Celsius)\n\nAbsence of cough\n\nEach of the Centor criteria score 1 point (maximum score of 4). A score of 0, 1 or 2 is thought to be associated with a 3\xa0to 17% likelihood of isolating streptococcus. A score of 3 or 4 is thought to be associated with a 32 to 56% likelihood of isolating streptococcus.'}
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https://www.nice.org.uk/guidance/ng84
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This guideline sets out an antimicrobial prescribing strategy for acute sore throat. It aims to limit antibiotic use and reduce antimicrobial resistance. Acute sore throat is often caused by a virus, lasts for about a week, and most people get better without antibiotics. Withholding antibiotics rarely leads to complications.
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99db0a05aedf4e8382c9fd8f2999d48449bd2dc7
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nice
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Lenvatinib with everolimus for previously treated advanced renal cell carcinoma
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Lenvatinib with everolimus for previously treated advanced renal cell carcinoma
Evidence-based recommendations on lenvatinib (Kisplyx) with everolimus for previously treated advanced renal cell carcinoma in adults.
# Recommendations
Lenvatinib plus everolimus is recommended as an option for treating advanced renal cell carcinoma in adults who have had 1 previous vascular endothelial growth factor (VEGF)-targeted therapy, only if:
their Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1 and
the company provides lenvatinib according to the commercial arrangement.
This recommendation is not intended to affect treatment with lenvatinib plus everolimus that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
In the NHS, advanced renal cell carcinoma that has progressed after 1 tyrosine kinase inhibitor is treated with axitinib, nivolumab or cabozantinib. The evidence from a single clinical trial suggests that, on average, people live around 10.1 months longer if they have lenvatinib plus everolimus rather than everolimus alone. In the trial, lenvatinib plus everolimus caused side effects, leading many patients to interrupt or even stop treatment. This is despite the patients enrolled in the trial being relatively fit (that is, they had an ECOG performance status score of 0 or 1).
The cost-effectiveness analyses for lenvatinib plus everolimus show it's more effective and less costly than cabozantinib and nivolumab. Compared with axitinib, the cost-effectiveness estimates are within what NICE normally considers acceptable. So, NICE is recommending lenvatinib plus everolimus as an option for use in the NHS in people with an ECOG performance status score of 0 or 1.# Information about lenvatinib
# Marketing authorisation
Lenvatinib (Kisplyx, Eisai) is indicated 'in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF)-targeted therapy'.
# Dosage in the marketing authorisation
The recommended daily dose of lenvatinib is 18 mg (1×10 mg capsule and 2×4 mg capsules) once daily, with 5 mg of everolimus once daily.
# Price
The list price of lenvatinib is £1,437.00 per 30‑capsule pack (4 mg and 10 mg). The list price of everolimus is £2,250.00 per 30‑tablet pack of 5 mg everolimus. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of lenvatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee considered evidence submitted by Eisai and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Current NHS treatments
## Up to 4 lines of treatment are available in the NHS for advanced renal cell carcinoma
In the NHS, most people with newly diagnosed advanced renal cell carcinoma will first be offered 1 of 2 tyrosine kinase inhibitors (TKI); pazopanib or sunitinib, as recommended in NICE technology appraisal guidance on pazopanib and sunitinib. If the cancer progresses and people are fit enough to have further treatment, most are then offered axitinib (a TKI), nivolumab (a programmed cell death protein 1 inhibitor), cabozantinib (a TKI), or everolimus (a mammalian target of rapamycin inhibitor), as recommended in NICE technology appraisal guidance on axitinib, nivolumab, cabozantinib and everolimus. If the cancer progresses again, people may have, as third-line treatment, whichever of axitinib, nivolumab, everolimus or cabozantinib was not used as second-line treatment. The committee recalled its previous discussion in the appraisal of cabozantinib that the use of everolimus was likely to shift to later than second or third line in the treatment pathway so that everolimus would be mainly used in clinical practice after 3 previous treatments, that is, as a fourth-line treatment. It concluded that the current treatment pathway offered options for NHS patients.
# Place in the treatment pathway
## Lenvatinib plus everolimus is a second-line treatment
According to the marketing authorisation, lenvatinib plus everolimus is indicated for advanced renal cell carcinoma after 1 previous vascular endothelial growth factor (VEGF)-targeted therapy. The clinical effectiveness evidence on lenvatinib plus everolimus was limited to second-line use, that is, all patients included in the main clinical trial had had only 1 previous treatment. The clinical expert explained that, in clinical practice, lenvatinib plus everolimus would not be expected to be used after more than 1 previous treatment given the absence of evidence beyond second-line treatment. The committee concluded that it would appraise lenvatinib plus everolimus for people who have had only 1 previous VEGF-targeted therapy, that is, as a second-line treatment.
# Comparators
## Axitinib, nivolumab and cabozantinib are the relevant comparators
The committee recalled that, at the point at which lenvatinib plus everolimus would be used (that is, after 1 previous treatment), axitinib, nivolumab, and cabozantinib are also treatment options. Everolimus is likely to be used as a fourth-line treatment (see section 3.1). The committee noted that the final scope included best supportive care as a comparator, although the company and the ERG did not consider it to be a relevant alternative to lenvatinib plus everolimus in clinical practice. The committee agreed that best supportive care may be suitable for a small group of people who are not fit enough to have active treatment, but it considered that this group was also unlikely to be offered lenvatinib plus everolimus. Also, the committee understood that, after positive NICE recommendation guidance on nivolumab and cabozantinib, there were even fewer people for whom no active therapy was appropriate, and they were unlikely to reflect those who would be offered lenvatinib plus everolimus. The committee concluded that the relevant comparators for lenvatinib plus everolimus were axitinib, nivolumab and cabozantinib.
# Clinical trial evidence
## HOPE 205 is an open-label randomised controlled trial
The main clinical evidence for lenvatinib plus everolimus came from HOPE 205, an open-label phase II randomised controlled trial comparing 3 treatments: lenvatinib plus everolimus (n=51), lenvatinib alone (n=52) and everolimus alone (n=50). The trial did not allow crossover. The committee agreed that it would focus on the comparison of lenvatinib plus everolimus with everolimus alone because lenvatinib alone was not licensed for advanced renal cell carcinoma. The primary outcome in the trial was investigator-assessed progression-free survival, with overall survival, tumour response and safety as secondary outcomes. Progression-free survival by independent review was assessed post hoc (that is, not planned in the study protocol) following a request from the regulators.
## HOPE 205 is a small open-label trial
The committee discussed the following limitations of HOPE 205:
As a phase II trial, HOPE 205 was designed so that 90 progression-free survival events were needed to detect a hazard ratio of 0.67 with 70% power using a 1-sided significance level of 0.15 for the comparison of lenvatinib plus everolimus with everolimus alone. The company explained that HOPE 205 was not designed to be a 'registration trial', but that the company submitted it for regulatory approval because it considered the reported results to be compelling. The committee recognised that, because the trial had a pre-determined significance level of 0.15, the investigators were willing to accept a risk of false positive results of 15%.
Because HOPE 205 was an open-label trial, both the patients and the investigators knew the allocated treatment. Also, unblinded investigators assessed the primary outcome progression-free survival. The committee recognised that the design of HOPE 205 was a source of bias.
HOPE 205 included a small number of patients (around 100 patients across the lenvatinib plus everolimus and the everolimus alone groups). This introduced considerable uncertainty around the estimates of efficacy and safety of lenvatinib plus everolimus, and meant that the differences between these estimates were less clear than if the trial had included more patients. The committee concluded that, given the clinical evidence to date, the results of HOPE 205 need to be interpreted with caution.
# Dose
## The modelled dose of lenvatinib plus everolimus should mirror HOPE 205
In HOPE 205, the median daily dose of lenvatinib was 13.6 mg, only 75% of the approved daily dose in the marketing authorisation of 18 mg. The company explained that it has an ongoing trial comparing the recommended dose of lenvatinib (18 mg) with a lower dose (14 mg), to assess whether the same efficacy can be achieved with improved tolerability. The clinical expert took this to suggest that there was uncertainty around the optimal dose of lenvatinib. The committee concluded that it can appraise lenvatinib only at its licensed dose, and that the modelled dose should appropriately reflect the estimates on the effectiveness and safety of lenvatinib plus everolimus from HOPE 205.
# Generalisability of trial results to the NHS
## Patients in HOPE 205 reflect people who would be offered second-line treatment in the NHS
The committee discussed whether patients in HOPE 205 reflected people who would have lenvatinib in the NHS, noting that 11 of the 37 study sites were in the UK. In particular, it discussed the following patient characteristics at baseline:
Most patients had had either sunitinib (63%) or pazopanib (22%) as their first VEGF-targeted therapy. The clinical expert explained that more people would be expected to have pazopanib in the NHS than they did in the trial because clinicians perceive pazopanib to have a better safety profile than sunitinib. However, the 2 drugs have the same mechanism of action, and so the clinical expert did not consider that the relatively low proportion of patients who had pazopanib in the trial would affect the generalisability of the results to people seen in the NHS.
More than half the patients in the trial had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, and none had an ECOG performance status score above 1. This reflected a fitter population than would generally be seen in the NHS. Although the committee was aware that clinical trials normally include relatively fit patients who may not represent clinical practice, it concluded that this was an important issue in this appraisal because people may need to be fit to be able to tolerate lenvatinib plus everolimus.The committee concluded that, overall, patients in HOPE 205 reflected people who would be offered second-line treatment in the NHS.
# Clinical trial results
## Lenvatinib plus everolimus increases progression-free survival compared with everolimus alone
In HOPE 205, lenvatinib plus everolimus increased median progression-free survival in the intention-to-treat population by 9.1 months compared with everolimus alone (14.6 months compared with 5.5 months; hazard ratio 0.40, 95% confidence interval 0.24 to 0.68; p=0.0005). The committee noted that progression-free survival assessed post hoc by independent review was similar, though the difference between the treatment groups was smaller; median progression-free survival was 12.8 months with lenvatinib plus everolimus and 5.6 months with everolimus alone, corresponding to a difference of 7.2 months (HR 0.45, 95% CI 0.26 to 0.79; p=0.003). The committee noted that the investigators and the independent assessors disagreed in around one-quarter of patients as to whether or not the disease had progressed. However, both assessments of disease progression suggested that lenvatinib plus everolimus was more effective than everolimus alone with respect to progression-free survival.
## The evidence that lenvatinib extends overall survival is statistically weak
Overall survival was based on the latest data cut of July 2015 (a median follow-up of 32.0 months for lenvatinib plus everolimus and of 32.7 months for everolimus alone). Patients who had lenvatinib plus everolimus lived longer than those who had everolimus alone (median survival 25.5 months versus 15.4 months; HR 0.59, 95% CI 0.36 to 0.97, based on the stratified Cox proportional hazard model). The p value using the stratified log-rank test was 0.065, which the committee recognised reflected statistically weak evidence on the survival benefit with lenvatinib plus everolimus. However, it was aware that HOPE 205 was not powered to detect statistically significant differences in terms of overall survival between treatment groups.
## Lenvatinib plus everolimus is more effective than everolimus alone but the size of the benefit is unclear
The ERG identified differences in the characteristics of patients and the disease at baseline, which suggested that patients in the lenvatinib plus everolimus group had a better prognosis that those in the everolimus group. For example, compared with the everolimus alone group, patients in the lenvatinib plus everolimus group had had previous VEGF-targeted therapy for longer, and were more likely to have had a complete or partial response to first-line VEGF-targeted therapy. The clinical expert explained that duration of previous therapy as a prognostic indicator was debatable and the evidence weak. The committee noted that the tumour burden was greater in patients randomised to lenvatinib plus everolimus than in those randomised to everolimus alone. It understood that the ERG did not consider that any individual difference in the characteristics at baseline would modify the effect of the study treatment, but that all differences taken together may have introduced bias in favour of lenvatinib plus everolimus. The committee agreed that the reported results may have overestimated the effectiveness of lenvatinib plus everolimus. This affected the precision with which the benefit of lenvatinib plus everolimus was estimated.
## The size of the benefit with lenvatinib plus compared with current NHS treatments cannot be robustly estimated
The clinical expert questioned the face validity of the increase in median progression-free survival in HOPE 205 with lenvatinib plus everolimus (9.1 months) because it exceeds that seen with first-line treatments (when cancer would be expected to respond better than to second-line treatment). The committee considered that this greater than expected benefit with first-line treatments could have resulted from lenvatinib plus everolimus being 2 treatments rather than 1 treatment. The clinical expert did not agree with this proposition because lenvatinib plus everolimus would have also been expected to be associated with benefits on overall survival in excess of first-line therapies. The clinical expert commented that clinicians would be unlikely to prefer lenvatinib plus everolimus to its comparators because of the uncertainties introduced by the design and size of HOPE 205. The committee concluded that the limitations of the trial, notably the small number of patients and a comparator not routinely used in the NHS, meant that the size of the benefit compared with current NHS treatments could not be robustly estimated.
# Safety
## Lenvatinib plus everolimus has more side effects than lenvatinib or everolimus alone
The committee considered the safety profile of lenvatinib plus everolimus, noting that:
Serious adverse events occurred in a higher proportion of patients taking lenvatinib plus everolimus (54.9%) than in patients taking everolimus alone (42.0%).
In the lenvatinib plus everolimus group, 72.5% of patients had grade III or higher treatment-emergent adverse events, compared with 54.0% of patients taking everolimus alone.
A larger proportion of patients had dose interruptions of lenvatinib (80.4%) or everolimus (76.5%) in the lenvatinib plus everolimus group compared with the everolimus alone group (54.0%), mainly because of adverse events.
Patients in HOPE 205 had treatment until disease progression, unacceptable toxicity or withdrawal of consent. The median time to stopping treatment (7.6 months) was half the median progression-free survival (14.6 months) in the trial, which suggested that many patients did not tolerate lenvatinib plus everolimus.
## It is important to take performance status into account
The committee considered it unsurprising that the combination of lenvatinib plus everolimus would be associated with more frequent adverse effects than everolimus alone. The clinical expert commented that the combination would be expected to increase the degree of toxicity of adverse events rather than the range of toxicity compared with either individual drug. The clinical expert also considered that it would be difficult to offer people a treatment that would lead to grade III or IV adverse events in three-quarters of them. The committee recalled that HOPE 205 included only patients with an ECOG performance status score of 0 or 1. It considered that people with worse performance status would be less likely to tolerate lenvatinib plus everolimus than patients in the trial. As a result, the effect of treatment seen in the trial was unlikely to be seen in people with lower performance status, partly because they would not have had treatment long enough to derive the same benefits. The committee concluded that lenvatinib plus everolimus has a high burden of adverse events and is not well tolerated, even by patients who are relatively fit compared with the average person who would have this treatment in clinical practice. Because of this, the committee agreed that it was important to consider performance status in the decision-making.
# Network meta-analysis
## The company's revised network is appropriate for decision-making
Because there were no head-to-head trials comparing lenvatinib with axitinib, nivolumab or cabozantinib, the company compared the treatments indirectly using a network meta-analysis. It included the randomised controlled trials HOPE 205, CHECKMATE-025 and METEOR (lenvatinib plus everolimus, nivolumab and cabozantinib respectively, each compared with everolimus), and estimated overall and progression-free survival curves for each treatment using fractional polynomials, as described by Janssen et al. (2011). In doing so, the company assumed that axitinib was as effective as everolimus with respect to overall and progression-free survival, which the committee recalled it had accepted in previous technology appraisals as a reasonable assumption in this therapy area. The committee concluded that the company's network using fractional polynomials was appropriate for decision-making.
## The model overestimates the progression-free survival benefit of lenvatinib plus everolimus compared with the observed effect
The data from HOPE 205 were relatively immature at the time of the analysis of progression-free survival (June 2014) because, across the lenvatinib plus everolimus and everolimus alone groups, disease had progressed in only 62% of patients. The modelled treatment effectiveness showed that the progression-free survival hazard ratios dropped sharply (that is, the effect of lenvatinib plus everolimus increased relative to the comparators) around 2 months after starting treatment and then increased (the effect of lenvatinib plus everolimus decreased) before becoming constant. The committee agreed that this was implausible and highly unlikely in clinical practice. It considered the possibility that the Kaplan–Meier curves, being close at the beginning then diverging, resulted in a relationship between treatments that the fractional polynomials could not pick up. The committee examined the trial-based fractional polynomial curves provided by the ERG to check the curve fits to the Kaplan–Meier data for lenvatinib plus everolimus and everolimus alone in HOPE 205. It agreed that how the curves fitted the progression-free and overall survival data was generally acceptable, although the curve for lenvatinib plus everolimus overestimated progression-free survival compared with the observed effect. The committee acknowledged the inherent uncertainty associated with comparing treatments indirectly, which, when added to other clinical uncertainties, meant that it could interpret the estimates of relative effectiveness only with caution.
# Structure of the economic model
## The structure of the model is suitable for decision-making
The company used a 3‑stage partitioned-survival economic model, which the committee considered appropriate to capture the natural history of the disease. The health states included in the model were pre-progressed disease, progressed disease and death. The company used data on time from randomisation to disease progression to determine the proportion of patients in the progression-free health state at a given time, and data on time to death to determine the proportion of patients who had reached the death state at a given time. The company calculated the proportion of patients in the post-progression health state as the difference between the proportion who had died and the proportion who had progressed. The committee concluded that the model was suitable for decision-making.
# Modelling of clinical effectiveness
## Survival curves generated using the ERG's own parameter values from the network meta-analysis are more appropriate than the company's curves
The committee discussed the extrapolation of progression-free and overall survival across the model time horizon (20 years) based on the company's network meta-analysis using fractional polynomials. The ERG considered that the company incorrectly applied fractional polynomials in its model, which resulted in an error when estimating survival probabilities. This caused the overall survival curves for each treatment to deviate implausibly around 60 months after the start of treatment. To address this, the ERG generated fractional polynomial curves for the entire time horizon using its own parameter values from its own network meta-analysis. The ERG's curves were largely similar to the company's up to 5 years after starting treatment, but did not deviate later as seen with the company's curves. The committee noted that the company acknowledged its error, and concluded that it would consider the model with the ERG's correction.
## Assuming that the effect of lenvatinib plus everolimus continues for up to 20 years is highly uncertain
Both the company and the ERG assumed that the effect of lenvatinib plus everolimus continued beyond the trial follow-up, even after the disease progressed or people stopped treatment. The committee was not presented with evidence to support this. The clinical expert considered that the treatment effect on overall survival was unlikely to continue after progression with lenvatinib plus everolimus, but might do so with the comparator nivolumab because it is an immunotherapy. The committee recalled that the evidence base underpinning the extrapolation was already uncertain (see section 3.9). It concluded that assuming the effect of lenvatinib plus everolimus continues for up to 20 years, based on a trial with a median follow-up of under 3 years for overall survival, was highly uncertain. It would have liked to have seen more conservative assumptions explored, for example, that the effect of treatment ceased at the end of the trial, or diminished over time beyond the trial follow-up.
# Modelling treatment duration
## The ERG's 2‑knot spline distribution is suitable for modelling treatment duration
The committee recognised that the duration of each treatment assumed in the model determined the total cost of treatment. The ERG disagreed with how the company estimated the proportion of patients who continued on any of the comparator treatments at any given cycle in the model. The company assumed that the ratio of median duration of treatment equalled the ratio of the hazard rates for stopping treatment (taken from the respective trial of each treatment), which the ERG considered incorrect. The ERG preferred fitting parametric distributions to digitised Kaplan–Meier data from each trial. The committee noted that the 2‑knot spline, followed by the log-normal distribution, best fitted the curves. To validate the company and ERG's curves, the committee compared the median time to stopping treatment estimated by the curves with that seen in the trials of the comparator treatments. The ERG's curves using the 2‑knot spline distribution produced the closest estimate to the trial data. The committee concluded it would consider the model incorporating the ERG's 2‑knot spline distribution.
# Modelling health-related quality of life
## Using utility values from the AXIS trial to model health-related quality of life is appropriate
The committee was aware that the HOPE 205 trial did not collect data on health-related quality of life, and that the company used utility values from the AXIS trial, which had compared axitinib with sorafenib for advanced renal cell carcinoma. The utility values from AXIS were 0.69 for the pre-progressed disease states and 0.61 for the progressed disease states. AXIS has been accepted as a valid source of utility data for this patient population in other NICE technology appraisals in this disease area. The committee concluded that the utility values from AXIS were appropriate.
## The utility values in the model do not reflect quality of life appropriately
To estimate the impact of adverse events on health-related quality of life, the company deducted a decrement (an amount reflecting the effect of adverse events on health-related quality of life) from the baseline utility values from AXIS. It estimated the total utility decrements separately for each treatment by assigning a utility decrement for grade 3 or higher adverse events based on the literature, then estimating an average utility decrement for each treatment weighted by the proportion of patients who had each adverse event. The estimates incorporated the average duration of each adverse event, taken directly from the HOPE 205 study for lenvatinib plus everolimus and estimated from the respective clinical trials for the comparators. In response to the appraisal consultation document, the company revised its utility decrements to −0.097 for lenvatinib plus everolimus, −0.072 for axitinib, −0.084 for cabozantinib and −0.008 for nivolumab. The committee recalled that the utility values used in the model should have reflected the high rate of serious adverse events associated with lenvatinib plus everolimus (see section 3.12). However, the utility decrement for lenvatinib plus everolimus remained small because it did not correlate with the observation in HOPE 205 that all patients who had lenvatinib plus everolimus had an adverse event, and that many stopped treatment because of these adverse events. The clinical expert shared the committee's concern, noting that the utility decrements applied by the company contradicted the available evidence on the safety of lenvatinib plus everolimus. Furthermore, the Cancer Drugs Fund clinical lead pointed out that the revised utility decrement for nivolumab also appeared too small given its immunotoxicity. The committee concluded that the utility values used in the model did not reflect quality of life appropriately.
# Cost and effect of subsequent treatments
## The company's and the ERG's approaches are reasonable for modelling subsequent treatments
The company did not originally include in its model the cost of therapies patients had in HOPE 205 after stopping study treatment. In response to a request for clarification from the ERG, the company chose to estimate the cost of subsequent therapies (that is, third-line treatment and beyond) based on the UK market share of the drugs. In contrast, the ERG argued that it was better to base these costs on the proportions of subsequent treatments in the trials for lenvatinib plus everolimus and for all comparators. The committee noted that either approach had little impact on the results. Although the committee appreciated that there may be arguments for using the company' or the ERG's costs of subsequent treatment, it concluded that either approach could be considered suitable for decision-making.
# Results of the cost-effectiveness analyses
## The ERG's base case is more appropriate for decision-making than the company's
The committee considered the cost-effectiveness results from the company's base case and the ERG's base case, including confidential discounts for all technologies. It noted that, in response to the appraisal consultation document, the company revised its patient access scheme discount. It agreed that the ERG's base case was more appropriate for decision-making because it used:
the ERG's own best-fitting fractional polynomials for overall and progression-free survival (see section 3.17)
the 2‑knot spline distribution to model treatment duration (see section 3.19).However, the committee recognised that the ERG's base case did not reflect all of its preferred analyses because:
it assumed that the effect of lenvatinib plus everolimus continues until the end of the time horizon of 20 years (see section 3.18)
the utility decrement for lenvatinib plus everolimus was too small given the incidence and severity of adverse events that occurred in HOPE 205 (see section 3.21).The committee concluded that it would use the ERG's base case for decision-making.
## Lenvatinib plus everolimus is a cost-effective use of NHS resources in people with an ECOG performance status score of 0 or 1
The committee noted that, in the ERG's deterministic base-case analysis, lenvatinib plus everolimus dominated cabozantinib and nivolumab, that is it was more effective and less costly. The incremental cost-effectiveness ratio for lenvatinib plus everolimus compared with axitinib was between £20,000 and £30,000 per quality-adjusted life year, which is the range normally accepted by NICE to represent cost-effective technologies. The committee appreciated that the uncertainty in the cost-effectiveness estimates came mainly from the limitations of HOPE 205 (see section 3.5), and from the modelling assumptions about the long-term performance of treatment (see section 3.18) and the impact of adverse events on health-related quality of life (see section 3.21). The committee also considered the value patients and clinicians place on having treatment options. On balance, the committee agreed that lenvatinib plus everolimus could be recommended for previously treated advanced renal cell carcinoma. It recalled that the evidence it had seen reflected patients with an ECOG performance status score of 0 or 1; less fit people would be less likely to tolerate treatment, and would be unlikely to derive the same benefits seen in HOPE 205 (see section 3.13). This meant that lenvatinib plus everolimus was unlikely to be cost effective in people with an ECOG performance status score above 1. The committee concluded that it could recommend lenvatinib plus everolimus, but only for people with an ECOG performance status score of 0 or 1.
# Other factors
## Future research
The committee heard that the company is considering an observational study to gather further data on the safety and quality of life of lenvatinib plus everolimus, aiming to have the results by 2020. The company said that this study is still in the early stages of development and that, while it might include comparators used in routine clinical practice, these are not yet defined. The committee understood that the study might include UK sites. It agreed that it had too little information about the study to enable it to determine its value. However, the committee encouraged further data collection on lenvatinib plus everolimus because this could provide comparative evidence against established NHS practice in England.
## Innovation
The committee discussed whether lenvatinib plus everolimus was an innovative treatment. The company argued that lenvatinib plus everolimus is considered innovative because the combination has shown a synergistic effect whereby the 2 treatments together lead to higher efficacy levels with respect to progression-free survival and response rate than each of the individual treatments. The committee noted that the clinical expert did not consider lenvatinib plus everolimus to be a step-change in managing the condition. It agreed that lenvatinib plus everolimus was unlikely to fulfil an unmet clinical need in a particular group of people. The committee concluded that there was no benefit to utility that was not otherwise accounted for in the modelling.
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{'Recommendations': "Lenvatinib plus everolimus is recommended as an option for treating advanced renal cell carcinoma in adults who have had 1\xa0previous vascular endothelial growth factor (VEGF)-targeted therapy, only if:\n\ntheir Eastern Cooperative Oncology Group (ECOG) performance status score is 0\xa0or\xa01 and\n\nthe company provides lenvatinib according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with lenvatinib plus everolimus that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nIn the NHS, advanced renal cell carcinoma that has progressed after 1\xa0tyrosine kinase inhibitor is treated with axitinib, nivolumab or cabozantinib. The evidence from a single clinical trial suggests that, on average, people live around 10.1\xa0months longer if they have lenvatinib plus everolimus rather than everolimus alone. In the trial, lenvatinib plus everolimus caused side effects, leading many patients to interrupt or even stop treatment. This is despite the patients enrolled in the trial being relatively fit (that is, they had an ECOG performance status score of 0\xa0or\xa01).\n\nThe cost-effectiveness analyses for lenvatinib plus everolimus show it's more effective and less costly than cabozantinib and nivolumab. Compared with axitinib, the cost-effectiveness estimates are within what NICE normally considers acceptable. So, NICE is recommending lenvatinib plus everolimus as an option for use in the NHS in people with an ECOG performance status score of 0\xa0or\xa01.", 'Information about lenvatinib': "# Marketing authorisation\n\nLenvatinib (Kisplyx, Eisai) is indicated 'in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF)-targeted therapy'.\n\n# Dosage in the marketing authorisation\n\nThe recommended daily dose of lenvatinib is 18\xa0mg (1×10\xa0mg capsule and 2×4\xa0mg capsules) once daily, with 5\xa0mg of everolimus once daily.\n\n# Price\n\nThe list price of lenvatinib is £1,437.00 per 30‑capsule pack (4\xa0mg and 10\xa0mg). The list price of everolimus is £2,250.00 per 30‑tablet pack of 5\xa0mg everolimus. The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of lenvatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eisai and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Current NHS treatments\n\n## Up to 4\xa0lines of treatment are available in the NHS for advanced renal cell carcinoma\n\nIn the NHS, most people with newly diagnosed advanced renal cell carcinoma will first be offered 1\xa0of\xa02 tyrosine kinase inhibitors (TKI);\xa0pazopanib\xa0or\xa0sunitinib, as recommended in NICE technology appraisal guidance on pazopanib and sunitinib. If the cancer progresses and people are fit enough to have further treatment, most are then offered\xa0axitinib\xa0(a TKI),\xa0nivolumab\xa0(a programmed cell death protein\xa01 [PD‑1] inhibitor),\xa0cabozantinib\xa0(a TKI), or\xa0everolimus\xa0(a mammalian target of rapamycin [mTOR] inhibitor), as recommended in NICE technology appraisal guidance on axitinib, nivolumab, cabozantinib and everolimus. If the cancer progresses again, people may have, as third-line treatment, whichever of axitinib, nivolumab, everolimus or cabozantinib was not used as second-line treatment. The committee recalled its previous discussion in the appraisal of cabozantinib that the use of everolimus was likely to shift to later than second or third line in the treatment pathway so that everolimus would be mainly used in clinical practice after 3\xa0previous treatments, that is, as a fourth-line treatment. It concluded that the current treatment pathway offered options for NHS patients.\n\n# Place in the treatment pathway\n\n## Lenvatinib plus everolimus is a second-line treatment\n\nAccording to the marketing authorisation, lenvatinib plus everolimus is indicated for advanced renal cell carcinoma after 1\xa0previous vascular endothelial growth factor (VEGF)-targeted therapy. The clinical effectiveness evidence on lenvatinib plus everolimus was limited to second-line use, that is, all patients included in the main clinical trial had had only 1\xa0previous treatment. The clinical expert explained that, in clinical practice, lenvatinib plus everolimus would not be expected to be used after more than 1\xa0previous treatment given the absence of evidence beyond second-line treatment. The committee concluded that it would appraise lenvatinib plus everolimus for people who have had only 1\xa0previous VEGF-targeted therapy, that is, as a second-line treatment.\n\n# Comparators\n\n## Axitinib, nivolumab and cabozantinib are the relevant comparators\n\nThe committee recalled that, at the point at which lenvatinib plus everolimus would be used (that is, after 1\xa0previous treatment), axitinib, nivolumab, and cabozantinib are also treatment options. Everolimus is likely to be used as a fourth-line treatment (see section\xa03.1). The committee noted that the final scope included best supportive care as a comparator, although the company and the ERG did not consider it to be a relevant alternative to lenvatinib plus everolimus in clinical practice. The committee agreed that best supportive care may be suitable for a small group of people who are not fit enough to have active treatment, but it considered that this group was also unlikely to be offered lenvatinib plus everolimus. Also, the committee understood that, after positive NICE recommendation guidance on nivolumab and cabozantinib, there were even fewer people for whom no active therapy was appropriate, and they were unlikely to reflect those who would be offered lenvatinib plus everolimus. The committee concluded that the relevant comparators for lenvatinib plus everolimus were axitinib, nivolumab and cabozantinib.\n\n# Clinical trial evidence\n\n## HOPE\xa0205 is an open-label randomised controlled trial\n\nThe main clinical evidence for lenvatinib plus everolimus came from HOPE\xa0205, an open-label phase\xa0II randomised controlled trial comparing 3\xa0treatments: lenvatinib plus everolimus (n=51), lenvatinib alone (n=52) and everolimus alone (n=50). The trial did not allow crossover. The committee agreed that it would focus on the comparison of lenvatinib plus everolimus with everolimus alone because lenvatinib alone was not licensed for advanced renal cell carcinoma. The primary outcome in the trial was investigator-assessed progression-free survival, with overall survival, tumour response and safety as secondary outcomes. Progression-free survival by independent review was assessed post hoc (that is, not planned in the study protocol) following a request from the regulators.\n\n## HOPE\xa0205 is a small open-label trial\n\nThe committee discussed the following limitations of HOPE\xa0205:\n\nAs a phase\xa0II trial, HOPE\xa0205 was designed so that 90\xa0progression-free survival events were needed to detect a hazard ratio of 0.67 with 70% power using a 1-sided significance level of 0.15 for the comparison of lenvatinib plus everolimus with everolimus alone. The company explained that HOPE\xa0205 was not designed to be a 'registration trial', but that the company submitted it for regulatory approval because it considered the reported results to be compelling. The committee recognised that, because the trial had a pre-determined significance level of 0.15, the investigators were willing to accept a risk of false positive results of 15%.\n\nBecause HOPE\xa0205 was an open-label trial, both the patients and the investigators knew the allocated treatment. Also, unblinded investigators assessed the primary outcome progression-free survival. The committee recognised that the design of HOPE\xa0205 was a source of bias.\n\nHOPE\xa0205 included a small number of patients (around 100\xa0patients across the lenvatinib plus everolimus and the everolimus alone groups). This introduced considerable uncertainty around the estimates of efficacy and safety of lenvatinib plus everolimus, and meant that the differences between these estimates were less clear than if the trial had included more patients. The committee concluded that, given the clinical evidence to date, the results of HOPE\xa0205 need to be interpreted with caution.\n\n# Dose\n\n## The modelled dose of lenvatinib plus everolimus should mirror HOPE\xa0205\n\nIn HOPE\xa0205, the median daily dose of lenvatinib was 13.6\xa0mg, only 75% of the approved daily dose in the marketing authorisation of 18\xa0mg. The company explained that it has an ongoing trial comparing the recommended dose of lenvatinib (18\xa0mg) with a lower dose (14\xa0mg), to assess whether the same efficacy can be achieved with improved tolerability. The clinical expert took this to suggest that there was uncertainty around the optimal dose of lenvatinib. The committee concluded that it can appraise lenvatinib only at its licensed dose, and that the modelled dose should appropriately reflect the estimates on the effectiveness and safety of lenvatinib plus everolimus from HOPE\xa0205.\n\n# Generalisability of trial results to the NHS\n\n## Patients in HOPE\xa0205 reflect people who would be offered second-line treatment in the NHS\n\nThe committee discussed whether patients in HOPE\xa0205 reflected people who would have lenvatinib in the NHS, noting that 11\xa0of the 37\xa0study sites were in the UK. In particular, it discussed the following patient characteristics at baseline:\n\nMost patients had had either sunitinib (63%) or pazopanib (22%) as their first VEGF-targeted therapy. The clinical expert explained that more people would be expected to have pazopanib in the NHS than they did in the trial because clinicians perceive pazopanib to have a better safety profile than sunitinib. However, the 2\xa0drugs have the same mechanism of action, and so the clinical expert did not consider that the relatively low proportion of patients who had pazopanib in the trial would affect the generalisability of the results to people seen in the NHS.\n\nMore than half the patients in the trial had an Eastern Cooperative Oncology Group (ECOG) performance status score of\xa00, and none had an ECOG performance status score above\xa01. This reflected a fitter population than would generally be seen in the NHS. Although the committee was aware that clinical trials normally include relatively fit patients who may not represent clinical practice, it concluded that this was an important issue in this appraisal because people may need to be fit to be able to tolerate lenvatinib plus everolimus.The committee concluded that, overall, patients in HOPE\xa0205 reflected people who would be offered second-line treatment in the NHS.\n\n# Clinical trial results\n\n## Lenvatinib plus everolimus increases progression-free survival compared with everolimus alone\n\nIn HOPE\xa0205, lenvatinib plus everolimus increased median progression-free survival in the intention-to-treat population by 9.1\xa0months compared with everolimus alone (14.6\xa0months compared with 5.5\xa0months; hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.24 to 0.68; p=0.0005). The committee noted that progression-free survival assessed post hoc by independent review was similar, though the difference between the treatment groups was smaller; median progression-free survival was 12.8\xa0months with lenvatinib plus everolimus and 5.6\xa0months with everolimus alone, corresponding to a difference of 7.2\xa0months (HR\xa00.45, 95%\xa0CI 0.26 to 0.79; p=0.003). The committee noted that the investigators and the independent assessors disagreed in around one-quarter of patients as to whether or not the disease had progressed. However, both assessments of disease progression suggested that lenvatinib plus everolimus was more effective than everolimus alone with respect to progression-free survival.\n\n## The evidence that lenvatinib extends overall survival is statistically weak\n\nOverall survival was based on the latest data cut of July 2015 (a median follow-up of 32.0\xa0months for lenvatinib plus everolimus and of 32.7\xa0months for everolimus alone). Patients who had lenvatinib plus everolimus lived longer than those who had everolimus alone (median survival 25.5\xa0months versus 15.4\xa0months; HR 0.59, 95%\xa0CI 0.36 to 0.97, based on the stratified Cox proportional hazard model). The p\xa0value using the stratified log-rank test was 0.065, which the committee recognised reflected statistically weak evidence on the survival benefit with lenvatinib plus everolimus. However, it was aware that HOPE\xa0205 was not powered to detect statistically significant differences in terms of overall survival between treatment groups.\n\n## Lenvatinib plus everolimus is more effective than everolimus alone but the size of the benefit is unclear\n\nThe ERG identified differences in the characteristics of patients and the disease at baseline, which suggested that patients in the lenvatinib plus everolimus group had a better prognosis that those in the everolimus group. For example, compared with the everolimus alone group, patients in the lenvatinib plus everolimus group had had previous VEGF-targeted therapy for longer, and were more likely to have had a complete or partial response to first-line VEGF-targeted therapy. The clinical expert explained that duration of previous therapy as a prognostic indicator was debatable and the evidence weak. The committee noted that the tumour burden was greater in patients randomised to lenvatinib plus everolimus than in those randomised to everolimus alone. It understood that the ERG did not consider that any individual difference in the characteristics at baseline would modify the effect of the study treatment, but that all differences taken together may have introduced bias in favour of lenvatinib plus everolimus. The committee agreed that the reported results may have overestimated the effectiveness of lenvatinib plus everolimus. This affected the precision with which the benefit of lenvatinib plus everolimus was estimated.\n\n## The size of the benefit with lenvatinib plus compared with current NHS treatments cannot be robustly estimated\n\nThe clinical expert questioned the face validity of the increase in median progression-free survival in HOPE\xa0205 with lenvatinib plus everolimus (9.1\xa0months) because it exceeds that seen with first-line treatments (when cancer would be expected to respond better than to second-line treatment). The committee considered that this greater than expected benefit with first-line treatments could have resulted from lenvatinib plus everolimus being 2\xa0treatments rather than 1\xa0treatment. The clinical expert did not agree with this proposition because lenvatinib plus everolimus would have also been expected to be associated with benefits on overall survival in excess of first-line therapies. The clinical expert commented that clinicians would be unlikely to prefer lenvatinib plus everolimus to its comparators because of the uncertainties introduced by the design and size of HOPE\xa0205. The committee concluded that the limitations of the trial, notably the small number of patients and a comparator not routinely used in the NHS, meant that the size of the benefit compared with current NHS treatments could not be robustly estimated.\n\n# Safety\n\n## Lenvatinib plus everolimus has more side effects than lenvatinib or everolimus alone\n\nThe committee considered the safety profile of lenvatinib plus everolimus, noting that:\n\nSerious adverse events occurred in a higher proportion of patients taking lenvatinib plus everolimus (54.9%) than in patients taking everolimus alone (42.0%).\n\nIn the lenvatinib plus everolimus group, 72.5% of patients had grade\xa0III or higher treatment-emergent adverse events, compared with 54.0% of patients taking everolimus alone.\n\nA larger proportion of patients had dose interruptions of lenvatinib (80.4%) or everolimus (76.5%) in the lenvatinib plus everolimus group compared with the everolimus alone group (54.0%), mainly because of adverse events.\n\nPatients in HOPE\xa0205 had treatment until disease progression, unacceptable toxicity or withdrawal of consent. The median time to stopping treatment (7.6\xa0months) was half the median progression-free survival (14.6\xa0months) in the trial, which suggested that many patients did not tolerate lenvatinib plus everolimus.\n\n## It is important to take performance status into account\n\nThe committee considered it unsurprising that the combination of lenvatinib plus everolimus would be associated with more frequent adverse effects than everolimus alone. The clinical expert commented that the combination would be expected to increase the degree of toxicity of adverse events rather than the range of toxicity compared with either individual drug. The clinical expert also considered that it would be difficult to offer people a treatment that would lead to grade\xa0III or\xa0IV adverse events in three-quarters of them. The committee recalled that HOPE\xa0205 included only patients with an ECOG performance status score of\xa00 or\xa01. It considered that people with worse performance status would be less likely to tolerate lenvatinib plus everolimus than patients in the trial. As a result, the effect of treatment seen in the trial was unlikely to be seen in people with lower performance status, partly because they would not have had treatment long enough to derive the same benefits. The committee concluded that lenvatinib plus everolimus has a high burden of adverse events and is not well tolerated, even by patients who are relatively fit compared with the average person who would have this treatment in clinical practice. Because of this, the committee agreed that it was important to consider performance status in the decision-making.\n\n# Network meta-analysis\n\n## The company's revised network is appropriate for decision-making\n\nBecause there were no head-to-head trials comparing lenvatinib with axitinib, nivolumab or cabozantinib, the company compared the treatments indirectly using a network meta-analysis. It included the randomised controlled trials HOPE\xa0205, CHECKMATE-025 and METEOR (lenvatinib plus everolimus, nivolumab and cabozantinib respectively, each compared with everolimus), and estimated overall and progression-free survival curves for each treatment using fractional polynomials, as described by Janssen et al. (2011). In doing so, the company assumed that axitinib was as effective as everolimus with respect to overall and progression-free survival, which the committee recalled it had accepted in previous technology appraisals as a reasonable assumption in this therapy area. The committee concluded that the company's network using fractional polynomials was appropriate for decision-making.\n\n## The model overestimates the progression-free survival benefit of lenvatinib plus everolimus compared with the observed effect\n\nThe data from HOPE\xa0205 were relatively immature at the time of the analysis of progression-free survival (June 2014) because, across the lenvatinib plus everolimus and everolimus alone groups, disease had progressed in only 62% of patients. The modelled treatment effectiveness showed that the progression-free survival hazard ratios dropped sharply (that is, the effect of lenvatinib plus everolimus increased relative to the comparators) around 2\xa0months after starting treatment and then increased (the effect of lenvatinib plus everolimus decreased) before becoming constant. The committee agreed that this was implausible and highly unlikely in clinical practice. It considered the possibility that the Kaplan–Meier curves, being close at the beginning then diverging, resulted in a relationship between treatments that the fractional polynomials could not pick up. The committee examined the trial-based fractional polynomial curves provided by the ERG to check the curve fits to the Kaplan–Meier data for lenvatinib plus everolimus and everolimus alone in HOPE\xa0205. It agreed that how the curves fitted the progression-free and overall survival data was generally acceptable, although the curve for lenvatinib plus everolimus overestimated progression-free survival compared with the observed effect. The committee acknowledged the inherent uncertainty associated with comparing treatments indirectly, which, when added to other clinical uncertainties, meant that it could interpret the estimates of relative effectiveness only with caution.\n\n# Structure of the economic model\n\n## The structure of the model is suitable for decision-making\n\nThe company used a 3‑stage partitioned-survival economic model, which the committee considered appropriate to capture the natural history of the disease. The health states included in the model were pre-progressed disease, progressed disease and death. The company used data on time from randomisation to disease progression to determine the proportion of patients in the progression-free health state at a given time, and data on time to death to determine the proportion of patients who had reached the death state at a given time. The company calculated the proportion of patients in the post-progression health state as the difference between the proportion who had died and the proportion who had progressed. The committee concluded that the model was suitable for decision-making.\n\n# Modelling of clinical effectiveness\n\n## Survival curves generated using the ERG's own parameter values from the network meta-analysis are more appropriate than the company's curves\n\nThe committee discussed the extrapolation of progression-free and overall survival across the model time horizon (20\xa0years) based on the company's network meta-analysis using fractional polynomials. The ERG considered that the company incorrectly applied fractional polynomials in its model, which resulted in an error when estimating survival probabilities. This caused the overall survival curves for each treatment to deviate implausibly around 60\xa0months after the start of treatment. To address this, the ERG generated fractional polynomial curves for the entire time horizon using its own parameter values from its own network meta-analysis. The ERG's curves were largely similar to the company's up to 5\xa0years after starting treatment, but did not deviate later as seen with the company's curves. The committee noted that the company acknowledged its error, and concluded that it would consider the model with the ERG's correction.\n\n## Assuming that the effect of lenvatinib plus everolimus continues for up to 20\xa0years is highly uncertain\n\nBoth the company and the ERG assumed that the effect of lenvatinib plus everolimus continued beyond the trial follow-up, even after the disease progressed or people stopped treatment. The committee was not presented with evidence to support this. The clinical expert considered that the treatment effect on overall survival was unlikely to continue after progression with lenvatinib plus everolimus, but might do so with the comparator nivolumab because it is an immunotherapy. The committee recalled that the evidence base underpinning the extrapolation was already uncertain (see section 3.9). It concluded that assuming the effect of lenvatinib plus everolimus continues for up to 20\xa0years, based on a trial with a median follow-up of under 3\xa0years for overall survival, was highly uncertain. It would have liked to have seen more conservative assumptions explored, for example, that the effect of treatment ceased at the end of the trial, or diminished over time beyond the trial follow-up.\n\n# Modelling treatment duration\n\n## The ERG's 2‑knot spline distribution is suitable for modelling treatment duration\n\nThe committee recognised that the duration of each treatment assumed in the model determined the total cost of treatment. The ERG disagreed with how the company estimated the proportion of patients who continued on any of the comparator treatments at any given cycle in the model. The company assumed that the ratio of median duration of treatment equalled the ratio of the hazard rates for stopping treatment (taken from the respective trial of each treatment), which the ERG considered incorrect. The ERG preferred fitting parametric distributions to digitised Kaplan–Meier data from each trial. The committee noted that the 2‑knot spline, followed by the log-normal distribution, best fitted the curves. To validate the company and ERG's curves, the committee compared the median time to stopping treatment estimated by the curves with that seen in the trials of the comparator treatments. The ERG's curves using the 2‑knot spline distribution produced the closest estimate to the trial data. The committee concluded it would consider the model incorporating the ERG's 2‑knot spline distribution.\n\n# Modelling health-related quality of life\n\n## Using utility values from the AXIS trial to model health-related quality of life is appropriate\n\nThe committee was aware that the HOPE\xa0205 trial did not collect data on health-related quality of life, and that the company used utility values from the AXIS trial, which had compared axitinib with sorafenib for advanced renal cell carcinoma. The utility values from AXIS were 0.69\xa0for the pre-progressed disease states and 0.61\xa0for the progressed disease states. AXIS has been accepted as a valid source of utility data for this patient population in other NICE technology appraisals in this disease area. The committee concluded that the utility values from AXIS were appropriate.\n\n## The utility values in the model do not reflect quality of life appropriately\n\nTo estimate the impact of adverse events on health-related quality of life, the company deducted a decrement (an amount reflecting the effect of adverse events on health-related quality of life) from the baseline utility values from AXIS. It estimated the total utility decrements separately for each treatment by assigning a utility decrement for grade\xa03 or higher adverse events based on the literature, then estimating an average utility decrement for each treatment weighted by the proportion of patients who had each adverse event. The estimates incorporated the average duration of each adverse event, taken directly from the HOPE\xa0205 study for lenvatinib plus everolimus and estimated from the respective clinical trials for the comparators. In response to the appraisal consultation document, the company revised its utility decrements to −0.097 for lenvatinib plus everolimus, −0.072 for axitinib, −0.084 for cabozantinib and −0.008 for nivolumab. The committee recalled that the utility values used in the model should have reflected the high rate of serious adverse events associated with lenvatinib plus everolimus (see section\xa03.12). However, the utility decrement for lenvatinib plus everolimus remained small because it did not correlate with the observation in HOPE\xa0205 that all patients who had lenvatinib plus everolimus had an adverse event, and that many stopped treatment because of these adverse events. The clinical expert shared the committee's concern, noting that the utility decrements applied by the company contradicted the available evidence on the safety of lenvatinib plus everolimus. Furthermore, the Cancer Drugs Fund clinical lead pointed out that the revised utility decrement for nivolumab also appeared too small given its immunotoxicity. The committee concluded that the utility values used in the model did not reflect quality of life appropriately.\n\n# Cost and effect of subsequent treatments\n\n## The company's and the ERG's approaches are reasonable for modelling subsequent treatments\n\nThe company did not originally include in its model the cost of therapies patients had in HOPE\xa0205 after stopping study treatment. In response to a request for clarification from the ERG, the company chose to estimate the cost of subsequent therapies (that is, third-line treatment and beyond) based on the UK market share of the drugs. In contrast, the ERG argued that it was better to base these costs on the proportions of subsequent treatments in the trials for lenvatinib plus everolimus and for all comparators. The committee noted that either approach had little impact on the results. Although the committee appreciated that there may be arguments for using the company' or the ERG's costs of subsequent treatment, it concluded that either approach could be considered suitable for decision-making.\n\n# Results of the cost-effectiveness analyses\n\n## The ERG's base case is more appropriate for decision-making than the company's\n\nThe committee considered the cost-effectiveness results from the company's base case and the ERG's base case, including confidential discounts for all technologies. It noted that, in response to the appraisal consultation document, the company revised its patient access scheme discount. It agreed that the ERG's base case was more appropriate for decision-making because it used:\n\nthe ERG's own best-fitting fractional polynomials for overall and progression-free survival (see section\xa03.17)\n\nthe 2‑knot spline distribution to model treatment duration (see section\xa03.19).However, the committee recognised that the ERG's base case did not reflect all of its preferred analyses because:\n\nit assumed that the effect of lenvatinib plus everolimus continues until the end of the time horizon of 20\xa0years (see section\xa03.18)\n\nthe utility decrement for lenvatinib plus everolimus was too small given the incidence and severity of adverse events that occurred in HOPE\xa0205 (see section\xa03.21).The committee concluded that it would use the ERG's base case for decision-making.\n\n## Lenvatinib plus everolimus is a cost-effective use of NHS resources in people with an ECOG performance status score of 0\xa0or\xa01\n\nThe committee noted that, in the ERG's deterministic base-case analysis, lenvatinib plus everolimus dominated cabozantinib and nivolumab, that is it was more effective and less costly. The incremental cost-effectiveness ratio for lenvatinib plus everolimus compared with axitinib was between £20,000 and £30,000 per quality-adjusted life year, which is the range normally accepted by NICE to represent cost-effective technologies. The committee appreciated that the uncertainty in the cost-effectiveness estimates came mainly from the limitations of HOPE\xa0205 (see section\xa03.5), and from the modelling assumptions about the long-term performance of treatment (see section\xa03.18) and the impact of adverse events on health-related quality of life (see section\xa03.21). The committee also considered the value patients and clinicians place on having treatment options. On balance, the committee agreed that lenvatinib plus everolimus could be recommended for previously treated advanced renal cell carcinoma. It recalled that the evidence it had seen reflected patients with an ECOG performance status score of 0\xa0or\xa01; less fit people would be less likely to tolerate treatment, and would be unlikely to derive the same benefits seen in HOPE\xa0205 (see section 3.13). This meant that lenvatinib plus everolimus was unlikely to be cost effective in people with an ECOG performance status score above\xa01. The committee concluded that it could recommend lenvatinib plus everolimus, but only for people with an ECOG performance status score of 0\xa0or\xa01.\n\n# Other factors\n\n## Future research\n\nThe committee heard that the company is considering an observational study to gather further data on the safety and quality of life of lenvatinib plus everolimus, aiming to have the results by 2020. The company said that this study is still in the early stages of development and that, while it might include comparators used in routine clinical practice, these are not yet defined. The committee understood that the study might include UK sites. It agreed that it had too little information about the study to enable it to determine its value. However, the committee encouraged further data collection on lenvatinib plus everolimus because this could provide comparative evidence against established NHS practice in England.\n\n## Innovation\n\nThe committee discussed whether lenvatinib plus everolimus was an innovative treatment. The company argued that lenvatinib plus everolimus is considered innovative because the combination has shown a synergistic effect whereby the 2\xa0treatments together lead to higher efficacy levels with respect to progression-free survival and response rate than each of the individual treatments. The committee noted that the clinical expert did not consider lenvatinib plus everolimus to be a step-change in managing the condition. It agreed that lenvatinib plus everolimus was unlikely to fulfil an unmet clinical need in a particular group of people. The committee concluded that there was no benefit to utility that was not otherwise accounted for in the modelling."}
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https://www.nice.org.uk/guidance/ta498
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Evidence-based recommendations on lenvatinib (Kisplyx) with everolimus for previously treated advanced renal cell carcinoma in adults.
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ac35e0ab1ed31622d1f2653dbc87a7eab64acd7e
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nice
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Glecaprevir–pibrentasvir for treating chronic hepatitis C
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Glecaprevir–pibrentasvir for treating chronic hepatitis C
Evidence-based recommendations on glecaprevir–pibrentasvir (Maviret) for treating chronic hepatitis C in adults.
# Recommendations
Glecaprevir–pibrentasvir is recommended, within its marketing authorisation, as an option for treating chronic hepatitis C in adults, only if the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit.
It is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.
Why the committee made these recommendations
Current treatment options for chronic hepatitis C depend on genotype, cirrhosis status and treatment history. Glecaprevir–pibrentasvir is suitable for all genotypes and has a shorter treatment duration than most other direct-acting antiviral treatments.
Clinical trials show that glecaprevir–pibrentasvir is effective for treating chronic hepatitis C across all genotypes. There was only 1 trial directly comparing glecaprevir–pibrentasvir with other direct-acting antiviral regimens, but comparing individual arms of clinical trials of other direct-acting antivirals suggests that glecaprevir–pibrentasvir works as well as most direct-acting antiviral drugs that NICE already recommends for treating hepatitis C.
The analysis shows that cost-effectiveness estimates for glecaprevir–pibrentasvir across all populations are substantially below what NICE usually considers acceptable. It is therefore recommended for treating chronic hepatitis C.# Information about glecaprevir–pibrentasvir
# Marketing authorisation
Glecaprevir–pibrentasvir (Maviret, AbbVie) has a marketing authorisation in the UK for the 'treatment of chronic hepatitis C virus infection in adults'. This includes genotypes 1–6, with or without compensated cirrhosis, in people with untreated disease or disease previously treated with interferon-based treatment or sofosbuvir plus ribavirin. It is not approved for people whose previous treatment included a NS3/4A and/or NS5A inhibitor.
# Dosage in the marketing authorisation
The dosage is 300 mg/120 mg orally once daily. Treatment duration is 8, 12 or 16 weeks depending on genotype, cirrhosis status and whether the person has had previous treatment.
# Price
The list price per pack is £12,993.66. The total costs are £25,987.32 for an 8-week course, £38,980.98 for 12 weeks and £51,974.64 for 16 weeks. The company has agreed a nationally available price reduction for glecaprevir–pibrentasvir with the Commercial Medicines Unit. The contract prices agreed through the framework are commercial in confidence.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## People with hepatitis C would welcome an additional treatment option that is suitable for all genotypes and free from peginterferon
The use of interferon-based treatments has reduced substantially in clinical practice because of the introduction of newer direct-acting antivirals for all hepatitis C virus (HCV) genotypes, with the exception of genotype 2. Clinical and patient experts stated that glecaprevir–pibrentasvir is an important treatment because it is effective in all genotypes, which reduces the need for baseline genotype testing and could improve access to treatment. Unlike sofosbuvir-based regimens, glecaprevir–pibrentasvir is suitable for people with severe renal impairment. This is particularly important for genotypes 2, 3, 5 and 6 in which the only interferon-free treatments available have a sofosbuvir component. In addition to being free from interferon, ribavirin and sofosbuvir, glecaprevir–pibrentasvir has a short treatment duration of 8 weeks for disease without cirrhosis for most HCV genotypes. The committee recognised that patients and clinicians would welcome an additional effective and tolerable treatment for all HCV genotypes and concluded that glecaprevir–pibrentasvir is a valuable treatment option.
## The relevant comparators are included
The company did not include some of the comparators listed in the NICE scope, noting that they are no longer used in clinical practice:
daclatasvir plus sofosbuvir for genotypes 1 and 4
peginterferon alfa plus ribavirin for all genotypes (except genotype 2, in people who are treatment naive, without cirrhosis, and who are eligible for treatment with interferon)
sofosbuvir plus with ribavirin for genotypes 1 and 4. The clinical experts confirmed that these comparators are rarely used in NHS practice for those populations and could therefore be excluded. The committee concluded that the company had included the most relevant comparators.
# Clinical effectiveness
## Glecaprevir–pibrentasvir is effective for treating chronic hepatitis C
The key clinical evidence for glecaprevir–pibrentasvir came from 7 clinical trials. Only 1 trial included an active comparator (glecaprevir–pibrentasvir compared with sofosbuvir–daclatasvir). One trial was placebo controlled and the remaining 5 trials did not have a comparator. The trials included people who had not had treatment for their hepatitis C, and people whose hepatitis C had not adequately responded to interferon-based treatment or sofosbuvir plus ribavirin. Results showed that for all genotypes, irrespective of cirrhosis stage or treatment history, the rate of sustained virological response at 12 weeks after the end of treatment ranged from 87.5% to 100.0%. The ERG noted that patient numbers in the trials were low and only 4 out of the 24 subgroups included more than 100 patients, which causes considerable uncertainty in the rates of sustained virological response. The committee was aware that patient numbers would be low in some subgroups because of the low incidence of disease of certain genotypes. The clinical experts stated that glecaprevir–pibrentasvir is considered similar in effectiveness to the new direct-acting antiviral drugs. The committee concluded that glecaprevir–pibrentasvir is effective for treating chronic hepatitis C across all subgroups and in all genotypes.
## Glecaprevir–pibrentasvir is generally well tolerated
The most commonly reported adverse events with glecaprevir–pibrentasvir are headache and fatigue. The committee noted the relatively favourable safety and tolerability profile, irrespective of cirrhosis stage, treatment experience and degree of renal impairment. The clinical experts stated that glecaprevir–pibrentasvir has a similar tolerability profile to other direct-acting antiviral regimens. The committee concluded that the adverse events associated with glecaprevir–pibrentasvir were generally tolerable.
# Cost-effectiveness analysis
## The company's model structure is acceptable for decision-making
The structure of the company's model and its assumptions about the natural history of the disease including distinguishing between no cirrhosis (further subdivided into fibrosis severity) and compensated cirrhosis was similar to models used for other NICE technology appraisals for chronic hepatitis C. The model did not include onward transmission of disease or reinfection. In its scenario analyses, the ERG explored using reinfection rates from Simmons et al. (2016), which calculated the reinfection probability as 0.0033. This had no impact on the results. The committee had previously accepted similar models that excluded disease transmission and reinfection, so it concluded that the structure of the model was acceptable for decision-making.
## The company's naive indirect comparison leads to uncertainty in the model results
The company used a naive indirect comparison to compare glecaprevir–pibrentasvir with the relevant comparators. Due to the lack of comparative trial data for glecaprevir–pibrentasvir and the comparators a conventional indirect treatment comparison was not feasible. The rates of sustained virological response for the comparators in the company's model were selected from individual arms of randomised controlled trials. The company had used some of the same rates of sustained virological response for comparator technologies as those used in the NICE technology appraisal guidance on sofosbuvir–velpatasvir. The rates of sustained virological response for the direct-acting antivirals were similar to those for glecaprevir–pibrentasvir in its trials. The ERG stated that the company's choice of study for each comparator was often arbitrary. The committee noted that this approach meant that the results were at risk of the kind of bias normally associated with observational studies. It concluded that the company's method of estimating efficacy in the model introduced some uncertainty in the results.
## The company's transition probabilities are appropriate for decision-making
The company used the same sources for non-treatment-specific transition probabilities as those used in previous NICE technology appraisals on hepatitis C. These included Thein et al. (2008) and Kanwal et al. (2014) for fibrosis progression, and Cardoso et al. (2010) and Fattovich et al. (1997) for non-fibrosis progression. The committee was generally satisfied with this approach. In a scenario analysis, the ERG explored using Grishchenko et al. (2009) which had also been accepted for fibrosis progression in previous appraisals, but this had no impact on the results. The committee therefore concluded that the company's transition probabilities were appropriate for decision-making.
## The company's utility values are acceptable for decision-making
In its base-case analyses, the company used utility data from the literature (Wright et al. 2006) in line with the previous NICE technology appraisals on hepatitis C to inform the difference in utility of a health state with or without sustained virological response. In a scenario analysis the company used utility data collected from clinical trials using the EQ‑5D, but this did not change the results. The average sustained virological response-related utility increments from the company's trials (0.025 to 0.029) were smaller than that from Wright et al. (0.05), which has consistently been used in previous hepatitis C NICE technology appraisals. The ERG explored the impact of applying a zero gain in utility after sustained virological response but this also had no impact on the results. None of the other utility scenario analyses done by the ERG had any significant impact on the results. The committee therefore accepted the company's base-case utility estimates but emphasised that in future hepatitis C appraisals, utility values from the literature will no longer be considered acceptable if there are appropriate utility values collected from clinical trials.
# Cost-effectiveness results
## Glecaprevir–pibrentasvir is cost effective and is therefore recommended
Using the confidential price discounts for glecaprevir–pibrentasvir and its comparators (where applicable), the results showed that glecaprevir–pibrentasvir was the most cost-effective treatment in all groups (with incremental cost-effectives ratios substantially below £20,000 per quality-adjusted life year gained), except for people with untreated genotype 4 HCV without cirrhosis. In this group glecaprevir–pibrentasvir was the cheapest treatment with the lowest total QALYs. The company's deterministic sensitivity analysis showed that the model was primarily driven by the rates of sustained virological response, which the committee had previously concluded led to uncertainty in the model (section 3.6). The committee was aware that the rate of sustained virological response used to inform this subgroup analysis (untreated genotype 4 HCV without cirrhosis) was based on small patient numbers and was lower than those used for the comparators. The clinical experts had stated that glecaprevir–pibrentasvir is considered similar in effectiveness to the new direct-acting antiviral drugs (section 3.3), and considered that any difference in sustained virological response rate was probably a result of the small patient numbers in the group. The committee recalled the clinical experts' comments (section 3.1) that glecaprevir–pibrentasvir is likely to be effective in all subgroups regardless of genotype, treatment history or cirrhosis status. It also recalled that glecaprevir–pibrentasvir was the most cost-effective treatment in all of the other genotype 4 subgroups. In addition, because of the small patient numbers of people with genotype 4 HCV, it had previously accepted sustained virological response rates from genotype 1 as a proxy for genotype 4 rates in some hepatitis C appraisals. Therefore on the balance of evidence available, the committee considered that glecaprevir–pibrentasvir would be equally cost effective for treating genotype 4, previously untreated chronic hepatitis C in people without cirrhosis. The committee concluded that glecaprevir–pibrentasvir could be recommended within its marketing authorisation as a cost-effective use of NHS resources for treating hepatitis C.
# Other factors
## Treatment and prescribing decisions
Previous NICE technology appraisal guidance on hepatitis C included recommendations on treatment and prescribing decisions because of capacity constraints within the NHS. The clinical experts stated that many people eligible for treatment, particularly people with cirrhosis, have now been treated, creating additional capacity to treat more. The clinical experts also stated that having more affordable drugs with shorter treatment durations also creates additional capacity. However, NHS England commented that there is considerable value in recommending that multidisciplinary teams in the operational delivery networks should prioritise treatment for people with the highest unmet clinical need. NHS England considers that the capacity constraints in the NHS have not changed sufficiently and that not including this recommendation would create major challenges. On balance, the committee accepted that it was appropriate to include the recommendation on treatment and prescribing decisions (see section 1.2) as in previous NICE guidance on hepatitis C treatments.
## Innovation
The committee considered whether glecaprevir–pibrentasvir could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee agreed with the company that there is an unmet need for interferon-free regimens to treat people with previously treated genotype 3 hepatitis C, particularly those with severe renal impairment. However, the committee concluded that it had taken these potential benefits into account when considering the cost effectiveness of glecaprevir–pibrentasvir.
## Equality
The committee noted potential equality issues raised during the NICE scoping process that there are proportionately more people from Asian and minority ethnic groups, and more people who inject drugs, who have genotype 3 or genotype 4 HCV than other HCV genotypes. Having decided that glecaprevir–pibrentasvir should be recommended for all genotypes, the committee agreed that its recommendations for these groups would not have a different effect on people protected by equality legislation than on the wider population.
|
{'Recommendations': 'Glecaprevir–pibrentasvir is recommended, within its marketing authorisation, as an option for treating chronic hepatitis\xa0C in adults, only if the company provides the drug at the same price or lower than that agreed with the Commercial Medicines Unit.\n\nIt is recommended that the decision to treat and prescribing decisions are made by multidisciplinary teams in the operational delivery networks put in place by NHS England, to prioritise treatment for people with the highest unmet clinical need.\n\nWhy the committee made these recommendations\n\nCurrent treatment options for chronic hepatitis\xa0C depend on genotype, cirrhosis status and treatment history. Glecaprevir–pibrentasvir is suitable for all genotypes and has a shorter treatment duration than most other direct-acting antiviral treatments.\n\nClinical trials show that glecaprevir–pibrentasvir is effective for treating chronic hepatitis\xa0C across all genotypes. There was only 1 trial directly comparing glecaprevir–pibrentasvir with other direct-acting antiviral regimens, but comparing individual arms of clinical trials of other direct-acting antivirals suggests that glecaprevir–pibrentasvir works as well as most direct-acting antiviral drugs that NICE already recommends for treating hepatitis\xa0C.\n\nThe analysis shows that cost-effectiveness estimates for glecaprevir–pibrentasvir across all populations are substantially below what NICE usually considers acceptable. It is therefore recommended for treating chronic hepatitis\xa0C.', 'Information about glecaprevir–pibrentasvir ': "# Marketing authorisation\n\nGlecaprevir–pibrentasvir (Maviret, AbbVie) has a marketing authorisation in the UK for the 'treatment of chronic hepatitis\xa0C virus infection in adults'. This includes genotypes\xa01–6, with or without compensated cirrhosis, in people with untreated disease or disease previously treated with interferon-based treatment or sofosbuvir plus ribavirin. It is not approved for people whose previous treatment included a NS3/4A and/or NS5A inhibitor.\n\n# Dosage in the marketing authorisation\n\nThe dosage is 300\xa0mg/120\xa0mg orally once daily. Treatment duration is 8, 12 or 16 weeks depending on genotype, cirrhosis status and whether the person has had previous treatment.\n\n# Price\n\nThe list price per pack is £12,993.66. The total costs are £25,987.32 for an 8-week course, £38,980.98 for 12 weeks and £51,974.64 for 16 weeks. The company has agreed a nationally available price reduction for glecaprevir–pibrentasvir with the Commercial Medicines Unit. The contract prices agreed through the framework are commercial in confidence.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## People with hepatitis\xa0C would welcome an additional treatment option that is suitable for all genotypes and free from peginterferon\n\nThe use of interferon-based treatments has reduced substantially in clinical practice because of the introduction of newer direct-acting antivirals for all hepatitis\xa0C virus (HCV) genotypes, with the exception of genotype 2. Clinical and patient experts stated that glecaprevir–pibrentasvir is an important treatment because it is effective in all genotypes, which reduces the need for baseline genotype testing and could improve access to treatment. Unlike sofosbuvir-based regimens, glecaprevir–pibrentasvir is suitable for people with severe renal impairment. This is particularly important for genotypes 2, 3, 5 and 6 in which the only interferon-free treatments available have a sofosbuvir component. In addition to being free from interferon, ribavirin and sofosbuvir, glecaprevir–pibrentasvir has a short treatment duration of 8\xa0weeks for disease without cirrhosis for most HCV genotypes. The committee recognised that patients and clinicians would welcome an additional effective and tolerable treatment for all HCV genotypes and concluded that glecaprevir–pibrentasvir is a valuable treatment option.\n\n## The relevant comparators are included\n\nThe company did not include some of the comparators listed in the NICE scope, noting that they are no longer used in clinical practice:\n\ndaclatasvir plus sofosbuvir for genotypes 1 and 4\n\npeginterferon alfa plus ribavirin for all genotypes (except genotype 2, in people who are treatment naive, without cirrhosis, and who are eligible for treatment with interferon)\n\nsofosbuvir plus with ribavirin for genotypes 1 and 4. The clinical experts confirmed that these comparators are rarely used in NHS practice for those populations and could therefore be excluded. The committee concluded that the company had included the most relevant comparators.\n\n# Clinical effectiveness\n\n## Glecaprevir–pibrentasvir is effective for treating chronic hepatitis\xa0C\n\nThe key clinical evidence for glecaprevir–pibrentasvir came from 7 clinical trials. Only 1 trial included an active comparator (glecaprevir–pibrentasvir compared with sofosbuvir–daclatasvir). One trial was placebo controlled and the remaining 5 trials did not have a comparator. The trials included people who had not had treatment for their hepatitis C, and people whose hepatitis C had not adequately responded to interferon-based treatment or sofosbuvir plus ribavirin. Results showed that for all genotypes, irrespective of cirrhosis stage or treatment history, the rate of sustained virological response at 12 weeks after the end of treatment ranged from 87.5% to 100.0%. The ERG noted that patient numbers in the trials were low and only 4 out of the 24 subgroups included more than 100 patients, which causes considerable uncertainty in the rates of sustained virological response. The committee was aware that patient numbers would be low in some subgroups because of the low incidence of disease of certain genotypes. The clinical experts stated that glecaprevir–pibrentasvir is considered similar in effectiveness to the new direct-acting antiviral drugs. The committee concluded that glecaprevir–pibrentasvir is effective for treating chronic hepatitis\xa0C across all subgroups and in all genotypes.\n\n## Glecaprevir–pibrentasvir is generally well tolerated\n\nThe most commonly reported adverse events with glecaprevir–pibrentasvir are headache and fatigue. The committee noted the relatively favourable safety and tolerability profile, irrespective of cirrhosis stage, treatment experience and degree of renal impairment. The clinical experts stated that glecaprevir–pibrentasvir has a similar tolerability profile to other direct-acting antiviral regimens. The committee concluded that the adverse events associated with glecaprevir–pibrentasvir were generally tolerable.\n\n# Cost-effectiveness analysis\n\n## The company's model structure is acceptable for decision-making\n\nThe structure of the company's model and its assumptions about the natural history of the disease including distinguishing between no cirrhosis (further subdivided into fibrosis severity) and compensated cirrhosis was similar to models used for other NICE technology appraisals for chronic hepatitis\xa0C. The model did not include onward transmission of disease or reinfection. In its scenario analyses, the ERG explored using reinfection rates from Simmons et al. (2016), which calculated the reinfection probability as 0.0033. This had no impact on the results. The committee had previously accepted similar models that excluded disease transmission and reinfection, so it concluded that the structure of the model was acceptable for decision-making.\n\n## The company's naive indirect comparison leads to uncertainty in the model results\n\nThe company used a naive indirect comparison to compare glecaprevir–pibrentasvir with the relevant comparators. Due to the lack of comparative trial data for glecaprevir–pibrentasvir and the comparators a conventional indirect treatment comparison was not feasible. The rates of sustained virological response for the comparators in the company's model were selected from individual arms of randomised controlled trials. The company had used some of the same rates of sustained virological response for comparator technologies as those used in the NICE technology appraisal guidance on sofosbuvir–velpatasvir. The rates of sustained virological response for the direct-acting antivirals were similar to those for glecaprevir–pibrentasvir in its trials. The ERG stated that the company's choice of study for each comparator was often arbitrary. The committee noted that this approach meant that the results were at risk of the kind of bias normally associated with observational studies. It concluded that the company's method of estimating efficacy in the model introduced some uncertainty in the results.\n\n## The company's transition probabilities are appropriate for decision-making\n\nThe company used the same sources for non-treatment-specific transition probabilities as those used in previous NICE technology appraisals on hepatitis\xa0C. These included Thein et al. (2008) and Kanwal et al. (2014) for fibrosis progression, and Cardoso et al. (2010) and Fattovich et al. (1997) for non-fibrosis progression. The committee was generally satisfied with this approach. In a scenario analysis, the ERG explored using Grishchenko et al. (2009) which had also been accepted for fibrosis progression in previous appraisals, but this had no impact on the results. The committee therefore concluded that the company's transition probabilities were appropriate for decision-making.\n\n## The company's utility values are acceptable for decision-making\n\nIn its base-case analyses, the company used utility data from the literature (Wright et al. 2006) in line with the previous NICE technology appraisals on hepatitis\xa0C to inform the difference in utility of a health state with or without sustained virological response. In a scenario analysis the company used utility data collected from clinical trials using the EQ‑5D, but this did not change the results. The average sustained virological response-related utility increments from the company's trials (0.025 to 0.029) were smaller than that from Wright et al. (0.05), which has consistently been used in previous hepatitis\xa0C NICE technology appraisals. The ERG explored the impact of applying a zero gain in utility after sustained virological response but this also had no impact on the results. None of the other utility scenario analyses done by the ERG had any significant impact on the results. The committee therefore accepted the company's base-case utility estimates but emphasised that in future hepatitis\xa0C appraisals, utility values from the literature will no longer be considered acceptable if there are appropriate utility values collected from clinical trials.\n\n# Cost-effectiveness results\n\n## Glecaprevir–pibrentasvir is cost effective and is therefore recommended\n\nUsing the confidential price discounts for glecaprevir–pibrentasvir and its comparators (where applicable), the results showed that glecaprevir–pibrentasvir was the most cost-effective treatment in all groups (with incremental cost-effectives ratios [ICERs] substantially below £20,000 per quality-adjusted life year [QALY] gained), except for people with untreated genotype 4 HCV without cirrhosis. In this group glecaprevir–pibrentasvir was the cheapest treatment with the lowest total QALYs. The company's deterministic sensitivity analysis showed that the model was primarily driven by the rates of sustained virological response, which the committee had previously concluded led to uncertainty in the model (section 3.6). The committee was aware that the rate of sustained virological response used to inform this subgroup analysis (untreated genotype 4 HCV without cirrhosis) was based on small patient numbers and was lower than those used for the comparators. The clinical experts had stated that glecaprevir–pibrentasvir is considered similar in effectiveness to the new direct-acting antiviral drugs (section 3.3), and considered that any difference in sustained virological response rate was probably a result of the small patient numbers in the group. The committee recalled the clinical experts' comments (section 3.1) that glecaprevir–pibrentasvir is likely to be effective in all subgroups regardless of genotype, treatment history or cirrhosis status. It also recalled that glecaprevir–pibrentasvir was the most cost-effective treatment in all of the other genotype 4 subgroups. In addition, because of the small patient numbers of people with genotype 4 HCV, it had previously accepted sustained virological response rates from genotype 1 as a proxy for genotype 4 rates in some hepatitis\xa0C appraisals. Therefore on the balance of evidence available, the committee considered that glecaprevir–pibrentasvir would be equally cost effective for treating genotype 4, previously untreated chronic hepatitis\xa0C in people without cirrhosis. The committee concluded that glecaprevir–pibrentasvir could be recommended within its marketing authorisation as a cost-effective use of NHS resources for treating hepatitis\xa0C.\n\n# Other factors\n\n## Treatment and prescribing decisions\n\nPrevious NICE technology appraisal guidance on hepatitis\xa0C included recommendations on treatment and prescribing decisions because of capacity constraints within the NHS. The clinical experts stated that many people eligible for treatment, particularly people with cirrhosis, have now been treated, creating additional capacity to treat more. The clinical experts also stated that having more affordable drugs with shorter treatment durations also creates additional capacity. However, NHS England commented that there is considerable value in recommending that multidisciplinary teams in the operational delivery networks should prioritise treatment for people with the highest unmet clinical need. NHS England considers that the capacity constraints in the NHS have not changed sufficiently and that not including this recommendation would create major challenges. On balance, the committee accepted that it was appropriate to include the recommendation on treatment and prescribing decisions (see section 1.2) as in previous NICE guidance on hepatitis C treatments.\n\n## Innovation\n\nThe committee considered whether glecaprevir–pibrentasvir could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee agreed with the company that there is an unmet need for interferon-free regimens to treat people with previously treated genotype 3 hepatitis\xa0C, particularly those with severe renal impairment. However, the committee concluded that it had taken these potential benefits into account when considering the cost effectiveness of glecaprevir–pibrentasvir.\n\n## Equality\n\nThe committee noted potential equality issues raised during the NICE scoping process that there are proportionately more people from Asian and minority ethnic groups, and more people who inject drugs, who have genotype 3 or genotype 4 HCV than other HCV genotypes. Having decided that glecaprevir–pibrentasvir should be recommended for all genotypes, the committee agreed that its recommendations for these groups would not have a different effect on people protected by equality legislation than on the wider population."}
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https://www.nice.org.uk/guidance/ta499
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Evidence-based recommendations on glecaprevir–pibrentasvir (Maviret) for treating chronic hepatitis C in adults.
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b6e63637f03f9398ce0fa46257eb989a1845534a
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nice
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Ceritinib for untreated ALK-positive non-small-cell lung cancer
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Ceritinib for untreated ALK-positive non-small-cell lung cancer
Evidence-based recommendations on ceritinib (Zykadia) for untreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer in adults.
# Recommendations
Ceritinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase (ALK)‑positive advanced non-small-cell lung cancer in adults, only if the company provides it with the discount agreed in the patient access scheme.
Why the committee made this recommendation
Most people with untreated ALK‑positive advanced non-small-cell lung cancer are offered crizotinib. Chemotherapy may be offered if the person's ALK mutation status isn't known, and therefore is not a relevant comparator for ceritinib. There are no trials directly comparing ceritinib with crizotinib; the clinical trial compares ceritinib with chemotherapy.
Because the clinical trial has not finished, it is unable to show how much ceritinib prolongs life compared with chemotherapy. But it shows that ceritinib is more effective than chemotherapy at increasing the length of time people live without their disease progressing. An indirect comparison suggests that ceritinib is more effective than crizotinib. Clinical experts support using ceritinib instead of crizotinib.
The most plausible cost-effectiveness estimate for ceritinib compared with crizotinib is around what NICE normally considers acceptable. Therefore ceritinib can be recommended as an option for adults with untreated ALK‑positive advanced non-small-cell lung cancer.# Information about ceritinib
Marketing authorisation indication
Ceritinib (Zykadia, Novartis) as monotherapy is indicated for 'the first-line treatment of adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer'.
Dosage in the marketing authorisation
Ceritinib is taken orally, without food, at the same time each day. The recommended dose is 750 mg once daily. The summary of product characteristics recommends that treatment should continue as long as clinical benefit is observed.
Price
A 30‑day supply of ceritinib (150 capsules) costs £4,923.45 (excluding VAT; British national formulary online ).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ceritinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatment pathway and relevant comparators
## Crizotinib is the only relevant comparator
The committee understood that the standard of care in England for people with confirmed anaplastic lymphoma kinase (ALK)‑positive non-small-cell lung cancer is crizotinib (a first-generation ALK inhibitor). This is followed, after the disease has progressed, by ceritinib (a second-generation ALK inhibitor). Crizotinib was the only comparator in the company's cost-effectiveness analysis. The company did not compare ceritinib with chemotherapy, stating in its submission that, in current NHS practice, most people with untreated ALK‑positive advanced non-small-cell lung cancer take crizotinib. In written statements clinical experts explained that chemotherapy is offered as the first treatment option only if ALK status has not yet been confirmed. Therefore the committee understood that people with untreated disease having chemotherapy in practice would not be eligible for ceritinib. The committee concluded that crizotinib is the only relevant comparator for ceritinib in people with untreated ALK‑positive advanced non-small-cell lung cancer.
## Treatment with an ALK inhibitor may continue beyond disease progression
The summary of product characteristics for ceritinib, and the protocol for the phase 3 clinical trial of ceritinib (ASCEND‑4), states that treatment should continue as long as clinical benefit is observed. More than three‑quarters of patients in ASCEND‑4 had at least 1 dose of ceritinib after disease progression. The clinical experts said that this reflects clinical practice. They explained when it might be appropriate to continue treatment with ALK inhibitors after disease progression, for example, if there is evidence of disease progression at only 1 tumour location but otherwise the disease is well-controlled. The clinical experts also explained that they would wait until the disease has progressed at multiple sites before changing treatment, because there are limited alternative options. They said that people taking ceritinib are more likely to continue treatment beyond disease progression than people taking crizotinib. This is because the only option after ceritinib is chemotherapy; there is no clinical evidence to support giving crizotinib after ceritinib, whereas people on crizotinib can switch to ceritinib. The clinical experts suggested that in the future, as more treatment options become available, people might switch to an alternative therapy more quickly. The committee concluded that in current practice treatment with ceritinib, and to a lesser extent crizotinib, continues beyond disease progression.
# Clinical effectiveness compared with chemotherapy
## Ceritinib improves progression-free survival
The committee noted that ceritinib improves progression-free survival compared with chemotherapy, and that the difference between treatment arms in ASCEND‑4 was statistically significant. The median progression-free survival was 16.6 months with ceritinib and 8.1 months with chemotherapy in ASCEND‑4, producing a hazard ratio of 0.55 (95% confidence interval 0.42 to 0.73, p<0.0001). The committee concluded that ceritinib is associated with a significant benefit in progression-free survival compared with chemotherapy.
## Survival data from the clinical trial of ceritinib are immature
The committee was aware that the overall survival data from the trial are immature and that median overall survival was not reached in the ceritinib arm. It also acknowledged the ERG's concerns that the survival results may be biased because:
Patients were allowed to continue ceritinib after disease progression if clinical benefit was seen.
Patients whose disease progressed while taking ceritinib could switch to other active treatments (crizotinib, docetaxel or platinum-based chemotherapy).
Patients randomised to chemotherapy could switch to ceritinib when their disease progressed.The committee noted that the second-line treatments taken by patients in the trial were different to the treatments available in England, recalling that ceritinib would not be followed by crizotinib (see section 3.2). The committee was therefore concerned that the trial survival results might not be generalisable to current clinical practice. It acknowledged that the trial results appeared promising, noting that the difference between ceritinib and chemotherapy for overall survival was approaching statistical significance. But it agreed that it was difficult to establish the magnitude of survival benefit for ceritinib because the trial data are immature. The committee concluded that it should account for this uncertainty in its decision-making.
# Indirect comparison of ceritinib and crizotinib
## Ceritinib appears to be more effective than crizotinib at extending progression-free survival
Because there were no head-to-head trial data for ceritinib and crizotinib, the company did 2 matching-adjusted indirect comparisons (MAIC) using the results from ASCEND‑4. The first MAIC used results from the PROFILE‑1014 trial, which compared crizotinib with chemotherapy, and the second MAIC used results from the ALEX trial, which compared crizotinib with alectinib. Both MAICs showed that ceritinib extended progression-free survival compared with crizotinib, and that the difference between treatments was statistically significant, which reflected the clinical experts' expectations. The committee understood that the results of both MAICs were subject to a high risk of bias because there was no common comparator arm in the trials being compared; the committee was aware that the MAIC method is inappropriate without a common comparator. The ERG explained that it could not be certain whether the results from each MAIC are any more reliable than the results of a naive comparison of the unadjusted trial data. The committee was aware of the issues with the MAIC, but concluded that an indirect comparison of individual trial arms was the only way to compare ceritinib and crizotinib.
# Clinical evidence in the economic model
## Both crizotinib clinical trials are relevant to decision-making
The company's base-case cost-effectiveness model estimated the relative efficacy of ceritinib compared with crizotinib using hazard ratios from its indirect comparison of ASCEND‑4 with PROFILE‑1014; hazard ratios informed by ALEX were included in a scenario analysis. The ERG explained that it had no preference for the results of 1 indirect comparison over the other (that is, whether to consider the results based on PROFILE‑1014 or ALEX). The committee was aware that the company had used inappropriate methods in the indirect comparison with PROFILE‑1014, because it had matched the whole ASCEND‑4 population to the whole PROFILE‑1014 population instead of matching only the patients in the ceritinib treatment arms. But the committee considered that results from PROFILE‑1014 might be more relevant to clinical practice because patients continued crizotinib treatment beyond disease progression, which was not permitted in ALEX. The committee noted that both indirect comparisons resulted in a similar hazard ratio for progression-free survival and for overall survival. The ERG explained that the company's cost-effectiveness results were very sensitive to small changes in these hazard ratios. The committee concluded that it should consider cost-effectiveness results based on PROFILE‑1014 and results from ALEX in its decision-making.
# Extrapolating clinical trial data in the economic model
## The company's extrapolation of overall survival is appropriate
The company extrapolated overall survival in its model using the exponential function. The ERG considered that the estimates of long-term survival produced with the exponential curve (which cannot be reported because the company marked them as academic in confidence) were optimistic compared with clinical experience of ALK inhibitors and real-world data on the survival of people who have had crizotinib. The ERG suggested in its report that the Gompertz curve might be more appropriate to model overall survival. This was because it predicted a 5‑year survival rate that reflected estimates from its clinical advisers (20%), and estimates from a real-world study of first-line treatment with crizotinib (which cannot be reported because the study authors provided them in confidence). However, the company explained that recently published data from PROFILE‑1014 suggested that 56.6% of patients who had crizotinib would be alive at 4 years and 44% would be alive at 5 years, which supports using the exponential function to extrapolate survival in the model. The clinical experts noted that the survival rates in PROFILE‑1014 were higher than in real-world studies. They suggested that this could be because a substantial proportion of people in PROFILE‑1014 had subsequent lines of therapy, noting that survival rates have improved considerably in recent years. The clinical experts agreed that the population in PROFILE‑1014 was generalisable to clinical practice and, on balance, considered that the survival estimates from PROFILE‑1014 could be realistic. The ERG highlighted that all parametric models predicted lower survival rates than the recent PROFILE‑1014 data. The committee concluded that, although there is some uncertainty about the long-term prognosis for this population, the exponential function is likely to be the most appropriate way to model overall survival.
## Time on treatment should be estimated using patient-level data
In its base-case model, the company estimated the duration of treatment with ceritinib and crizotinib by extrapolating the median duration of treatment from the clinical trial of each drug. The ERG explained that this differed from the company's approach to modelling progression-free survival and therefore assumes no relationship between the 2 outcomes, which is inappropriate. The committee was aware that the company's approach produced unrealistic estimates of treatment duration. The committee concluded that time on treatment should be modelled in the same way as progression-free survival, that is, using patient-level data and assuming proportional hazards (that is, a constant relative treatment effect).
# Health-related quality of life
## The company overestimated quality of life for people with progressed disease
The company estimated the quality of life associated with progressed disease using published utility values from a real-world study of patients having treatment for advanced non-small-cell lung cancer (Chouaid et al. 2013). The company calculated a weighted average of the utilities reported for people in different health states. The ERG considered that the resulting utility value of 0.641 for progressed disease was too high because the company had included irrelevant patient groups in its weighted average calculation (for example, people having second-line treatment who were progression-free). The committee concluded that the ERG's recalculated utility estimate of 0.56 for progressed disease was more appropriate than the company's estimate.
## Quality-of-life estimates should distinguish between people who continue first-line treatment after progression and people who switch treatment
The committee was aware that, for quality of life, the ERG's alternative base-case cost-effectiveness analysis distinguished between people having first-line treatment after disease progression and people switching treatment after disease progression. To do this, the ERG created an additional health state ('sustained utility on progression'). The utility value in this health state was 0.68, which the ERG calculated by using the midpoint of the progression-free utility (estimated by the company as 0.81) and the ERG's updated utility of 0.56 for the progressed disease health state (see section 3.9). The committee agreed that it was appropriate to assume a better quality-of-life benefit for people continuing treatment after disease progression than those with progressed disease who switched treatment, but noted that the ERG's estimate was not evidence-based. The clinical experts considered that this additional health state was less relevant for people in the crizotinib arm than in the ceritinib arm, because people on crizotinib are more likely to switch treatment after disease progression (see section 3.2). The committee acknowledged this, and the uncertainty around the utility value for this health state, but considered that the change to utility values in the ERG's alternative base case was appropriate for decision-making.
# Costs
## It is appropriate to exclude the cost of testing for the ALK mutation
The company did not include the cost of ALK mutation testing in its analyses because it is part of routine clinical practice at diagnosis. Written statements from experts supported the company's rationale for excluding the cost of the test. The committee concluded that it was appropriate to exclude the cost of the test.
## Costs of treatments taken after disease progression should be based on the clinical trial
The company's base-case cost-effectiveness analysis assumed that 60% of people had second-line systemic treatment, based on feedback from its clinical advisers. This was higher than reported in clinical trials, in which 35% of patients who had first-line ceritinib (in ASCEND‑4) and 43% of patients who had first-line crizotinib (in PROFILE‑1014) had active second-line treatment after disease progression. The company's justification was that the trials have limited post-progression follow‑up time and therefore more patients would have started second-line treatment after the data cut‑off for the trials. The clinical experts explained that, in practice, most people would have second-line treatment after stopping ceritinib or crizotinib. One clinical expert suggested that 70–80% of people who have had crizotinib will subsequently have ceritinib. The committee noted that the model did not include third- or fourth-line treatments, which it understood would be offered in practice. However, the ERG suggested that it was more appropriate to use data from the clinical trials to estimate the costs of post-progression treatment, to be consistent with the efficacy data in the model. Because there were no scenarios modelling costs and outcomes relating to treatment sequence, the committee concluded that post-progression treatment costs should be based on the trial data.
# Innovation
## The benefits of ceritinib are adequately captured in the model
The clinical experts considered that second-generation ALK inhibitors are an innovative class of drugs. They have a broader spectrum of activity than first-generation ALK inhibitors and may replace crizotinib as the standard of care internationally. Ceritinib is more potent than crizotinib and has a greater binding affinity to its target (the ALK protein). The company stated in its submission that these features allow a reduced dosing frequency and translate into clinically meaningful improvements in progression-free survival compared with crizotinib. The committee concluded that ceritinib may be innovative, but it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years (QALYs) and the resulting cost-effectiveness estimates.
# Cost-effectiveness estimate
## Ceritinib is recommended as a cost-effective treatment
The committee agreed with all of the changes in the ERG's alternative base-case cost-effectiveness analysis, except the use of the Gompertz model to extrapolate overall survival (see section 3.7). It agreed that the most plausible incremental cost-effectiveness ratio (ICER) was somewhere between the result of the ERG's analysis using PROFILE‑1014 to estimate crizotinib's relative efficacy and the scenario based on ALEX (with the exponential model for overall survival). The committee noted that using ALEX increased the ICER for ceritinib compared with crizotinib. When the confidential patient access schemes for both technologies were applied, the ICER for ceritinib was between £20,000 and £30,000 per QALY gained compared with crizotinib, regardless of whether the PROFILE‑1014 or ALEX data were used. NICE cannot report the exact ICERs because the patient access schemes are confidential. The committee concluded that ceritinib is a cost-effective use of NHS resources in people with untreated ALK‑positive non-small-cell lung cancer, if it is provided with the discount agreed in the patient access scheme.
# Other factors
No equality or social value judgement issues were identified.
NICE's advice about life-extending treatments for people with a short life expectancy did not apply.
|
{'Recommendations': "Ceritinib is recommended, within its marketing authorisation, as an option for untreated anaplastic lymphoma kinase (ALK)‑positive advanced non-small-cell lung cancer in adults, only if the company provides it with the discount agreed in the patient access scheme.\n\nWhy the committee made this recommendation\n\nMost people with untreated ALK‑positive advanced non-small-cell lung cancer are offered crizotinib. Chemotherapy may be offered if the person's ALK mutation status isn't known, and therefore is not a relevant comparator for ceritinib. There are no trials directly comparing ceritinib with crizotinib; the clinical trial compares ceritinib with chemotherapy.\n\nBecause the clinical trial has not finished, it is unable to show how much ceritinib prolongs life compared with chemotherapy. But it shows that ceritinib is more effective than chemotherapy at increasing the length of time people live without their disease progressing. An indirect comparison suggests that ceritinib is more effective than crizotinib. Clinical experts support using ceritinib instead of crizotinib.\n\nThe most plausible cost-effectiveness estimate for ceritinib compared with crizotinib is around what NICE normally considers acceptable. Therefore ceritinib can be recommended as an option for adults with untreated ALK‑positive advanced non-small-cell lung cancer.", 'Information about ceritinib': "Marketing authorisation indication\n\nCeritinib (Zykadia, Novartis) as monotherapy is indicated for 'the first-line treatment of adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer'.\n\nDosage in the marketing authorisation\n\nCeritinib is taken orally, without food, at the same time each day. The recommended dose is 750\xa0mg once daily. The summary of product characteristics recommends that treatment should continue as long as clinical benefit is observed.\n\nPrice\n\nA 30‑day supply of ceritinib (150\xa0capsules) costs £4,923.45 (excluding VAT; British national formulary [BNF] online [accessed October\xa02017]).\n\n\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ceritinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatment pathway and relevant comparators\n\n## Crizotinib is the only relevant comparator\n\nThe committee understood that the standard of care in England for people with confirmed anaplastic lymphoma kinase (ALK)‑positive non-small-cell lung cancer is crizotinib (a first-generation ALK inhibitor). This is followed, after the disease has progressed, by ceritinib (a second-generation ALK inhibitor). Crizotinib was the only comparator in the company's cost-effectiveness analysis. The company did not compare ceritinib with chemotherapy, stating in its submission that, in current NHS practice, most people with untreated ALK‑positive advanced non-small-cell lung cancer take crizotinib. In written statements clinical experts explained that chemotherapy is offered as the first treatment option only if ALK status has not yet been confirmed. Therefore the committee understood that people with untreated disease having chemotherapy in practice would not be eligible for ceritinib. The committee concluded that crizotinib is the only relevant comparator for ceritinib in people with untreated ALK‑positive advanced non-small-cell lung cancer.\n\n## Treatment with an ALK inhibitor may continue beyond disease progression\n\nThe summary of product characteristics for ceritinib, and the protocol for the phase\xa03 clinical trial of ceritinib (ASCEND‑4), states that treatment should continue as long as clinical benefit is observed. More than three‑quarters of patients in ASCEND‑4 had at least 1\xa0dose of ceritinib after disease progression. The clinical experts said that this reflects clinical practice. They explained when it might be appropriate to continue treatment with ALK inhibitors after disease progression, for example, if there is evidence of disease progression at only 1\xa0tumour location but otherwise the disease is well-controlled. The clinical experts also explained that they would wait until the disease has progressed at multiple sites before changing treatment, because there are limited alternative options. They said that people taking ceritinib are more likely to continue treatment beyond disease progression than people taking crizotinib. This is because the only option after ceritinib is chemotherapy; there is no clinical evidence to support giving crizotinib after ceritinib, whereas people on crizotinib can switch to ceritinib. The clinical experts suggested that in the future, as more treatment options become available, people might switch to an alternative therapy more quickly. The committee concluded that in current practice treatment with ceritinib, and to a lesser extent crizotinib, continues beyond disease progression.\n\n# Clinical effectiveness compared with chemotherapy\n\n## Ceritinib improves progression-free survival\n\nThe committee noted that ceritinib improves progression-free survival compared with chemotherapy, and that the difference between treatment arms in ASCEND‑4 was statistically significant. The median progression-free survival was 16.6\xa0months with ceritinib and 8.1\xa0months with chemotherapy in ASCEND‑4, producing a hazard ratio of 0.55 (95% confidence interval 0.42 to 0.73, p<0.0001). The committee concluded that ceritinib is associated with a significant benefit in progression-free survival compared with chemotherapy.\n\n## Survival data from the clinical trial of ceritinib are immature\n\nThe committee was aware that the overall survival data from the trial are immature and that median overall survival was not reached in the ceritinib arm. It also acknowledged the ERG's concerns that the survival results may be biased because:\n\nPatients were allowed to continue ceritinib after disease progression if clinical benefit was seen.\n\nPatients whose disease progressed while taking ceritinib could switch to other active treatments (crizotinib, docetaxel or platinum-based chemotherapy).\n\nPatients randomised to chemotherapy could switch to ceritinib when their disease progressed.The committee noted that the second-line treatments taken by patients in the trial were different to the treatments available in England, recalling that ceritinib would not be followed by crizotinib (see section\xa03.2). The committee was therefore concerned that the trial survival results might not be generalisable to current clinical practice. It acknowledged that the trial results appeared promising, noting that the difference between ceritinib and chemotherapy for overall survival was approaching statistical significance. But it agreed that it was difficult to establish the magnitude of survival benefit for ceritinib because the trial data are immature. The committee concluded that it should account for this uncertainty in its decision-making.\n\n# Indirect comparison of ceritinib and crizotinib\n\n## Ceritinib appears to be more effective than crizotinib at extending progression-free survival\n\nBecause there were no head-to-head trial data for ceritinib and crizotinib, the company did 2\xa0matching-adjusted indirect comparisons (MAIC) using the results from ASCEND‑4. The first MAIC used results from the PROFILE‑1014 trial, which compared crizotinib with chemotherapy, and the second MAIC used results from the ALEX trial, which compared crizotinib with alectinib. Both MAICs showed that ceritinib extended progression-free survival compared with crizotinib, and that the difference between treatments was statistically significant, which reflected the clinical experts' expectations. The committee understood that the results of both MAICs were subject to a high risk of bias because there was no common comparator arm in the trials being compared; the committee was aware that the MAIC method is inappropriate without a common comparator. The ERG explained that it could not be certain whether the results from each MAIC are any more reliable than the results of a naive comparison of the unadjusted trial data. The committee was aware of the issues with the MAIC, but concluded that an indirect comparison of individual trial arms was the only way to compare ceritinib and crizotinib.\n\n# Clinical evidence in the economic model\n\n## Both crizotinib clinical trials are relevant to decision-making\n\nThe company's base-case cost-effectiveness model estimated the relative efficacy of ceritinib compared with crizotinib using hazard ratios from its indirect comparison of ASCEND‑4 with PROFILE‑1014; hazard ratios informed by ALEX were included in a scenario analysis. The ERG explained that it had no preference for the results of 1\xa0indirect comparison over the other (that is, whether to consider the results based on PROFILE‑1014 or ALEX). The committee was aware that the company had used inappropriate methods in the indirect comparison with PROFILE‑1014, because it had matched the whole ASCEND‑4 population to the whole PROFILE‑1014 population instead of matching only the patients in the ceritinib treatment arms. But the committee considered that results from PROFILE‑1014 might be more relevant to clinical practice because patients continued crizotinib treatment beyond disease progression, which was not permitted in ALEX. The committee noted that both indirect comparisons resulted in a similar hazard ratio for progression-free survival and for overall survival. The ERG explained that the company's cost-effectiveness results were very sensitive to small changes in these hazard ratios. The committee concluded that it should consider cost-effectiveness results based on PROFILE‑1014 and results from ALEX in its decision-making.\n\n# Extrapolating clinical trial data in the economic model\n\n## The company's extrapolation of overall survival is appropriate\n\nThe company extrapolated overall survival in its model using the exponential function. The ERG considered that the estimates of long-term survival produced with the exponential curve (which cannot be reported because the company marked them as academic in confidence) were optimistic compared with clinical experience of ALK inhibitors and real-world data on the survival of people who have had crizotinib. The ERG suggested in its report that the Gompertz curve might be more appropriate to model overall survival. This was because it predicted a 5‑year survival rate that reflected estimates from its clinical advisers (20%), and estimates from a real-world study of first-line treatment with crizotinib (which cannot be reported because the study authors provided them in confidence). However, the company explained that recently published data from PROFILE‑1014 suggested that 56.6% of patients who had crizotinib would be alive at 4\xa0years and 44% would be alive at 5\xa0years, which supports using the exponential function to extrapolate survival in the model. The clinical experts noted that the survival rates in PROFILE‑1014 were higher than in real-world studies. They suggested that this could be because a substantial proportion of people in PROFILE‑1014 had subsequent lines of therapy, noting that survival rates have improved considerably in recent years. The clinical experts agreed that the population in PROFILE‑1014 was generalisable to clinical practice and, on balance, considered that the survival estimates from PROFILE‑1014 could be realistic. The ERG highlighted that all parametric models predicted lower survival rates than the recent PROFILE‑1014 data. The committee concluded that, although there is some uncertainty about the long-term prognosis for this population, the exponential function is likely to be the most appropriate way to model overall survival.\n\n## Time on treatment should be estimated using patient-level data\n\nIn its base-case model, the company estimated the duration of treatment with ceritinib and crizotinib by extrapolating the median duration of treatment from the clinical trial of each drug. The ERG explained that this differed from the company's approach to modelling progression-free survival and therefore assumes no relationship between the 2\xa0outcomes, which is inappropriate. The committee was aware that the company's approach produced unrealistic estimates of treatment duration. The committee concluded that time on treatment should be modelled in the same way as progression-free survival, that is, using patient-level data and assuming proportional hazards (that is, a constant relative treatment effect).\n\n# Health-related quality of life\n\n## The company overestimated quality of life for people with progressed disease\n\nThe company estimated the quality of life associated with progressed disease using published utility values from a real-world study of patients having treatment for advanced non-small-cell lung cancer (Chouaid et al. 2013). The company calculated a weighted average of the utilities reported for people in different health states. The ERG considered that the resulting utility value of 0.641 for progressed disease was too high because the company had included irrelevant patient groups in its weighted average calculation (for example, people having second-line treatment who were progression-free). The committee concluded that the ERG's recalculated utility estimate of 0.56 for progressed disease was more appropriate than the company's estimate.\n\n## Quality-of-life estimates should distinguish between people who continue first-line treatment after progression and people who switch treatment\n\nThe committee was aware that, for quality of life, the ERG's alternative base-case cost-effectiveness analysis distinguished between people having first-line treatment after disease progression and people switching treatment after disease progression. To do this, the ERG created an additional health state ('sustained utility on progression'). The utility value in this health state was 0.68, which the ERG calculated by using the midpoint of the progression-free utility (estimated by the company as 0.81) and the ERG's updated utility of 0.56 for the progressed disease health state (see section\xa03.9). The committee agreed that it was appropriate to assume a better quality-of-life benefit for people continuing treatment after disease progression than those with progressed disease who switched treatment, but noted that the ERG's estimate was not evidence-based. The clinical experts considered that this additional health state was less relevant for people in the crizotinib arm than in the ceritinib arm, because people on crizotinib are more likely to switch treatment after disease progression (see section\xa03.2). The committee acknowledged this, and the uncertainty around the utility value for this health state, but considered that the change to utility values in the ERG's alternative base case was appropriate for decision-making.\n\n# Costs\n\n## It is appropriate to exclude the cost of testing for the ALK mutation\n\nThe company did not include the cost of ALK mutation testing in its analyses because it is part of routine clinical practice at diagnosis. Written statements from experts supported the company's rationale for excluding the cost of the test. The committee concluded that it was appropriate to exclude the cost of the test.\n\n## Costs of treatments taken after disease progression should be based on the clinical trial\n\nThe company's base-case cost-effectiveness analysis assumed that 60% of people had second-line systemic treatment, based on feedback from its clinical advisers. This was higher than reported in clinical trials, in which 35% of patients who had first-line ceritinib (in ASCEND‑4) and 43% of patients who had first-line crizotinib (in PROFILE‑1014) had active second-line treatment after disease progression. The company's justification was that the trials have limited post-progression follow‑up time and therefore more patients would have started second-line treatment after the data cut‑off for the trials. The clinical experts explained that, in practice, most people would have second-line treatment after stopping ceritinib or crizotinib. One clinical expert suggested that 70–80% of people who have had crizotinib will subsequently have ceritinib. The committee noted that the model did not include third- or fourth-line treatments, which it understood would be offered in practice. However, the ERG suggested that it was more appropriate to use data from the clinical trials to estimate the costs of post-progression treatment, to be consistent with the efficacy data in the model. Because there were no scenarios modelling costs and outcomes relating to treatment sequence, the committee concluded that post-progression treatment costs should be based on the trial data.\n\n# Innovation\n\n## The benefits of ceritinib are adequately captured in the model\n\nThe clinical experts considered that second-generation ALK inhibitors are an innovative class of drugs. They have a broader spectrum of activity than first-generation ALK inhibitors and may replace crizotinib as the standard of care internationally. Ceritinib is more potent than crizotinib and has a greater binding affinity to its target (the ALK protein). The company stated in its submission that these features allow a reduced dosing frequency and translate into clinically meaningful improvements in progression-free survival compared with crizotinib. The committee concluded that ceritinib may be innovative, but it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years (QALYs) and the resulting cost-effectiveness estimates.\n\n# Cost-effectiveness estimate\n\n## Ceritinib is recommended as a cost-effective treatment\n\nThe committee agreed with all of the changes in the ERG's alternative base-case cost-effectiveness analysis, except the use of the Gompertz model to extrapolate overall survival (see section\xa03.7). It agreed that the most plausible incremental cost-effectiveness ratio (ICER) was somewhere between the result of the ERG's analysis using PROFILE‑1014 to estimate crizotinib's relative efficacy and the scenario based on ALEX (with the exponential model for overall survival). The committee noted that using ALEX increased the ICER for ceritinib compared with crizotinib. When the confidential patient access schemes for both technologies were applied, the ICER for ceritinib was between £20,000 and £30,000 per QALY gained compared with crizotinib, regardless of whether the PROFILE‑1014 or ALEX data were used. NICE cannot report the exact ICERs because the patient access schemes are confidential. The committee concluded that ceritinib is a cost-effective use of NHS resources in people with untreated ALK‑positive non-small-cell lung cancer, if it is provided with the discount agreed in the patient access scheme.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.\n\nNICE's advice about life-extending treatments for people with a short life expectancy did not apply."}
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https://www.nice.org.uk/guidance/ta500
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Evidence-based recommendations on ceritinib (Zykadia) for untreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer in adults.
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5bbd9c3a19c4aad7f149e28a946bda68f0fdd7de
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nice
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Age-related macular degeneration
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Age-related macular degeneration
This guideline covers diagnosing and managing age-related macular degeneration (AMD) in adults. It aims to improve the speed at which people are diagnosed and treated to prevent loss of sight.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Classifying age-related macular degeneration
Classify age-related macular degeneration (AMD) using table 1.
AMD classification
Definition
Normal eyes
No signs of age-related macular degeneration (AMD)
Small ('hard') drusen (less than 63 micrometres) only
Early AMD
Low risk of progression:
medium drusen (63 micrometres or more and less than 125 micrometres) or
pigmentary abnormalities
Medium risk of progression:
large drusen (125 micrometres or more) or
reticular drusen or
medium drusen with pigmentary abnormalities
High risk of progression:
large drusen (125 micrometres or more) with pigmentary abnormalities or
reticular drusen with pigmentary abnormalities or
vitelliform lesion without significant visual loss (best-corrected acuity better than 6/18) or
atrophy smaller than 175 micrometres and not involving the fovea
Late AMD (indeterminate)
Retinal pigment epithelial (RPE) degeneration and dysfunction (presence of degenerative AMD changes with subretinal or intraretinal fluid in the absence of neovascularisation)
Serous pigment epithelial detachment (PED) without neovascularisation
Late AMD (wet active)
Classic choroidal neovascularisation (CNV)
Occult (fibrovascular PED and serous PED with neovascularisation)
Mixed (predominantly or minimally classic CNV with occult CNV)
Retinal angiomatous proliferation (RAP)
Polypoidal choroidal vasculopathy (PCV)
Late AMD (dry)
Geographic atrophy (in the absence of neovascular AMD)
Significant visual loss (6/18 or worse) associated with:
dense or confluent drusen or
advanced pigmentary changes and/or atrophy or
vitelliform lesion
Late AMD (wet inactive)
Fibrous scar
Sub-foveal atrophy or fibrosis secondary to an RPE tear
Atrophy (absence or thinning of RPE and/or retina)
Cystic degeneration (persistent intraretinal fluid or tubulations unresponsive to treatment)
Note that eyes may still develop or have a recurrence of late AMD (wet active)
Do not refer to late AMD (wet inactive) as 'dry AMD'.
# Information and support
Provide people with AMD, and their family members or carers (as appropriate), with information that is:
available on an ongoing basis
relevant to the stage of the person's condition
tailored to the person's needs
delivered in a caring and sensitive fashion.Be aware of the obligation to provide accessible information as detailed in the NHS Accessible Information Standard. For more guidance on providing information to people and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services.
Provide opportunities to discuss AMD with the person. Topics to cover should include:
what AMD is and how common it is
types of AMD
causes of AMD
stopping smoking and other lifestyle advice
how AMD may progress and possible complications
the possibility of developing visual hallucinations associated with retinal dysfunction (Charles Bonnet syndrome)
vision standards for driving
tests and investigations
treatment options, including possible benefits and risks
who to contact for practical and emotional support
where the person's appointments will take place
which healthcare professionals will be responsible for the person's care
expected wait times for consultations, investigations and treatments
the benefits and entitlements available through certification and registration when sight impaired or severely sight impaired
when, where and how to seek help with vision changes (see the section on monitoring AMD)
signposting to other sources of information and support.
Provide information in accessible formats for people with AMD to take away at their first appointment, and then whenever they ask for it (see recommendation 1.2.1). The information should cover the following:
information about AMD and treatment pathways, including likely timescales
key contact details – for example, who to contact if appointments need to be altered
advice about what to do and where to go if vision deteriorates
available support (including transport and parking permits)
links to local and national support groups.
Allow enough time to discuss the person's concerns and questions about their diagnosis, treatment and prospects for their vision. Assess the person's priorities when making management decisions.
Promote peer support for people with AMD, particularly for people who are beginning intravitreal injections, who may be reassured by discussion with someone who has previously had the same treatment.
# Risk factors
If you suspect AMD, recognise that the following risk factors make it more likely that the person has AMD:
-lder age
presence of AMD in the other eye
family history of AMD
smoking
hypertension
BMI of 30 kg/m2 or higher
diet low in omega 3 and 6, vitamins, carotenoid and minerals
diet high in fat
lack of exercise.
# Diagnosis and referral
Offer fundus examination as part of the ocular examination to people presenting with changes in vision (including micropsia and metamorphopsia) or visual disturbances.
## Early AMD
Confirm a diagnosis of early AMD using slit-lamp biomicroscopic fundus examination alone.
Do not refer people with asymptomatic early AMD to hospital eye services for further diagnostic tests.
## Late AMD (dry)
Confirm a diagnosis of late AMD (dry) using slit-lamp biomicroscopic fundus examination.
Refer people with late AMD (dry) to hospital eye services only:
for certification of sight impairment or
if this is how people access low-vision services in the local pathway (see recommendation 1.6.5) or
if they develop new visual symptoms that may suggest late AMD (wet active) or
if it would help them to participate in research into new treatments for late AMD (dry).
## Late AMD (wet active)
Make an urgent referral for people with suspected late AMD (wet active) to a macula service, whether or not they report any visual impairment. The referral should normally be made within 1 working day but does not need emergency referral.
Offer optical coherence tomography (OCT) to people with suspected late AMD (wet active).
Do not offer fundus fluorescein angiography (FFA) to people with suspected late AMD (wet active) if clinical examination and OCT exclude neovascularisation.
Offer FFA to people with suspected late AMD (wet active) to confirm the diagnosis if OCT does not exclude neovascular disease.
For eyes with confirmed late AMD (wet active) for which antiangiogenic treatment is recommended (see the section on pharmacological management of AMD), offer treatment as soon as possible (within 14 days of referral to the macular service).
## Referral pathway
Commissioners and providers should agree a clear local pathway for people with AMD, which should cover:
referral from primary to secondary care, with direct referral preferred
discharge from secondary to primary care, covering ongoing management and re-referral when necessary.
# Pharmacological management of AMD
## Antiangiogenic therapies
Offer intravitreal anti-vascular endothelial growth factor (VEGF) treatment for late AMD (wet active) for eyes with visual acuity within the range specified in recommendation 1.5.6. At the time of publication (January 2018), bevacizumab did not have a UK marketing authorisation for, and is considered by the Medicines and Healthcare products Regulatory Agency (MHRA) to be an unlicensed medication in, this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the prescribing decision. Informed consent would need to be obtained and documented. See the General Medical Council's prescribing guidance: prescribing unlicensed medicines, and the MHRA's guidance on the supply of unlicensed medicinal products (specials), for further information. The guideline may inform any decision on the use of bevacizumab outside its UK marketing authorisation but does not amount to an approval of or a recommendation for such use.
Be aware that no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials considered by the guideline committee. Given the guideline committee's view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.
In eyes with visual acuity of 6/96 or worse, consider anti-VEGF treatment for late AMD (wet active) only if a benefit in the person's overall visual function is expected (for example, if the affected eye is the person's better-seeing eye).
Be aware that anti-VEGF treatment for eyes with late AMD (wet active) and visual acuity better than 6/12 is clinically effective and may be cost effective depending on the regimen used. At the time of publication (January 2018), bevacizumab did not have a UK marketing authorisation for, and is considered by the Medicines and Healthcare products Regulatory Agency (MHRA) to be an unlicensed medication in, this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the prescribing decision. Informed consent would need to be obtained and documented. See the General Medical Council's prescribing guidance: prescribing unlicensed medicines, and the MHRA's guidance on the supply of unlicensed medicinal products (specials), for further information. The guideline may inform any decision on the use of bevacizumab outside its UK marketing authorisation but does not amount to an approval of or a recommendation for such use. Given the guideline committee's view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.
Ensure intraocular injections are given by suitably trained healthcare professionals, for example:
medical specialists, such as ophthalmologists
nurse practitioners, optometrists and technicians with experience in giving intraocular injections.If the injection is delivered by someone who is not medically qualified, ensure that cover is in place to manage any ophthalmological or medical complications.
Ranibizumab, within its marketing authorisation, is recommended as an option for the treatment of wet age-related macular degeneration if:
all of the following circumstances apply in the eye to be treated:
the best-corrected visual acuity is between 6/12 and 6/96
there is no permanent structural damage to the central fovea
the lesion size is less than or equal to 12 disc areas in greatest linear dimension
there is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)and
the manufacturer provides ranibizumab with the discount agreed in the patient access scheme (as revised in 2012).
Pegaptanib is not recommended for the treatment of wet age-related macular degeneration.
People who are currently receiving pegaptanib for any lesion type should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
Aflibercept solution for injection is recommended as an option for treating wet age-related macular degeneration only if:
it is used in accordance with the recommendations for ranibizumab in NICE's technology appraisal guidance on ranibizumab and pegaptanib for the treatment of age-related macular degeneration and
the manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme.
People currently receiving aflibercept solution for injection whose disease does not meet the criteria in recommendation 1.5.9 should be able to continue treatment until they and their clinician consider it appropriate to stop.
Do not offer photodynamic therapy alone for late AMD (wet active).
## Adjunctive therapies
Do not offer photodynamic therapy as an adjunct to anti-VEGF as first-line treatment for late AMD (wet active).
Only offer photodynamic therapy as an adjunct to anti-VEGF as second-line treatment for late AMD (wet active) in the context of a randomised controlled trial.
Do not offer intravitreal corticosteroids as an adjunct to anti-VEGF for late AMD (wet active).
## Switching and stopping antiangiogenic treatment for late AMD (wet)
Consider switching anti-VEGF treatment for people with late AMD (wet active) if there are practical reasons for doing so (for example, if a different medicine can be given in a regimen the person prefers), but be aware that clinical benefits are likely to be limited.
Consider observation without giving anti-VEGF treatment if the disease appears stable (in this event, see the sections on monitoring and self-monitoring).
Consider stopping anti-VEGF treatment if the eye develops severe, progressive loss of visual acuity despite treatment as recommended in the section on antiangiogenic therapies.
Stop anti-VEGF treatment if the eye develops late AMD (wet inactive) with no prospect of functional improvement.
Ensure that patients are actively involved in all decisions about the stopping or switching of treatment (see the section on information and support).
# Non-pharmacological management of AMD
## Strategies to slow the progression of AMD
Do not offer thermal laser therapy (for example, argon, diode) for treating drusen in people with early AMD.
## Supporting people with AMD and visual impairment
Be aware that people with AMD are at an increased risk of depression. Identify and manage the depression according to the NICE guideline on depression in adults with a chronic physical health problem.
Be aware that many people with AMD have other significant comorbidities. For guidance on optimising care for adults with multiple long-term conditions, see the NICE guideline on multimorbidity.
Offer certification of visual impairment to all people with AMD as soon as they become eligible, even if they are still receiving active treatment.
Consider referring people with AMD causing visual impairment to low-vision services.
Consider a group-based rehabilitation programme in addition to a low-vision service to promote independent living for people with AMD.
Consider eccentric viewing training for people with central vision loss in both eyes.
# Monitoring AMD
Do not routinely monitor people with early AMD or late AMD (dry) through hospital eye services.
Advise people with late AMD (dry), or people with AMD who have been discharged from hospital eye services to:
self-monitor their AMD
consult their eye-care professional as soon as possible if their vision changes (see recommendation 1.7.5)
continue to attend routine sight-tests with their community optometrist.
For people being monitored for late AMD (wet inactive), review both eyes at their monitoring appointments.
## Self-monitoring
Discuss self-monitoring with people with AMD, and explain the strategies available.
Advise people with AMD to report any new symptoms or changes in the following to their eye-care professional as soon as possible:
blurred or grey patch in their vision
straight lines appearing distorted
-bjects appearing smaller than normal.
Encourage and support people with AMD who may lack confidence to self-monitor their symptoms.
If people are not able to self-manage their AMD, discuss AMD monitoring techniques with their family members or carers (as appropriate).
## Monitoring for late AMD (wet active)
Offer people with late AMD (wet active) ongoing monitoring with OCT for both eyes.
Offer fundus examination or colour photography if OCT appearances are stable, but:
there is a decline in visual acuity or
the person reports a decline in visual function.
Consider FFA to identify unrecognised neovascularisation if OCT appearances are stable, but:
there is a decline in visual acuity or
the person reports a decline in visual function.
If OCT results suggest macular abnormalities but the abnormalities are not responding to treatment, think about:
using alternative imaging
alternative diagnoses.
# Terms used in this guideline
## Low vision
People with low vision have visual impairments that cause restriction in their everyday lives and that cannot be corrected by surgery, medicine, or glasses or contact lenses. This definition includes, but is not limited to, those who are registered as sight impaired or severely sight impaired. It can include blurred vision, blind spots or tunnel vision. A low-vision service provides a range of services for people with low vision to enable them to make use of their eyesight to achieve maximum potential.
## Hospital eye services
Services set in secondary care providing diagnosis or treatment of the eye or vision-related conditions.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of recommendations for research are detailed in the full guideline.
# Strategies to slow the progression of age-related macular degeneration (AMD)
What is the effectiveness of antioxidant and zinc supplements on AMD disease progression for people with early AMD at high risk of progression in the context of a randomised controlled trial?
## Why this is important
Age-related eye disease study (AREDS 2001) examined the effect of antioxidant supplementation on AMD progression using the AREDS formation, which included beta carotene, vitamin E, vitamin C and zinc. Although the study showed some beneficial effects of the combined antioxidant supplementation in a subgroup of participants, the effects of each of the formula components on AMD progression were unclear. Additionally, 1 of the ingredients (beta carotene) in the AREDS 2001 formulation is associated with a possible risk of lung cancer among smokers. The AREDS research group introduced a new formulation that excluded beta carotene in the AREDS2 study, but the effect of AREDS2 formulation on AMD disease progression is unknown because of a complicated study design involving secondary randomisation and no placebo control. Therefore, a well-conducted randomised trial would provide an evidence base for the benefits and risks of individual components of the antioxidant supplements, and provide the ability to establish the treatment effect of antioxidant supplementation (the AREDS2 formula) on AMD progression by comparing AREDS2 formula with no treatment (for instance normal diet).
# Organisational models for AMD diagnosis and management
What is the long-term effectiveness, in terms of patient-relevant outcomes including visual acuity and quality of life, of different models of care that aim to reduce time from initial presentation to referral, diagnosis and treatment?
## Why this is important
There is robust evidence showing that visual loss is linked with delays to diagnosis and/or treatment. However, there is a lack of evidence evaluating the impact of any particular model of care/services in reducing any of the time intervals throughout the referral and treatment process, or the subsequent influence of different models of care on peoples' visual acuity and quality of life. A well-conducted trial would, therefore, provide the evidence base to assess the long-term effectiveness of different organisational models on referral, diagnosis and treatment for people with late AMD (wet active).
# Stopping rules for antiangiogenic treatment for late AMD (wet)
When should anti-vascular endothelial growth factor (VEGF) treatment be suspended or stopped in people with late AMD (wet)?
## Why this is important
Anti-VEGF treatment is associated with inconvenience, risk of adverse events and – especially when aflibercept or ranibizumab is used – substantial costs. People typically receive anti-VEGF for extended periods, and it is unclear whether it is always beneficial. After successful treatment, the disease can become sufficiently dormant that treatment could be safely suspended. After ineffective treatment, there may be no benefit in continuing to treat eyes with advanced damage. The committee agreed that this gap in evidence could be addressed by a 2‑stage research strategy. Observational research (for example, using registries recording administration of anti-VEGF and relevant outcomes) should be undertaken to establish the point at which the benefits of continuing treatment are unclear. This would involve eyes in which disease has responded well to treatment, and eyes in which pathological appearances or visual acuity suggest that disease is not responding to antiangiogenic treatment. This research should then be used to establish a protocol for suspending or stopping treatment. The protocol would be assessed in a non-inferiority randomised controlled trial (RCT) in which participants would be randomised to protocol-dependent stopping rules or usual care (continued treatment at clinician discretion). The committee agreed that the first step would be necessary to fulfil the ethical requirements of an RCT, as no consensus currently exists about the point(s) at which it may be safe to stop treatment.
# Frequency of monitoring
What is the long-term cost effectiveness, in terms of patient-relevant outcomes including best-corrected visual acuity and quality of life, of different review frequencies/strategies for people at risk of progression to late AMD (wet active)?
## Why this is important
There is currently no evidence on the different frequencies for monitoring people with AMD. This means that it is not possible to identify an optimum monitoring strategy for people at different stages of AMD, leading to uncertainty in how to correctly manage treatment for individuals or how to configure eye-care services to support patients. A study of the needs of people at risk of progression to late AMD (wet active) to identify the optimum review arrangements would remove this uncertainty. Trials would need to measure visual outcomes and health service resource use to measure the trade-offs between the optimal management of people at risk of disease progression in relation to the use of resource.
# Self-monitoring strategies
Does earlier detection of the incidence of late AMD (wet active) by self-monitoring in people diagnosed with early AMD, indeterminate AMD or late AMD (dry) lead to earlier treatment and better long-term outcomes?
## Why this is important
A review of the evidence demonstrated that self-monitoring interventions result in earlier diagnosis for people with late AMD (wet active). However, the evidence failed to demonstrate that earlier diagnosis would result in improvements in long-term outcomes such as visual acuity, and also failed to capture potential negative effects of self-monitoring (including the potential for increased anxiety). A study could be carried out to follow up a cohort of people diagnosed with early, indeterminate or late AMD (dry) to the time when the diagnosis of late AMD (wet active) is established. Comparisons would include time to diagnosis of late AMD (wet active), time to treatment, long-term visual acuity and participants' quality of life. This would help to establish the association between early detection and early treatment plus good long-term vision outcome. It would also help any such positive effects to be weighed against the potential for harm.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice webpages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
Age-related macular degeneration (AMD) is the term given to ageing changes without any other obvious cause that occurs in the central area of the retina (macula), sometimes with new blood vessel formation (wet AMD). It is the most common form of macular degeneration.
AMD is a painless condition that generally leads to the gradual impairment of vision, but it can sometimes cause a rapid reduction in vision. It predominantly affects the central vision, which is used for reading and recognising faces. Normal macular ageing changes are a common incidental finding on a routine visit to the optometrist, but AMD may also be detected this way before it is symptomatic, or people may present with difficulty in performing daily activities such as driving, reading and recognising faces.
Various ways of classifying AMD have been proposed. This guideline considers the best approach and recommends that a distinction is drawn between 'early' and 'late' disease. Within 'late' disease, distinction should be drawn between disease that is 'wet active' (neovascular lesions that may benefit from treatment), 'wet inactive' (neovascular disease with irreversible structural damage) and 'dry' (non-neovascular disease, including geographic atrophy). An additional category – late AMD (indeterminate) – is introduced to reflect rarer subtypes. For more details, see the age-related macular degeneration classification table.
The consequences of this condition for vision can be severe. AMD is the most common cause of visual impairment in the developed world, and the Royal National Institute of Blind People (RNIB) reports that AMD is the most common cause of certification for vision impairment. In an Australian cohort study of people with early stage AMD, the risk of progression to intermediate or advanced AMD within 5 years was 17%. However, early AMD is not always significantly progressive because 83% did not progress and AMD lesions appeared to have improved and regressed in 8% of people.
The prevalence of late AMD in the UK among people aged 50 years or over is 2.4% (from a meta-analysis applied to UK 2007–09 population data). This increases to 4.8% in people aged 65 years or over, and 12.2% in people aged 80 years or over. The same study found the prevalence of geographic atrophy to be 1.3 to 6.7%, and the prevalence of neovascular AMD to be 1.2 to 6.3%. Estimates indicate that around 39,800 people develop neovascular AMD in the UK each year; given a total UK population of 60 million, this equates to 663 new cases per million per year.
There has been a significant increase in hospital activity in England for episodes with a primary diagnosis of AMD, from less than 10,000 episodes in the years 2005/06 to over 75,000 episodes in the years 2013/14. The most common primary procedure administered in hospital to people with a primary diagnosis of macular degeneration involves intravitreal injection. The cost of aflibercept and ranibizumab, medicines for the treatment of late AMD (wet active), is significant. In 2015/16, ranibizumab was second and aflibercept was fourth in the list of medicines with positive NICE technology appraisals on which the NHS spent most money. Between them, they accounted for a total of around £450 million expended (although some of these costs relate to use for other licensed indications).
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Classifying age-related macular degeneration\n\nClassify age-related macular degeneration (AMD) using table\xa01.\n\nAMD classification\n\nDefinition\n\nNormal eyes\n\nNo signs of age-related macular degeneration (AMD)\n\nSmall ('hard') drusen (less than 63\xa0micrometres) only\n\nEarly AMD\n\nLow risk of progression:\n\nmedium drusen (63\xa0micrometres or more and less than 125\xa0micrometres) or\n\npigmentary abnormalities\n\nMedium risk of progression:\n\nlarge drusen (125\xa0micrometres or more) or\n\nreticular drusen or\n\nmedium drusen with pigmentary abnormalities\n\nHigh risk of progression:\n\nlarge drusen (125\xa0micrometres or more) with pigmentary abnormalities or\n\nreticular drusen with pigmentary abnormalities or\n\nvitelliform lesion without significant visual loss (best-corrected acuity better than 6/18) or\n\natrophy smaller than 175\xa0micrometres and not involving the fovea\n\nLate AMD (indeterminate)\n\nRetinal pigment epithelial (RPE) degeneration and dysfunction (presence of degenerative AMD changes with subretinal or intraretinal fluid in the absence of neovascularisation)\n\nSerous pigment epithelial detachment (PED) without neovascularisation\n\nLate AMD (wet active)\n\nClassic choroidal neovascularisation (CNV)\n\nOccult (fibrovascular PED and serous PED with neovascularisation)\n\nMixed (predominantly or minimally classic CNV with occult CNV)\n\nRetinal angiomatous proliferation (RAP)\n\nPolypoidal choroidal vasculopathy (PCV)\n\nLate AMD (dry)\n\nGeographic atrophy (in the absence of neovascular AMD)\n\nSignificant visual loss (6/18 or worse) associated with:\n\ndense or confluent drusen or\n\nadvanced pigmentary changes and/or atrophy or\n\nvitelliform lesion\n\nLate AMD (wet inactive)\n\nFibrous scar\n\nSub-foveal atrophy or fibrosis secondary to an RPE tear\n\nAtrophy (absence or thinning of RPE and/or retina)\n\nCystic degeneration (persistent intraretinal fluid or tubulations unresponsive to treatment)\n\nNote that eyes may still develop or have a recurrence of late AMD (wet active)\n\nDo not refer to late AMD (wet inactive) as 'dry AMD'.\n\n# Information and support\n\nProvide people with AMD, and their family members or carers (as appropriate), with information that is:\n\navailable on an ongoing basis\n\nrelevant to the stage of the person's condition\n\ntailored to the person's needs\n\ndelivered in a caring and sensitive fashion.Be aware of the obligation to provide accessible information as detailed in the NHS Accessible Information Standard. For more guidance on providing information to people and discussing their preferences with them, see the NICE guideline on patient experience in adult NHS services.\n\nProvide opportunities to discuss AMD with the person. Topics to cover should include:\n\nwhat AMD is and how common it is\n\ntypes of AMD\n\ncauses of AMD\n\nstopping smoking and other lifestyle advice\n\nhow AMD may progress and possible complications\n\nthe possibility of developing visual hallucinations associated with retinal dysfunction (Charles Bonnet syndrome)\n\nvision standards for driving\n\ntests and investigations\n\ntreatment options, including possible benefits and risks\n\nwho to contact for practical and emotional support\n\nwhere the person's appointments will take place\n\nwhich healthcare professionals will be responsible for the person's care\n\nexpected wait times for consultations, investigations and treatments\n\nthe benefits and entitlements available through certification and registration when sight impaired or severely sight impaired\n\nwhen, where and how to seek help with vision changes (see the section\xa0on monitoring AMD)\n\nsignposting to other sources of information and support.\n\nProvide information in accessible formats for people with AMD to take away at their first appointment, and then whenever they ask for it (see recommendation\xa01.2.1). The information should cover the following:\n\ninformation about AMD and treatment pathways, including likely timescales\n\nkey contact details – for example, who to contact if appointments need to be altered\n\nadvice about what to do and where to go if vision deteriorates\n\navailable support (including transport and parking permits)\n\nlinks to local and national support groups.\n\nAllow enough time to discuss the person's concerns and questions about their diagnosis, treatment and prospects for their vision. Assess the person's priorities when making management decisions.\n\nPromote peer support for people with AMD, particularly for people who are beginning intravitreal injections, who may be reassured by discussion with someone who has previously had the same treatment.\n\n# Risk factors\n\nIf you suspect AMD, recognise that the following risk factors make it more likely that the person has AMD:\n\nolder age\n\npresence of AMD in the other eye\n\nfamily history of AMD\n\nsmoking\n\nhypertension\n\nBMI of 30\xa0kg/m2 or higher\n\ndiet low in omega 3\xa0and\xa06, vitamins, carotenoid and minerals\n\ndiet high in fat\n\nlack of exercise.\n\n# Diagnosis and referral\n\nOffer fundus examination as part of the ocular examination to people presenting with changes in vision (including micropsia and metamorphopsia) or visual disturbances.\n\n## Early AMD\n\nConfirm a diagnosis of early AMD using slit-lamp biomicroscopic fundus examination alone.\n\nDo not refer people with asymptomatic early AMD to hospital eye services for further diagnostic tests.\n\n## Late AMD (dry)\n\nConfirm a diagnosis of late AMD (dry) using slit-lamp biomicroscopic fundus examination.\n\nRefer people with late AMD (dry) to hospital eye services only:\n\nfor certification of sight impairment or\n\nif this is how people access low-vision services in the local pathway (see recommendation\xa01.6.5) or\n\nif they develop new visual symptoms that may suggest late AMD (wet active) or\n\nif it would help them to participate in research into new treatments for late AMD (dry).\n\n## Late AMD (wet active)\n\nMake an urgent referral for people with suspected late AMD (wet active) to a macula service, whether or not they report any visual impairment. The referral should normally be made within 1\xa0working day but does not need emergency referral.\n\nOffer optical coherence tomography (OCT) to people with suspected late AMD (wet active).\n\nDo not offer fundus fluorescein angiography (FFA) to people with suspected late AMD (wet active) if clinical examination and OCT exclude neovascularisation.\n\nOffer FFA to people with suspected late AMD (wet active) to confirm the diagnosis if OCT does not exclude neovascular disease.\n\nFor eyes with confirmed late AMD (wet active) for which antiangiogenic treatment is recommended (see the section\xa0on pharmacological management of AMD), offer treatment as soon as possible (within 14\xa0days of referral to the macular service).\n\n## Referral pathway\n\nCommissioners and providers should agree a clear local pathway for people with AMD, which should cover:\n\nreferral from primary to secondary care, with direct referral preferred\n\ndischarge from secondary to primary care, covering ongoing management and re-referral when necessary.\n\n# Pharmacological management of AMD\n\n## Antiangiogenic therapies\n\nOffer intravitreal anti-vascular endothelial growth factor (VEGF) treatment for late AMD (wet active) for eyes with visual acuity within the range specified in recommendation\xa01.5.6. At the time of publication (January\xa02018), bevacizumab did not have a UK marketing authorisation for, and is considered by the Medicines and Healthcare products Regulatory Agency (MHRA) to be an unlicensed medication in, this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the prescribing decision. Informed consent would need to be obtained and documented. See the General Medical Council's prescribing guidance: prescribing unlicensed medicines, and the MHRA's guidance on the supply of unlicensed medicinal products (specials), for further information. The guideline may inform any decision on the use of bevacizumab outside its UK marketing authorisation but does not amount to an approval of or a recommendation for such use.\n\nBe aware that no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials considered by the guideline committee. Given the guideline committee's view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.\n\nIn eyes with visual acuity of 6/96 or worse, consider anti-VEGF treatment for late AMD (wet active) only if a benefit in the person's overall visual function is expected (for example, if the affected eye is the person's better-seeing eye).\n\nBe aware that anti-VEGF treatment for eyes with late AMD (wet active) and visual acuity better than 6/12 is clinically effective and may be cost effective depending on the regimen used. At the time of publication (January 2018), bevacizumab did not have a UK marketing authorisation for, and is considered by the Medicines and Healthcare products Regulatory Agency (MHRA) to be an unlicensed medication in, this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the prescribing decision. Informed consent would need to be obtained and documented. See the General Medical Council's prescribing guidance: prescribing unlicensed medicines, and the MHRA's guidance on the supply of unlicensed medicinal products (specials), for further information. The guideline may inform any decision on the use of bevacizumab outside its UK marketing authorisation but does not amount to an approval of or a recommendation for such use. Given the guideline committee's view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs.\n\nEnsure intraocular injections are given by suitably trained healthcare professionals, for example:\n\nmedical specialists, such as ophthalmologists\n\nnurse practitioners, optometrists and technicians with experience in giving intraocular injections.If the injection is delivered by someone who is not medically qualified, ensure that cover is in place to manage any ophthalmological or medical complications.\n\nRanibizumab, within its marketing authorisation, is recommended as an option for the treatment of wet age-related macular degeneration if:\n\nall of the following circumstances apply in the eye to be treated:\n\n\n\nthe best-corrected visual acuity is between 6/12 and 6/96\n\nthere is no permanent structural damage to the central fovea\n\nthe lesion size is less than or equal to 12\xa0disc areas in greatest linear dimension\n\nthere is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)and\n\n\n\nthe manufacturer provides ranibizumab with the discount agreed in the patient access scheme (as revised in\xa02012). [This recommendation is from NICE's technology appraisal guidance on ranibizumab and pegaptanib for the treatment of age-related macular degeneration.]\n\nPegaptanib is not recommended for the treatment of wet age-related macular degeneration. [This recommendation is from NICE's technology appraisal guidance on ranibizumab and pegaptanib for the treatment of age-related macular degeneration.]\n\nPeople who are currently receiving pegaptanib for any lesion type should have the option to continue therapy until they and their clinicians consider it appropriate to stop. [This recommendation is from NICE's technology appraisal guidance on ranibizumab and pegaptanib for the treatment of age-related macular degeneration.]\n\nAflibercept solution for injection is recommended as an option for treating wet age-related macular degeneration only if:\n\nit is used in accordance with the recommendations for ranibizumab in NICE's technology appraisal guidance\xa0on ranibizumab and pegaptanib for the treatment of age-related macular degeneration [re-issued in May 2012 (see recommendation\xa01.5.6)] and\n\nthe manufacturer provides aflibercept solution for injection with the discount agreed in the patient access scheme. [This recommendation is adapted from NICE's technology appraisal guidance on aflibercept solution for injection for treating wet age-related macular degeneration.]\n\nPeople currently receiving aflibercept solution for injection whose disease does not meet the criteria in\xa0recommendation 1.5.9 should be able to continue treatment until they and their clinician consider it appropriate to stop. [This recommendation is from NICE's technology appraisal guidance on aflibercept solution for injection for treating wet age-related macular degeneration.]\n\nDo not offer photodynamic therapy alone for late AMD (wet active).\n\n## Adjunctive therapies\n\nDo not offer photodynamic therapy as an adjunct to anti-VEGF as first-line treatment for late AMD (wet active).\n\nOnly offer photodynamic therapy as an adjunct to anti-VEGF as second-line treatment for late AMD (wet active) in the context of a randomised controlled trial.\n\nDo not offer intravitreal corticosteroids as an adjunct to anti-VEGF for late AMD (wet active).\n\n## Switching and stopping antiangiogenic treatment for late AMD (wet)\n\nConsider switching anti-VEGF treatment for people with late AMD (wet active) if there are practical reasons for doing so (for example, if a different medicine can be given in a regimen the person prefers), but be aware that clinical benefits are likely to be limited.\n\nConsider observation without giving anti-VEGF treatment if the disease appears stable (in this event, see the sections on monitoring and self-monitoring).\n\nConsider stopping anti-VEGF treatment if the eye develops severe, progressive loss of visual acuity despite treatment as recommended in the section on antiangiogenic therapies.\n\nStop anti-VEGF treatment if the eye develops late AMD (wet inactive) with no prospect of functional improvement.\n\nEnsure that patients are actively involved in all decisions about the stopping or switching of treatment (see the section on information and support).\n\n# Non-pharmacological management of AMD\n\n## Strategies to slow the progression of AMD\n\nDo not offer thermal laser therapy (for example, argon, diode) for treating drusen in people with early AMD.\n\n## Supporting people with AMD and visual impairment\n\nBe aware that people with AMD are at an increased risk of depression. Identify and manage the depression according to the NICE guideline on depression in adults with a chronic physical health problem.\n\nBe aware that many people with AMD have other significant comorbidities. For guidance on optimising care for adults with multiple long-term conditions, see the NICE guideline on multimorbidity.\n\nOffer certification of visual impairment to all people with AMD as soon as they become eligible, even if they are still receiving active treatment.\n\nConsider referring people with AMD causing visual impairment to low-vision services.\n\nConsider a group-based rehabilitation programme in addition to a low-vision service to promote independent living for people with AMD.\n\nConsider eccentric viewing training for people with central vision loss in both eyes.\n\n# Monitoring AMD\n\nDo not routinely monitor people with early AMD or late AMD (dry) through hospital eye services.\n\nAdvise people with late AMD (dry), or people with AMD who have been discharged from hospital eye services to:\n\nself-monitor their AMD\n\nconsult their eye-care professional as soon as possible if their vision changes (see recommendation\xa01.7.5)\n\ncontinue to attend routine sight-tests with their community optometrist.\n\nFor people being monitored for late AMD (wet inactive), review both eyes at their monitoring appointments.\n\n## Self-monitoring\n\nDiscuss self-monitoring with people with AMD, and explain the strategies available.\n\nAdvise people with AMD to report any new symptoms or changes in the following to their eye-care professional as soon as possible:\n\nblurred or grey patch in their vision\n\nstraight lines appearing distorted\n\nobjects appearing smaller than normal.\n\nEncourage and support people with AMD who may lack confidence to self-monitor their symptoms.\n\nIf people are not able to self-manage their AMD, discuss AMD monitoring techniques with their family members or carers (as appropriate).\n\n## Monitoring for late AMD (wet active)\n\nOffer people with late AMD (wet active) ongoing monitoring with OCT for both eyes.\n\nOffer fundus examination or colour photography if OCT appearances are stable, but:\n\nthere is a decline in visual acuity or\n\nthe person reports a decline in visual function.\n\nConsider FFA to identify unrecognised neovascularisation if OCT appearances are stable, but:\n\nthere is a decline in visual acuity or\n\nthe person reports a decline in visual function.\n\nIf OCT results suggest macular abnormalities but the abnormalities are not responding to treatment, think about:\n\nusing alternative imaging\n\nalternative diagnoses.\n\n# Terms used in this guideline\n\n## Low vision\n\nPeople with low vision have visual impairments that cause restriction in their everyday lives and that cannot be corrected by surgery, medicine, or glasses or contact lenses. This definition includes, but is not limited to, those who are registered as sight impaired or severely sight impaired. It can include blurred vision, blind spots or tunnel vision. A low-vision service provides a range of services for people with low vision to enable them to make use of their eyesight to achieve maximum potential.\n\n## Hospital eye services\n\nServices set in secondary care providing diagnosis or treatment of the eye or vision-related conditions.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of recommendations for research are detailed in the full guideline.\n\n# Strategies to slow the progression of age-related macular degeneration (AMD)\n\nWhat is the effectiveness of antioxidant and zinc supplements on AMD disease progression for people with early AMD at high risk of progression in the context of a randomised controlled trial?\n\n## Why this is important\n\nAge-related eye disease study (AREDS\xa02001) examined the effect of antioxidant supplementation on AMD progression using the AREDS formation, which included beta\xa0carotene, vitamin\xa0E, vitamin\xa0C and zinc. Although the study showed some beneficial effects of the combined antioxidant supplementation in a subgroup of participants, the effects of each of the formula components on AMD progression were unclear. Additionally, 1\xa0of the ingredients (beta\xa0carotene) in the AREDS\xa02001 formulation is associated with a possible risk of lung cancer among smokers. The AREDS research group introduced a new formulation that excluded beta\xa0carotene in the AREDS2 study, but the effect of AREDS2 formulation on AMD disease progression is unknown because of a complicated study design involving secondary randomisation and no placebo control. Therefore, a well-conducted randomised trial would provide an evidence base for the benefits and risks of individual components of the antioxidant supplements, and provide the ability to establish the treatment effect of antioxidant supplementation (the AREDS2 formula) on AMD progression by comparing AREDS2 formula with no treatment (for instance normal diet).\n\n# Organisational models for AMD diagnosis and management\n\nWhat is the long-term effectiveness, in terms of patient-relevant outcomes including visual acuity and quality of life, of different models of care that aim to reduce time from initial presentation to referral, diagnosis and treatment?\n\n## Why this is important\n\nThere is robust evidence showing that visual loss is linked with delays to diagnosis and/or treatment. However, there is a lack of evidence evaluating the impact of any particular model of care/services in reducing any of the time intervals throughout the referral and treatment process, or the subsequent influence of different models of care on peoples' visual acuity and quality of life. A well-conducted trial would, therefore, provide the evidence base to assess the long-term effectiveness of different organisational models on referral, diagnosis and treatment for people with late AMD (wet active).\n\n# Stopping rules for antiangiogenic treatment for late AMD (wet)\n\nWhen should anti-vascular endothelial growth factor (VEGF) treatment be suspended or stopped in people with late AMD (wet)?\n\n## Why this is important\n\nAnti-VEGF treatment is associated with inconvenience, risk of adverse events and – especially when aflibercept or ranibizumab is used – substantial costs. People typically receive anti-VEGF for extended periods, and it is unclear whether it is always beneficial. After successful treatment, the disease can become sufficiently dormant that treatment could be safely suspended. After ineffective treatment, there may be no benefit in continuing to treat eyes with advanced damage. The committee agreed that this gap in evidence could be addressed by a 2‑stage research strategy. Observational research (for example, using registries recording administration of anti-VEGF and relevant outcomes) should be undertaken to establish the point at which the benefits of continuing treatment are unclear. This would involve eyes in which disease has responded well to treatment, and eyes in which pathological appearances or visual acuity suggest that disease is not responding to antiangiogenic treatment. This research should then be used to establish a protocol for suspending or stopping treatment. The protocol would be assessed in a non-inferiority randomised controlled trial (RCT) in which participants would be randomised to protocol-dependent stopping rules or usual care (continued treatment at clinician discretion). The committee agreed that the first step would be necessary to fulfil the ethical requirements of an RCT, as no consensus currently exists about the point(s) at which it may be safe to stop treatment.\n\n# Frequency of monitoring\n\nWhat is the long-term cost effectiveness, in terms of patient-relevant outcomes including best-corrected visual acuity and quality of life, of different review frequencies/strategies for people at risk of progression to late AMD (wet active)?\n\n## Why this is important\n\nThere is currently no evidence on the different frequencies for monitoring people with AMD. This means that it is not possible to identify an optimum monitoring strategy for people at different stages of AMD, leading to uncertainty in how to correctly manage treatment for individuals or how to configure eye-care services to support patients. A study of the needs of people at risk of progression to late AMD (wet active) to identify the optimum review arrangements would remove this uncertainty. Trials would need to measure visual outcomes and health service resource use to measure the trade-offs between the optimal management of people at risk of disease progression in relation to the use of resource.\n\n# Self-monitoring strategies\n\nDoes earlier detection of the incidence of late AMD (wet active) by self-monitoring in people diagnosed with early AMD, indeterminate AMD or late AMD (dry) lead to earlier treatment and better long-term outcomes?\n\n## Why this is important\n\nA review of the evidence demonstrated that self-monitoring interventions result in earlier diagnosis for people with late AMD (wet active). However, the evidence failed to demonstrate that earlier diagnosis would result in improvements in long-term outcomes such as visual acuity, and also failed to capture potential negative effects of self-monitoring (including the potential for increased anxiety). A study could be carried out to follow up a cohort of people diagnosed with early, indeterminate or late AMD (dry) to the time when the diagnosis of late AMD (wet active) is established. Comparisons would include time to diagnosis of late AMD (wet active), time to treatment, long-term visual acuity and participants' quality of life. This would help to establish the association between early detection and early treatment plus good long-term vision outcome. It would also help any such positive effects to be weighed against the potential for harm.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See NICE's into practice webpages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': "Age-related macular degeneration (AMD) is the term given to ageing changes without any other obvious cause that occurs in the central area of the retina (macula), sometimes with new blood vessel formation (wet AMD). It is the most common form of macular degeneration.\n\nAMD is a painless condition that generally leads to the gradual impairment of vision, but it can sometimes cause a rapid reduction in vision. It predominantly affects the central vision, which is used for reading and recognising faces. Normal macular ageing changes are a common incidental finding on a routine visit to the optometrist, but AMD may also be detected this way before it is symptomatic, or people may present with difficulty in performing daily activities such as driving, reading and recognising faces.\n\nVarious ways of classifying AMD have been proposed. This guideline considers the best approach and recommends that a distinction is drawn between 'early' and 'late' disease. Within 'late' disease, distinction should be drawn between disease that is 'wet active' (neovascular lesions that may benefit from treatment), 'wet inactive' (neovascular disease with irreversible structural damage) and 'dry' (non-neovascular disease, including geographic atrophy). An additional category – late AMD (indeterminate) – is introduced to reflect rarer subtypes. For more details, see the age-related macular degeneration classification table.\n\nThe consequences of this condition for vision can be severe. AMD is the most common cause of visual impairment in the developed world, and the Royal National Institute of Blind People (RNIB) reports that AMD is the most common cause of certification for vision impairment. In an Australian cohort study of people with early stage AMD, the risk of progression to intermediate or advanced AMD within 5\xa0years was\xa017%. However, early AMD is not always significantly progressive because 83% did not progress and AMD lesions appeared to have improved and regressed in 8% of people.\n\nThe prevalence of late AMD in the UK among people aged 50\xa0years or over is\xa02.4% (from a meta-analysis applied to UK 2007–09 population data). This increases to 4.8% in people aged 65\xa0years or over, and 12.2% in people aged 80\xa0years or over. The same study found the prevalence of geographic atrophy to be 1.3 to 6.7%, and the prevalence of neovascular AMD to be 1.2 to 6.3%. Estimates indicate that around 39,800\xa0people develop neovascular AMD in the UK each year; given a total UK population of 60\xa0million, this equates to 663\xa0new cases per million per year.\n\nThere has been a significant increase in hospital activity in England for episodes with a primary diagnosis of AMD, from less than 10,000\xa0episodes in the years 2005/06 to over 75,000\xa0episodes in the years\xa02013/14. The most common primary procedure administered in hospital to people with a primary diagnosis of macular degeneration involves intravitreal injection. The cost of aflibercept and ranibizumab, medicines for the treatment of late AMD (wet active), is significant. In 2015/16, ranibizumab was second and aflibercept was fourth in the list of medicines with positive NICE technology appraisals on which the NHS spent most money. Between them, they accounted for a total of around £450\xa0million expended (although some of these costs relate to use for other licensed indications)."}
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https://www.nice.org.uk/guidance/ng82
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This guideline covers diagnosing and managing age-related macular degeneration (AMD) in adults. It aims to improve the speed at which people are diagnosed and treated to prevent loss of sight.
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0e4293dab516ad2b167f15d3944684a82da2592f
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nice
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Golimumab for treating non-radiographic axial spondyloarthritis
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Golimumab for treating non-radiographic axial spondyloarthritis
Evidence-based recommendations on golimumab (Simponi) for severe non-radiographic axial spondyloarthritis. This drug is for adults who have tried nonsteroidal anti-inflammatory drugs (NSAIDs), but they have not worked.
# Recommendations
Golimumab is recommended, within its marketing authorisation, as an option for treating severe non-radiographic axial spondyloarthritis in adults whose disease has responded inadequately to, or who cannot tolerate, nonsteroidal anti-inflammatory drugs.
If patients and their clinicians consider golimumab to be one of a range of suitable treatments, including adalimumab, etanercept and certolizumab pegol, the least expensive (taking into account administration costs and patient access schemes) should be chosen.
Assess the response to golimumab 12 weeks after the start of treatment. Continue treatment only if there is clear evidence of response, defined as:
a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2 or more units and
a reduction in the spinal pain visual analogue scale (VAS) score by 2 cm or more.
When using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.
Why the committee made these recommendations
NICE already recommends adalimumab, etanercept and certolizumab pegol for treating non-radiographic axial spondyloarthritis. An indirect comparison shows that golimumab provides similar overall health benefits to these drugs. The acquisition costs of golimumab are the same as or less than those of adalimumab and etanercept, and in the longer term, would be similar to those of certolizumab pegol.
Because it is has similar overall health benefits and costs to adalimumab, etanercept and certolizumab pegol, golimumab is recommended for treating non-radiographic axial spondyloarthritis in the NHS.# The technology
# Marketing authorisation
Golimumab ((Simponi, Merck Sharp & Dohme) is indicated for the treatment of 'adults with severe, active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C‑reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs)'.
# Recommended dose and schedule
Golimumab is administered by subcutaneous injection. The recommended dosage is 50 mg once a month, on the same date each month. The summary of product characteristics recommends that continued golimumab therapy should be reconsidered if there is no evidence of therapeutic benefit within 12 to 14 weeks of starting treatment (that is, after 3 to 4 doses). For patients with a body weight greater than 100 kg whose disease does not respond adequately after 3 or 4 doses (50 mg each), the summary of product characteristics states that increasing the dosage of golimumab to 100 mg once a month may be considered. If there is still no evidence of therapeutic benefit after 3 to 4 additional doses of 100 mg, continued golimumab therapy should be reconsidered.
# Price
The list price of golimumab is £762.97 for a 50‑mg pre‑filled disposable injection and £1,525.94 for a 100‑mg pre‑filled disposable injection (excluding VAT; British national formulary online ). Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100‑mg dose of golimumab available to the NHS at the same cost as the 50‑mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Assuming a patient has 50 mg every month, the annual cost of treatment with golimumab is estimated at £9,156. Because of the patient access scheme, this cost would remain the same for patients with a body weight greater than 100 kg whose disease does not respond adequately to 50 mg per month and who subsequently have monthly doses of 100 mg.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Comparators
## The comparison of golimumab with adalimumab, etanercept and certolizumab pegol is appropriate
NICE has already produced technology appraisal guidance on adalimumab, etanercept and certolizumab pegol for non-radiographic axial spondyloarthritis, which recommends that if more than one treatment is suitable then the least expensive treatment (taking into consideration costs and patient access schemes) should be used. The company presented a cost comparison case, in which it proposed that:
the overall health benefits associated with golimumab are similar to or greater than those associated with adalimumab, etanercept and certolizumab pegol
the acquisition cost of golimumab is similar to or lower than those associated with adalimumab, etanercept and certolizumab pegol.The committee understood that treatment with adalimumab, etanercept and certolizumab pegol is standard for non-radiographic axial spondyloarthritis in the NHS. The committee concluded that it was appropriate for the company to compare golimumab with adalimumab, etanercept and certolizumab pegol.
# Clinical effectiveness
## Golimumab is clinically effective compared with placebo
The company presented results of the GO‑AHEAD trial which compared golimumab with placebo in 198 people with non-radiographic axial spondyloarthritis. Golimumab showed statistically significant improvement in all outcomes at 16 weeks (Assessment in Spondyloarthritis International Society 20, ASAS 40, Bath Ankylosing Spondylitis Disease Activity Index 50 and ASAS partial response) compared with placebo in the full analysis set and in the population with objective markers of active disease (abnormal MRI and/or elevated C‑reactive protein at baseline). The committee agreed that golimumab is a clinically effective treatment compared with placebo.
## Golimumab has similar clinical effectiveness to adalimumab, etanercept and certolizumab pegol
The company presented a fixed-effects network meta-analysis, which compared the clinical effectiveness outcomes of golimumab with those of adalimumab, etanercept and certolizumab pegol (all assessed at 12 weeks). The network meta-analysis included the pivotal trial for golimumab (GO‑AHEAD) and the same trials that were assessed for the NICE technology appraisal of adalimumab, etanercept and certolizumab pegol for the comparator treatments. The network meta-analysis showed a statistically significant benefit for golimumab compared with placebo for all outcomes (ASAS 20, ASAS 40 and BASDAI 50). The clinical effectiveness of golimumab was similar to adalimumab, etanercept and certolizumab pegol for Bath Ankylosing Spondylitis Functional Index (BASFI), BASDAI and Bath Ankylosing Spondylitis Metrology Index (BASMI) scores. Golimumab was statistically significantly superior to etanercept and adalimumab for change from baseline in BASFI score, etanercept for change from baseline in BASDAI score, and adalimumab for change from baseline in BASMI score. The ERG's view was that a random-effects network meta-analysis would have been more suitable for capturing variation between the trials. The point estimates in the ERG's random-effects network meta-analysis were similar to those in the company's submission, but had wider confidence intervals. The committee considered the impact of using 12‑week outcomes for golimumab in the network meta-analysis (for consistency with the comparator treatments) compared with the 16‑week outcomes reported in the GO‑AHEAD trial. An additional analysis conducted by the ERG showed that the network meta-analysis results were robust regardless of whether 12- or 16‑week outcomes were used. The committee concluded that the clinical effectiveness of golimumab was likely to be similar to those of the comparators.
# Adverse events
## Adverse events with golimumab are likely to be similar to those with adalimumab, etanercept and certolizumab pegol
The adverse event profile for golimumab is well established and is similar to those of adalimumab, etanercept and certolizumab pegol. Patients receiving the 100‑mg dose of golimumab may or may not have a greater risk of adverse events than those receiving the 50‑mg dose. The committee concluded that the adverse events associated with golimumab were likely to be similar to those associated with adalimumab, etanercept and certolizumab pegol when treating non-radiographic axial spondyloarthritis.
# Overall health benefits
## Golimumab provides similar overall health benefits to adalimumab, etanercept and certolizumab pegol
The committee agreed that the network meta-analysis provided by the company was suitable for the purpose of decision-making. It considered the clinical effectiveness and adverse event profiles of golimumab to be similar to those of the comparator treatments and that, therefore, golimumab was likely to provide similar overall health benefits.
# Resource use
## It is appropriate to assume that all resource use and costs other than drug acquisition costs are identical across golimumab and the comparators
The company assumed that resource use and costs including drug administration, treatment initiation and monitoring, management of adverse events and long-term disease management are identical across golimumab and the comparators. The committee agreed with the company's assumption.
# Cost comparison results
## Golimumab meets the criteria for a successful cost comparison
The company presented results of a cost comparison analysis for the first and subsequent years of treatment. It showed that the acquisition cost of golimumab is the same as that of adalimumab in the first and subsequent years of treatment (£9,156), and lower than the cost of etanercept in the first and subsequent years (£9,295). The acquisition cost of certolizumab pegol in the first year (£5,720) is lower than that of golimumab because of a patient access scheme which provides the first 10 vials of certolizumab pegol at no cost, but its cost in subsequent years (£9,295) is higher than that of golimumab. The committee concluded that the criteria for a positive cost comparison were met, because:
the overall health benefits of golimumab are similar to those of adalimumab, etanercept and certolizumab pegol
the acquisition costs of golimumab are similar to or lower than those of adalimumab, etanercept and certolizumab pegol (taking into account that although certolizumab pegol is approximately half the cost of golimumab in the first year, the subsequent annual cost in the long term is higher than that of golimumab).The committee therefore recommended golimumab as a cost-effective use of NHS resources for treating non-radiographic axial spondyloarthritis in adults.
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{'Recommendations': 'Golimumab is recommended, within its marketing authorisation, as an option for treating severe non-radiographic axial spondyloarthritis in adults whose disease has responded inadequately to, or who cannot tolerate, nonsteroidal anti-inflammatory drugs.\n\nIf patients and their clinicians consider golimumab to be one of a range of suitable treatments, including adalimumab, etanercept and certolizumab pegol, the least expensive (taking into account administration costs and patient access schemes) should be chosen.\n\nAssess the response to golimumab 12\xa0weeks after the start of treatment. Continue treatment only if there is clear evidence of response, defined as:\n\na reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pre-treatment value or by 2\xa0or more units and\n\na reduction in the spinal pain visual analogue scale (VAS) score by 2\xa0cm or more.\n\nWhen using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.\n\nWhy the committee made these recommendations\n\nNICE already recommends adalimumab, etanercept and certolizumab pegol for treating non-radiographic axial spondyloarthritis. An indirect comparison shows that golimumab provides similar overall health benefits to these drugs. The acquisition costs of golimumab are the same as or less than those of adalimumab and etanercept, and in the longer term, would be similar to those of certolizumab pegol.\n\nBecause it is has similar overall health benefits and costs to adalimumab, etanercept and certolizumab pegol, golimumab is recommended for treating non-radiographic axial spondyloarthritis in the NHS.', 'The technology': "# Marketing authorisation\n\nGolimumab ((Simponi, Merck Sharp & Dohme) is indicated for the treatment of 'adults with severe, active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C‑reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs)'.\n\n# Recommended dose and schedule\n\nGolimumab is administered by subcutaneous injection. The recommended dosage is 50\xa0mg once a month, on the same date each month. The summary of product characteristics recommends that continued golimumab therapy should be reconsidered if there is no evidence of therapeutic benefit within 12\xa0to 14\xa0weeks of starting treatment (that is, after 3\xa0to 4\xa0doses). For patients with a body weight greater than 100\xa0kg whose disease does not respond adequately after 3\xa0or 4\xa0doses (50\xa0mg each), the summary of product characteristics states that increasing the dosage of golimumab to 100\xa0mg once a month may be considered. If there is still no evidence of therapeutic benefit after 3\xa0to 4\xa0additional doses of 100\xa0mg, continued golimumab therapy should be reconsidered.\n\n# Price\n\nThe list price of golimumab is £762.97 for a 50‑mg pre‑filled disposable injection and £1,525.94 for a 100‑mg pre‑filled disposable injection (excluding VAT; British national formulary [BNF] online [accessed September 2017]). Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100‑mg dose of golimumab available to the NHS at the same cost as the 50‑mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Assuming a patient has 50\xa0mg every month, the annual cost of treatment with golimumab is estimated at £9,156. Because of the patient access scheme, this cost would remain the same for patients with a body weight greater than 100\xa0kg whose disease does not respond adequately to 50\xa0mg per month and who subsequently have monthly doses of 100\xa0mg.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Comparators\n\n## The comparison of golimumab with adalimumab, etanercept and certolizumab pegol is appropriate\n\nNICE has already produced technology appraisal guidance on adalimumab, etanercept and certolizumab pegol for non-radiographic axial spondyloarthritis, which recommends that if more than one treatment is suitable then the least expensive treatment (taking into consideration costs and patient access schemes) should be used. The company presented a cost comparison case, in which it proposed that:\n\nthe overall health benefits associated with golimumab are similar to or greater than those associated with adalimumab, etanercept and certolizumab pegol\n\nthe acquisition cost of golimumab is similar to or lower than those associated with adalimumab, etanercept and certolizumab pegol.The committee understood that treatment with adalimumab, etanercept and certolizumab pegol is standard for non-radiographic axial spondyloarthritis in the NHS. The committee concluded that it was appropriate for the company to compare golimumab with adalimumab, etanercept and certolizumab pegol.\n\n# Clinical effectiveness\n\n## Golimumab is clinically effective compared with placebo\n\nThe company presented results of the GO‑AHEAD trial which compared golimumab with placebo in 198\xa0people with non-radiographic axial spondyloarthritis. Golimumab showed statistically significant improvement in all outcomes at 16\xa0weeks (Assessment in Spondyloarthritis International Society [ASAS]\xa020, ASAS\xa040, Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]\xa050 and ASAS partial response) compared with placebo in the full analysis set and in the population with objective markers of active disease (abnormal MRI and/or elevated C‑reactive protein [CRP] at baseline). The committee agreed that golimumab is a clinically effective treatment compared with placebo.\n\n## Golimumab has similar clinical effectiveness to adalimumab, etanercept and certolizumab pegol\n\nThe company presented a fixed-effects network meta-analysis, which compared the clinical effectiveness outcomes of golimumab with those of adalimumab, etanercept and certolizumab pegol (all assessed at 12\xa0weeks). The network meta-analysis included the pivotal trial for golimumab (GO‑AHEAD) and the same trials that were assessed for the NICE technology appraisal of adalimumab, etanercept and certolizumab pegol for the comparator treatments. The network meta-analysis showed a statistically significant benefit for golimumab compared with placebo for all outcomes (ASAS\xa020, ASAS\xa040 and BASDAI\xa050). The clinical effectiveness of golimumab was similar to adalimumab, etanercept and certolizumab pegol for Bath Ankylosing Spondylitis Functional Index (BASFI), BASDAI and Bath Ankylosing Spondylitis Metrology Index (BASMI) scores. Golimumab was statistically significantly superior to etanercept and adalimumab for change from baseline in BASFI score, etanercept for change from baseline in BASDAI score, and adalimumab for change from baseline in BASMI score. The ERG's view was that a random-effects network meta-analysis would have been more suitable for capturing variation between the trials. The point estimates in the ERG's random-effects network meta-analysis were similar to those in the company's submission, but had wider confidence intervals. The committee considered the impact of using 12‑week outcomes for golimumab in the network meta-analysis (for consistency with the comparator treatments) compared with the 16‑week outcomes reported in the GO‑AHEAD trial. An additional analysis conducted by the ERG showed that the network meta-analysis results were robust regardless of whether 12- or 16‑week outcomes were used. The committee concluded that the clinical effectiveness of golimumab was likely to be similar to those of the comparators.\n\n# Adverse events\n\n## Adverse events with golimumab are likely to be similar to those with adalimumab, etanercept and certolizumab pegol\n\nThe adverse event profile for golimumab is well established and is similar to those of adalimumab, etanercept and certolizumab pegol. Patients receiving the 100‑mg dose of golimumab may or may not have a greater risk of adverse events than those receiving the 50‑mg dose. The committee concluded that the adverse events associated with golimumab were likely to be similar to those associated with adalimumab, etanercept and certolizumab pegol when treating non-radiographic axial spondyloarthritis.\n\n# Overall health benefits\n\n## Golimumab provides similar overall health benefits to adalimumab, etanercept and certolizumab pegol\n\nThe committee agreed that the network meta-analysis provided by the company was suitable for the purpose of decision-making. It considered the clinical effectiveness and adverse event profiles of golimumab to be similar to those of the comparator treatments and that, therefore, golimumab was likely to provide similar overall health benefits.\n\n# Resource use\n\n## It is appropriate to assume that all resource use and costs other than drug acquisition costs are identical across golimumab and the comparators\n\nThe company assumed that resource use and costs including drug administration, treatment initiation and monitoring, management of adverse events and long-term disease management are identical across golimumab and the comparators. The committee agreed with the company's assumption.\n\n# Cost comparison results\n\n## Golimumab meets the criteria for a successful cost comparison\n\nThe company presented results of a cost comparison analysis for the first and subsequent years of treatment. It showed that the acquisition cost of golimumab is the same as that of adalimumab in the first and subsequent years of treatment (£9,156), and lower than the cost of etanercept in the first and subsequent years (£9,295). The acquisition cost of certolizumab pegol in the first year (£5,720) is lower than that of golimumab because of a patient access scheme which provides the first 10\xa0vials of certolizumab pegol at no cost, but its cost in subsequent years (£9,295) is higher than that of golimumab. The committee concluded that the criteria for a positive cost comparison were met, because:\n\nthe overall health benefits of golimumab are similar to those of adalimumab, etanercept and certolizumab pegol\n\nthe acquisition costs of golimumab are similar to or lower than those of adalimumab, etanercept and certolizumab pegol (taking into account that although certolizumab pegol is approximately half the cost of golimumab in the first year, the subsequent annual cost in the long term is higher than that of golimumab).The committee therefore recommended golimumab as a cost-effective use of NHS resources for treating non-radiographic axial spondyloarthritis in adults."}
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https://www.nice.org.uk/guidance/ta497
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Evidence-based recommendations on golimumab (Simponi) for severe non-radiographic axial spondyloarthritis. This drug is for adults who have tried nonsteroidal anti-inflammatory drugs (NSAIDs), but they have not worked.
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c017b79a827a37cd0b344e2510fa419c5be1c432
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nice
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Autism spectrum disorder in under 19s: recognition, referral and diagnosis
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Autism spectrum disorder in under 19s: recognition, referral and diagnosis
This guideline covers recognising and diagnosing autism spectrum disorder in children and young people from birth up to 19 years. It also covers referral. It aims to improve the experience of children, young people and those who care for them.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Local pathway for recognition, referral and diagnostic assessment of possible autism
A local autism multi-agency strategy group should be set up, with managerial, commissioner and clinical representation from child health and mental health services, education, social care, parent and carer service users, and the voluntary sector.
The local autism strategy group should appoint a lead professional to be responsible for the local autism pathway for recognition, referral and diagnosis of children and young people. The aims of the group should include:
improving early recognition of autism by raising awareness of the features suggesting possible autism through multi-agency training (see tables 1 to 3 in the appendix)
making sure the relevant professionals (healthcare, social care, education and voluntary sector) are aware of the local autism pathway and how to access diagnostic services
supporting the smooth transition to adult services for young people going through the diagnostic pathway
ensuring data collection and audit of the pathway takes place.
In each area a multidisciplinary group (the autism team) should be set up. The core membership should include a:
paediatrician and/or child and adolescent psychiatrist
speech and language therapist
psychologist with training and experience in working with autistic children and young people.
The autism team should either include or have regular access to the following professionals if they are not already in the team:
paediatrician or paediatric neurologist
child and adolescent psychiatrist
psychologist with training and experience complementary to the psychologist in the core team
-ccupational therapist.
Consider including in the autism team (or arranging access for the team to) other relevant professionals who may be able to contribute to the autism diagnostic assessment. For example, a specialist health visitor or nurse, specialist teacher or social worker.
The autism team should have the skills and competencies to:
carry out an autism diagnostic assessment
communicate with autistic children and young people and children and young people who may be autistic, and with their parents and carers, and sensitively share the diagnosis with them.
Autism team members should:
provide advice to professionals about whether to refer children and young people for autism diagnostic assessments
decide on the assessment needs of those referred or when referral to another service will be needed
carry out the autism diagnostic assessment
share the outcome of the autism diagnostic assessment with parents and carers, and with children and young people if appropriate
with parent or carer consent and, if appropriate, the consent of the child or young person, share information from the autism diagnostic assessment directly with relevant services, for example through a school visit by an autism team member
-ffer information to children, young people and parents and carers about appropriate services and support.
Provide a single point of referral for access to the autism team.
The autism team should either have the skills (or have access to professionals that have the skills) needed to carry out an autism diagnostic assessment, for children and young people with special circumstances including:
coexisting conditions such as severe visual and hearing impairments, motor disorders including cerebral palsy, severe learning (intellectual) disabilities, complex language disorders or complex mental health disorders
looked-after children and young people.
If young people present at the time of transition to adult services, the autism team should consider carrying out the autism diagnostic assessment jointly with the adult autism team, regardless of the young person's intellectual ability.
# Recognising children and young people who may be autistic
Consider the possibility of autism if there are concerns about development or behaviour, but be aware that there may be other explanations for individual signs and symptoms.
Always take parents' or carers' concerns and, if appropriate, the child's or young person's concerns, about behaviour or development seriously, even if these are not shared by others.
When considering the possibility of autism and whether to refer a child or young person to the autism team, be critical about your professional competence and seek advice from a colleague if in doubt about the next step.
To help identify the features suggesting possible autism, use tables 1 to 3 (see the appendix). Do not rule out autism if the exact features described in the tables are not evident; they should be used for guidance, but do not include all possible manifestations of autism.
When considering the possibility of autism, be aware that:
autism may be under-recognised in girls leading to underdiagnosis
signs and symptoms should be seen in the context of the child's or young person's overall development
signs and symptoms will not always have been recognised by parents, carers, children or young people themselves or by other professionals
when older children or young people present for the first time with possible autism, signs or symptoms may have previously been masked by the child or young person's coping mechanisms and/or a supportive environment
it is necessary to take account of cultural variation, but do not assume that language delay is accounted for because English is not the family's first language or by early hearing difficulties
autism may be missed in children or young people with a learning (intellectual) disability
autism may be missed in children or young people who are verbally able
important information about early development may not be readily available for some children and young people, for example looked-after children and those in the criminal justice system
signs and symptoms may not be accounted for by disruptive home experiences or parental or carer mental or physical illness.
When considering the possibility of autism, ask about the child or young person's use and understanding of their first language.
Do not rule out autism because of:
good eye contact, smiling and showing affection to family members
reported pretend play or normal language milestones
difficulties appearing to resolve after a needs-based intervention (such as a supportive structured learning environment)
a previous assessment that concluded that there was no autism, if new information becomes available.
Discuss developmental or behavioural concerns about a child or young person with parents or carers, and the child or young person themselves if appropriate. Discuss sensitively the possible causes, which may include autism, emphasising that there may be many explanations for the child's or young person's behaviour.
Be aware that if parents or carers or the child or young person themselves have not suspected a developmental or behavioural condition, raising the possibility may cause distress, and that:
it may take time for them to come to terms with the concern
they may not share the concern.
Take time to listen to parents or carers and, if appropriate, the child or young person, to discuss concerns and agree any actions to follow including referral.
# Referring children and young people to the autism team
Refer children younger than 3 years to the autism team if there is regression in language or social skills.
Refer first to a paediatrician or paediatric neurologist (who can refer to the autism team if necessary) children and young people:
-lder than 3 years with regression in language
-f any age with regression in motor skills.
Consider referring children and young people to the autism team if you are concerned about possible autism on the basis of reported or observed features suggesting possible autism (see tables 1 to 3 in the appendix). Take account of:
the severity and duration of the features suggesting possible autism
the extent to which the features suggesting possible autism are present across different settings (for example, home and school)
the impact of the features suggesting possible autism on the child or young person and on their family
the level of parental or carer concern and, if appropriate, the concerns of the child or young person
factors associated with an increased prevalence of autism (see box 1)
the likelihood of an alternative diagnosis.
## Box 1 Factors associated with an increased prevalence of autism
A sibling with autism.
Birth defects associated with central nervous system malformation and/or dysfunction, including cerebral palsy.
Gestational age less than 35 weeks.
Parental schizophrenia-like psychosis or affective disorder.
Maternal use of sodium valproate in pregnancy.
A learning (intellectual) disability.
Attention deficit hyperactivity disorder.
Neonatal encephalopathy or epileptic encephalopathy, including infantile spasms.
Chromosomal disorders such as Down's syndrome.
Genetic disorders such as fragile X.
Muscular dystrophy.
Neurofibromatosis.
Tuberous sclerosis.
If you have concerns about development or behaviour but are not sure whether the signs and/or symptoms suggest autism, consider:
consulting a member of the autism team who can provide advice to help you decide if a referral to the autism team is necessary
referring to another service. That service can then refer to the autism team if necessary.
Be aware that tools to identify children and young people with an increased likelihood of autism may be useful in gathering information about features suggesting possible autism in a structured way but are not essential and should not be used to make or rule out a diagnosis of autism. Also be aware that:
a positive score on tools to identify an increased likelihood of autism may support a decision to refer but can also be for reasons other than autism
a negative score does not rule out autism.
When referring children and young people to the autism team, include in the referral letter the following information:
reported information from parents, carers and professionals about signs and/or symptoms of concern
your own observations of the signs and/or symptoms.
When referring children and young people to the autism team, include in the referral letter the following information, if available:
antenatal and perinatal history
developmental milestones
factors associated with an increased prevalence of autism (see box 1 in recommendation 1.3.3)
relevant medical history and investigations
information from previous assessments.
Explain to parents or carers and, if appropriate, the child or young person, what will happen on referral to the autism team or another service.
If you do not think concerns are sufficient to prompt a referral, consider a period of watchful waiting. If you remain concerned about autism, reconsider your referral decision.
If the parents or carers or if appropriate, the child or young person, prefer not to be referred to the autism team, consider a period of watchful waiting. If you remain concerned about autism, reconsider referral.
If a concern has been raised but there are no features suggesting possible autism or other reasons to suspect autism, use professional judgment to decide what to do next.
For a short explanation of why the committee updated box 1 in recommendation 1.3.3 and how this might affect practice, see the rationale and impact section on factors associated with an increased prevalence of autism .
Full details of the evidence and the committee's discussion are in evidence review A: factors and neurodevelopmental disorders that increase the likelihood of a diagnosis of autism spectrum disorder.
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# After referral to the autism team
When a child or young person is referred to the autism team, at least one member of the autism team should consider whether to carry out:
an autism diagnostic assessment and/or
an alternative assessment.
Carry out an autism diagnostic assessment if there is regression in language or social skills in a child younger than 3 years.
Refer first to a paediatrician or paediatric neurologist (if this has not already happened) children or young people:
-lder than 3 years with regression in language
-f any age with regression in motor skills.The paediatrician or paediatric neurologist can refer back to the autism team if necessary.
When deciding whether to carry out an autism diagnostic assessment, take account of the following (unless the child is under 3 years and has regression in language or social skills – see recommendation 1.4.2):
the severity and duration of the signs and/or symptoms
the extent to which the signs and/or symptoms are present across different settings (for example, home and school)
the impact of the signs and/or symptoms on the child or young person and on their family or carer
the level of parental or carer concern, and if appropriate the concerns of the child or young person
factors associated with an increased prevalence of autism (see box 1 in recommendation 1.3.3)
the likelihood of an alternative diagnosis.
If there is insufficient information to decide whether an autism diagnostic assessment is needed, gather any available information from healthcare professionals. With consent from parents or carers and, if appropriate, the child or young person, seek information from schools or other agencies.
If there is uncertainty about whether an autism diagnostic assessment is needed after information has been gathered, offer a consultation to gather information directly from the child or young person and their family or carers.
Once it has been decided to carry out an autism diagnostic assessment, with consent from parents or carers (and the child or young person if appropriate):
seek a report from the pre-school or school if one has not already been made available
gather any additional health or social care information, including results from hearing and vision assessments.
Avoid repeated information gathering and assessments by efficient communication between professionals and agencies.
# Autism diagnostic assessment for children and young people
Start the autism diagnostic assessment within 3 months of the referral to the autism team.
A case coordinator in the autism team should be identified for every child or young person who is to have an autism diagnostic assessment.
The autism case coordinator should:
act as a single point of contact for the parents or carers and, if appropriate, the child or young person being assessed, through whom they can communicate with the rest of the autism team
keep parents or carers and, if appropriate, the child or young person, up-to-date about the likely time and sequence of assessments
arrange the provision of information and support for parents, carers, children and young people as directed by the autism team
gather information relevant to the autism diagnostic assessment (see recommendation 1.4.7).
Discuss with the parents or carers and, if appropriate, the child or young person, how information should be shared throughout the autism diagnostic assessment, including communicating the outcome of the assessment. Take into account, for example, the child or young person's age and ability to understand.
Include in every autism diagnostic assessment:
detailed questions about parent's or carer's concerns and, if appropriate, the child's or young person's concerns
details of the child's or young person's experiences of home life, education and social care
a developmental history, focusing on developmental and behavioural features consistent with ICD-11 or DSM-5 criteria (consider using an autism-specific tool to gather this information)
assessment (through interaction with and observation of the child or young person) of social and communication skills and behaviours, focusing on features consistent with ICD-11 or DSM-5 criteria (consider using an autism-specific tool to gather this information)
a medical history, including prenatal, perinatal and family history, and past and current health conditions
a physical examination
consideration of the differential diagnosis (see recommendation 1.5.7)
systematic assessment for conditions that may coexist with autism (see recommendation 1.5.15)
development of a profile of the child's or young person's strengths, skills, impairments and needs that can be used to create a needs-based management plan, taking into account family and educational context.
communication of assessment findings to the parent or carer and, if appropriate, the child or young person.
Perform a general physical examination and look specifically for:
skin stigmata of neurofibromatosis or tuberous sclerosis using a Wood's light
signs of injury, for example self-harm or child maltreatment (see the NICE guidelines on self-harm in over 8s and child maltreatment)
congenital anomalies and dysmorphic features including macrocephaly or microcephaly.
Consider the following differential diagnoses for autism and whether specific assessments are needed to help interpret the autism history and observations:
Neurodevelopmental disorders:
specific language delay or disorder
a learning (intellectual) disability or global developmental delay
developmental coordination disorder (DCD).
Mental and behavioural disorders:
attention deficit hyperactivity disorder (ADHD)
mood disorder
anxiety disorder
attachment disorders
-ppositional defiant disorder (ODD)
conduct disorder
-bsessive compulsive disorder (OCD)
psychosis.
Conditions in which there is developmental regression:
Rett syndrome
epileptic encephalopathy.
Other conditions:
severe hearing impairment
severe visual impairment
maltreatment
selective mutism.
Consider which assessments are needed to construct a profile for each child or young person, for example:
intellectual ability and learning style
academic skills
speech, language and communication
fine and gross motor skills
adaptive behaviour (including self-help skills)
mental and emotional health (including self-esteem)
physical health and nutrition
sensory sensitivities
behaviour likely to affect day-to-day functioning and social participation
socialisation skills.
If there are discrepancies during the autism diagnostic assessment between reported signs or symptoms and the findings of the autism observation in the clinical setting, consider:
gathering additional information from other sources and/or
carrying out further autism‑specific observations in different settings, such as the school, nursery, other social setting or at home.
Use information from all sources, together with clinical judgment, to diagnose autism based on ICD-11 or DSM-5 criteria.
Do not rely on any autism-specific diagnostic tool alone to diagnose autism.
Be aware that in some children and young people there may be uncertainty about the diagnosis of autism, particularly in:
children younger than 24 months
children or young people with a developmental age of less than 18 months
children or young people for whom there is a lack of available information about their early life (for example, some looked-after or adopted children)
-lder teenagers
children or young people with a complex coexisting mental health disorder (for example ADHD, conduct disorder, a possible attachment disorder), sensory impairment (for example severe hearing or visual impairment), or a motor disorder such as cerebral palsy.
Be aware that some children and young people will have features of behaviour that are seen in the autism spectrum but do not reach the ICD‑11 or DSM-5 diagnostic criteria for definitive diagnosis. Based on their profile, consider referring to appropriate services.
If the outcome of the autism diagnostic assessment clearly indicates that the child or young person does not have autism, consider referring them to appropriate services based on their profile.
Consider whether the child or young person may have any of the following as a coexisting condition, and if suspected carry out appropriate assessments and referrals:
Mental and behaviour problems and disorders:
ADHD
anxiety disorders and phobias
mood disorders
-ppositional defiant behaviour
tics or Tourette syndrome
OCD
self-injurious behaviour.
Neurodevelopmental problems and disorders:
global delay or a learning (intellectual) disability
motor coordination problems or DCD
academic learning problems, for example in literacy or numeracy
speech and language disorder.
Medical or genetic problems and disorders:
epilepsy and epileptic encephalopathy
chromosome disorders
genetic abnormalities, including fragile X
tuberous sclerosis
muscular dystrophy
neurofibromatosis.
Functional problems and disorders:
feeding problems, including restricted diets
urinary incontinence or enuresis
constipation, altered bowel habit, faecal incontinence or encopresis
sleep disturbances
vision or hearing impairment.
Be aware that in children and young people with communication difficulties it may be difficult to recognise functional problems or mental health problems.
# After the autism diagnostic assessment
If there is uncertainty after the autism diagnostic assessment about the diagnosis, consider keeping the child or young person under review, taking into account any new information.
If any of the following apply after assessment, consider obtaining a second opinion (including referral to a specialised tertiary autism team if necessary):
continued uncertainty about the diagnosis
disagreement about the diagnosis within the autism team
disagreement with parents or carers or, if appropriate, the child or young person, about the diagnosis
a lack of local access to particular skills and competencies needed to reach a diagnosis in a child or young person who has a complex coexisting condition, such as a severe sensory or motor impairment or mental health problem
a lack of response as expected to any therapeutic interventions provided to the child or young person.
During the autism diagnostic assessment, consider any potential risk of harm to, and from, the child or young person and take appropriate action.
# Medical investigations
Do not routinely perform any medical investigations as part of an autism diagnostic assessment, but consider the following in individual circumstances and based on physical examination, clinical judgment and the child or young person's profile:
genetic tests, as recommended by your regional genetics centre, if there are specific dysmorphic features, congenital anomalies and/or evidence of a learning (intellectual) disability
electroencephalography if there is suspicion of epilepsy (see the NICE guideline on epilepsies).
# Communicating the results from the autism diagnostic assessment
After the autism diagnostic assessment discuss the findings, including the profile, sensitively, in person and without delay with the parents or carers and, if appropriate, the child or young person. Explain the basis of conclusions even if the diagnosis of autism was not reached.
Use recognised good practice when sharing a diagnosis with parents, carers, children and young people.
For children and young people with a diagnosis of autism, discuss and share information with parents or carers and, if appropriate, the child or young person, to explain:
what autism is
how autism is likely to affect the child or young person's development and function.
Provide parents or carers and, if appropriate, the child or young person, with a written report of the autism diagnostic assessment. This should explain the findings of the assessment and the reasons for the conclusions drawn.
Share information, including the written report of the diagnostic assessment, with the GP.
With parental or carer consent and, if appropriate, the consent of the child or young person, share information with key professionals involved in the child's or young person's care, including those in education and social care.
With parental or carer consent and, if appropriate, the consent of the child or young person, make the profile available to professionals in education (for example, through a school visit by a member of the autism team) and, if appropriate, social care. This is so it can contribute to the child or young person's individual education plan and needs-based management plan.
For children and young people with a diagnosis of autism, offer a follow-up appointment with an appropriate member of the autism team within 6 weeks of the end of the autism assessment for further discussion (for example about the conclusions of the assessment and the implications for the child or young person).
For children and young people with a diagnosis of autism, discuss with parents or carers the risk of autism occurring in siblings and future children.
# Information and support for families and carers
Provide individual information on support available locally for parents, carers, and autistic children and young people, according to the family's needs. This may include:
contact details for:
local and national support organisations (who may provide, for example, an opportunity to meet other families with experience of autism, or information about specific courses for parents and carers and/or young people)
-rganisations that can provide advice on welfare benefits
-rganisations that can provide information on educational support and social care
information to help prepare for the future, for example transition to adult services. # Recommendations for research
The guideline committee has made the following recommendations for research
# Training professionals
Does training professionals to recognise features suggesting possible autism lead to earlier assessment of needs and earlier diagnosis (and by implication reduce morbidity/improve health outcomes) among children and young people compared with no training?
## Why this is important
Successful training of healthcare professionals in the Netherlands has been shown to improve their ability, confidence and skills in identifying children or young people who need an autism diagnostic assessment. A fully trained workforce can identify the number of autistic children or young people and provide accurate information both for planning individual care and at a strategic level for planning appropriate service provision.
If training improves earlier recognition and referral, this could be of particular benefit to at-risk groups for which there is evidence that autism is currently under-diagnosed, such as girls, and children and young people:
with parents of lower educational attainment
with English as an additional language
with sensory impairments
with a learning (intellectual) disability.
Before extending training to a wider population, it is important to better understand its effectiveness in terms of age, number of children and young people at referral, and time between parents' concerns and autism diagnosis.
# Gathering information in schools or nurseries
Does routine additional information from educational settings (such as nursery or school) improve accuracy in diagnosing autism among children or young people up to the age of 19 compared with signs and symptoms alone?
## Why this is important
Autism is primarily characterised by difficulties in social reciprocity, social communication and social understanding, along with rigid and repetitive ways of thinking and behaving. Diagnostic accuracy may be improved by interpreting information about how the child or young person presents in social settings away from the home and immediate family.
Nurseries or schools are the most obvious settings from which such information may be collected. However, the degree to which information from teachers and schools helps in accurate diagnosis has not been well tested.
# Additional assessments
Do additional assessments (for IQ, language ability and motor ability) improve accuracy in diagnosing autism among preschool children (younger than 5 years) compared with signs and symptoms alone?
## Why this is important
Current NHS practice varies widely with regard to the proportion of children having an autism diagnostic assessment who also routinely undergo assessments of IQ, language and motor abilities.
As a consequence we do not know whether such assessments aid more accurate diagnosis of autism. This is particularly important if a differential or coexisting diagnostic decision is called for and/or if there may be specific management implications.
Studies may prove valuable to parents in terms of explaining some of the child's behaviours, leading to more targeted and informed support for the child, parents and the wider family.
# Comparative genomic hybridisation array
What is the effectiveness and acceptability of comparative genomic hybridisation (CGH) array compared with current genetic testing in autistic children and young people?
## Why this is important
Recent scientific advances have led to the detection of genetic abnormalities that may partly or wholly explain why a child or young person has autism. As the tests become increasingly sophisticated (for example, using methods such as CGH array that detect more subtle variations), more genetic abnormalities are being identified, although their causal role in autism is not always clear. Improved detection of genetic causes of autism could increase the precision of genetic counselling for parents of an autistic child or young person and also for the wider family. At present, the yield of abnormal genetic results using CGH array is known to be higher in those with dysmorphic features and/or a learning (intellectual) disability, but this may extend to the wider autism population with increasing test sophistication. Before extending CGH array testing to a wider population, it is important to have a better understanding of its diagnostic yield. It is also essential to identify any negative consequences that may result from routine testing. # Rationale and impact
# Factors associated with an increased prevalence of autism
## Why the committee updated box 1 in recommendation 1.3.3
The evidence showed that children and young people with attention deficit hyperactivity disorder (ADHD) are more likely to have autism spectrum disorder than those without ADHD. Therefore ADHD was added to the list of factors associated with an increased prevalence of autism.
## How the updated recommendation might affect practice
Including ADHD as a factor associated with an increased prevalence of autism will help to promote early diagnosis of autism spectrum disorder. It also allows for joint assessment for both conditions in children and young people with signs or symptoms that could be caused by either condition.
The committee agreed that this supports current practice and is unlikely to lead to a substantial resource impact.
Return to recommendations# Context
This guideline was updated in 2017 to include attention deficit hyperactivity disorder (ADHD) in the list of factors that should be taken into account when considering a referral for possible autism spectrum disorder and when considering whether to carry out an autism spectrum disorder diagnostic assessment. This is because there is evidence showing an increased prevalence of autism spectrum disorders in children and young people with ADHD. In addition, it is important that clinicians do not exclude or delay referral for possible autism spectrum disorder because of an earlier diagnosis of ADHD.
The term autism describes qualitative differences and impairments in reciprocal social interaction and social communication, combined with restricted interests and rigid and repetitive behaviours. Autism spectrum disorders are diagnosed in children, young people and adults if these behaviours meet the criteria defined in the International Statistical Classification of Diseases and Related Health Problems (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and have a significant impact on function. The overarching category term used in ICD-11 is pervasive developmental disorder (PDD), a term now used synonymously with autism spectrum disorder (excluding Rett's syndrome); it is a behaviourally defined group of disorders, which is heterogeneous in both cause and manifestation.
DSM-5 refers to autism spectrum disorder as a single condition with different levels of symptom severity in 2 core domains: 1) deficits in social communication and social interaction and 2) restricted repetitive behaviours (RRBs), interests, and activities and sensory anomalies. Autism spectrum disorder encompasses the 4 separate disorders from the previous DSM-IV: autistic disorder (autism), Asperger's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. Because both components are required for diagnosis of autism spectrum disorder, social (pragmatic) communication disorder is diagnosed if no RRBs are present. Note that childhood disintegrative disorder is excluded from ASD in DSM-5.
The guideline development group recognised that individuals and groups prefer a variety of terms, including autism spectrum disorder, autistic spectrum condition, autistic spectrum difference and neuro-diversity. For clarity and consistency, in this guideline the term 'autism' is used throughout, in keeping with the use of 'autism' in the government's 2010 strategy for adults with autism. However in this guideline 'autism' refers to 'autism spectrum disorders'.
Autism is a lifelong disorder that has a great impact on the child or young person and their family or carers. When autism is diagnosed, families and carers and the child or young person themselves can experience a variety of emotions, shock and concern about the implications for the future. They may also have a profound sense of relief that others agree with their observations and concerns. Diagnosis and the assessment of needs can offer an understanding of why a child or young person is different from their peers and can open doors to support and services in education, health services and social care, and a route into voluntary organisations and contact with other children and families with similar experiences. All of these can improve the lives of the child or young person and their family.
The core autism behaviours are typically present in early childhood, but features are not always apparent until the circumstances of the child or young person change, for example when the child goes to nursery or primary school or moves to secondary school. Autism is strongly associated with a number of coexisting conditions. Recent studies have shown that approximately 70% of autistic people also meet diagnostic criteria for at least one other (often unrecognised) psychiatric disorder that is further impairing their psychosocial functioning. A learning (intellectual) disability (intelligence quotient below 70) occurs in approximately 50% of young autistic people.
Autism was once thought to be an uncommon developmental disorder, but recent studies have reported increased prevalence and the condition is now thought to occur in at least 1% of children. This rising prevalence has increased demand for diagnostic services for children and young people of all ages in the health service.
Health services have a key role in recognising and diagnosing autism. Levels of understanding of autism among healthcare and other relevant professionals and availability of services differ greatly from one area to another. In addition, children and young people with certain coexisting conditions such as a learning (intellectual) disability are less likely to be diagnosed with autism, leading to inequalities in healthcare and service provision.
Coordination between health agencies and other key services such as education, social care and the voluntary sector is important. Multi-agency staff should also work in partnership with the autistic child or young person and their family or carers.
This guideline aims to improve recognition, referral and diagnosis, and the experience of children, young people and those who care for them. NICE has also produced a guideline on autism spectrum disorder in under 19s: support and management.# Appendix: Features suggesting possible autism
# Using tables 1 to 3
The features suggesting possible autism in tables 1 to 3 are a combination of delay in expected features of development and the presence of unusual features, and are intended to alert professionals to the possibility of autism in a child or young person about whom concerns have been raised. They are not intended to be used alone, but to help professionals recognise a pattern of impairments in reciprocal social and communication skills, together with unusual restricted and repetitive behaviours.
Social interaction and reciprocal communication behaviours
Spoken language
Language delay (in babble or words, for example less than ten words by the age of 2 years).
Regression in or loss of use of speech.
Spoken language (if present) may include unusual:
non-speech like vocalisations
-dd or flat intonation
frequent repetition of set words and phrases ('echolalia')
reference to self by name or 'you' or 'she/he' beyond 3 years.
Reduced and/or infrequent use of language for communication, for example use of single words although able to speak in sentences.
Responding to others
Absent or delayed response to name being called, despite normal hearing.
Reduced or absent responsive social smiling.
Reduced or absent responsiveness to other people's facial expressions or feelings.
Unusually negative response to the requests of others (demand avoidant behaviour).
Rejection of cuddles initiated by parent or carer, although may initiate cuddles themselves.
Interacting with others
Reduced or absent awareness of personal space, or unusually intolerant of people entering their personal space.
Reduced or absent social interest in others, including children of his/her own age – may reject others; if interested in others, may approach others inappropriately, seeming to be aggressive or disruptive.
Reduced or absent imitation of others' actions.
Reduced or absent initiation of social play with others, plays alone.
Reduced or absent enjoyment of situations that most children like, for example, birthday parties.
Reduced or absent sharing of enjoyment.
Eye contact, pointing and other gestures
Reduced or absent use of gestures and facial expressions to communicate (although may place adult's hand on objects).
Reduced and poorly integrated gestures, facial expressions, body orientation, eye contact (looking at people's eyes when speaking) and speech used in social communication.
Reduced or absent social use of eye contact, assuming adequate vision.
Reduced or absent joint attention shown by lack of:
gaze switching
following a point (looking where the other person points to – may look at hand)
using pointing at or showing objects to share interest.
Ideas and imagination
Reduced or absent imagination and variety of pretend play.
Unusual or restricted interests and/or rigid and repetitive behaviours
Repetitive 'stereotypical' movements such as hand flapping, body rocking while standing, spinning, finger flicking.
Repetitive or stereotyped play, for example opening and closing doors.
Over-focused or unusual interests.
Excessive insistence on following own agenda.
Extremes of emotional reactivity to change or new situations, insistence on things being 'the same'.
Over or under reaction to sensory stimuli, for example textures, sounds, smells.
Excessive reaction to taste, smell, texture or appearance of food or extreme food fads.
Social interaction and reciprocal communication behaviours
Spoken language
Spoken language may be unusual in several ways:
very limited use
monotonous tone
repetitive speech, frequent use of stereotyped (learnt) phrases, content dominated by excessive information on topics of own interest
talking 'at' others rather than sharing a two-way conversation
responses to others can seem rude or inappropriate.
Responding to others
Reduced or absent response to other people's facial expression or feelings.
Reduced or delayed response to name being called, despite normal hearing.
Subtle difficulties in understanding other's intentions; may take things literally and misunderstand sarcasm or metaphor.
Unusually negative response to the requests of others (demand avoidant behaviour).
Interacting with others
Reduced or absent awareness of personal space, or unusually intolerant of people entering their personal space.
Reduced or absent social interest in people, including children of his/her own age – may reject others; if interested in others, may approach others inappropriately, seeming to be aggressive or disruptive.
Reduced or absent greeting and farewell behaviours.
Reduced or absent awareness of socially expected behaviour.
Reduced or absent ability to share in the social play or ideas of others, plays alone.
Unable to adapt style of communication to social situations, for example may be overly formal or inappropriately familiar.
Reduced or absent enjoyment of situations that most children like.
Eye contact, pointing and other gestures
Reduced and poorly integrated gestures, facial expressions and body orientation, eye contact (looking at people's eyes when speaking) and speech used in social communication.
Reduced or absent social use of eye contact, assuming adequate vision.
Reduced or absent joint attention shown by lack of:
gaze switching
following a point (looking where the other person points to – may look at hand)
using pointing at or showing objects to share interest.
Ideas and imagination
Reduced or absent flexible imaginative play or creativity, although scenes seen on visual media (for example, television) may be re-enacted.
Makes comments without awareness of social niceties or hierarchies.
Unusual or restricted interests and/or rigid and repetitive behaviours
Repetitive 'stereotypical' movements such as hand flapping, body rocking while standing, spinning, finger flicking.
Play repetitive and oriented towards objects rather than people.
Over-focused or unusual interests.
Rigid expectation that other children should adhere to rules of play.
Excessive insistence on following own agenda.
Extremes of emotional reactivity that are excessive for the circumstances.
Strong preferences for familiar routines and things being 'just right'.
Dislike of change, which often leads to anxiety or other forms of distress (including aggression).
Over or under reaction to sensory stimuli, for example textures, sounds, smells.
Excessive reaction to taste, smell, texture or appearance of food or extreme food fads.
Other factors that may support a concern about autism
Unusual profile of skills or deficits (for example, social or motor coordination skills poorly developed, while particular areas of knowledge, reading or vocabulary skills are advanced for chronological or mental age).
Social and emotional development more immature than other areas of development, excessive trusting (naivety), lack of common sense, less independent than peers.
Social interaction and reciprocal communication behaviours
Spoken language
Spoken language may be unusual in several ways:
very limited use
monotonous tone
repetitive speech, frequent use of stereotyped (learnt) phrases, content dominated by excessive information on topics of own interest
talking 'at' others rather than sharing a two-way conversation
responses to others can seem rude or inappropriate.
Interacting with others
Reduced or absent awareness of personal space, or unusually intolerant of people entering their personal space.
Long-standing difficulties in reciprocal social communication and interaction: few close friends or reciprocal relationships.
Reduced or absent understanding of friendship; often an unsuccessful desire to have friends (although may find it easier with adults or younger children).
Social isolation and apparent preference for aloneness.
Reduced or absent greeting and farewell behaviours.
Lack of awareness and understanding of socially expected behaviour.
Problems losing at games, turn-taking and understanding 'changing the rules'.
May appear unaware or uninterested in what other young people his or her age are interested in.
Unable to adapt style of communication to social situations, for example, may be overly formal or inappropriately familiar.
Subtle difficulties in understanding other's intentions; may take things literally and misunderstand sarcasm or metaphor.
Makes comments without awareness of social niceties or hierarchies.
Unusually negative response to the requests of others (demand avoidant behaviour).
Eye contact, pointing and other gestures
Poorly integrated gestures, facial expressions, body orientation, eye contact (looking at people's eyes when speaking) assuming adequate vision, and spoken language used in social communication.
Ideas and imagination
History of a lack of flexible social imaginative play and creativity, although scenes seen on visual media (for example, television) may be re-enacted.
Unusual or restricted interests and/or rigid and repetitive behaviours
Repetitive 'stereotypical' movements such as hand flapping, body rocking while standing, spinning, finger flicking.
Preference for highly specific interests or hobbies.
A strong adherence to rules or fairness that leads to argument.
Highly repetitive behaviours or rituals that negatively affect the young person's daily activities.
Excessive emotional distress at what seems trivial to others, for example change in routine.
Dislike of change, which often leads to anxiety or other forms of distress including aggression.
Over or under reaction to sensory stimuli, for example textures, sounds, smells.
Excessive reaction to taste, smell, texture or appearance of food and/or extreme food fads.
Other factors that may support a concern about autism
Unusual profile of skills and deficits (for example, social or motor coordination skills poorly developed, while particular areas of knowledge, reading or vocabulary skills are advanced for chronological or mental age).
Social and emotional development more immature than other areas of development, excessive trusting (naivety), lack of common sense, less independent than peers.
ISBN: 978-1-4731-1788-4
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Local pathway for recognition, referral and diagnostic assessment of possible autism\n\nA local autism multi-agency strategy group should be set up, with managerial, commissioner and clinical representation from child health and mental health services, education, social care, parent and carer service users, and the voluntary sector. \n\nThe local autism strategy group should appoint a lead professional to be responsible for the local autism pathway for recognition, referral and diagnosis of children and young people. The aims of the group should include:\n\nimproving early recognition of autism by raising awareness of the features suggesting possible autism through multi-agency training (see tables 1 to 3 in the appendix)\n\nmaking sure the relevant professionals (healthcare, social care, education and voluntary sector) are aware of the local autism pathway and how to access diagnostic services\n\nsupporting the smooth transition to adult services for young people going through the diagnostic pathway\n\nensuring data collection and audit of the pathway takes place. \n\nIn each area a multidisciplinary group (the autism team) should be set up. The core membership should include a:\n\npaediatrician and/or child and adolescent psychiatrist\n\nspeech and language therapist\n\npsychologist with training and experience in working with autistic children and young people. \n\nThe autism team should either include or have regular access to the following professionals if they are not already in the team:\n\npaediatrician or paediatric neurologist\n\nchild and adolescent psychiatrist\n\npsychologist with training and experience complementary to the psychologist in the core team\n\noccupational therapist. \n\nConsider including in the autism team (or arranging access for the team to) other relevant professionals who may be able to contribute to the autism diagnostic assessment. For example, a specialist health visitor or nurse, specialist teacher or social worker. \n\nThe autism team should have the skills and competencies to:\n\ncarry out an autism diagnostic assessment\n\ncommunicate with autistic children and young people and children and young people who may be autistic, and with their parents and carers, and sensitively share the diagnosis with them. \n\nAutism team members should:\n\nprovide advice to professionals about whether to refer children and young people for autism diagnostic assessments\n\ndecide on the assessment needs of those referred or when referral to another service will be needed\n\ncarry out the autism diagnostic assessment\n\nshare the outcome of the autism diagnostic assessment with parents and carers, and with children and young people if appropriate\n\nwith parent or carer consent and, if appropriate, the consent of the child or young person, share information from the autism diagnostic assessment directly with relevant services, for example through a school visit by an autism team member\n\noffer information to children, young people and parents and carers about appropriate services and support. \n\nProvide a single point of referral for access to the autism team. \n\nThe autism team should either have the skills (or have access to professionals that have the skills) needed to carry out an autism diagnostic assessment, for children and young people with special circumstances including:\n\ncoexisting conditions such as severe visual and hearing impairments, motor disorders including cerebral palsy, severe learning (intellectual) disabilities, complex language disorders or complex mental health disorders\n\nlooked-after children and young people. \n\nIf young people present at the time of transition to adult services, the autism team should consider carrying out the autism diagnostic assessment jointly with the adult autism team, regardless of the young person's intellectual ability. \n\n# Recognising children and young people who may be autistic\n\nConsider the possibility of autism if there are concerns about development or behaviour, but be aware that there may be other explanations for individual signs and symptoms. \n\nAlways take parents' or carers' concerns and, if appropriate, the child's or young person's concerns, about behaviour or development seriously, even if these are not shared by others. \n\nWhen considering the possibility of autism and whether to refer a child or young person to the autism team, be critical about your professional competence and seek advice from a colleague if in doubt about the next step. \n\nTo help identify the features suggesting possible autism, use tables 1 to 3 (see the appendix). Do not rule out autism if the exact features described in the tables are not evident; they should be used for guidance, but do not include all possible manifestations of autism. \n\nWhen considering the possibility of autism, be aware that:\n\nautism may be under-recognised in girls leading to underdiagnosis\n\nsigns and symptoms should be seen in the context of the child's or young person's overall development\n\nsigns and symptoms will not always have been recognised by parents, carers, children or young people themselves or by other professionals\n\nwhen older children or young people present for the first time with possible autism, signs or symptoms may have previously been masked by the child or young person's coping mechanisms and/or a supportive environment\n\nit is necessary to take account of cultural variation, but do not assume that language delay is accounted for because English is not the family's first language or by early hearing difficulties\n\nautism may be missed in children or young people with a learning (intellectual) disability\n\nautism may be missed in children or young people who are verbally able\n\nimportant information about early development may not be readily available for some children and young people, for example looked-after children and those in the criminal justice system\n\nsigns and symptoms may not be accounted for by disruptive home experiences or parental or carer mental or physical illness. \n\nWhen considering the possibility of autism, ask about the child or young person's use and understanding of their first language. \n\nDo not rule out autism because of:\n\ngood eye contact, smiling and showing affection to family members\n\nreported pretend play or normal language milestones\n\ndifficulties appearing to resolve after a needs-based intervention (such as a supportive structured learning environment)\n\na previous assessment that concluded that there was no autism, if new information becomes available. \n\nDiscuss developmental or behavioural concerns about a child or young person with parents or carers, and the child or young person themselves if appropriate. Discuss sensitively the possible causes, which may include autism, emphasising that there may be many explanations for the child's or young person's behaviour. \n\nBe aware that if parents or carers or the child or young person themselves have not suspected a developmental or behavioural condition, raising the possibility may cause distress, and that:\n\nit may take time for them to come to terms with the concern\n\nthey may not share the concern. \n\nTake time to listen to parents or carers and, if appropriate, the child or young person, to discuss concerns and agree any actions to follow including referral. \n\n# Referring children and young people to the autism team\n\nRefer children younger than 3\xa0years to the autism team if there is regression in language or social skills. \n\nRefer first to a paediatrician or paediatric neurologist (who can refer to the autism team if necessary) children and young people:\n\nolder than 3\xa0years with regression in language\n\nof any age with regression in motor skills. \n\nConsider referring children and young people to the autism team if you are concerned about possible autism on the basis of reported or observed features suggesting possible autism (see tables 1 to 3 in the appendix). Take account of:\n\nthe severity and duration of the features suggesting possible autism\n\nthe extent to which the features suggesting possible autism are present across different settings (for example, home and school)\n\nthe impact of the features suggesting possible autism on the child or young person and on their family\n\nthe level of parental or carer concern and, if appropriate, the concerns of the child or young person\n\nfactors associated with an increased prevalence of autism (see box\xa01)\n\nthe likelihood of an alternative diagnosis. \n\n## Box 1 Factors associated with an increased prevalence of autism \n\nA sibling with autism.\n\nBirth defects associated with central nervous system malformation and/or dysfunction, including cerebral palsy.\n\nGestational age less than 35 weeks.\n\nParental schizophrenia-like psychosis or affective disorder.\n\nMaternal use of sodium valproate in pregnancy.\n\nA learning (intellectual) disability.\n\nAttention deficit hyperactivity disorder.\n\nNeonatal encephalopathy or epileptic encephalopathy, including infantile spasms.\n\nChromosomal disorders such as Down's syndrome.\n\nGenetic disorders such as fragile X.\n\nMuscular dystrophy.\n\nNeurofibromatosis.\n\nTuberous sclerosis.\n\nIf you have concerns about development or behaviour but are not sure whether the signs and/or symptoms suggest autism, consider:\n\nconsulting a member of the autism team who can provide advice to help you decide if a referral to the autism team is necessary\n\nreferring to another service. That service can then refer to the autism team if necessary. \n\nBe aware that tools to identify children and young people with an increased likelihood of autism may be useful in gathering information about features suggesting possible autism in a structured way but are not essential and should not be used to make or rule out a diagnosis of autism. Also be aware that:\n\na positive score on tools to identify an increased likelihood of autism may support a decision to refer but can also be for reasons other than autism\n\na negative score does not rule out autism. \n\nWhen referring children and young people to the autism team, include in the referral letter the following information:\n\nreported information from parents, carers and professionals about signs and/or symptoms of concern\n\nyour own observations of the signs and/or symptoms. \n\nWhen referring children and young people to the autism team, include in the referral letter the following information, if available:\n\nantenatal and perinatal history\n\ndevelopmental milestones\n\nfactors associated with an increased prevalence of autism (see box\xa01 in recommendation\xa01.3.3)\n\nrelevant medical history and investigations\n\ninformation from previous assessments. \n\nExplain to parents or carers and, if appropriate, the child or young person, what will happen on referral to the autism team or another service. \n\nIf you do not think concerns are sufficient to prompt a referral, consider a period of watchful waiting. If you remain concerned about autism, reconsider your referral decision. \n\nIf the parents or carers or if appropriate, the child or young person, prefer not to be referred to the autism team, consider a period of watchful waiting. If you remain concerned about autism, reconsider referral. \n\nIf a concern has been raised but there are no features suggesting possible autism or other reasons to suspect autism, use professional judgment to decide what to do next. \n\nFor a short explanation of why the committee updated box 1 in recommendation 1.3.3 and how this might affect practice, see the rationale and impact section on factors associated with an increased prevalence of autism\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: factors and neurodevelopmental disorders that increase the likelihood of a diagnosis of autism spectrum disorder.\n\nLoading. Please wait.\n\n# After referral to the autism team\n\nWhen a child or young person is referred to the autism team, at least one member of the autism team should consider whether to carry out:\n\nan autism diagnostic assessment and/or\n\nan alternative assessment. \n\nCarry out an autism diagnostic assessment if there is regression in language or social skills in a child younger than 3\xa0years. \n\nRefer first to a paediatrician or paediatric neurologist (if this has not already happened) children or young people:\n\nolder than 3\xa0years with regression in language\n\nof any age with regression in motor skills.The paediatrician or paediatric neurologist can refer back to the autism team if necessary. \n\nWhen deciding whether to carry out an autism diagnostic assessment, take account of the following (unless the child is under 3\xa0years and has regression in language or social skills – see recommendation\xa01.4.2):\n\nthe severity and duration of the signs and/or symptoms\n\nthe extent to which the signs and/or symptoms are present across different settings (for example, home and school)\n\nthe impact of the signs and/or symptoms on the child or young person and on their family or carer\n\nthe level of parental or carer concern, and if appropriate the concerns of the child or young person\n\nfactors associated with an increased prevalence of autism (see box\xa01 in recommendation\xa01.3.3)\n\nthe likelihood of an alternative diagnosis. \n\nIf there is insufficient information to decide whether an autism diagnostic assessment is needed, gather any available information from healthcare professionals. With consent from parents or carers and, if appropriate, the child or young person, seek information from schools or other agencies. \n\nIf there is uncertainty about whether an autism diagnostic assessment is needed after information has been gathered, offer a consultation to gather information directly from the child or young person and their family or carers. \n\nOnce it has been decided to carry out an autism diagnostic assessment, with consent from parents or carers (and the child or young person if appropriate):\n\nseek a report from the pre-school or school if one has not already been made available\n\ngather any additional health or social care information, including results from hearing and vision assessments. \n\nAvoid repeated information gathering and assessments by efficient communication between professionals and agencies. \n\n# Autism diagnostic assessment for children and young people\n\nStart the autism diagnostic assessment within 3\xa0months of the referral to the autism team. \n\nA case coordinator in the autism team should be identified for every child or young person who is to have an autism diagnostic assessment. \n\nThe autism case coordinator should:\n\nact as a single point of contact for the parents or carers and, if appropriate, the child or young person being assessed, through whom they can communicate with the rest of the autism team\n\nkeep parents or carers and, if appropriate, the child or young person, up-to-date about the likely time and sequence of assessments\n\narrange the provision of information and support for parents, carers, children and young people as directed by the autism team\n\ngather information relevant to the autism diagnostic assessment (see recommendation\xa01.4.7). \n\nDiscuss with the parents or carers and, if appropriate, the child or young person, how information should be shared throughout the autism diagnostic assessment, including communicating the outcome of the assessment. Take into account, for example, the child or young person's age and ability to understand. \n\nInclude in every autism diagnostic assessment:\n\ndetailed questions about parent's or carer's concerns and, if appropriate, the child's or young person's concerns\n\ndetails of the child's or young person's experiences of home life, education and social care\n\na developmental history, focusing on developmental and behavioural features consistent with ICD-11 or DSM-5 criteria (consider using an autism-specific tool to gather this information)\n\nassessment (through interaction with and observation of the child or young person) of social and communication skills and behaviours, focusing on features consistent with ICD-11 or DSM-5 criteria (consider using an autism-specific tool to gather this information)\n\na medical history, including prenatal, perinatal and family history, and past and current health conditions\n\na physical examination\n\nconsideration of the differential diagnosis (see recommendation\xa01.5.7)\n\nsystematic assessment for conditions that may coexist with autism (see recommendation\xa01.5.15)\n\ndevelopment of a profile of the child's or young person's strengths, skills, impairments and needs that can be used to create a needs-based management plan, taking into account family and educational context.\n\ncommunication of assessment findings to the parent or carer and, if appropriate, the child or young person. [2011, amended 2017]\n\nPerform a general physical examination and look specifically for:\n\nskin stigmata of neurofibromatosis or tuberous sclerosis using a Wood's light\n\nsigns of injury, for example self-harm or child maltreatment (see the NICE guidelines on self-harm in over 8s and child maltreatment)\n\ncongenital anomalies and dysmorphic features including macrocephaly or microcephaly. \n\nConsider the following differential diagnoses for autism and whether specific assessments are needed to help interpret the autism history and observations:\n\nNeurodevelopmental disorders:\n\n\n\nspecific language delay or disorder\n\na learning (intellectual) disability or global developmental delay\n\ndevelopmental coordination disorder (DCD).\n\n\n\nMental and behavioural disorders:\n\n\n\nattention deficit hyperactivity disorder (ADHD)\n\nmood disorder\n\nanxiety disorder\n\nattachment disorders\n\noppositional defiant disorder (ODD)\n\nconduct disorder\n\nobsessive compulsive disorder (OCD)\n\npsychosis.\n\n\n\nConditions in which there is developmental regression:\n\n\n\nRett syndrome\n\nepileptic encephalopathy.\n\n\n\nOther conditions:\n\n\n\nsevere hearing impairment\n\nsevere visual impairment\n\nmaltreatment\n\nselective mutism. \n\n\n\nConsider which assessments are needed to construct a profile for each child or young person, for example:\n\nintellectual ability and learning style\n\nacademic skills\n\nspeech, language and communication\n\nfine and gross motor skills\n\nadaptive behaviour (including self-help skills)\n\nmental and emotional health (including self-esteem)\n\nphysical health and nutrition\n\nsensory sensitivities\n\nbehaviour likely to affect day-to-day functioning and social participation\n\nsocialisation skills. \n\nIf there are discrepancies during the autism diagnostic assessment between reported signs or symptoms and the findings of the autism observation in the clinical setting, consider:\n\ngathering additional information from other sources and/or\n\ncarrying out further autism‑specific observations in different settings, such as the school, nursery, other social setting or at home. \n\nUse information from all sources, together with clinical judgment, to diagnose autism based on ICD-11 or DSM-5 criteria. [2011, amended 2017]\n\nDo not rely on any autism-specific diagnostic tool alone to diagnose autism. \n\nBe aware that in some children and young people there may be uncertainty about the diagnosis of autism, particularly in:\n\nchildren younger than 24\xa0months\n\nchildren or young people with a developmental age of less than 18\xa0months\n\nchildren or young people for whom there is a lack of available information about their early life (for example, some looked-after or adopted children)\n\nolder teenagers\n\nchildren or young people with a complex coexisting mental health disorder (for example ADHD, conduct disorder, a possible attachment disorder), sensory impairment (for example severe hearing or visual impairment), or a motor disorder such as cerebral palsy. \n\nBe aware that some children and young people will have features of behaviour that are seen in the autism spectrum but do not reach the ICD‑11 or DSM-5 diagnostic criteria for definitive diagnosis. Based on their profile, consider referring to appropriate services. [2011, amended 2017]\n\nIf the outcome of the autism diagnostic assessment clearly indicates that the child or young person does not have autism, consider referring them to appropriate services based on their profile. \n\nConsider whether the child or young person may have any of the following as a coexisting condition, and if suspected carry out appropriate assessments and referrals:\n\nMental and behaviour problems and disorders:\n\n\n\nADHD\n\nanxiety disorders and phobias\n\nmood disorders\n\noppositional defiant behaviour\n\ntics or Tourette syndrome\n\nOCD\n\nself-injurious behaviour.\n\n\n\nNeurodevelopmental problems and disorders:\n\n\n\nglobal delay or a learning (intellectual) disability\n\nmotor coordination problems or DCD\n\nacademic learning problems, for example in literacy or numeracy\n\nspeech and language disorder.\n\n\n\nMedical or genetic problems and disorders:\n\n\n\nepilepsy and epileptic encephalopathy\n\nchromosome disorders\n\ngenetic abnormalities, including fragile X\n\ntuberous sclerosis\n\nmuscular dystrophy\n\nneurofibromatosis.\n\n\n\nFunctional problems and disorders:\n\n\n\nfeeding problems, including restricted diets\n\nurinary incontinence or enuresis\n\nconstipation, altered bowel habit, faecal incontinence or encopresis\n\nsleep disturbances\n\nvision or hearing impairment. \n\n\n\nBe aware that in children and young people with communication difficulties it may be difficult to recognise functional problems or mental health problems. \n\n# After the autism diagnostic assessment\n\nIf there is uncertainty after the autism diagnostic assessment about the diagnosis, consider keeping the child or young person under review, taking into account any new information. \n\nIf any of the following apply after assessment, consider obtaining a second opinion (including referral to a specialised tertiary autism team if necessary):\n\ncontinued uncertainty about the diagnosis\n\ndisagreement about the diagnosis within the autism team\n\ndisagreement with parents or carers or, if appropriate, the child or young person, about the diagnosis\n\na lack of local access to particular skills and competencies needed to reach a diagnosis in a child or young person who has a complex coexisting condition, such as a severe sensory or motor impairment or mental health problem\n\na lack of response as expected to any therapeutic interventions provided to the child or young person. \n\nDuring the autism diagnostic assessment, consider any potential risk of harm to, and from, the child or young person and take appropriate action. \n\n# Medical investigations\n\nDo not routinely perform any medical investigations as part of an autism diagnostic assessment, but consider the following in individual circumstances and based on physical examination, clinical judgment and the child or young person's profile:\n\ngenetic tests, as recommended by your regional genetics centre, if there are specific dysmorphic features, congenital anomalies and/or evidence of a learning (intellectual) disability\n\nelectroencephalography if there is suspicion of epilepsy (see the NICE guideline on epilepsies). \n\n# Communicating the results from the autism diagnostic assessment\n\nAfter the autism diagnostic assessment discuss the findings, including the profile, sensitively, in person and without delay with the parents or carers and, if appropriate, the child or young person. Explain the basis of conclusions even if the diagnosis of autism was not reached. \n\nUse recognised good practice when sharing a diagnosis with parents, carers, children and young people. \n\nFor children and young people with a diagnosis of autism, discuss and share information with parents or carers and, if appropriate, the child or young person, to explain:\n\nwhat autism is\n\nhow autism is likely to affect the child or young person's development and function. \n\nProvide parents or carers and, if appropriate, the child or young person, with a written report of the autism diagnostic assessment. This should explain the findings of the assessment and the reasons for the conclusions drawn. \n\nShare information, including the written report of the diagnostic assessment, with the GP. \n\nWith parental or carer consent and, if appropriate, the consent of the child or young person, share information with key professionals involved in the child's or young person's care, including those in education and social care. \n\nWith parental or carer consent and, if appropriate, the consent of the child or young person, make the profile available to professionals in education (for example, through a school visit by a member of the autism team) and, if appropriate, social care. This is so it can contribute to the child or young person's individual education plan and needs-based management plan. \n\nFor children and young people with a diagnosis of autism, offer a follow-up appointment with an appropriate member of the autism team within 6\xa0weeks of the end of the autism assessment for further discussion (for example about the conclusions of the assessment and the implications for the child or young person). \n\nFor children and young people with a diagnosis of autism, discuss with parents or carers the risk of autism occurring in siblings and future children. \n\n# Information and support for families and carers\n\nProvide individual information on support available locally for parents, carers, and autistic children and young people, according to the family's needs. This may include:\n\ncontact details for:\n\n\n\nlocal and national support organisations (who may provide, for example, an opportunity to meet other families with experience of autism, or information about specific courses for parents and carers and/or young people)\n\norganisations that can provide advice on welfare benefits\n\norganisations that can provide information on educational support and social care\n\n\n\ninformation to help prepare for the future, for example transition to adult services. ", 'Recommendations for research': "The guideline committee has made the following recommendations for research\n\n# Training professionals\n\nDoes training professionals to recognise features suggesting possible autism lead to earlier assessment of needs and earlier diagnosis (and by implication reduce morbidity/improve health outcomes) among children and young people compared with no training?\n\n## Why this is important\n\nSuccessful training of healthcare professionals in the Netherlands has been shown to improve their ability, confidence and skills in identifying children or young people who need an autism diagnostic assessment. A fully trained workforce can identify the number of autistic children or young people and provide accurate information both for planning individual care and at a strategic level for planning appropriate service provision.\n\nIf training improves earlier recognition and referral, this could be of particular benefit to at-risk groups for which there is evidence that autism is currently under-diagnosed, such as girls, and children and young people:\n\nwith parents of lower educational attainment\n\nwith English as an additional language\n\nwith sensory impairments\n\nwith a learning (intellectual) disability.\n\nBefore extending training to a wider population, it is important to better understand its effectiveness in terms of age, number of children and young people at referral, and time between parents' concerns and autism diagnosis. \n\n# Gathering information in schools or nurseries\n\nDoes routine additional information from educational settings (such as nursery or school) improve accuracy in diagnosing autism among children or young people up to the age of 19 compared with signs and symptoms alone?\n\n## Why this is important\n\nAutism is primarily characterised by difficulties in social reciprocity, social communication and social understanding, along with rigid and repetitive ways of thinking and behaving. Diagnostic accuracy may be improved by interpreting information about how the child or young person presents in social settings away from the home and immediate family.\n\nNurseries or schools are the most obvious settings from which such information may be collected. However, the degree to which information from teachers and schools helps in accurate diagnosis has not been well tested. \n\n# Additional assessments\n\nDo additional assessments (for IQ, language ability and motor ability) improve accuracy in diagnosing autism among preschool children (younger than 5\xa0years) compared with signs and symptoms alone?\n\n## Why this is important\n\nCurrent NHS practice varies widely with regard to the proportion of children having an autism diagnostic assessment who also routinely undergo assessments of IQ, language and motor abilities.\n\nAs a consequence we do not know whether such assessments aid more accurate diagnosis of autism. This is particularly important if a differential or coexisting diagnostic decision is called for and/or if there may be specific management implications.\n\nStudies may prove valuable to parents in terms of explaining some of the child's behaviours, leading to more targeted and informed support for the child, parents and the wider family. \n\n# Comparative genomic hybridisation array\n\nWhat is the effectiveness and acceptability of comparative genomic hybridisation (CGH) array compared with current genetic testing in autistic children and young people?\n\n## Why this is important\n\nRecent scientific advances have led to the detection of genetic abnormalities that may partly or wholly explain why a child or young person has autism. As the tests become increasingly sophisticated (for example, using methods such as CGH array that detect more subtle variations), more genetic abnormalities are being identified, although their causal role in autism is not always clear. Improved detection of genetic causes of autism could increase the precision of genetic counselling for parents of an autistic child or young person and also for the wider family. At present, the yield of abnormal genetic results using CGH array is known to be higher in those with dysmorphic features and/or a learning (intellectual) disability, but this may extend to the wider autism population with increasing test sophistication. Before extending CGH array testing to a wider population, it is important to have a better understanding of its diagnostic yield. It is also essential to identify any negative consequences that may result from routine testing. ", 'Rationale and impact': '# Factors associated with an increased prevalence of autism\n\n## Why the committee updated box 1 in recommendation 1.3.3\n\nThe evidence showed that children and young people with attention deficit hyperactivity disorder (ADHD) are more likely to have autism spectrum disorder than those without ADHD. Therefore ADHD was added to the list of factors associated with an increased prevalence of autism.\n\n## How the updated recommendation might affect practice\n\nIncluding ADHD as a factor associated with an increased prevalence of autism will help to promote early diagnosis of autism spectrum disorder. It also allows for joint assessment for both conditions in children and young people with signs or symptoms that could be caused by either condition.\n\nThe committee agreed that this supports current practice and is unlikely to lead to a substantial resource impact.\n\nReturn to recommendations', 'Context': "This guideline was updated in 2017 to include attention deficit hyperactivity disorder (ADHD) in the list of factors that should be taken into account when considering a referral for possible autism spectrum disorder and when considering whether to carry out an autism spectrum disorder diagnostic assessment. This is because there is evidence showing an increased prevalence of autism spectrum disorders in children and young people with ADHD. In addition, it is important that clinicians do not exclude or delay referral for possible autism spectrum disorder because of an earlier diagnosis of ADHD.\n\nThe term autism describes qualitative differences and impairments in reciprocal social interaction and social communication, combined with restricted interests and rigid and repetitive behaviours. Autism spectrum disorders are diagnosed in children, young people and adults if these behaviours meet the criteria defined in the International Statistical Classification of Diseases and Related Health Problems (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and have a significant impact on function. The overarching category term used in ICD-11 is pervasive developmental disorder (PDD), a term now used synonymously with autism spectrum disorder (excluding Rett's syndrome); it is a behaviourally defined group of disorders, which is heterogeneous in both cause and manifestation.\n\nDSM-5 refers to autism spectrum disorder as a single condition with different levels of symptom severity in 2 core domains: 1) deficits in social communication and social interaction and 2) restricted repetitive behaviours (RRBs), interests, and activities and sensory anomalies. Autism spectrum disorder encompasses the 4 separate disorders from the previous DSM-IV: autistic disorder (autism), Asperger's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. Because both components are required for diagnosis of autism spectrum disorder, social (pragmatic) communication disorder is diagnosed if no RRBs are present. Note that childhood disintegrative disorder is excluded from ASD in DSM-5.\n\nThe guideline development group recognised that individuals and groups prefer a variety of terms, including autism spectrum disorder, autistic spectrum condition, autistic spectrum difference and neuro-diversity. For clarity and consistency, in this guideline the term 'autism' is used throughout, in keeping with the use of 'autism' in the government's 2010 strategy for adults with autism. However in this guideline 'autism' refers to 'autism spectrum disorders'.\n\nAutism is a lifelong disorder that has a great impact on the child or young person and their family or carers. When autism is diagnosed, families and carers and the child or young person themselves can experience a variety of emotions, shock and concern about the implications for the future. They may also have a profound sense of relief that others agree with their observations and concerns. Diagnosis and the assessment of needs can offer an understanding of why a child or young person is different from their peers and can open doors to support and services in education, health services and social care, and a route into voluntary organisations and contact with other children and families with similar experiences. All of these can improve the lives of the child or young person and their family.\n\nThe core autism behaviours are typically present in early childhood, but features are not always apparent until the circumstances of the child or young person change, for example when the child goes to nursery or primary school or moves to secondary school. Autism is strongly associated with a number of coexisting conditions. Recent studies have shown that approximately 70% of autistic people also meet diagnostic criteria for at least one other (often unrecognised) psychiatric disorder that is further impairing their psychosocial functioning. A learning (intellectual) disability (intelligence quotient [IQ]\xa0below\xa070) occurs in approximately 50% of young autistic people.\n\nAutism was once thought to be an uncommon developmental disorder, but recent studies have reported increased prevalence and the condition is now thought to occur in at least 1% of children. This rising prevalence has increased demand for diagnostic services for children and young people of all ages in the health service.\n\nHealth services have a key role in recognising and diagnosing autism. Levels of understanding of autism among healthcare and other relevant professionals and availability of services differ greatly from one area to another. In addition, children and young people with certain coexisting conditions such as a learning (intellectual) disability are less likely to be diagnosed with autism, leading to inequalities in healthcare and service provision.\n\nCoordination between health agencies and other key services such as education, social care and the voluntary sector is important. Multi-agency staff should also work in partnership with the autistic child or young person and their family or carers.\n\nThis guideline aims to improve recognition, referral and diagnosis, and the experience of children, young people and those who care for them. NICE has also produced a guideline on autism spectrum disorder in under 19s: support and management.", 'Appendix: Features suggesting possible autism': "# Using tables 1 to 3\n\nThe features suggesting possible autism in tables 1 to 3 are a combination of delay in expected features of development and the presence of unusual features, and are intended to alert professionals to the possibility of autism in a child or young person about whom concerns have been raised. They are not intended to be used alone, but to help professionals recognise a pattern of impairments in reciprocal social and communication skills, together with unusual restricted and repetitive behaviours.\n\nSocial interaction and reciprocal communication behaviours\n\nSpoken language\n\nLanguage delay (in babble or words, for example less than ten words by the age of 2\xa0years).\n\nRegression in or loss of use of speech.\n\nSpoken language (if present) may include unusual:\n\n\n\nnon-speech like vocalisations\n\nodd or flat intonation\n\nfrequent repetition of set words and phrases ('echolalia')\n\nreference to self by name or 'you' or 'she/he' beyond 3\xa0years.\n\n\n\nReduced and/or infrequent use of language for communication, for example use of single words although able to speak in sentences.\n\nResponding to others\n\nAbsent or delayed response to name being called, despite normal hearing.\n\nReduced or absent responsive social smiling.\n\nReduced or absent responsiveness to other people's facial expressions or feelings.\n\nUnusually negative response to the requests of others (demand avoidant behaviour).\n\nRejection of cuddles initiated by parent or carer, although may initiate cuddles themselves.\n\nInteracting with others\n\nReduced or absent awareness of personal space, or unusually intolerant of people entering their personal space.\n\nReduced or absent social interest in others, including children of his/her own age – may reject others; if interested in others, may approach others inappropriately, seeming to be aggressive or disruptive.\n\nReduced or absent imitation of others' actions.\n\nReduced or absent initiation of social play with others, plays alone.\n\nReduced or absent enjoyment of situations that most children like, for example, birthday parties.\n\nReduced or absent sharing of enjoyment.\n\nEye contact, pointing and other gestures\n\nReduced or absent use of gestures and facial expressions to communicate (although may place adult's hand on objects).\n\nReduced and poorly integrated gestures, facial expressions, body orientation, eye contact (looking at people's eyes when speaking) and speech used in social communication.\n\nReduced or absent social use of eye contact, assuming adequate vision.\n\nReduced or absent joint attention shown by lack of:\n\n\n\ngaze switching\n\nfollowing a point (looking where the other person points to – may look at hand)\n\nusing pointing at or showing objects to share interest.\n\n\n\nIdeas and imagination\n\nReduced or absent imagination and variety of pretend play.\n\nUnusual or restricted interests and/or rigid and repetitive behaviours\n\nRepetitive 'stereotypical' movements such as hand flapping, body rocking while standing, spinning, finger flicking.\n\nRepetitive or stereotyped play, for example opening and closing doors.\n\nOver-focused or unusual interests.\n\nExcessive insistence on following own agenda.\n\nExtremes of emotional reactivity to change or new situations, insistence on things being 'the same'.\n\nOver or under reaction to sensory stimuli, for example textures, sounds, smells.\n\nExcessive reaction to taste, smell, texture or appearance of food or extreme food fads.\n\nSocial interaction and reciprocal communication behaviours\n\nSpoken language\n\nSpoken language may be unusual in several ways:\n\n\n\nvery limited use\n\nmonotonous tone\n\nrepetitive speech, frequent use of stereotyped (learnt) phrases, content dominated by excessive information on topics of own interest\n\ntalking 'at' others rather than sharing a two-way conversation\n\nresponses to others can seem rude or inappropriate.\n\n\n\nResponding to others\n\nReduced or absent response to other people's facial expression or feelings.\n\nReduced or delayed response to name being called, despite normal hearing.\n\nSubtle difficulties in understanding other's intentions; may take things literally and misunderstand sarcasm or metaphor.\n\nUnusually negative response to the requests of others (demand avoidant behaviour).\n\nInteracting with others\n\nReduced or absent awareness of personal space, or unusually intolerant of people entering their personal space.\n\nReduced or absent social interest in people, including children of his/her own age – may reject others; if interested in others, may approach others inappropriately, seeming to be aggressive or disruptive.\n\nReduced or absent greeting and farewell behaviours.\n\nReduced or absent awareness of socially expected behaviour.\n\nReduced or absent ability to share in the social play or ideas of others, plays alone.\n\nUnable to adapt style of communication to social situations, for example may be overly formal or inappropriately familiar.\n\nReduced or absent enjoyment of situations that most children like.\n\nEye contact, pointing and other gestures\n\nReduced and poorly integrated gestures, facial expressions and body orientation, eye contact (looking at people's eyes when speaking) and speech used in social communication.\n\nReduced or absent social use of eye contact, assuming adequate vision.\n\nReduced or absent joint attention shown by lack of:\n\n\n\ngaze switching\n\nfollowing a point (looking where the other person points to – may look at hand)\n\nusing pointing at or showing objects to share interest.\n\n\n\nIdeas and imagination\n\nReduced or absent flexible imaginative play or creativity, although scenes seen on visual media (for example, television) may be re-enacted.\n\nMakes comments without awareness of social niceties or hierarchies.\n\nUnusual or restricted interests and/or rigid and repetitive behaviours\n\nRepetitive 'stereotypical' movements such as hand flapping, body rocking while standing, spinning, finger flicking.\n\nPlay repetitive and oriented towards objects rather than people.\n\nOver-focused or unusual interests.\n\nRigid expectation that other children should adhere to rules of play.\n\nExcessive insistence on following own agenda.\n\nExtremes of emotional reactivity that are excessive for the circumstances.\n\nStrong preferences for familiar routines and things being 'just right'.\n\nDislike of change, which often leads to anxiety or other forms of distress (including aggression).\n\nOver or under reaction to sensory stimuli, for example textures, sounds, smells.\n\nExcessive reaction to taste, smell, texture or appearance of food or extreme food fads.\n\nOther factors that may support a concern about autism\n\nUnusual profile of skills or deficits (for example, social or motor coordination skills poorly developed, while particular areas of knowledge, reading or vocabulary skills are advanced for chronological or mental age).\n\nSocial and emotional development more immature than other areas of development, excessive trusting (naivety), lack of common sense, less independent than peers.\n\nSocial interaction and reciprocal communication behaviours\n\nSpoken language\n\nSpoken language may be unusual in several ways:\n\n\n\nvery limited use\n\nmonotonous tone\n\nrepetitive speech, frequent use of stereotyped (learnt) phrases, content dominated by excessive information on topics of own interest\n\ntalking 'at' others rather than sharing a two-way conversation\n\nresponses to others can seem rude or inappropriate.\n\n\n\nInteracting with others\n\nReduced or absent awareness of personal space, or unusually intolerant of people entering their personal space.\n\nLong-standing difficulties in reciprocal social communication and interaction: few close friends or reciprocal relationships.\n\nReduced or absent understanding of friendship; often an unsuccessful desire to have friends (although may find it easier with adults or younger children).\n\nSocial isolation and apparent preference for aloneness.\n\nReduced or absent greeting and farewell behaviours.\n\nLack of awareness and understanding of socially expected behaviour.\n\nProblems losing at games, turn-taking and understanding 'changing the rules'.\n\nMay appear unaware or uninterested in what other young people his or her age are interested in.\n\nUnable to adapt style of communication to social situations, for example, may be overly formal or inappropriately familiar.\n\nSubtle difficulties in understanding other's intentions; may take things literally and misunderstand sarcasm or metaphor.\n\nMakes comments without awareness of social niceties or hierarchies.\n\nUnusually negative response to the requests of others (demand avoidant behaviour).\n\nEye contact, pointing and other gestures\n\nPoorly integrated gestures, facial expressions, body orientation, eye contact (looking at people's eyes when speaking) assuming adequate vision, and spoken language used in social communication.\n\nIdeas and imagination\n\nHistory of a lack of flexible social imaginative play and creativity, although scenes seen on visual media (for example, television) may be re-enacted.\n\nUnusual or restricted interests and/or rigid and repetitive behaviours\n\nRepetitive 'stereotypical' movements such as hand flapping, body rocking while standing, spinning, finger flicking.\n\nPreference for highly specific interests or hobbies.\n\nA strong adherence to rules or fairness that leads to argument.\n\nHighly repetitive behaviours or rituals that negatively affect the young person's daily activities.\n\nExcessive emotional distress at what seems trivial to others, for example change in routine.\n\nDislike of change, which often leads to anxiety or other forms of distress including aggression.\n\nOver or under reaction to sensory stimuli, for example textures, sounds, smells.\n\nExcessive reaction to taste, smell, texture or appearance of food and/or extreme food fads.\n\nOther factors that may support a concern about autism\n\nUnusual profile of skills and deficits (for example, social or motor coordination skills poorly developed, while particular areas of knowledge, reading or vocabulary skills are advanced for chronological or mental age).\n\nSocial and emotional development more immature than other areas of development, excessive trusting (naivety), lack of common sense, less independent than peers.\n\nISBN: 978-1-4731-1788-4"}
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https://www.nice.org.uk/guidance/cg128
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This guideline covers recognising and diagnosing autism spectrum disorder in children and young people from birth up to 19 years. It also covers referral. It aims to improve the experience of children, young people and those who care for them.
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e831e7bd0734ac6ce02987b7e7da45d50129c506
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nice
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Transcutaneous microwave ablation for severe primary axillary hyperhidrosis
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Transcutaneous microwave ablation for severe primary axillary hyperhidrosis
Evidence-based recommendations on transcutaneous microwave ablation for severe primary axillary hyperhidrosis in adults. This involves using microwaves to destroy sweat glands in the armpit.
# Recommendations
Current evidence on the safety and efficacy of transcutaneous microwave ablation for severe primary axillary hyperhidrosis is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do transcutaneous microwave ablation for severe primary axillary hyperhidrosis should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In particular, during the consent process patients should be informed about the possibility of nerve damage. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having transcutaneous microwave ablation for severe primary axillary hyperhidrosis (see section 7.3).
NICE encourages further research into transcutaneous microwave ablation for severe primary axillary hyperhidrosis and may update the guidance on publication of further evidence. Further research should include information on patient selection, objective measures of physiological effect, patient-reported outcome measures and long-term outcomes.# Indications and current treatments
Primary axillary hyperhidrosis typically begins during childhood or adolescence, but can happen at any age. It is usually life-long, although in a few people symptoms can spontaneously improve over time. Severe primary axillary hyperhidrosis can be defined as a score of 3 or 4 on the Hyperhidrosis Disease Severity Scale. Excessive sweating can have a profound effect on quality of life, interfering with daily activities and causing anxiety and embarrassment.
First-line management of primary axillary hyperhidrosis includes lifestyle measures such as avoiding known triggers and tight clothing, and using antiperspirants (including aluminium chloride hexahydrate). Other treatments include iontophoresis, botulinum-toxin A injection, and oral medications such as anticholinergics, antimuscarinics, beta-blockers, antihypertensives and anxiolytics. If these do not work, surgical options include local sweat-gland excision by subcutaneous curettage, tumescent liposuction, or thoracic sympathectomy.# The procedure
Transcutaneous microwave ablation for primary severe axillary hyperhidrosis is done under local anaesthesia using a machine with a hand-piece that emits microwaves. After numbing the underarm with several injections of local anaesthesia, the hand-piece is placed on the area where the sweat glands are and microwaves are applied, with the intention of ablating the sweat glands. The machine has a cooling system that prevents damage to the superficial skin layers and a vacuum system that lifts the underlying skin to help isolate the target tissue from underlying structures. The procedure takes about 1 hour; patients typically have a second treatment session about 3 months later to get the greatest benefit. Patients may need to take oral analgesics and apply ice packs to reduce swelling of the treated area for a few days after the procedure.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a randomised controlled trial (RCT) of 120 patients who had active or sham microwave ablation for severe primary axillary hyperhidrosis, the proportion of patients with an Hyperhidrosis Disease Severity Scale (HDSS) score of 1 or 2 (unnoticeable or tolerable sweating) was 89% (72/81) and 54% (21/39) respectively at 30‑day follow-up (p<0.001). At 6‑month follow-up, 67% and 44% had an HDSS score of 1 or 2 (p=0.02) respectively. In the active treatment group, 69% of patients had an HDSS score of 1 or 2 at the 9‑month and 12‑month follow-up. The proportion of patients with an HDSS score reduced by 2 or more at 6‑month follow-up was 47% in the active treatment group and 13% in the sham group (p<0.001). The proportion of patients, who had active treatment, with an HDSS score reduced by 2 or more at the 9- and 12‑month follow-up was 42% and 38% respectively. In a case series of 20 patients, the mean reduction in HDSS score at a mean follow-up of 5 months was 2 (95% CI 1.85 to 2.15, p<0.0001), and 95% (19/20) had an HDSS score of 2 or lower. In a case series of 31 patients, 90% (28/31) of patients had HDSS scores of 1 or 2 at 12‑month follow-up; 94% (29/31) of patients had at least a 1‑point drop and 55% (17/31) had a drop of 2 or more points in HDSS.
In the RCT of 120 patients who had active or sham microwave ablation, the proportion of patients with a 50% or more reduction in weighed sweat compared with baseline was 80% and 67% respectively at 30‑day follow-up (p=0.07), and 63% and 59% (p=0.69) respectively at 6‑month follow-up. The proportion of patients with a 75% or more reduction was 62% in the active group and 39% in the sham group (p=0.01) at 30‑day follow-up, and 41% and 36% (p=0.60) respectively at 6‑month follow-up. In the case series of 31 patients, 90% (28/31) of patients had at least a 50% reduction in axillary sweat from baseline at 30‑day follow-up.
In the case series of 31 patients, 85% (23/31) had an improvement of at least 5 points on the Dermatologic Life Quality Index (score ranges from 0 to 30 with higher scores indicating poorer quality of life) at 12‑month follow-up.
In the case series of 31 patients, 90% (27/30), 96% (27/28), 93% (25/27) and 89% (23/26) of patients were very or somewhat satisfied after 30 days, 3 months, 6 months and 12 months respectively. In the case series of 20 patients, all patients stated that they would have the treatment again.
The specialist adviser listed the key efficacy outcomes as dryness (measured by the HDSS), and improved quality of life (number of episodes of bothersome sweating per week).# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Transient neuropathy of the left arm with associated muscle weakness after the procedure was reported in 1 patient in a case series of 31 patients. The neuropathy had improved by 6 months, after which the patient was lost to follow-up. Transient median and ulnar neuropathy was described in 1 patient in a case report. After 6 months of rehabilitation, the patient's motor power and sensory deficit had improved but the thenar muscles remained atrophic. Brachial plexus injury was described in 1 patient in a case report. The patient had sensory and motor dysfunction in her fingers, which had not fully recovered after 6 months of rehabilitation.
Altered sensation in the skin of the upper arm (change in sensitivity, tingling or numbness) was reported in 10% (8/81) of patients who had active microwave ablation (mean duration 67 days) and 3% (1/39) of patients who had a sham treatment (duration 79 days) in a RCT of 120 patients. Temporary numbness was reported in 20% of patients in a case series of 20 patients. Altered sensation in the skin of the axillae was reported in 65% of patients in the case series of 31 patients (median duration 37 days, range 4 days to 4 months). Altered sensation in the skin of the treated limb was reported in 39% (12/31) of patients in the same study (median duration 50 days, range 6 days to 12 months). Loss of sensation in the lateral area of both forearms was reported in 1 patient in a case series of 11 patients. This gradually improved, and the patient recovered fully within 3 months.
Blisters, burns or ulcerations were reported in 5% (4/81) of patients in the active treatment group (mean duration 28 days, range 12 to 40) and no patients in the sham treatment group in the RCT of 120 patients.
Axillary bumps or nodules were reported in 3% (2/81) of patients in the active treatment group (mean duration 30 days, range 8 to 52) and 3% (1/39) of patients in the sham treatment group (2 episodes; duration 10 to 12 days). Nodule formation, lasting up to 4 weeks, was reported in 25% of patients in the case series of 20 patients. Palpable bumps under the skin of the axillae was reported in 71% of patients in the case series of 31 patients (median duration 41 days; still present in 2 patients at study exit).
Compensatory sweating was reported in 3% (2/81) of patients in the active treatment group and no patients in the sham treatment group in the RCT of 120 patients.
There are several reports on the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) website, describing events after microwave ablation for axillary hyperhidrosis. These include nerve damage, infections, abscesses, ulcers, burns, cellulitis, blisters and skin or tissue necrosis. It is not possible to calculate the incidence of these events because the total number of procedures is unknown.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly happen, even if they have never done so). For this procedure, a specialist adviser described the following anecdotal adverse event: infection. They considered that scarring was a theoretical adverse event.# Further information
Patient commentary was sought but none was received.
For related NICE guidance, see the NICE website.
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
# Information for patients
NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2749-4
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{'Recommendations': "Current evidence on the safety and efficacy of transcutaneous microwave ablation for severe primary axillary hyperhidrosis is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transcutaneous microwave ablation for severe primary axillary hyperhidrosis should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In particular, during the consent process patients should be informed about the possibility of nerve damage. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having transcutaneous microwave ablation for severe primary axillary hyperhidrosis (see section\xa07.3).\n\nNICE encourages further research into transcutaneous microwave ablation for severe primary axillary hyperhidrosis and may update the guidance on publication of further evidence. Further research should include information on patient selection, objective measures of physiological effect, patient-reported outcome measures and long-term outcomes.", 'Indications and current treatments': 'Primary axillary hyperhidrosis typically begins during childhood or adolescence, but can happen at any age. It is usually life-long, although in a few people symptoms can spontaneously improve over time. Severe primary axillary hyperhidrosis can be defined as a score of\xa03 or\xa04 on the Hyperhidrosis Disease Severity Scale. Excessive sweating can have a profound effect on quality of life, interfering with daily activities and causing anxiety and embarrassment.\n\nFirst-line management of primary axillary hyperhidrosis includes lifestyle measures such as avoiding known triggers and tight clothing, and using antiperspirants (including aluminium chloride hexahydrate). Other treatments include iontophoresis, botulinum-toxin\xa0A injection, and oral medications such as anticholinergics, antimuscarinics, beta-blockers, antihypertensives and anxiolytics. If these do not work, surgical options include local sweat-gland excision by subcutaneous curettage, tumescent liposuction, or thoracic sympathectomy.', 'The procedure': 'Transcutaneous microwave ablation for primary severe axillary hyperhidrosis is done under local anaesthesia using a machine with a hand-piece that emits microwaves. After numbing the underarm with several injections of local anaesthesia, the hand-piece is placed on the area where the sweat glands are and microwaves are applied, with the intention of ablating the sweat glands. The machine has a cooling system that prevents damage to the superficial skin layers and a vacuum system that lifts the underlying skin to help isolate the target tissue from underlying structures. The procedure takes about 1\xa0hour; patients typically have a second treatment session about 3\xa0months later to get the greatest benefit. Patients may need to take oral analgesics and apply ice packs to reduce swelling of the treated area for a few days after the procedure.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 120\xa0patients who had active or sham microwave ablation for severe primary axillary hyperhidrosis, the proportion of patients with an Hyperhidrosis Disease Severity Scale (HDSS) score of 1\xa0or 2\xa0(unnoticeable or tolerable sweating) was 89% (72/81) and 54% (21/39) respectively at 30‑day follow-up (p<0.001). At 6‑month follow-up, 67% and 44% had an HDSS score of 1\xa0or 2\xa0(p=0.02) respectively. In the active treatment group, 69% of patients had an HDSS score of 1\xa0or 2\xa0at the 9‑month and 12‑month follow-up. The proportion of patients with an HDSS score reduced by 2\xa0or more at 6‑month follow-up was 47% in the active treatment group and 13% in the sham group (p<0.001). The proportion of patients, who had active treatment, with an HDSS score reduced by 2\xa0or more at the 9- and 12‑month follow-up was 42% and 38% respectively. In a case series of 20\xa0patients, the mean reduction in HDSS score at a mean follow-up of 5\xa0months was 2\xa0(95% [confidence interval] CI 1.85 to 2.15, p<0.0001), and 95% (19/20) had an HDSS score of 2\xa0or lower. In a case series of 31\xa0patients, 90% (28/31) of patients had HDSS scores of\xa01 or\xa02 at 12‑month follow-up; 94% (29/31) of patients had at least a 1‑point drop and 55% (17/31) had a drop of 2\xa0or more points in HDSS.\n\nIn the RCT of 120\xa0patients who had active or sham microwave ablation, the proportion of patients with a 50% or more reduction in weighed sweat compared with baseline was 80% and 67% respectively at 30‑day follow-up (p=0.07), and 63% and 59% (p=0.69) respectively at 6‑month follow-up. The proportion of patients with a 75% or more reduction was 62% in the active group and 39% in the sham group (p=0.01) at 30‑day follow-up, and 41% and 36% (p=0.60) respectively at 6‑month follow-up. In the case series of 31\xa0patients, 90% (28/31) of patients had at least a 50% reduction in axillary sweat from baseline at 30‑day follow-up.\n\nIn the case series of 31\xa0patients, 85% (23/31) had an improvement of at least 5\xa0points on the Dermatologic Life Quality Index (score ranges from 0 to 30 with higher scores indicating poorer quality of life) at 12‑month follow-up.\n\nIn the case series of 31\xa0patients, 90% (27/30), 96% (27/28), 93% (25/27) and 89% (23/26) of patients were very or somewhat satisfied after 30\xa0days, 3\xa0months, 6\xa0months and 12\xa0months respectively. In the case series of 20\xa0patients, all patients stated that they would have the treatment again.\n\nThe specialist adviser listed the key efficacy outcomes as dryness (measured by the HDSS), and improved quality of life (number of episodes of bothersome sweating per week).', 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nTransient neuropathy of the left arm with associated muscle weakness after the procedure was reported in 1\xa0patient in a case series of 31\xa0patients. The neuropathy had improved by 6\xa0months, after which the patient was lost to follow-up. Transient median and ulnar neuropathy was described in 1\xa0patient in a case report. After 6\xa0months of rehabilitation, the patient's motor power and sensory deficit had improved but the thenar muscles remained atrophic. Brachial plexus injury was described in 1\xa0patient in a case report. The patient had sensory and motor dysfunction in her fingers, which had not fully recovered after 6\xa0months of rehabilitation.\n\nAltered sensation in the skin of the upper arm (change in sensitivity, tingling or numbness) was reported in 10% (8/81) of patients who had active microwave ablation (mean duration 67\xa0days) and 3% (1/39) of patients who had a sham treatment (duration 79\xa0days) in a RCT of 120\xa0patients. Temporary numbness was reported in 20% of patients in a case series of 20\xa0patients. Altered sensation in the skin of the axillae was reported in 65% of patients in the case series of 31\xa0patients (median duration 37\xa0days, range 4\xa0days to 4\xa0months). Altered sensation in the skin of the treated limb was reported in 39% (12/31) of patients in the same study (median duration 50\xa0days, range 6\xa0days to 12\xa0months). Loss of sensation in the lateral area of both forearms was reported in 1\xa0patient in a case series of 11\xa0patients. This gradually improved, and the patient recovered fully within 3\xa0months.\n\nBlisters, burns or ulcerations were reported in 5% (4/81) of patients in the active treatment group (mean duration 28\xa0days, range 12 to 40) and no patients in the sham treatment group in the RCT of 120\xa0patients.\n\nAxillary bumps or nodules were reported in 3% (2/81) of patients in the active treatment group (mean duration 30\xa0days, range 8 to 52) and 3% (1/39) of patients in the sham treatment group (2\xa0episodes; duration 10\xa0to 12\xa0days). Nodule formation, lasting up to 4\xa0weeks, was reported in 25% of patients in the case series of 20\xa0patients. Palpable bumps under the skin of the axillae was reported in 71% of patients in the case series of 31\xa0patients (median duration 41\xa0days; still present in 2\xa0patients at study exit).\n\nCompensatory sweating was reported in 3% (2/81) of patients in the active treatment group and no patients in the sham treatment group in the RCT of 120\xa0patients.\n\nThere are several reports on the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) website, describing events after microwave ablation for axillary hyperhidrosis. These include nerve damage, infections, abscesses, ulcers, burns, cellulitis, blisters and skin or tissue necrosis. It is not possible to calculate the incidence of these events because the total number of procedures is unknown.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly happen, even if they have never done so). For this procedure, a specialist adviser described the following anecdotal adverse event: infection. They considered that scarring was a theoretical adverse event.", 'Further information': "Patient commentary was sought but none was received.\n\nFor related NICE guidance, see the NICE website.\n\nThis guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2749-4"}
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https://www.nice.org.uk/guidance/ipg601
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Evidence-based recommendations on transcutaneous microwave ablation for severe primary axillary hyperhidrosis in adults. This involves using microwaves to destroy sweat glands in the armpit.
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64eff196018b2345fd03864367ae56d4a40bca85
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nice
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Artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure
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Artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure
Evidence-based recommendations on artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure. This involves replacing the 2 lower chambers of the heart with a mechanical device to improve circulation until heart transplantation.
# Recommendations
Current evidence on the safety and efficacy of total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure (see section 6.3).
Clinicians should enter details about all patients having total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure onto an appropriate registry and review local clinical outcomes.
Patient selection should be done by a multidisciplinary team experienced in managing end-stage refractory biventricular heart failure in patients needing a heart transplant, for whom a donor organ is not expected to be available before their own heart fails completely.
This technically challenging procedure should only be done in centres specialising in heart transplantation. Only cardiothoracic surgeons with specific expertise and training in inserting the device should carry it out.
NICE encourages further research into total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure, including well matched comparative studies. NICE may update the guidance on publication of further evidence.# Indications and current treatments
Biventricular heart failure results from structural or functional abnormalities of the heart. It leads to reduced blood flow to body tissues and oedema in the lungs (causing breathlessness) and the periphery (causing swelling of the legs). Other symptoms include reduced exercise tolerance, fatigue and malaise.
Medical treatment of heart failure involves drugs, such as diuretics and inotropic agents, to improve heart function. Invasive therapies, such as electrophysiological interventions, coronary revascularisation, valve replacement or repair, may also be used for patients with end-stage refractory biventricular heart failure. When these therapies no longer work, left ventricular or biventricular assist devices or heart transplantation may be considered.# The procedure
A total artificial heart (TAH) can be implanted to provide circulatory support with the aim that the patient survives while waiting for a donor heart to become available (a technique known as 'bridge to transplantation'). In this procedure, the device replaces the heart function completely.
Implantation of a TAH is done with the patient under general anaesthesia and on cardiopulmonary bypass. The native left and right ventricles, and all 4 cardiac valves are excised. The TAH device is implanted and attached to the atria, for blood inflow, and pulmonary artery and aorta, for blood outflow. Depending on the type of TAH, power is supplied either by drive lines connected percutaneously to an external biventricular pneumatic pump (which may be portable or static) or by batteries that are implanted internally and can be recharged through the skin using a transcutaneous energy transfer system. When the device begins to pump and restores blood flow around the body, cardiopulmonary bypass is stopped and the chest incision is closed.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a non-randomised prospective comparative study of patients at risk of imminent death from irreversible biventricular heart failure, total artificial heart (TAH) implantation (n=81) was compared with no TAH implantation (matched historical controls; n=35). The rates of survival to heart transplantation were 79% (95% confidence interval 68% to 87%) in the TAH group compared with 46% in the control group (p<0.001). The 1‑year survival to heart transplantation rates were 70% (95% CI 63% to 77%) and 31% respectively (p<0.001).In a non-randomised retrospective comparative study (United Network of Organ Sharing database analysis) comparing TAH support (n=212) with biventricular assisted device (BIVAD) support (n=366) as a bridge to transplantation (BTT) in adult patients, device support survival rates were similar in both groups (p=0.8): 95% compared with 93% at 30 days and 77% compared with 69% at 1 year.In a non-randomised retrospective comparative study comparing TAH support (n=81) with paracorporeal BIVAD support (n=67) as a BTT in 148 adult patients, device support survival rates were similar between the groups (p=0.87): 76% compared with 72% at 30 days; 63% compared with 61% at 2 months; and 46% compared with 53% at 6 months respectively.In a case series of 101 patients at risk of imminent death from irreversible biventricular heart failure and eligible for transplant, survival to heart transplantation with TAH implantation as a BTT was 68% (69/101). In a case series of 90 patients with biventricular failure treated by TAH implantation as a BTT, actuarial survival on device was 74±5%, 63±6% and 47±8% at 30, 60 and 180 days after implantation respectively. In a case series of 27 patients with TAH implantation as a BTT, 44% (12/27) of patients were discharged from hospital within a median of 88 days after implantation (range 35 to 152 days). Support time between discharge and transplantation was spent out of hospital in 87% of patients.
In the non-randomised prospective comparative study comparing patients with TAH implantation (n=81) with matched historical controls (n=35), the survival rates at 1 and 5 years after transplantation in the TAH group were 86% and 64% compared with 69% and 34% in the control group respectively (p values not reported). In the non-randomised retrospective comparative study (UNOS database analysis) comparing TAH support with BIVAD support, survival rates after transplantation were 88% compared with 93% at 30 days, 78% compared with 83% at 1 year, and 67% compared with 73% at 3 years respectively (p=0.06). In the non-randomised comparative study of 148 patients, survival rates after transplantation in the TAH group (n=51) and the paracorporeal BIVAD group (n=39) were similar (p=0.60): 77% compared with 76% at 1year; 72% compared with 70% at 3 years; and 70% compared with 58% at 5 years. In the case series of 101 patients with TAH implantation, survival after transplantation at 1, 5 and 10 years was 77%, 61% and 41% respectively. In the case series of 90 patients with TAH implantation, actuarial survival rates after transplantation were 78±6%, 71±6% and 63±8% at 1, 5 and 8 years respectively. In the case series of 27 patients with TAH implantation, survival after transplantation (n=12) at a median 20‑month follow-up was 91%.
In the non-randomised prospective comparative study comparing patients who had TAH implantation (n=81) with matched historical controls (n=35), the overall survival rate at 1 year was 70% (95% CI 63% to 77%) and 31% respectively (p<0.001). In the case series of 101 patients with TAH implantation, the overall survival at 1, 5, 10 and 15 years was 55% (n=56), 43% (n=35), 28% (n=18), and 26% (n=3) respectively.
In the non-randomised prospective comparative study comparing patients with TAH implantation (n=81) with matched historical controls (n=35), quality of life in the TAH group improved significantly: 75% of patients were out of bed 1 week after implantation and mobility (defined as ability to walk more than 100 feet) was seen in 61% of patients (method of measurement not reported). In the case series of 27 patients with TAH implantation, the quality of life results for 12 patients at home (measured using a modified ED‑5D defined by INTERMACS) showed that only 1 young patient was able to return to school. Patients and families reported the console's noise as bothersome.
The specialist advisers listed the key efficacy outcomes as survival to hospital discharge, survival and successful BTT at 6 and 12 months, and survival after transplantation.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a non-randomised retrospective comparative study of 578 patients (United Network of Organ Sharing database analysis), rates of deaths were not significantly different between total artificial heart (TAH) and biventricular assisted device (BIVAD) groups: 10% (22/212) compared with 12% (45/366), p=0.7 while on support; and 30% (64/212) compared with 30% (111/366), p=0.9 after transplantation. The causes of death while on device support (infection, multi-organ failure, stroke or haemorrhage) and after heart transplantation (acute rejection, infection, cardiac arrest, multi-organ failure and stroke) for both groups were also similar. In a non-randomised prospective comparative study of 130 patients, rates of death before transplantation were 21% (17/81) in the TAH group compared with 54% (19/35) in the control group (p value not reported). Causes of the 17 deaths before transplantation in the TAH group were multi-organ failure (7), procedural or technical complications (4), bleeding (2), sepsis (2), congestive heart failure (1) and pulmonary oedema (1). In the same group after transplantation, there were 6 deaths (3 graft failure, 1 sepsis, 1 procedural or technical complication and 1 multi-organ failure). Rates of deaths in a non-randomised retrospective comparative study of 148 patients were not significantly different between TAH and BIVAD support groups while on support (37% compared with 39%; p=0.87). Death occurred in 32% (32/101) of patients in a case series of 101 patients with TAH implantation; 70% were within the first 14 days. Causes of deaths were multi-organ failure (13), pneumonia or pulmonary oedema (6), sepsis (5), neurologic injury (4, including 1 stroke, 1 hypoxic damage from hypotension and 2 intracranial haemorrhage), pancreatic abscess (1), small intestinal ischaemia (1), disseminated intravascular coagulopathy (1), and disseminated coccidiodomycosis (1).
Bleeding events were reported in 62% (59/95) of patients in the TAH group in the non-randomised prospective comparative study of 130 patients. Of these events, 50% occurred during TAH implantation and were mainly tamponade or mediastinal bleeding (needing surgery and blood transfusion) within 21 days. Two patients died from bleeding: 1 during TAH implantation and 1 during heart transplantation). Bleeding (from various sites) at a mean of 4 days was reported in 43% (43/101) of patients in the case series of 101 patients. Reoperations for haemorrhage (mediastinal explorations) were done in 25% (25/101) of patients. The surgical revision rate for bleeding or haematoma was significantly lower in the TAH group than the BIVAD group in the non-randomised comparative study (23% compared with 42% respectively; p=0.03). Surgical re-exploration for bleeding, haematoma or infection was reported in 39% (35/90) of patients while on device support in the case series of 90 patients. Haemorrhagic events (at a median time of 249 days) were reported in 14% (7/47) of patients in the case series of 47 patients with TAH support for more than 1 year. These included cerebral haemorrhage (n=3), subarachnoid haemorrhage (n=2), and gastrointestinal bleeding (n=2).
Device malfunction events were reported in 17% (16/95) of patients in the TAH group in the non-randomised prospective comparative study of 130 patients. One patient died because of perforation in 1 of the layers of the device's left ventricular diaphragm on day 124. Fitting complications were reported in 5% (5/95) of patients in the TAH group in the same study; 2 patients died because of poor fitting and 3 patients had repeat surgery to reposition the device. Device failure was reported in 10% (5/47) of patients in the case series of 47 patients with TAH support for more than 1 year; there were 3 membrane ruptures (2 patients died), 1 air hole in the driveline and 1 lower pump output. Device malfunction (technical problems with the alarm and computer monitoring system needing console change) was reported in 1 patient during hospitalisation in the case series of 27 patients. Malfunctions were reported in 25% (3/12) of patients discharged home after TAH implantation. In 2 patients, an air leak occurred in the driveline to the ventricle, which was sealed with a silicon band. In 1 patient, alarm triggering was caused by auricular compression during some movements (stretching and yawning) and the patient was advised to avoid them.
The renal failure rate was significantly higher in the TAH support group than the BIVAD support group after implantation (24% compared with 10% ; p<0.0001) and after transplantation (26% compared with 14% ; p=0.0001) in the non-randomised retrospective comparative study (UNOS database analysis). Renal failure (needing postoperative renal replacement therapy) was reported in 64% (30/47) of patients in the case series of 47 patients with TAH support for more than 1 year. Recovery of renal function occurred in 73% (22/47) of patients but therapy continued in 17% (8/47) of patients.
The infection rate after implantation was significantly lower in the TAH group than the BIVAD group (22% compared with 28% ; p=0.005) in the non-randomised retrospective comparative study (UNOS database analysis). Infections (7 blood, 50 respiratory, 5 mediastinal, 28 genitourinary, 12 gastrointestinal, 17 driveline and 6 in catheters) were reported in 77% (73/95) of patients in the TAH group in the non-randomised prospective comparative study of 130 patients. Infections contributed to death in 7 patients and delayed transplantation in 5 patients. Infections (commonly in the lungs and urinary tract) were reported in 64% (64/101) of patients in the case series of 101 patients. Rates of postoperative mediastinitis (TAH 12% compared with BIVAD 5% ; p=0.14) or driveline infections (1 patient with TAH compared with 2 patients with BIVAD; p=0.61) were similar in both groups during support in the non-randomised comparative study of 148 patients.
Neurologic events (10 stroke, 4 transient ischaemic attack, 5 anoxic encephalopathy, 1 metabolic encephalopathy, 4 seizure and 1 syncope) were reported in 27% (26/95) of patients in the TAH group in the non-randomised prospective comparative study of 130 patients. Transplantation was delayed in 6 patients. Neurologic events were reported in 16% (16/101) of patients in the case series of 101 patients. Strokes were reported in 8% (8/101) of patients (5 within 9 days). Peripheral emboli (1 celiac artery, 2 spleen, 1 superior mesenteric artery, 2 kidney, 2 retina) were reported in 8% (8/101) of patients, 4 of whom died. Strokes rates were not significantly different between the TAH and BIVAD groups during support in the non-randomised prospective comparative study of 148 patients (TAH 12% compared with BIVAD 24% ; p=0.08). Strokes were reported in 10% (9/90) of patients while on device support in the case series of 90 patients with TAH implantation. Thromboembolic events (at a median time of 500 days) were reported in 19% (9/47) of patients in the case series of 47 patients with TAH support for more than 1 year; 6 had a transient ischaemic attack and 3 had a major cerebrovascular accident with hemiparesis or aphasia.
Technical or procedural problems (obstruction of the mechanical tricuspid valve of the TAH because of migration of the central venous catheter) were reported in 3% (3/95) of patients in the TAH group in the non-randomised prospective comparative study of 130 patients. This caused death in 1 patient. Catheter entrapment of a central line in the tricuspid valve was reported in 2 patients in the case series of 101 patients with TAH implantation. Both these patients had irreversible brain damage from device arrest and died.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not describe any anecdotal or theoretical adverse events.# Further information
For related NICE guidance, see the NICE website.
Patient commentary was sought but none was received.
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2751-7
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{'Recommendations': "Current evidence on the safety and efficacy of total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure (see section\xa06.3).\n\nClinicians should enter details about all patients having total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure onto an appropriate registry and review local clinical outcomes.\n\nPatient selection should be done by a multidisciplinary team experienced in managing end-stage refractory biventricular heart failure in patients needing a heart transplant, for whom a donor organ is not expected to be available before their own heart fails completely.\n\nThis technically challenging procedure should only be done in centres specialising in heart transplantation. Only cardiothoracic surgeons with specific expertise and training in inserting the device should carry it out.\n\nNICE encourages further research into total artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure, including well matched comparative studies. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Biventricular heart failure results from structural or functional abnormalities of the heart. It leads to reduced blood flow to body tissues and oedema in the lungs (causing breathlessness) and the periphery (causing swelling of the legs). Other symptoms include reduced exercise tolerance, fatigue and malaise.\n\nMedical treatment of heart failure involves drugs, such as diuretics and inotropic agents, to improve heart function. Invasive therapies, such as electrophysiological interventions, coronary revascularisation, valve replacement or repair, may also be used for patients with end-stage refractory biventricular heart failure. When these therapies no longer work, left ventricular or biventricular assist devices or heart transplantation may be considered.', 'The procedure': "A total artificial heart (TAH) can be implanted to provide circulatory support with the aim that the patient survives while waiting for a donor heart to become available (a technique known as 'bridge to transplantation'). In this procedure, the device replaces the heart function completely.\n\nImplantation of a TAH is done with the patient under general anaesthesia and on cardiopulmonary bypass. The native left and right ventricles, and all 4\xa0cardiac valves are excised. The TAH device is implanted and attached to the atria, for blood inflow, and pulmonary artery and aorta, for blood outflow. Depending on the type of TAH, power is supplied either by drive lines connected percutaneously to an external biventricular pneumatic pump (which may be portable or static) or by batteries that are implanted internally and can be recharged through the skin using a transcutaneous energy transfer system. When the device begins to pump and restores blood flow around the body, cardiopulmonary bypass is stopped and the chest incision is closed.", 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a non-randomised prospective comparative study of patients at risk of imminent death from irreversible biventricular heart failure, total artificial heart (TAH) implantation (n=81) was compared with no TAH implantation (matched historical controls; n=35). The rates of survival to heart transplantation were 79% (95% confidence interval [CI] 68% to 87%) in the TAH group compared with 46% in the control group (p<0.001). The 1‑year survival to heart transplantation rates were 70% (95% CI 63% to 77%) and 31% respectively (p<0.001).In a non-randomised retrospective comparative study (United Network of Organ Sharing [UNOS] database analysis) comparing TAH support (n=212) with biventricular assisted device (BIVAD) support (n=366) as a bridge to transplantation (BTT) in adult patients, device support survival rates were similar in both groups (p=0.8): 95% compared with 93% at 30\xa0days and 77% compared with 69% at 1\xa0year.In a non-randomised retrospective comparative study comparing TAH support (n=81) with paracorporeal BIVAD support (n=67) as a BTT in 148\xa0adult patients, device support survival rates were similar between the groups (p=0.87): 76% compared with 72% at 30\xa0days; 63% compared with 61% at 2\xa0months; and 46% compared with 53% at 6\xa0months respectively.In a case series of 101\xa0patients at risk of imminent death from irreversible biventricular heart failure and eligible for transplant, survival to heart transplantation with TAH implantation as a BTT was 68% (69/101). In a case series of 90\xa0patients with biventricular failure treated by TAH implantation as a BTT, actuarial survival on device was 74±5%, 63±6% and 47±8% at 30, 60 and 180\xa0days after implantation respectively. In a case series of 27\xa0patients with TAH implantation as a BTT, 44% (12/27) of patients were discharged from hospital within a median of 88\xa0days after implantation (range\xa035 to 152\xa0days). Support time between discharge and transplantation was spent out of hospital in 87% of patients.\n\nIn the non-randomised prospective comparative study comparing patients with TAH implantation (n=81) with matched historical controls (n=35), the survival rates at 1\xa0and 5\xa0years after transplantation in the TAH group were 86% and 64% compared with 69% and 34% in the control group respectively (p values not reported). In the non-randomised retrospective comparative study (UNOS database analysis) comparing TAH support with BIVAD support, survival rates after transplantation were 88% compared with 93% at 30\xa0days, 78% compared with 83% at 1\xa0year, and 67% compared with 73% at 3\xa0years respectively (p=0.06). In the non-randomised comparative study of 148\xa0patients, survival rates after transplantation in the TAH group (n=51) and the paracorporeal BIVAD group (n=39) were similar (p=0.60): 77% compared with 76% at\xa01year; 72% compared with 70% at 3\xa0years; and 70% compared with 58% at 5\xa0years. In the case series of 101\xa0patients with TAH implantation, survival after transplantation at 1, 5 and 10\xa0years was 77%, 61% and 41% respectively. In the case series of 90\xa0patients with TAH implantation, actuarial survival rates after transplantation were 78±6%, 71±6% and 63±8% at 1, 5 and 8\xa0years respectively. In the case series of 27\xa0patients with TAH implantation, survival after transplantation (n=12) at a median 20‑month follow-up was 91%.\n\nIn the non-randomised prospective comparative study comparing patients who had TAH implantation (n=81) with matched historical controls (n=35), the overall survival rate at 1\xa0year was 70% (95% CI 63% to 77%) and 31% respectively (p<0.001). In the case series of 101\xa0patients with TAH implantation, the overall survival at 1, 5, 10 and 15\xa0years was 55% (n=56), 43% (n=35), 28% (n=18), and 26% (n=3) respectively.\n\nIn the non-randomised prospective comparative study comparing patients with TAH implantation (n=81) with matched historical controls (n=35), quality of life in the TAH group improved significantly: 75% of patients were out of bed 1\xa0week after implantation and mobility (defined as ability to walk more than 100\xa0feet) was seen in 61% of patients (method of measurement not reported). In the case series of 27\xa0patients with TAH implantation, the quality of life results for 12\xa0patients at home (measured using a modified ED‑5D defined by INTERMACS) showed that only 1\xa0young patient was able to return to school. Patients and families reported the console's noise as bothersome.\n\nThe specialist advisers listed the key efficacy outcomes as survival to hospital discharge, survival and successful BTT at 6\xa0and 12\xa0months, and survival after transplantation.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a non-randomised retrospective comparative study of 578\xa0patients (United Network of Organ Sharing [UNOS] database analysis), rates of deaths were not significantly different between total artificial heart (TAH) and biventricular assisted device (BIVAD) groups: 10% (22/212) compared with 12% (45/366), p=0.7 while on support; and 30% (64/212) compared with 30% (111/366), p=0.9 after transplantation. The causes of death while on device support (infection, multi-organ failure, stroke or haemorrhage) and after heart transplantation (acute rejection, infection, cardiac arrest, multi-organ failure and stroke) for both groups were also similar. In a non-randomised prospective comparative study of 130\xa0patients, rates of death before transplantation were 21% (17/81) in the TAH group compared with 54% (19/35) in the control group (p value not reported). Causes of the 17\xa0deaths before transplantation in the TAH group were multi-organ failure (7), procedural or technical complications (4), bleeding (2), sepsis (2), congestive heart failure (1) and pulmonary oedema (1). In the same group after transplantation, there were 6\xa0deaths (3\xa0graft failure, 1\xa0sepsis, 1\xa0procedural or technical complication and 1\xa0multi-organ failure). Rates of deaths in a non-randomised retrospective comparative study of 148\xa0patients were not significantly different between TAH and BIVAD support groups while on support (37% compared with 39%; p=0.87). Death occurred in 32% (32/101) of patients in a case series of 101\xa0patients with TAH implantation; 70% were within the first 14\xa0days. Causes of deaths were multi-organ failure (13), pneumonia or pulmonary oedema (6), sepsis (5), neurologic injury (4, including 1 stroke, 1 hypoxic damage from hypotension and 2 intracranial haemorrhage), pancreatic abscess (1), small intestinal ischaemia (1), disseminated intravascular coagulopathy (1), and disseminated coccidiodomycosis (1).\n\nBleeding events were reported in 62% (59/95) of patients in the TAH group in the non-randomised prospective comparative study of 130\xa0patients. Of these events, 50% occurred during TAH implantation and were mainly tamponade or mediastinal bleeding (needing surgery and blood transfusion) within 21\xa0days. Two patients died from bleeding: 1 during TAH implantation and 1 during heart transplantation). Bleeding (from various sites) at a mean of 4\xa0days was reported in 43% (43/101) of patients in the case series of 101\xa0patients. Reoperations for haemorrhage (mediastinal explorations) were done in 25% (25/101) of patients. The surgical revision rate for bleeding or haematoma was significantly lower in the TAH group than the BIVAD group in the non-randomised comparative study (23% [17/81] compared with 42% [28/67] respectively; p=0.03). Surgical re-exploration for bleeding, haematoma or infection was reported in 39% (35/90) of patients while on device support in the case series of 90\xa0patients. Haemorrhagic events (at a median time of 249\xa0days) were reported in 14% (7/47) of patients in the case series of 47\xa0patients with TAH support for more than 1\xa0year. These included cerebral haemorrhage (n=3), subarachnoid haemorrhage (n=2), and gastrointestinal bleeding (n=2).\n\nDevice malfunction events were reported in 17% (16/95) of patients in the TAH group in the non-randomised prospective comparative study of 130\xa0patients. One patient died because of perforation in 1 of the layers of the device's left ventricular diaphragm on day\xa0124. Fitting complications were reported in 5% (5/95) of patients in the TAH group in the same study; 2\xa0patients died because of poor fitting and 3\xa0patients had repeat surgery to reposition the device. Device failure was reported in 10% (5/47) of patients in the case series of 47\xa0patients with TAH support for more than 1\xa0year; there were 3\xa0membrane ruptures (2\xa0patients died), 1\xa0air hole in the driveline and 1\xa0lower pump output. Device malfunction (technical problems with the alarm and computer monitoring system needing console change) was reported in 1\xa0patient during hospitalisation in the case series of 27\xa0patients. Malfunctions were reported in 25% (3/12) of patients discharged home after TAH implantation. In 2\xa0patients, an air leak occurred in the driveline to the ventricle, which was sealed with a silicon band. In 1\xa0patient, alarm triggering was caused by auricular compression during some movements (stretching and yawning) and the patient was advised to avoid them.\n\nThe renal failure rate was significantly higher in the TAH support group than the BIVAD support group after implantation (24% [52/212] compared with 10% [35/366]; p<0.0001) and after transplantation (26% [56/212] compared with 14% [49/366]; p=0.0001) in the non-randomised retrospective comparative study (UNOS database analysis). Renal failure (needing postoperative renal replacement therapy) was reported in 64% (30/47) of patients in the case series of 47\xa0patients with TAH support for more than 1\xa0year. Recovery of renal function occurred in 73% (22/47) of patients but therapy continued in 17% (8/47) of patients.\n\nThe infection rate after implantation was significantly lower in the TAH group than the BIVAD group (22% [46/212] compared with 28% [104/366]; p=0.005) in the non-randomised retrospective comparative study (UNOS database analysis). Infections (7\xa0blood, 50\xa0respiratory, 5\xa0mediastinal, 28\xa0genitourinary, 12\xa0gastrointestinal, 17\xa0driveline and 6\xa0in catheters) were reported in 77% (73/95) of patients in the TAH group in the non-randomised prospective comparative study of 130\xa0patients. Infections contributed to death in 7\xa0patients and delayed transplantation in 5\xa0patients. Infections (commonly in the lungs and urinary tract) were reported in 64% (64/101) of patients in the case series of 101\xa0patients. Rates of postoperative mediastinitis (TAH 12% [9/81] compared with BIVAD 5% [3/67]; p=0.14) or driveline infections (1\xa0patient with TAH compared with 2\xa0patients with BIVAD; p=0.61) were similar in both groups during support in the non-randomised comparative study of 148\xa0patients.\n\nNeurologic events (10\xa0stroke, 4\xa0transient ischaemic attack, 5\xa0anoxic encephalopathy, 1\xa0metabolic encephalopathy, 4\xa0seizure and 1\xa0syncope) were reported in 27% (26/95) of patients in the TAH group in the non-randomised prospective comparative study of 130\xa0patients. Transplantation was delayed in 6\xa0patients. Neurologic events were reported in 16% (16/101) of patients in the case series of 101\xa0patients. Strokes were reported in 8% (8/101) of patients (5 within 9\xa0days). Peripheral emboli (1\xa0celiac artery, 2\xa0spleen, 1\xa0superior mesenteric artery, 2\xa0kidney, 2\xa0retina) were reported in 8% (8/101) of patients, 4\xa0of whom died. Strokes rates were not significantly different between the TAH and BIVAD groups during support in the non-randomised prospective comparative study of 148\xa0patients (TAH 12% [9/81] compared with BIVAD 24% [16/67]; p=0.08). Strokes were reported in 10% (9/90) of patients while on device support in the case series of 90\xa0patients with TAH implantation. Thromboembolic events (at a median time of 500\xa0days) were reported in 19% (9/47) of patients in the case series of 47\xa0patients with TAH support for more than 1\xa0year; 6\xa0had a transient ischaemic attack and 3\xa0had a major cerebrovascular accident with hemiparesis or aphasia.\n\nTechnical or procedural problems (obstruction of the mechanical tricuspid valve of the TAH because of migration of the central venous catheter) were reported in 3% (3/95) of patients in the TAH group in the non-randomised prospective comparative study of 130\xa0patients. This caused death in 1\xa0patient. Catheter entrapment of a central line in the tricuspid valve was reported in 2\xa0patients in the case series of 101\xa0patients with TAH implantation. Both these patients had irreversible brain damage from device arrest and died.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not describe any anecdotal or theoretical adverse events.", 'Further information': "For related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received.\n\nThis guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2751-7"}
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https://www.nice.org.uk/guidance/ipg602
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Evidence-based recommendations on artificial heart implantation as a bridge to transplantation for end-stage refractory biventricular heart failure. This involves replacing the 2 lower chambers of the heart with a mechanical device to improve circulation until heart transplantation.
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25447f7215cbfafd1cfd970db4ab43c0e48322d2
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nice
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Subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death
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Subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death
Evidence-based recommendations on subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death. This involves placing a device under the skin of the chest, which detects and treats fast heartbeats called tachyarrhythmias.
# Recommendations
Current evidence on the safety and efficacy of subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Clinicians should enter details about all patients having subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death onto a register by submitting data to the National Audit of Cardiac Rhythm Management database at the UK National Institute for Cardiovascular Outcomes Research (NICOR), and should review local clinical outcomes.
The procedure should only be done by clinicians with specific training on inserting the device.# Indications and current treatments
Sudden cardiac death is often caused by ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation). The most common cause of ventricular arrhythmias is underlying heart disease.
Prevention of sudden cardiac death can be primary, which is defined as preventing a first life-threatening arrhythmic event in someone who is at high risk of such an event. Or, it can be secondary, which refers to preventing further life-threatening events in survivors of previous serious ventricular arrhythmias. Treatment with an implantable cardioverter defibrillator (ICD) is recommended in NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure for patients with arrhythmias and those at risk of sudden cardiac death.
An ICD consists of a generator, which contains a battery, capacitor and sophisticated electronic circuitry, and 1 or more leads. The device senses and detects arrhythmias, and delivers pacing impulses or defibrillating shocks to the heart as necessary, to restore normal cardiac rhythm. A conventional transvenous ICD consists of a generator under the skin below the clavicle and 1 or more leads passed through a vein into the heart.# The procedure
An entirely subcutaneous implantable cardioverter defibrillator (ICD) differs from a transvenous ICD in that a single lead is placed subcutaneously. This single lead comprises 2 sensing ring electrodes and a shocking coil. The subcutaneous ICD senses cardiac signals, but the lead is not directly attached to the heart. Also, unlike a conventional transvenous ICD, the subcutaneous device is not designed to provide long-term pacing.
The implantation procedure is carried out with the patient under general anaesthesia, or with local anaesthesia and sedation. Implantation is guided by anatomical landmarks with or without the use of fluoroscopy or other medical imaging. A subcutaneous pocket for the generator is created on the left side of the chest. The lead is tunnelled subcutaneously from the pocket to a small incision at the lower end of the sternum. Then, it is tunnelled to the upper end of the sternum so that the sensing ring electrodes and shocking coil lie alongside the sternum. The lead can be secured using either a 2- or 3‑incision technique, and is then connected to the generator in the pocket. Finally, the incisions are closed and the sensing and recording functions of the subcutaneous ICD are adjusted using an external programmer. Ventricular fibrillation is induced to test that the subcutaneous ICD can appropriately detect and correct it.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a matched-controlled study of 138 patients comparing 69 patients with subcutaneous implantable cardioverter defibrillators (ICD) and 69 patients with transvenous ICDs, the conversion rates of induced ventricular fibrillation at implantation were similar (p=0.81): 90% (60/67) for 65 J of energy (15‑J safety margin) in the subcutaneous ICD group and 91% (59/65) for a device-dependent 10‑J safety margin in the transvenous ICD group. In a systematic review of 5,380 patients from 16 studies, the defibrillator threshold test was successful on the first attempt in 89% of patients (range 70 to 100%) and in 96% after reprogramming.
In a retrospective propensity-matched cohort study of 280 patients (140 with subcutaneous ICDs and 140 with transvenous ICDs), appropriate ICD intervention rates (shocks and anti-tachycardia pacing) were lower in the subcutaneous ICD group, at 17% (95% confidence intervals 6 to 26%) compared with 31% (95% CI 23 to 40%) in the transvenous ICD group (hazard ratio 2.42; p=0.01). However, the incidence of appropriate shocks was similar in both groups (HR 1.46; p=0.36). In a case series of 889 patients, which combined patients from the IDE study and from an international registry (Effortless), 111 episodes of spontaneous ventricular arrhythmias were treated in 59 patients within a mean 22‑month follow-up; 90% (100/111) of these events were stopped with 1 shock and 98% (109/111) were stopped within the 5 available shocks. In the systematic review of 5,380 patients, the range of the first shock efficacy rate was 58 to 90% and the overall shock efficacy rate was 96% or more.
In the prospective case series of 321 patients, the mean time to therapy (defined as the interval starting 2,000 milliseconds after the last induction artefact and ending at the onset of the shock deflection on a standard ECG) was 14.6 seconds (range 9.6 to 29.7 seconds). A time to therapy of greater than 18.0 seconds was noted in 13% of episodes. In an international registry of 985 patients, there was a statistically significant difference between the mean (± standard deviation) time to therapy for induced episodes and for spontaneous episodes (15.1±3.5 seconds compared with 18.4±4.3 seconds, p<0.001).
In the retrospective propensity-matched cohort study of 280 patients comparing 140 patients with subcutaneous ICDs and 140 patients with transvenous ICDs, 5‑year patient survival was similar in both groups (96% and 95% respectively, p=0.42).
In a propensity-matched case-control study of 334 patients comparing 167 patients from the Effortless registry with 167 patients with transvenous ICDs from the Midas prospective observational study cohort, there were no statistically significant differences between groups on physical (p=0.8157) and mental quality-of-life scores measured using the SF‑12 questionnaire (p=0.9080) at baseline, and 3 months and 6 months after implantation in adjusted analyses. The evolution in physical (p=0.0503) and mental scores (p=0.3772) during 6‑month follow-up was similar for both cohorts. Both patients with subcutaneous ICDs and patients with transvenous ICDs experienced statistically significant improvements in physical and mental quality of life between implantation and 3‑month follow-up (p<0.0001) and 6‑month follow-up (p<0.0001). However, the difference between 3- and 6‑month follow-up was not statistically significant.
In the systematic review of 5,380 patients, the median device longevity was 5.0 years (range 4.4 to 5.6 years).
The specialist advisers listed the following key efficacy outcomes: successful detection of ventricular arrhythmias, successful delivery of shock to restore normal rhythm, prevention of sudden death and low rate of inappropriate shocks.
Seven commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Death was reported in 1% (2/140) of patients in the subcutaneous implantable cardioverter defibrillators (ICD) group (1 from a non-cardiac cause and 1 from a cardiac cause) and in 4% (6/140) of patients in the transvenous ICD group (3 from non-cardiac causes, 2 from cardiac causes and 1 for an unknown reason) in a retrospective propensity-matched cohort study of 280 patients with a 5‑year follow-up. Death from congestive heart failure was reported in 1 patient in the subcutaneous ICD group in a matched-controlled study of 138 patients comparing 69 patients with subcutaneous ICDs and 69 matched patients with transvenous ICDs (average follow-up 217 days). All-cause mortality rate was 3% (26/882) in a case series of 889 patients with a mean 22‑month follow-up that combined patients from a prospective case series and from an international registry (Effortless). There was only 1 known arrhythmic death due to Loeffler's syndrome. The 3‑year Kaplan–Meier estimate was 5% (95% confidence interval 1 to 9%), with 26 deaths (3%). Death was reported in 5% (48/985) of patients in an international registry of 985 patients, within a 3.1‑year follow-up. The primary cause was cardiac-related in 44% (21/48) of these patients: 1 was arrhythmic and the other deaths related to pump failure (14 deaths), ischaemic events (2 deaths) or other cardiac causes (4 deaths), and 98% (47/48) of deaths occurred outside the perioperative window of 30 days. No deaths were associated with the subcutaneous ICD system procedure.
Inappropriate shock rate was 21% in the subcutaneous ICD group (17% because of oversensing and 4% because of supraventricular tachycardia) compared with 19% in the transvenous ICD group (1% because of oversensing and 18% because of supraventricular tachycardia) in the retrospective propensity-matched cohort study of 280 patients. In the same study, inappropriate sensing rate was 3% in the subcutaneous ICD group and zero in the transvenous ICD group. The estimated 3‑year inappropriate shock rate was 13% in the case series of 889 patients. The causes were T‑wave oversensing in 39%, supraventricular arrhythmia above the discrimination zone in 24%, low amplitude signal in 21%, non-cardiac oversensing in 8%, oversensing of ventricular tachycardia and fibrillation below the rate zone in 4%, other or combined types of cardiac oversensing in 2%, supraventricular arrhythmia discrimination errors in 1%, and committed shock for ventricular tachycardia and fibrillation in 1%. Inappropriate shocks were reported in 8% (15/985) of patients during the first year and in 12% (115/985) of patients within a mean 3.1‑year follow-up in the international registry of 985 patients (some of these patients were also included in the case series of 889 patients). The causes were oversensing in 11 of the patients and supraventricular tachycardia above the discrimination zone (normal device function) in 2 of the patients (no cause reported for the other 2 patients). Inappropriate shocks were reported in 4% of patients (range 0 to 15%) in the systematic review of 5,380 patients. The most common cause was T‑wave oversensing. Inappropriate therapy due to supraventricular tachycardia, and artefact from noise or myopotentials were rare.
Pulse generator replacement due to battery depletion did not differ between the groups at 5‑year follow-up in the retrospective propensity-matched cohort study of 280 patients (p=0.18). Premature battery depletion was reported in 5 patients in the case series of 889 patients. Rapid battery depletion causing premature elective replacement of the device was reported in 9% (5/55) of devices, with a mean service time of 1.5 years, in a case series of 55 patients; 71% of devices were still in service at 5‑year follow-up. Premature battery depletion was reported in 1% of patients (range 0 to 9%, 16 events, 1,384 patients from 10 studies) in the systematic review of 5,380 patients.
Failure to communicate with the device was reported in less than 1% of patients (range 0 to 1%, 4 events, 1,249 patients from 8 studies) in the systematic review of 5,380 patients.
Twiddler syndrome rate was 1% in both groups in the retrospective propensity-matched cohort study of 280 patients.
Device failure rate was 1% in the subcutaneous ICD group and none in the transvenous ICD group in the retrospective propensity-matched cohort study of 280 patients. Failure of the device to convert during the procedure was reported in 7 patients in the US registry of 1,637 patients. Failure of the device to cardiovert ventricular arrhythmia was reported in 1 patient out of 69 patients in a propensity-matched case-control study of 138 patients within a mean 31‑month follow-up.
Explantation of the subcutaneous ICD for pacing was reported in 4 patients because of the need for ventricular pacing in the case series of 889 patients: 1 patient developed a new bradycardia indication; in 1 patient, the device was explanted because of the need for anti-tachycardia pacing; and 1 patient with 3 ventricular tachycardia storm events had replacement with a transvenous ICD in an attempt to suppress ventricular arrhythmias using overdrive pacing. In addition, 1 device was extracted for a cardiac resynchronisation therapy upgrade. Device replacement was reported in 47% (26/55) of patients and device explantation (permanent removal) was reported in 9% (5/55) of patients during a median 5.8‑year follow-up in the case series of 55 patients. The indications for device replacement or explantation were battery depletion in 81% (25/31) of patients, replacement with a transvenous ICD system in 13% (4/31), infection in 1 patient and 'other' in 1 patient. The median time for device replacement was 5 years (first quartile–third quartile, 4.4 to 5.6 years) and the event-free rates for device replacement were 94% (95% CI 83 to 98%) after 2 years, 89% (95% CI 76 to 96%) after 4 years and 30% (95% CI 15 to 46%) after 6 years. Device explantation was reported in 4% of patients (range 0 to 12%, 57 events, 1,514 patients from 11 studies) in the systematic review of 5,380 patients. The explant indications were pocket infection (2%, 29 events, 1,585 patients, number of studies not reported), need for pacing, inappropriate shocks and unsuccessful defibrillation threshold testing. Generator repositioning or explant for erosion were needed in 2% of patients (total number of patients not reported).
Erosion rate was 3% in the subcutaneous ICD group and 2% in the transvenous ICD group in the retrospective propensity-matched cohort study of 280 patients. Erosion was reported in 1% (11) of patients in the case series of 889 patients.
Infection needing device removal or revision was reported in 2% (14) of patients in the case series of 889 patients. In the same study, incision or superficial infection were reported in 3 patients. Pocket infection was reported in 3% of patients (range 0 to 19%, 44 events, 1,654 patients from 14 studies) in the systematic review of 5,380 patients.
Haematoma was reported in less than1% of patients (range 0 to 3%, 22 events, 5,044 patients from 10 studies) in the systematic review of 5,380 patients.
Delayed wound healing was reported in less than 1% of patients (range 0 to 19%, 7 events, 1,145 patients from 7 studies) in the systematic review of 5,380 patients.
Suboptimal electrode position was reported in 7 patients in the case series of 889 patients. In the same study, suboptimal pulse generator position was reported in 2 patients and, suboptimal pulse generator and electrode position were reported in 4 patients.
Electrode movement was reported in 5 patients in the case series of 889 patients. The lead complication rate was statistically significantly lower in the subcutaneous ICD group than in the transvenous ICD group in the retrospective propensity-matched cohort study of 280 patients (1% versus 12%; p=0.03). The only lead complication reported in the subcutaneous ICD group was lead movement, which occurred in 1 patient out of 140.
Pleural effusion was reported in 1 patient in the US registry of 1,637 patients.
Pneumothorax was reported in 1 patient in the US registry of 1,637 patients.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: discomfort around the device. They did not identify any theoretical adverse events.
Seven commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information
For related NICE guidance, see the NICE website.
# Information for patients
NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2753-1
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{'Recommendations': 'Current evidence on the safety and efficacy of subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians should enter details about all patients having subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death onto a register by submitting data to the National Audit of Cardiac Rhythm Management database at the UK National Institute for Cardiovascular Outcomes Research (NICOR), and should review local clinical outcomes.\n\nThe procedure should only be done by clinicians with specific training on inserting the device.', 'Indications and current treatments': "Sudden cardiac death is often caused by ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation). The most common cause of ventricular arrhythmias is underlying heart disease.\n\nPrevention of sudden cardiac death can be primary, which is defined as preventing a first life-threatening arrhythmic event in someone who is at high risk of such an event. Or, it can be secondary, which refers to preventing further life-threatening events in survivors of previous serious ventricular arrhythmias. Treatment with an implantable cardioverter defibrillator (ICD) is recommended in NICE's technology appraisal guidance on implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure for patients with arrhythmias and those at risk of sudden cardiac death.\n\nAn ICD consists of a generator, which contains a battery, capacitor and sophisticated electronic circuitry, and 1\xa0or more leads. The device senses and detects arrhythmias, and delivers pacing impulses or defibrillating shocks to the heart as necessary, to restore normal cardiac rhythm. A conventional transvenous ICD consists of a generator under the skin below the clavicle and 1\xa0or more leads passed through a vein into the heart.", 'The procedure': 'An entirely subcutaneous implantable cardioverter defibrillator (ICD) differs from a transvenous ICD in that a single lead is placed subcutaneously. This single lead comprises 2\xa0sensing ring electrodes and a shocking coil. The subcutaneous ICD senses cardiac signals, but the lead is not directly attached to the heart. Also, unlike a conventional transvenous ICD, the subcutaneous device is not designed to provide long-term pacing.\n\nThe implantation procedure is carried out with the patient under general anaesthesia, or with local anaesthesia and sedation. Implantation is guided by anatomical landmarks with or without the use of fluoroscopy or other medical imaging. A subcutaneous pocket for the generator is created on the left side of the chest. The lead is tunnelled subcutaneously from the pocket to a small incision at the lower end of the sternum. Then, it is tunnelled to the upper end of the sternum so that the sensing ring electrodes and shocking coil lie alongside the sternum. The lead can be secured using either a 2-\xa0or 3‑incision technique, and is then connected to the generator in the pocket. Finally, the incisions are closed and the sensing and recording functions of the subcutaneous ICD are adjusted using an external programmer. Ventricular fibrillation is induced to test that the subcutaneous ICD can appropriately detect and correct it.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a matched-controlled study of 138\xa0patients comparing 69\xa0patients with subcutaneous implantable cardioverter defibrillators (ICD) and 69\xa0patients with transvenous ICDs, the conversion rates of induced ventricular fibrillation at implantation were similar (p=0.81): 90% (60/67) for 65\xa0J of energy (15‑J safety margin) in the subcutaneous ICD group and 91% (59/65) for a device-dependent 10‑J safety margin in the transvenous ICD group. In a systematic review of 5,380\xa0patients from 16\xa0studies, the defibrillator threshold test was successful on the first attempt in 89% of patients (range 70 to 100%) and in 96% after reprogramming.\n\nIn a retrospective propensity-matched cohort study of 280\xa0patients (140\xa0with subcutaneous ICDs and 140\xa0with transvenous ICDs), appropriate ICD intervention rates (shocks and anti-tachycardia pacing) were lower in the subcutaneous ICD group, at 17% (95% confidence intervals [CI] 6 to 26%) compared with 31% (95%\xa0CI 23 to 40%) in the transvenous ICD group (hazard ratio [HR]\xa02.42; p=0.01). However, the incidence of appropriate shocks was similar in both groups (HR\xa01.46; p=0.36). In a case series of 889\xa0patients, which combined patients from the IDE study and from an international registry (Effortless), 111\xa0episodes of spontaneous ventricular arrhythmias were treated in 59\xa0patients within a mean 22‑month follow-up; 90% (100/111) of these events were stopped with 1\xa0shock and 98% (109/111) were stopped within the 5\xa0available shocks. In the systematic review of 5,380\xa0patients, the range of the first shock efficacy rate was 58 to 90% and the overall shock efficacy rate was 96% or more.\n\nIn the prospective case series of 321\xa0patients, the mean time to therapy (defined as the interval starting 2,000\xa0milliseconds after the last induction artefact and ending at the onset of the shock deflection on a standard ECG) was 14.6\xa0seconds (range 9.6\xa0to 29.7\xa0seconds). A time to therapy of greater than 18.0\xa0seconds was noted in 13% of episodes. In an international registry of 985\xa0patients, there was a statistically significant difference between the mean (± standard deviation) time to therapy for induced episodes and for spontaneous episodes (15.1±3.5\xa0seconds compared with 18.4±4.3\xa0seconds, p<0.001).\n\nIn the retrospective propensity-matched cohort study of 280\xa0patients comparing 140\xa0patients with subcutaneous ICDs and 140\xa0patients with transvenous ICDs, 5‑year patient survival was similar in both groups (96% and 95% respectively, p=0.42).\n\nIn a propensity-matched case-control study of 334\xa0patients comparing 167\xa0patients from the Effortless registry with 167\xa0patients with transvenous ICDs from the Midas prospective observational study cohort, there were no statistically significant differences between groups on physical (p=0.8157) and mental quality-of-life scores measured using the SF‑12 questionnaire (p=0.9080) at baseline, and 3\xa0months and 6\xa0months after implantation in adjusted analyses. The evolution in physical (p=0.0503) and mental scores (p=0.3772) during 6‑month follow-up was similar for both cohorts. Both patients with subcutaneous ICDs and patients with transvenous ICDs experienced statistically significant improvements in physical and mental quality of life between implantation and 3‑month follow-up (p<0.0001) and 6‑month follow-up (p<0.0001). However, the difference between 3- and 6‑month follow-up was not statistically significant.\n\nIn the systematic review of 5,380\xa0patients, the median device longevity was 5.0\xa0years (range 4.4\xa0to 5.6\xa0years).\n\nThe specialist advisers listed the following key efficacy outcomes: successful detection of ventricular arrhythmias, successful delivery of shock to restore normal rhythm, prevention of sudden death and low rate of inappropriate shocks.\n\nSeven commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nDeath was reported in 1% (2/140) of patients in the subcutaneous implantable cardioverter defibrillators (ICD) group (1\xa0from a non-cardiac cause and 1\xa0from a cardiac cause) and in 4% (6/140) of patients in the transvenous ICD group (3\xa0from non-cardiac causes, 2\xa0from cardiac causes and 1\xa0for an unknown reason) in a retrospective propensity-matched cohort study of 280\xa0patients with a 5‑year follow-up. Death from congestive heart failure was reported in 1\xa0patient in the subcutaneous ICD group in a matched-controlled study of 138\xa0patients comparing 69\xa0patients with subcutaneous ICDs and 69\xa0matched patients with transvenous ICDs (average follow-up 217\xa0days). All-cause mortality rate was 3% (26/882) in a case series of 889\xa0patients with a mean 22‑month follow-up that combined patients from a prospective case series and from an international registry (Effortless). There was only 1\xa0known arrhythmic death due to Loeffler's syndrome. The 3‑year Kaplan–Meier estimate was 5% (95% confidence interval [CI] 1 to 9%), with 26\xa0deaths (3%). Death was reported in 5% (48/985) of patients in an international registry of 985\xa0patients, within a 3.1‑year follow-up. The primary cause was cardiac-related in 44% (21/48) of these patients: 1\xa0was arrhythmic and the other deaths related to pump failure (14\xa0deaths), ischaemic events (2\xa0deaths) or other cardiac causes (4\xa0deaths), and 98% (47/48) of deaths occurred outside the perioperative window of 30\xa0days. No deaths were associated with the subcutaneous ICD system procedure.\n\nInappropriate shock rate was 21% in the subcutaneous ICD group (17% because of oversensing and 4% because of supraventricular tachycardia) compared with 19% in the transvenous ICD group (1% because of oversensing and 18% because of supraventricular tachycardia) in the retrospective propensity-matched cohort study of 280\xa0patients. In the same study, inappropriate sensing rate was 3% in the subcutaneous ICD group and zero in the transvenous ICD group. The estimated 3‑year inappropriate shock rate was 13% in the case series of 889\xa0patients. The causes were T‑wave oversensing in 39%, supraventricular arrhythmia above the discrimination zone in 24%, low amplitude signal in 21%, non-cardiac oversensing in 8%, oversensing of ventricular tachycardia and fibrillation below the rate zone in 4%, other or combined types of cardiac oversensing in 2%, supraventricular arrhythmia discrimination errors in 1%, and committed shock for ventricular tachycardia and fibrillation in 1%. Inappropriate shocks were reported in 8% (15/985) of patients during the first year and in 12% (115/985) of patients within a mean 3.1‑year follow-up in the international registry of 985\xa0patients (some of these patients were also included in the case series of 889\xa0patients). The causes were oversensing in 11\xa0of the patients and supraventricular tachycardia above the discrimination zone (normal device function) in 2\xa0of the patients (no cause reported for the other 2\xa0patients). Inappropriate shocks were reported in 4% of patients (range 0 to 15%) in the systematic review of 5,380\xa0patients. The most common cause was T‑wave oversensing. Inappropriate therapy due to supraventricular tachycardia, and artefact from noise or myopotentials were rare.\n\nPulse generator replacement due to battery depletion did not differ between the groups at 5‑year follow-up in the retrospective propensity-matched cohort study of 280\xa0patients (p=0.18). Premature battery depletion was reported in 5\xa0patients in the case series of 889\xa0patients. Rapid battery depletion causing premature elective replacement of the device was reported in 9% (5/55) of devices, with a mean service time of 1.5\xa0years, in a case series of 55\xa0patients; 71% of devices were still in service at 5‑year follow-up. Premature battery depletion was reported in 1% of patients (range 0 to 9%, 16\xa0events, 1,384\xa0patients from 10\xa0studies) in the systematic review of 5,380\xa0patients.\n\nFailure to communicate with the device was reported in less than 1% of patients (range 0 to 1%, 4\xa0events, 1,249\xa0patients from 8\xa0studies) in the systematic review of 5,380\xa0patients.\n\nTwiddler syndrome rate was 1% in both groups in the retrospective propensity-matched cohort study of 280\xa0patients.\n\nDevice failure rate was 1% in the subcutaneous ICD group and none in the transvenous ICD group in the retrospective propensity-matched cohort study of 280\xa0patients. Failure of the device to convert during the procedure was reported in 7\xa0patients in the US registry of 1,637\xa0patients. Failure of the device to cardiovert ventricular arrhythmia was reported in 1\xa0patient out of 69\xa0patients in a propensity-matched case-control study of 138\xa0patients within a mean 31‑month follow-up.\n\nExplantation of the subcutaneous ICD for pacing was reported in 4\xa0patients because of the need for ventricular pacing in the case series of 889\xa0patients: 1\xa0patient developed a new bradycardia indication; in 1\xa0patient, the device was explanted because of the need for anti-tachycardia pacing; and 1\xa0patient with 3\xa0ventricular tachycardia storm events had replacement with a transvenous ICD in an attempt to suppress ventricular arrhythmias using overdrive pacing. In addition, 1\xa0device was extracted for a cardiac resynchronisation therapy upgrade. Device replacement was reported in 47% (26/55) of patients and device explantation (permanent removal) was reported in 9% (5/55) of patients during a median 5.8‑year follow-up in the case series of 55\xa0patients. The indications for device replacement or explantation were battery depletion in 81% (25/31) of patients, replacement with a transvenous ICD system in 13% (4/31), infection in 1\xa0patient and 'other' in 1\xa0patient. The median time for device replacement was 5\xa0years (first quartile–third quartile, 4.4\xa0to 5.6\xa0years) and the event-free rates for device replacement were 94% (95% CI 83 to 98%) after 2\xa0years, 89% (95%\xa0CI 76 to 96%) after 4\xa0years and 30% (95%\xa0CI 15 to 46%) after 6\xa0years. Device explantation was reported in 4% of patients (range 0 to 12%, 57\xa0events, 1,514\xa0patients from 11\xa0studies) in the systematic review of 5,380\xa0patients. The explant indications were pocket infection (2%, 29\xa0events, 1,585\xa0patients, number of studies not reported), need for pacing, inappropriate shocks and unsuccessful defibrillation threshold testing. Generator repositioning or explant for erosion were needed in 2% of patients (total number of patients not reported).\n\nErosion rate was 3% in the subcutaneous ICD group and 2% in the transvenous ICD group in the retrospective propensity-matched cohort study of 280\xa0patients. Erosion was reported in 1% (11) of patients in the case series of 889\xa0patients.\n\nInfection needing device removal or revision was reported in 2% (14) of patients in the case series of 889\xa0patients. In the same study, incision or superficial infection were reported in 3\xa0patients. Pocket infection was reported in 3% of patients (range 0 to 19%, 44\xa0events, 1,654\xa0patients from 14\xa0studies) in the systematic review of 5,380\xa0patients.\n\nHaematoma was reported in less than1% of patients (range 0 to 3%, 22\xa0events, 5,044\xa0patients from 10\xa0studies) in the systematic review of 5,380\xa0patients.\n\nDelayed wound healing was reported in less than 1% of patients (range 0 to 19%, 7\xa0events, 1,145\xa0patients from 7\xa0studies) in the systematic review of 5,380\xa0patients.\n\nSuboptimal electrode position was reported in 7\xa0patients in the case series of 889\xa0patients. In the same study, suboptimal pulse generator position was reported in 2\xa0patients and, suboptimal pulse generator and electrode position were reported in 4\xa0patients.\n\nElectrode movement was reported in 5\xa0patients in the case series of 889\xa0patients. The lead complication rate was statistically significantly lower in the subcutaneous ICD group than in the transvenous ICD group in the retrospective propensity-matched cohort study of 280\xa0patients (1% versus 12%; p=0.03). The only lead complication reported in the subcutaneous ICD group was lead movement, which occurred in 1\xa0patient out of\xa0140.\n\nPleural effusion was reported in 1\xa0patient in the US registry of 1,637\xa0patients.\n\nPneumothorax was reported in 1\xa0patient in the US registry of 1,637\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: discomfort around the device. They did not identify any theoretical adverse events.\n\nSeven commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2753-1'}
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https://www.nice.org.uk/guidance/ipg603
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Evidence-based recommendations on subcutaneous implantable cardioverter defibrillator insertion for preventing sudden cardiac death. This involves placing a device under the skin of the chest, which detects and treats fast heartbeats called tachyarrhythmias.
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2017b1a0fc6e93e63f2e7369e317743bb48d9939
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nice
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Endobronchial valve insertion to reduce lung volume in emphysema
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Endobronchial valve insertion to reduce lung volume in emphysema
Evidence-based recommendations on endobronchial valve insertion to reduce lung volume in emphysema. This involves placing small one-way valves in some airways leading to damaged parts of the lungs.
# Recommendations
Current evidence on the safety and efficacy of endobronchial valve insertion to reduce lung volume in emphysema is adequate in quantity and quality to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection should be done by a multidisciplinary team experienced in managing emphysema, which should typically include a chest physician, a radiologist, a thoracic surgeon and a respiratory nurse.
Patients selected for treatment should have had pulmonary rehabilitation.
The procedure should only be done to occlude volumes of the lung where there is no collateral ventilation, by clinicians with specific training in doing the procedure.# Indications and current treatments
Emphysema is a chronic lung disease in which the walls of the air sacs (alveoli) in the lungs weaken and disintegrate. This leaves behind abnormally large air spaces that stay filled with air even when the patient breathes out. The most common symptoms of emphysema are shortness of breath, coughing, fatigue and weight loss. Recurrent illnesses (such as chest infections) often lead to exacerbations, for which patients may need hospitalisation. Emphysema is usually smoking related but may also be inherited.
Treatment options include pulmonary rehabilitation (exercise training, breathing retraining, and patient and carer education), smoking cessation, and the use of inhaled or oral bronchodilators and corticosteroids. Oxygen therapy may also be indicated in more severe cases. Lung volume reduction surgery is an option for patients who experience breathlessness, and whose pulmonary function test results show severe obstruction and enlarged lungs. Such surgery can be done thoracoscopically (using video-assisted thoracoscopy or thoracotomy) or using an open approach (using a sternotomy or thoracotomy). Lung transplantation surgery may also be an option. Certain therapies under clinical investigation such as coiling, use of sealants and thermal ablation may be used in regional lung disease.# The procedure
The aim of insertion of endobronchial valves (also known as intrabronchial valves) to reduce lung volume in emphysema is to achieve atelectasis of selected lung segments. It uses an endoscopic approach, which is less invasive than open or thoracoscopic lung volume reduction surgery. Before the procedure, it is usual practice to assess the presence of collateral ventilation (when air enters a lobe of the lung through a passage that bypasses the normal airway). A surrogate for this is CT scanning to assess the completeness of fissures. A functional approach, specially developed for use before airway valve insertion, involves a specially designed balloon catheter with a flow sensor.
Endobronchial valve insertion is done with the patient under sedation or general anaesthesia. Using a delivery catheter passed through a bronchoscope, a synthetic valve is placed in the target location and fixed to the bronchial wall. The valve is designed to prevent air inflow during inspiration but to allow air and mucus to exit during expiration. Several valves may be needed (1 or more for each segment of the lung to be treated). Patients may sometimes be given antibiotics or corticosteroids. Two devices with different designs are available for interventional lung volume reduction – 1 is duckbill shaped and the other umbrella shaped.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
A systematic review (SR) and meta-analysis included 5 randomised controlled trials (RCTs) of patients (n=703) treated by duckbill-shaped endobronchial valve (EBV) insertion and 3 RCTs of patients (n=372) treated by umbrella-shaped EBV insertion, both compared with standard medical care (SMC). These 2 groups were analysed separately. In a meta-analysis of the 5 RCTs of duckbill EBV insertion compared with SMC, there was a statistically significant difference in 1% change from baseline in forced expiratory volume in 1 second (FEV1) in favour of duckbill EBV insertion (standardised mean difference 0.48, 95% confidence interval 0.32 to 0.64, p<0.00001, I2=42). In 2 RCTs (n=143) from the same meta-analysis, a 2% increase in FEV1 was statistically significantly more frequent in patients treated by duckbill EBV than in those treated by SMC at 90‑day follow-up (SMD 0.77, 95% CI 0.43 to 1.11, p<0.00001, I2 = 0%). In the other 3 RCTs (n=560) from the same meta-analysis, a 2% increase in FEV1 was statistically significantly more frequent in patients treated by duckbill EBV than in those treated by SMC at 6‑month follow-up (SMD 0.40, 95% CI 0.22 to 0.58, p<0.00001, I2=41%). One RCT (n=73), which studied patients treated by the umbrella EBV, reported no statistically significant difference in FEV1 measurements at 3‑month follow-up (MD 0.90 litres, standard deviation 0.34) compared with patients having SMC (0.87 litres, SD 0.34, p=0.065). A second RCT (n=22) of the umbrella EBV reported statistically significantly improved FEV1 measurements in patients treated unilaterally (21.4%, SD 10.7%) but not in patients treated bilaterally (−3.1%, SD 15.0; MD 24.50%, 95% CI 13.61 to 35.39). The SR reported a statistically significantly larger change in FEV1 from baseline in patients with heterogeneous emphysema treated by duckbill EBV than in patients with homogeneous emphysema having the same treatment (MD 16.36%, 95% CI 9.02 to 23.71, p=0.00001, I2=0%, n=137, 2 RCTs).
In 3 RCTs (n=542) included in the SR there was a statistically significant increase in FEV1 from baseline in patients without collateral ventilation treated by duckbill EBV (MD 18.15%, 95% CI 11.81 to 24.49; p=0.000001, I2=0%). Three RCTs (n=542) reported no statistically significant increase in FEV1 after duckbill EBV treatment in patients with collateral ventilation (MD 2.48%, 95% CI −2.63 to 7.59, p=0.34, I2=0%). The SR reported that 2 RCTs showed statistically significant increases in FEV1 in patients with intact interlobar fissures as a surrogate for the absence of collateral ventilation (MD 17.80%, 95% CI 7.78 to 27.82, n=68; and MD 17.23%, 95% CI 8.10 to 26.36, n=93). In an RCT of 97 patients without collateral ventilation, an increase in FEV1 of greater than 12% from baseline was statistically significantly more frequent in patients treated by duckbill EBV (56% ) than in patients treated by SMC (3% , p<0.001) at 6‑month follow-up.
The SR reported a meta-analysis of 4 of the RCTs (n=379) of patients treated with duckbill EBV in whom the 6‑minute walking distance test was used to assess exercise capacity. The analysis showed a statistically significant increase in exercise capacity from baseline compared with SMC (MD 38.12 m, 95% CI 8.68 to 67.56, p=0.011, I2=78%).There was high variability between the studies. Three RCTs included in the SR reported a statistically significantly higher number of patients able to walk 26 m or more in the EBV-treated group compared with the SMC group. One RCT (n=321) found no statistically significant difference in the number of patients able to walk more than 26 m between the duckbill EBV and SMC groups (p=0.28). The SR reported a meta-analysis of 2 RCTs (n=316) that showed a statistically significant difference in exercise capacity from baseline favouring patients having SMC compared with patients treated by umbrella EBV (MD −19.54 m, 95% CI −37.11 to −1.98, p=0.029, I2=0%). In the RCT of 97 patients without collateral ventilation, an increase in 6‑minute walking distance of more than 26 m from baseline values was statistically significantly more frequent in patients treated by duckbill EBV (52% ) than in patients treated by SMC (13% , p<0.001) at 6‑month follow-up.
Five RCTs (n=695) included in the SR reported on quality of life measured by the St. George's respiratory questionnaire (SGRQ, 100 being the worst and 0 the best possible health status). In this analysis, patients treated by duckbill EBV had statistically significantly better quality of life than those having SMC (MD −7.29 units, 95% CI −11.12 to −3.45, p=0.0002, I2=67%) at a maximum follow-up of 12 months. The SR reported a meta-analysis of 2 RCTs (n=350) that showed no statistically significant difference in SGRQ score between patients treated by umbrella EBV and those having SMC (MD 2.64 units, 95% CI −0.28 to 5.56, p=0.076, I2=28%, high-quality evidence).
The specialist advisers listed the key efficacy outcomes to be lung function measurements, health status, exercise capacity, improvement in breathlessness, reduction in lung volume, and quality of life.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Mortality was not statistically significantly different in patients treated by duckbill endobronchial valve (EBV) insertion compared with patients having standard medical care (SMC; odds ratio 1.07, 95% confidence interval 0.47 to 2.43, I2=0) in a meta-analysis of 5 randomised controlled trials (RCTs; n=703) included in a systematic review (SR). Mortality was not statistically significantly different in patients treated by umbrella EBV compared with those having SMC (OR 4.95, 95% CI 0.85 to 28.94, p=0.076, I2=0%) in a meta-analysis of 2 RCTs (n=350) in the SR. One patient died from tension pneumothorax 4 days after valve insertion in a case series of 91 patients. One patient died from a pneumothorax-induced cardiac arrest within 30 days of duckbill EBV insertion in 1 RCT of 97 patients.
The rate of adverse events was statistically significantly higher in patients treated by duckbill EBV compared with those having SMC (OR 5.85, 95% CI 2.16 to 15.84) in a meta-analysis of 3 RCTs (n=482) in the SR. Serious adverse events were reported on 22 occasions in patients treated by umbrella EBV and in 6 patients having SMC in 1 RCT (n=277) included in the SR. The rate of adverse events was statistically significantly higher in patients treated by umbrella EBV than in those having SMC (OR 3.41, 95% CI 1.48 to 7.84) in a meta-analysis of 2 RCTs (n=350) in the SR.
Chronic obstructive pulmonary disease (COPD) exacerbation episodes were not statistically significantly more frequent in patients treated by duckbill EBV (64% ) compared with those having SMC (80% ) in an RCT (n=50) reported in the SR (p=0.42). COPD exacerbation episodes were reported in patients treated with the umbrella valve in 2 RCTs included in the SR: 7 in the valve group and 2 in the SMC group in 1 RCT (n=277) and 2 in the valve group and 2 in the SMC group in another RCT (n=22).
Respiratory failure occurred on 4 occasions in patients treated by umbrella valve in 1 RCT included in the SR, and in 1 patient in a case series of 343 patients without collateral ventilation treated by duckbill EBV.
Pneumonia episodes were not statistically significantly more frequent in patients treated by duckbill EBV (n=2) compared with patients having SMC (n=0) in an RCT (n=50) reported in the SR (p=0.49). The pneumonia rate was not statistically significantly different in patients treated by duckbill EBV (6% ) compared with those having SMC (3% ) in 1 RCT reported in the SR (p=1.0). Pneumonia distal to the valve was reported in 4% (9/220) of patients treated by duckbill EBV in 1 RCT included in the SR. Pneumonia distal to the valve was reported in 7% (6/91) of patients and bacterial bronchitis was reported in 1 of 91 patients in the case series of 91 patients at 12‑month follow-up. Pneumonia was reported in 1 of the 14 patients who were treated bilaterally by EBV in a case series of 49 patients. Pneumonia distal to the valve was reported in 5% (2/40) of patients treated by EBV in a case series of 40 patients.
Pneumothorax episodes were not statistically significantly more frequent in patients treated by duckbill EBV (n=2) compared with patients having SMC (n=1) in an RCT (n=50) reported in the SR (p=1.0). The pneumothorax rate was reported as 26% (11/43) and 18% (6/34) in patients treated by duckbill EBV in 2 RCTs included in the SR. Pneumothorax occurred on 3 occasions in patients treated by umbrella EBV in 1 RCT included in the SR. The pneumothorax rate was 6% (25/421) in a case series of 421 patients treated by duckbill EBV; the mean duration of pneumothorax in this study was 11 days (range 2 to 73 days). Pneumothorax occurred in 10% (35/343) of patients in the case series of 343 patients. Pneumothorax within 12 months of valve insertion was reported in 12% (11/91) of patients in the case series of 91 patients; 5 of these were judged to be serious and definitely device related. Pneumothorax was reported in 21% (3/14) of patients in the bilateral group and in 8% (3/35) of patients in the unilateral group in the case series of 49 patients treated by EBV. One patient had contralateral pneumothorax 15 days after the procedure in the case series of 40 patients. Pneumothorax occurred in 1% (5/343) of patients reported in the case series of 343 patients. Pneumothorax happened in 18% (70/381) of patients treated by EBV with duckbill or umbrella valves in the case series of 381 patients. In these 70 patients, pneumothorax resolved under observation in 13% (9/70), and 87% (61/70) needed chest tube insertion. In 51% (31/61) of patients pneumothorax did not resolve and valve removal was necessary. Persistent fistula (despite chest drain and valve removal) was present in 45% (14/31) of patients and required further intervention. In the same study 73% (51/70) of cases of pneumothorax happened within 3 days of EBV treatment.
Four episodes of valve expectoration were reported in 1 RCT (n=50) of the duckbill EBV included in the SR. Valve replacement was reported in 7% (3/43) of patients treated by duckbill EBV in 1 RCT (n=93) included in the SR. Valve expectoration, migration or aspiration were reported on 14 occasions in 1 RCT (n=171) of duckbill EBV reported in the SR. Valve replacement was needed in less than 1% (3/343) of patients reported in the case series of 343 patients. Valve migration was reported in 14% (2/14) of patients treated bilaterally by duckbill EBV in the case series of 49 patients. Valve removal (duckbill EBV) was needed in 2 cases in 1 RCT (n=50), in 12% (5/43) of patients in another RCT and in 14% (21/220) of patients in another RCT included in the SR. Valve removal was reported in 18% (16/91) of patients in the case series of 91 patients treated by duckbill EBV, and in 1 patient treated by EBV in the case series of 40 patients.
Haemoptysis was reported in less than 1% (1/220) of patients treated by duckbill EBV in 1 RCT included in the SR. Mild haemoptysis occurred in 1 of 343 patients in the case series of 343 patients. Haemoptysis was reported in 14% (2/14) of patients treated bilaterally by EBV in the case series of 49 patients.
Bronchospasm was reported in 1 patient treated by umbrella EBV in 1 RCT included in the SR. Bronchospasm within 3 days of the procedure was reported in 9% (8/91) of patients in the case series of 91 patients. One of these was described as serious, and associated with respiratory failure and myocardial infarction that began the evening after the procedure; the patient had further episodes of bronchospasm and the valves were removed on day 21. A second patient had valve removal on day 3 because the bronchospasm did not resolve.
Placement of a valve in the incorrect lobe was reported in 1% (3/220) of patients in 1 RCT included in the SR.
Hypoxia was reported in 1% (4/343) of patients, fistula in less than 1% (2/343), pleural effusion in less than 1% (2/343) and increased sputum in less than 1% (1/343) of patients in the case series of 343 patients. Injury to bronchi was reported in 3% (3/91) of patients in the case series of 91 patients (not further described). In the same case series, 2% (2/91) of patients reported transient hypercarbia; 1 patient needed overnight ventilator support.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed no anecdotal adverse events in addition to those in the literature. They considered that the following were theoretical adverse events: worsening of hypercapnia and pulmonary hypertension.# Further information
Patient commentary was sought but none was received.
For related NICE guidance, see the NICE website.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2755-5
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{'Recommendations': 'Current evidence on the safety and efficacy of endobronchial valve insertion to reduce lung volume in emphysema is adequate in quantity and quality to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection should be done by a multidisciplinary team experienced in managing emphysema, which should typically include a chest physician, a radiologist, a thoracic surgeon and a respiratory nurse.\n\nPatients selected for treatment should have had pulmonary rehabilitation.\n\nThe procedure should only be done to occlude volumes of the lung where there is no collateral ventilation, by clinicians with specific training in doing the procedure.', 'Indications and current treatments': 'Emphysema is a chronic lung disease in which the walls of the air sacs (alveoli) in the lungs weaken and disintegrate. This leaves behind abnormally large air spaces that stay filled with air even when the patient breathes out. The most common symptoms of emphysema are shortness of breath, coughing, fatigue and weight loss. Recurrent illnesses (such as chest infections) often lead to exacerbations, for which patients may need hospitalisation. Emphysema is usually smoking related but may also be inherited.\n\nTreatment options include pulmonary rehabilitation (exercise training, breathing retraining, and patient and carer education), smoking cessation, and the use of inhaled or oral bronchodilators and corticosteroids. Oxygen therapy may also be indicated in more severe cases. Lung volume reduction surgery is an option for patients who experience breathlessness, and whose pulmonary function test results show severe obstruction and enlarged lungs. Such surgery can be done thoracoscopically (using video-assisted thoracoscopy or thoracotomy) or using an open approach (using a sternotomy or thoracotomy). Lung transplantation surgery may also be an option. Certain therapies under clinical investigation such as coiling, use of sealants and thermal ablation may be used in regional lung disease.', 'The procedure': 'The aim of insertion of endobronchial valves (also known as intrabronchial valves) to reduce lung volume in emphysema is to achieve atelectasis of selected lung segments. It uses an endoscopic approach, which is less invasive than open or thoracoscopic lung volume reduction surgery. Before the procedure, it is usual practice to assess the presence of collateral ventilation (when air enters a lobe of the lung through a passage that bypasses the normal airway). A surrogate for this is CT scanning to assess the completeness of fissures. A functional approach, specially developed for use before airway valve insertion, involves a specially designed balloon catheter with a flow sensor.\n\nEndobronchial valve insertion is done with the patient under sedation or general anaesthesia. Using a delivery catheter passed through a bronchoscope, a synthetic valve is placed in the target location and fixed to the bronchial wall. The valve is designed to prevent air inflow during inspiration but to allow air and mucus to exit during expiration. Several valves may be needed (1\xa0or more for each segment of the lung to be treated). Patients may sometimes be given antibiotics or corticosteroids. Two devices with different designs are available for interventional lung volume reduction – 1\xa0is duckbill shaped and the other umbrella shaped.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA systematic review (SR) and meta-analysis included 5\xa0randomised controlled trials (RCTs) of patients (n=703) treated by duckbill-shaped endobronchial valve (EBV) insertion and 3\xa0RCTs of patients (n=372) treated by umbrella-shaped EBV insertion, both compared with standard medical care (SMC). These 2\xa0groups were analysed separately. In a meta-analysis of the 5\xa0RCTs of duckbill EBV insertion compared with SMC, there was a statistically significant difference in 1% change from baseline in forced expiratory volume in 1\xa0second (FEV1) in favour of duckbill EBV insertion (standardised mean difference [SMD] 0.48, 95% confidence interval [CI] 0.32 to 0.64, p<0.00001, I2=42). In 2\xa0RCTs (n=143) from the same meta-analysis, a 2% increase in FEV1 was statistically significantly more frequent in patients treated by duckbill EBV than in those treated by SMC at 90‑day follow-up (SMD\xa00.77, 95%\xa0CI 0.43 to 1.11, p<0.00001, I2 = 0%). In the other 3\xa0RCTs (n=560) from the same meta-analysis, a 2% increase in FEV1 was statistically significantly more frequent in patients treated by duckbill EBV than in those treated by SMC at 6‑month follow-up (SMD\xa00.40, 95%\xa0CI 0.22 to 0.58, p<0.00001, I2=41%). One RCT (n=73), which studied patients treated by the umbrella EBV, reported no statistically significant difference in FEV1 measurements at 3‑month follow-up (MD\xa00.90\xa0litres, standard deviation [SD] 0.34) compared with patients having SMC (0.87\xa0litres, SD\xa00.34, p=0.065). A second RCT (n=22) of the umbrella EBV reported statistically significantly improved FEV1 measurements in patients treated unilaterally (21.4%, SD\xa010.7%) but not in patients treated bilaterally (−3.1%, SD\xa015.0; MD\xa024.50%, 95%\xa0CI 13.61 to 35.39). The SR reported a statistically significantly larger change in FEV1 from baseline in patients with heterogeneous emphysema treated by duckbill EBV than in patients with homogeneous emphysema having the same treatment (MD\xa016.36%, 95%\xa0CI 9.02 to 23.71, p=0.00001, I2=0%, n=137, 2\xa0RCTs).\n\nIn 3\xa0RCTs (n=542) included in the SR there was a statistically significant increase in FEV1 from baseline in patients without collateral ventilation treated by duckbill EBV (MD\xa018.15%, 95%\xa0CI 11.81 to 24.49; p=0.000001, I2=0%). Three RCTs (n=542) reported no statistically significant increase in FEV1 after duckbill EBV treatment in patients with collateral ventilation (MD\xa02.48%, 95%\xa0CI −2.63 to 7.59, p=0.34, I2=0%). The SR reported that 2\xa0RCTs showed statistically significant increases in FEV1 in patients with intact interlobar fissures as a surrogate for the absence of collateral ventilation (MD\xa017.80%, 95%\xa0CI 7.78 to 27.82, n=68; and MD\xa017.23%, 95%\xa0CI 8.10 to 26.36, n=93). In an RCT of 97 patients without collateral ventilation, an increase in FEV1 of greater than 12% from baseline was statistically significantly more frequent in patients treated by duckbill EBV (56% [36/64]) than in patients treated by SMC (3% [1/31], p<0.001) at 6‑month follow-up.\n\nThe SR reported a meta-analysis of 4\xa0of the RCTs (n=379) of patients treated with duckbill EBV in whom the 6‑minute walking distance test was used to assess exercise capacity. The analysis showed a statistically significant increase in exercise capacity from baseline compared with SMC (MD\xa038.12\xa0m, 95%\xa0CI 8.68 to 67.56, p=0.011, I2=78%).There was high variability between the studies. Three RCTs included in the SR reported a statistically significantly higher number of patients able to walk 26\xa0m or more in the EBV-treated group compared with the SMC group. One RCT (n=321) found no statistically significant difference in the number of patients able to walk more than 26\xa0m between the duckbill EBV and SMC groups (p=0.28). The SR reported a meta-analysis of 2\xa0RCTs (n=316) that showed a statistically significant difference in exercise capacity from baseline favouring patients having SMC compared with patients treated by umbrella EBV (MD\xa0−19.54\xa0m, 95% CI\xa0−37.11 to −1.98, p=0.029, I2=0%). In the RCT of 97 patients without collateral ventilation, an increase in 6‑minute walking distance of more than 26\xa0m from baseline values was statistically significantly more frequent in patients treated by duckbill EBV (52% [33/63]) than in patients treated by SMC (13% [4/31], p<0.001) at 6‑month follow-up.\n\nFive RCTs (n=695) included in the SR reported on quality of life measured by the St. George's respiratory questionnaire (SGRQ, 100\xa0being the worst and 0\xa0the best possible health status). In this analysis, patients treated by duckbill EBV had statistically significantly better quality of life than those having SMC (MD\xa0−7.29 units, 95%\xa0CI −11.12 to −3.45, p=0.0002, I2=67%) at a maximum follow-up of 12\xa0months. The SR reported a meta-analysis of 2\xa0RCTs (n=350) that showed no statistically significant difference in SGRQ score between patients treated by umbrella EBV and those having SMC (MD\xa02.64 units, 95%\xa0CI −0.28 to 5.56, p=0.076, I2=28%, high-quality evidence).\n\nThe specialist advisers listed the key efficacy outcomes to be lung function measurements, health status, exercise capacity, improvement in breathlessness, reduction in lung volume, and quality of life.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nMortality was not statistically significantly different in patients treated by duckbill endobronchial valve (EBV) insertion compared with patients having standard medical care (SMC; odds ratio [OR] 1.07, 95% confidence interval [CI] 0.47 to 2.43, I2=0) in a meta-analysis of 5\xa0randomised controlled trials (RCTs; n=703) included in a systematic review (SR). Mortality was not statistically significantly different in patients treated by umbrella EBV compared with those having SMC (OR\xa04.95, 95%\xa0CI 0.85 to 28.94, p=0.076, I2=0%) in a meta-analysis of 2\xa0RCTs (n=350) in the SR. One patient died from tension pneumothorax 4\xa0days after valve insertion in a case series of 91\xa0patients. One patient died from a pneumothorax-induced cardiac arrest within 30\xa0days of duckbill EBV insertion in 1 RCT of 97 patients.\n\nThe rate of adverse events was statistically significantly higher in patients treated by duckbill EBV compared with those having SMC (OR\xa05.85, 95%\xa0CI 2.16 to 15.84) in a meta-analysis of 3\xa0RCTs (n=482) in the SR. Serious adverse events were reported on 22\xa0occasions in patients treated by umbrella EBV and in 6\xa0patients having SMC in 1\xa0RCT (n=277) included in the SR. The rate of adverse events was statistically significantly higher in patients treated by umbrella EBV than in those having SMC (OR\xa03.41, 95%\xa0CI 1.48 to 7.84) in a meta-analysis of 2\xa0RCTs (n=350) in the SR.\n\nChronic obstructive pulmonary disease (COPD) exacerbation episodes were not statistically significantly more frequent in patients treated by duckbill EBV (64% [16/25]) compared with those having SMC (80% [20/25]) in an RCT (n=50) reported in the SR (p=0.42). COPD exacerbation episodes were reported in patients treated with the umbrella valve in 2\xa0RCTs included in the SR: 7\xa0in the valve group and 2\xa0in the SMC group in 1\xa0RCT (n=277) and 2\xa0in the valve group and 2\xa0in the SMC group in another RCT (n=22).\n\nRespiratory failure occurred on 4\xa0occasions in patients treated by umbrella valve in 1\xa0RCT included in the SR, and in 1\xa0patient in a case series of 343\xa0patients without collateral ventilation treated by duckbill EBV.\n\nPneumonia episodes were not statistically significantly more frequent in patients treated by duckbill EBV (n=2) compared with patients having SMC (n=0) in an RCT (n=50) reported in the SR (p=0.49). The pneumonia rate was not statistically significantly different in patients treated by duckbill EBV (6% [2/34]) compared with those having SMC (3% [1/34]) in 1\xa0RCT reported in the SR (p=1.0). Pneumonia distal to the valve was reported in 4% (9/220) of patients treated by duckbill EBV in 1\xa0RCT included in the SR. Pneumonia distal to the valve was reported in 7% (6/91) of patients and bacterial bronchitis was reported in 1\xa0of 91\xa0patients in the case series of 91\xa0patients at 12‑month follow-up. Pneumonia was reported in 1\xa0of the 14\xa0patients who were treated bilaterally by EBV in a case series of 49\xa0patients. Pneumonia distal to the valve was reported in 5% (2/40) of patients treated by EBV in a case series of 40\xa0patients.\n\nPneumothorax episodes were not statistically significantly more frequent in patients treated by duckbill EBV (n=2) compared with patients having SMC (n=1) in an RCT (n=50) reported in the SR (p=1.0). The pneumothorax rate was reported as 26% (11/43) and 18% (6/34) in patients treated by duckbill EBV in 2\xa0RCTs included in the SR. Pneumothorax occurred on 3\xa0occasions in patients treated by umbrella EBV in 1\xa0RCT included in the SR. The pneumothorax rate was 6% (25/421) in a case series of 421\xa0patients treated by duckbill EBV; the mean duration of pneumothorax in this study was 11\xa0days (range 2 to 73\xa0days). Pneumothorax occurred in 10% (35/343) of patients in the case series of 343\xa0patients. Pneumothorax within 12\xa0months of valve insertion was reported in 12% (11/91) of patients in the case series of 91\xa0patients; 5\xa0of these were judged to be serious and definitely device related. Pneumothorax was reported in 21% (3/14) of patients in the bilateral group and in 8% (3/35) of patients in the unilateral group in the case series of 49\xa0patients treated by EBV. One patient had contralateral pneumothorax 15\xa0days after the procedure in the case series of 40\xa0patients. Pneumothorax occurred in 1% (5/343) of patients reported in the case series of 343\xa0patients. Pneumothorax happened in 18% (70/381) of patients treated by EBV with duckbill or umbrella valves in the case series of 381 patients. In these 70 patients, pneumothorax resolved under observation in 13% (9/70), and 87% (61/70) needed chest tube insertion. In 51% (31/61) of patients pneumothorax did not resolve and valve removal was necessary. Persistent fistula (despite chest drain and valve removal) was present in 45% (14/31) of patients and required further intervention. In the same study 73% (51/70) of cases of pneumothorax happened within 3 days of EBV treatment.\n\nFour episodes of valve expectoration were reported in 1\xa0RCT (n=50) of the duckbill EBV included in the SR. Valve replacement was reported in 7% (3/43) of patients treated by duckbill EBV in 1\xa0RCT (n=93) included in the SR. Valve expectoration, migration or aspiration were reported on 14\xa0occasions in 1\xa0RCT (n=171) of duckbill EBV reported in the SR. Valve replacement was needed in less than 1% (3/343) of patients reported in the case series of 343\xa0patients. Valve migration was reported in 14% (2/14) of patients treated bilaterally by duckbill EBV in the case series of 49\xa0patients. Valve removal (duckbill EBV) was needed in 2\xa0cases in 1\xa0RCT (n=50), in 12% (5/43) of patients in another RCT and in 14% (21/220) of patients in another RCT included in the SR. Valve removal was reported in 18% (16/91) of patients in the case series of 91\xa0patients treated by duckbill EBV, and in 1\xa0patient treated by EBV in the case series of 40\xa0patients.\n\nHaemoptysis was reported in less than 1% (1/220) of patients treated by duckbill EBV in 1\xa0RCT included in the SR. Mild haemoptysis occurred in 1\xa0of 343\xa0patients in the case series of 343\xa0patients. Haemoptysis was reported in 14% (2/14) of patients treated bilaterally by EBV in the case series of 49\xa0patients.\n\nBronchospasm was reported in 1\xa0patient treated by umbrella EBV in 1\xa0RCT included in the SR. Bronchospasm within 3\xa0days of the procedure was reported in 9% (8/91) of patients in the case series of 91\xa0patients. One of these was described as serious, and associated with respiratory failure and myocardial infarction that began the evening after the procedure; the patient had further episodes of bronchospasm and the valves were removed on day\xa021. A second patient had valve removal on day\xa03 because the bronchospasm did not resolve.\n\nPlacement of a valve in the incorrect lobe was reported in 1% (3/220) of patients in 1\xa0RCT included in the SR.\n\nHypoxia was reported in 1% (4/343) of patients, fistula in less than 1% (2/343), pleural effusion in less than 1% (2/343) and increased sputum in less than 1% (1/343) of patients in the case series of 343\xa0patients. Injury to bronchi was reported in 3% (3/91) of patients in the case series of 91\xa0patients (not further described). In the same case series, 2% (2/91) of patients reported transient hypercarbia; 1\xa0patient needed overnight ventilator support.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed no anecdotal adverse events in addition to those in the literature. They considered that the following were theoretical adverse events: worsening of hypercapnia and pulmonary hypertension.', 'Further information': 'Patient commentary was sought but none was received.\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2755-5'}
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https://www.nice.org.uk/guidance/ipg600
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Evidence-based recommendations on endobronchial valve insertion to reduce lung volume in emphysema. This involves placing small one-way valves in some airways leading to damaged parts of the lungs.
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52df7595c89924286568abe0c5506eea9d386640
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nice
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Palbociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
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Palbociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
Evidence-based recommendations on palbociclib (Ibrance) as initial endocrine-based therapy for hormone-receptor positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic (secondary) breast cancer in adults.
# Recommendations
Palbociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Palbociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.# The technology
Description of the technology
Palbociclib (Ibrance, Pfizer) is a selective, small-molecule inhibitor of cyclin-dependent kinases 4 and 6, which prevents DNA synthesis by stopping cell cycle progression from the G1 to S phase.
Marketing authorisation
Palbociclib is indicated for treating 'hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer:
in combination with an aromatase inhibitor
in combination with fulvestrant in women who have received prior endocrine therapy.
In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone agonist'.
This appraisal only considers the use of palbociclib in combination with an aromatase inhibitor.
Adverse reactions
The most common (20% or more) adverse reactions of any grade reported in patients having palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, alopecia and diarrhoea. The most common (2% or more) adverse reactions of grade 3 or over to palbociclib were neutropenia, leukopenia, anaemia, fatigue and infections. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
The recommended dose is 125 mg of palbociclib, taken orally, once daily for 21 consecutive days followed by 7 days off treatment (schedule 3/1) to make up a complete cycle of 28 days. Treatment with palbociclib should be continued as long as the patient is having a clinical benefit from therapy or until unacceptable toxicity occurs. Some adverse reactions may need to be managed by temporary dose interruptions or delays, dose reductions, or permanently stopping the treatment. For full details of dose reduction schedules, see the summary of product characteristics.
Price
£2,950 for a 21‑capsule pack of 125‑mg capsules (excluding VAT; MIMS online, accessed January 2017).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of palbociclib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of palbociclib, having considered evidence on the nature of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and the value placed on the benefits of palbociclib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical management
The committee was aware that metastatic breast cancer is an incurable condition. NICE recommends endocrine therapy (such as aromatase inhibitors) as first-line treatment for people with metastatic hormone receptor-positive and HER2-negative breast cancer. But if symptoms are severe or the disease is rapidly progressive, people may need chemotherapy. The committee discussed the company submission and the evidence from the clinical trials, which investigated palbociclib in combination with letrozole (an aromatase inhibitor) compared with letrozole alone. The clinical experts explained that in clinical practice the available aromatase inhibitors are all considered to be equivalent, because they have similar clinical effectiveness and acquisition costs. The committee also heard that palbociclib in combination with an aromatase inhibitor would be used for people who have not had previous treatment for metastatic breast cancer, and who would otherwise be offered an aromatase inhibitor alone. The clinical experts explained that after disease progression most people would have several lines of further therapy, including chemotherapy. In response to consultation the company estimated that, based on market research and clinical feedback, 30% of the population eligible for palbociclib with an aromatase inhibitor would have chemotherapy first-line for metastatic disease. However the clinical expert explained that NICE guidance and other clinical guidelines recommend aromatase inhibitors for this population, with first-line chemotherapy being reserved for patients whose disease is imminently life-threatening or requires early relief of symptoms. The expert and the Cancer Drugs Fund (CDF) clinical lead highlighted that in most specialist centres an aromatase inhibitor would be the treatment of choice when palbociclib in combination with an aromatase inhibitor is indicated. However, the expert also stated that real-world experience shows that some of these patients have chemotherapy. The clinical experts explained that in their opinion, the proportion of the eligible population having chemotherapy would be much less than the company's estimate of 30%. The committee concluded that the company submission had appropriately placed palbociclib in the treatment pathway, and that aromatase inhibitors are the comparator.
# Patient experience
The committee heard from the patient and clinical experts that quality of life is much lower for people whose disease is treated with chemotherapy than with endocrine therapy, because of the side effects of chemotherapy. Endocrine therapies are therefore preferred when possible. Palbociclib, by increasing the effect of aromatase inhibitors, has the potential to reduce the number of people who need first-line chemotherapy, and delay such treatment in others. The committee heard from the patient expert that staying in a progression-free state for as long as possible and being able to continue with normal activities, including working, is very highly valued by patients and their families, and this benefit should not be underestimated. The committee noted that during consultation, 8 UK clinicians in an advisory board, held by the company, advised that the quality-of-life difference between the progression-free and progressed states should be valued as highly as the difference between the progressed-disease state and death. The committee also took into account the consultation comments received emphasising how patients value delaying both disease progression and the need for chemotherapy. The committee agreed that people value delaying progression of the disease and an important consideration is delaying the time to chemotherapy.
# Clinical effectiveness
## Clinical trial evidence
The committee noted that the clinical-effectiveness evidence for palbociclib plus letrozole compared with letrozole alone came from 2 studies: PALOMA‑1 and PALOMA‑2. PALOMA‑2 was a larger (666 patients) placebo-controlled, double-blind trial, and PALOMA‑1 was a smaller (165 patients) open-label study. The committee discussed the generalisability of the PALOMA trials to UK clinical practice. It noted that PALOMA‑1 contained no UK patients, but 7 of the PALOMA‑2 sites were in the UK. The committee heard from the clinical experts that both trials had a greater proportion of people with metastatic disease when first diagnosed than is seen in UK practice (37% in PALOMA‑2 compared with about 5% to 10% in UK clinical practice). The committee noted that there was no significant difference in treatment response for people with metastatic disease at first diagnosis and were reassured by the clinical experts that a difference would not be expected. The committee agreed that the populations in both PALOMA trials were similar to the population seen in clinical practice in England. But the committee considered that, because PALOMA‑2 was a blinded larger trial, its results are likely to be more reliable for decision-making. The committee raised concerns that the higher incidence of haematological adverse events in the palbociclib arms of the trials would have resulted in some patients and investigators becoming unblinded to patient allocation during PALOMA‑2. The committee heard that to mitigate this, both investigator-assessed and blinded independent central review (BICR) of progression-free survival was carried out. The committee concluded that the BICR results would be more appropriate for decision-making.
## PALOMA‑1 progression-free and overall survival data
The committee noted that in the overall intention-to-treat population, the BICR median progression-free survival reported in PALOMA‑1 was 25.7 months for palbociclib plus letrozole, and 14.8 months for letrozole alone. This was reported as statistically significant when using a 1‑sided p value (p=0.0286), but not if a 2‑sided p value had been used. The median overall survival from an interim analysis, which was available at the time of the first committee meeting, was 37.5 months for palbociclib plus letrozole compared with 33.3 months for letrozole alone. This was not a statistically significant difference. In response to consultation the company submitted the final analysis for overall survival from PALOMA‑1, which showed a median overall survival of 37.5 months for palbociclib plus letrozole compared with 34.5 months for letrozole alone. The committee noted a slightly smaller difference in median overall survival gain of 3 months for palbociclib plus letrozole compared with letrozole alone than at the interim analysis (4.2 months), but again there was no statistically significant difference between the treatment arms. The committee concluded that in PALOMA‑1 palbociclib improved progression-free survival, but no significant improvement in overall survival had been shown.
## PALOMA‑2 progression-free and overall survival data
The committee noted that in the BICR intention-to-treat population, the median progression-free survival was 30.5 months for palbociclib plus letrozole compared with 19.3 months for letrozole alone (hazard ratio 0.653; confidence interval 0.505 to 0.844). The committee heard from the company that overall survival results from this trial are not available because the required number of events has not been reached, and the company remains blinded to the results. The committee concluded that in PALOMA‑2 palbociclib statistically significantly improved progression-free survival, but no data on overall survival are available.
## Relationship between progression-free and overall survival
The committee noted that progression-free survival gains were seen in both trials. But an overall survival gain was seen only in PALOMA‑1 and it was not statistically significant. The committee noted the ERG's comment that final overall survival data from PALOMA‑1 should be considered the best available evidence on overall survival. It also noted the small number of patients in PALOMA‑1, and considered that the results are associated with a wide confidence interval. The clinical experts indicated that they would expect an improved progression-free survival with metastatic breast cancer to result in some benefit in overall survival. However, they judged that the situation is complex and difficult to predict because of the number of further lines of treatment that the person would have, and because the precise relationship between progression-free and overall survival is unclear. The committee agreed that data from PALOMA‑2, when available, will reduce the uncertainty around overall survival gain attributable to palbociclib plus letrozole. However the best available evidence at present is from PALOMA‑1, which showed a non-statistically significant survival gain of less than the progression-free survival gain. The committee concluded that palbociclib has a clear and important benefit in improving progression-free survival, and that it is likely that this would result in some improvement in overall survival. However, it reiterated that the size of this benefit remains uncertain.
## Adverse effects of palbociclib
The committee noted that the trial evidence suggested a high incidence of haematological adverse events. It was aware that the marketing authorisation states that full blood counts must be done during treatment, so extra visits may be needed for monitoring. However, it heard from the clinical and patient experts that the adverse events are reversible and manageable. The clinical expert highlighted that many incidences of neutropenia observed in the trials were laboratory findings only and did not result in clinical infections. They expect that in clinical practice, many of these people will continue having palbociclib. In the trials people developing neutropenia may have discontinued treatment, because of protocol restrictions. The committee concluded that, although the incidence of neutropenia in particular was high, the adverse events were manageable and in clinical practice treatment discontinuation because of adverse events will be lower than in the trials.
# Cost effectiveness
The committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. It accepted the structure of the economic model developed by the company and considered it appropriate for decision-making.
## Data sources in the model
The committee noted that the company's original model used overall survival from PALOMA‑1, because this is the only source available, but it used progression-free survival data from PALOMA‑2. The ERG stated that it considers the mixing of the 2 data sets to be methodologically flawed, because it assumes that progression-free survival and overall survival were independent of one another. Therefore, the ERG preferred to use the PALOMA‑1 time-to-event data throughout. The committee noted that in the revised analyses submitted during consultation, the company used progression-free survival data from PALOMA‑1 and also the updated final overall survival data from PALOMA‑1 (see section 4.4). The committee noted that in the revised analyses the company had accepted all amendments suggested in the ERG's exploratory base case, except the modelling of overall survival.
## Modelling overall survival
In its revised analyses the company used 2 different approaches for modelling overall survival. The company's 'lower bound' survival was based on a parametric curve (exponential) fitted to the individual patient data from the final analysis of PALOMA‑1. This method closely resembled the ERG's preferred approach. The company also calculated its 'upper bound' survival, by increasing the overall survival gain in PALOMA‑1 to match the modelled progression-free survival gain (that is, 11.2 months). The committee recalled that the relationship between progression-free and overall survival is complex and difficult to predict, but that palbociclib would be expected to improve overall survival. It noted the company's comments that the lack of a statistically significant overall survival gain in PALOMA‑1 could be because overall survival data are confounded by randomness of response to post-progression treatments. The committee concluded that although it is possible that the overall survival gain might be better than that in PALOMA‑1, there is no evidence to support an assumption of overall survival gain equal to the progression-free survival gain without further overall survival data from PALOMA‑2.
## Costs for post-progression states
In its original submission the company did not include any treatment-related costs beyond first-line therapy. It included only disease-related costs, estimated using package 2 care from NICE's clinical guideline on advanced breast cancer. After seeking advice from clinical nurse specialists, and making adjustments to reflect current NHS practice and variations in lines of treatment, the company incorporated an average disease-related cost of £573.86 per cycle (28 days) in the post-progression state. The ERG did not agree that treatment-related cost such as drug acquisition costs for second-line therapy and beyond could be ignored. It recommended more precise costing. The company presented revised analyses with higher estimated costs for post-progression states (£2,000; £1,395; and £1,140 per cycle). The ERG estimated an average post-progression cost of £1,200 per cycle for active treatment states, and £975 per cycle for best supportive care. These estimates were based on a retrospective review of medical records for patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the UK (Kurosky et al. 2015), together with clinical advice. They also took into account the company's original estimates of disease-related costs. The CDF clinical lead also submitted average costs for second-, third- and fourth-line treatments, estimated in consultation with experts in the Chemotherapy Clinical Reference Group of NHS England. These estimates were presented as commercial in confidence because they included confidential pricing agreements and are therefore not presented here. The committee noted the different estimates and could not be sure which estimate could be considered the most plausible. However, the committee was reassured by the fact that, despite having used different sources, the estimates from the ERG and the CDF clinical lead are reasonably close. It therefore agreed that the ERG's estimates for post-progression costs are plausible.
## Utility value for progression-free state
In its original base case, the company used different utility values for people in the progression-free state having palbociclib plus letrozole (0.74) or letrozole alone (0.71). These values were derived from the corresponding treatment arms of PALOMA‑2. Taking into account that the difference in the EQ‑5D values between the 2 arms of PALOMA‑2 was not statistically significant, the ERG estimated an average utility value (0.72) by pooling EQ‑5D values for European patients from the first 21 cycles in PALOMA‑2. The committee noted the company's comments that the ERG's preferred estimate undervalues progression-free survival, because people with progression-free disease can have a near-normal life. The company referred to NICE's technology appraisal guidance on everolimus with exemestane for treating advanced breast cancer after endocrine therapy. This used a utility value of 0.771 for people with hormone receptor-positive, HER2-negative disease that recurred or progressed after treatment with an aromatase inhibitor, who were having second-line treatment with everolimus plus exemestane. It argued that people on first-line treatment (as in this appraisal) should be assumed to have at least the same quality of life as accepted for those having second-line treatment after progression. The company also presented a scenario using a utility value of 0.75 for progression-free survival, a midpoint between 0.72 and 0.77.
The committee discussed the most appropriate source of utility values for use in economic modelling, particularly those gathered directly in the relevant trials compared with those sourced from elsewhere. It noted that there is a strong preference for people wanting to delay starting chemotherapy (see section 4.2). It also noted that because EQ‑5D measures the health state of people at points in time, it may not fully capture a person's preference to avoid future events. The committee was aware that EQ‑5D data from trials is recommended for use in the NICE reference case. It was, however, aware that there has been inconsistency in the utility values used for similar disease stages across different NICE appraisals for metastatic breast cancer. The committee concluded that it is difficult to precisely predict the quality of life of someone with progression-free disease who is taking endocrine therapy. It agreed to explore a range of utility values for progression-free disease (0.72 to 0.77) for its deliberation on the cost effectiveness of palbociclib.
## Incremental cost-effectiveness ratios
The committee discussed the company's revised base case incorporating a confidential patient access scheme. It noted that the company had presented a range of incremental cost-effectiveness ratios (ICERs) using 2 approaches to modelling overall survival, 3 utility values for progression-free state (0.72, 0.75 and 0.77) and 3 estimates for post-progression costs (£1,140; £1,395; and £2,000 per cycle). These ICERs were presented as commercial in confidence to maintain confidentiality around the patient access scheme. The committee agreed that after applying a discount to the list price as agreed in the patient access scheme, and using a more realistic estimation of the subsequent treatment costs, the ICERs would be within the range that can be considered cost effective.
## Innovation
The committee discussed the innovative nature of palbociclib. It noted that the Medicines and Healthcare products Regulatory Agency recognises palbociclib as a promising innovative medicine. The committee agreed that there is a clinical need for better treatments for this patient group, and that it prolongs progression-free survival in this population. It recognised that this is important to patients and that no weight had been given in the cost-effectiveness analysis to the specific benefit of delaying chemotherapy with its attendant side effects, which patients consider important. The overall survival gain also remains an area of significant uncertainty, and could be greater than that shown in PALOMA‑1.
## Conclusion
The committee noted that there are uncertainties in the calculation for the most plausible ICERs, including:
-verall survival modelling; the relationship between the overall survival and progression-free survival
using overall survival data from PALOMA‑1, which implied that overall survival gain is 27.5% of progression-free survival gain or
assuming that overall survival gain is equal to the gain in progression-free survival
the utility value for progression-free disease
the cost of subsequent treatments.However the committee agreed that using a more realistic cost for progressive disease (closer to the ERG's estimate), and applying the discount agreed in the patient access scheme, results in ICERs that fall within the range considered a cost-effective use of NHS resources. Therefore, the committee recommended palbociclib in combination with an aromatase inhibitor as a cost-effective use of NHS resources for treating hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer in adults.
## Pharmaceutical Price Regulation Scheme (PPRS) 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Summary of appraisal committee's key conclusions
TA495
Appraisal title: Palbociclib with an aromatase inhibitor for previously untreated hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
Section
Key conclusion
Palbociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating previously untreated hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Palbociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.
The committee concluded that palbociclib improves progression-free survival, but no significant improvement in overall survival has been shown.
The committee agreed that with the discount agreed in the patient access scheme, palbociclib is a cost-effective use of NHS resources and it can be recommended.
Current practice
Clinical need of patients, including the availability of alternative treatments
NICE recommends endocrine therapy as first-line treatment for metastatic hormone receptor-positive and HER2-negative breast cancer but, if the symptoms are severe or the disease is rapidly progressing, people may need chemotherapy.
People having treatment value delaying progression of the disease and an important consideration is delaying the time to chemotherapy.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Palbociclib, by increasing the effect of aromatase inhibitors, may reduce the number of people who need first-line chemotherapy and delay such treatment in others.
Palbociclib is recognised by the Medicines and Healthcare products Regulatory Agency as a promisingly innovative medicine. The committee agreed that there is a clinical need for better treatments for this patient group, and that it prolongs progression-free-survival.
What is the position of the treatment in the pathway of care for the condition?
Palbociclib, in combination with an aromatase inhibitor, would be used for people who have not had previous treatment for metastatic breast cancer, and who would otherwise be offered an aromatase inhibitor alone.
Adverse reactions
Although the incidence of haematological adverse events in the palbociclib trials was high, they were reversible and manageable.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
Clinical-effectiveness evidence for palbociclib plus letrozole compared with letrozole alone came from 2 studies, PALOMA‑1 and PALOMA‑2. Because the PALOMA‑2 trial was a blinded larger trial, the committee considered that its results are likely to be more reliable for decision-making.
Final analysis for overall survival from PALOMA‑1 was submitted in response to consultation. However, overall survival results from PALOMA‑2 are not available because the required number of events has not been reached.
Data on progression-free survival were available from both trials.
to 4.5
Relevance to general clinical practice in the NHS
The relevance to general clinical practice was not raised during this appraisal.
Uncertainties generated by the evidence
Data from the trials showed that palbociclib improved progression-free survival, but no significant improvement in overall survival had been shown. An improved progression-free survival with metastatic breast cancer would be expected to have some benefit on overall survival. However, the size of benefit is uncertain.
to 4.6
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No specific groups of people were presented for whom the technology is particularly clinically effective.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee concluded that palbociclib has a clear and important benefit for improving progression-free survival, and that it is likely that this would result in some improvement in overall survival. However, the size of benefit is uncertain.
Evidence for cost effectiveness
Availability and nature of evidence
The committee accepted the structure of the economic model developed by the company and considered it appropriate for decision-making.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee concluded that it is possible that the overall survival gain may be better than that in PALOMA‑1 but, without further overall survival data from PALOMA‑2, an assumption of overall survival gain equal to the progression-free survival gain is not supported by any evidence.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
In its original base case, the company used different utility values for people in the progression-free state having palbociclib plus letrozole (0.74) or letrozole alone (0.71). These values were derived from the corresponding treatment arms of PALOMA‑2. The ERG estimated an average utility value (0.72) by pooling EQ‑5D values for European patients from the first 21 cycles in PALOMA‑2. The committee noted that because EQ‑5D measures the health state of people at points in time, it may not fully capture a person's preference to avoid future events. It was, however, aware that there has been inconsistency in the utility values used for similar disease stages across different NICE appraisals for metastatic breast cancer.
Are there specific groups of people for whom the technology is particularly cost effective?
No specific groups of people were presented for whom the technology is particularly cost effective.
What are the key drivers of cost effectiveness?
The approaches to modelling overall survival, the utility values for progression-free state and cost for post-progression disease states were the key drivers of the cost-effectiveness results.
to 4.13
Most likely cost-effectiveness estimate (given as an ICER)
The committee agreed that using a more realistic cost for progressive disease, and applying the discount agreed in the patient access scheme on the list price of the palbociclib, produced ICERs within the range considered a cost-effective use of NHS resources.
(These ICERs incorporated a confidential patient access scheme, and were presented as commercial in confidence.)
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of palbociclib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.
End-of-life considerations
No end-of-life considerations were raised during the appraisal.
Equalities considerations and social value judgements
No equality issues were raised during the appraisal.
|
{'Recommendations': 'Palbociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating hormone receptor-positive, human epidermal growth factor receptor\xa02-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Palbociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nPalbociclib (Ibrance, Pfizer) is a selective, small-molecule inhibitor of cyclin-dependent kinases\xa04 and\xa06, which prevents DNA synthesis by stopping cell cycle progression from the\xa0G1 to S\xa0phase.\n\nMarketing authorisation\n\nPalbociclib is indicated for treating 'hormone receptor (HR)-positive, human epidermal growth factor receptor\xa02 (HER2)-negative locally advanced or metastatic breast cancer:\n\nin combination with an aromatase inhibitor\n\nin combination with fulvestrant in women who have received prior endocrine therapy.\n\nIn pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone agonist'.\n\nThis appraisal only considers the use of palbociclib in combination with an aromatase inhibitor.\n\nAdverse reactions\n\nThe most common (20% or more) adverse reactions of any grade reported in patients having palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, alopecia and diarrhoea. The most common (2% or more) adverse reactions of grade\xa03 or over to palbociclib were neutropenia, leukopenia, anaemia, fatigue and infections. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dose is 125\xa0mg of palbociclib, taken orally, once daily for 21\xa0consecutive days followed by 7\xa0days off treatment (schedule\xa03/1) to make up a complete cycle of 28\xa0days. Treatment with palbociclib should be continued as long as the patient is having a clinical benefit from therapy or until unacceptable toxicity occurs. Some adverse reactions may need to be managed by temporary dose interruptions or delays, dose reductions, or permanently stopping the treatment. For full details of dose reduction schedules, see the summary of product characteristics.\n\nPrice\n\n£2,950 for a 21‑capsule pack of 125‑mg capsules (excluding VAT; MIMS online, accessed January 2017).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of palbociclib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of palbociclib, having considered evidence on the nature of hormone receptor-positive, human epidermal growth factor receptor\xa02 (HER2)-negative breast cancer and the value placed on the benefits of palbociclib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management\n\nThe committee was aware that metastatic breast cancer is an incurable condition. NICE recommends endocrine therapy (such as aromatase inhibitors) as first-line treatment for people with metastatic hormone receptor-positive and HER2-negative breast cancer. But if symptoms are severe or the disease is rapidly progressive, people may need chemotherapy. The committee discussed the company submission and the evidence from the clinical trials, which investigated palbociclib in combination with letrozole (an aromatase inhibitor) compared with letrozole alone. The clinical experts explained that in clinical practice the available aromatase inhibitors are all considered to be equivalent, because they have similar clinical effectiveness and acquisition costs. The committee also heard that palbociclib in combination with an aromatase inhibitor would be used for people who have not had previous treatment for metastatic breast cancer, and who would otherwise be offered an aromatase inhibitor alone. The clinical experts explained that after disease progression most people would have several lines of further therapy, including chemotherapy. In response to consultation the company estimated that, based on market research and clinical feedback, 30% of the population eligible for palbociclib with an aromatase inhibitor would have chemotherapy first-line for metastatic disease. However the clinical expert explained that NICE guidance and other clinical guidelines recommend aromatase inhibitors for this population, with first-line chemotherapy being reserved for patients whose disease is imminently life-threatening or requires early relief of symptoms. The expert and the Cancer Drugs Fund (CDF) clinical lead highlighted that in most specialist centres an aromatase inhibitor would be the treatment of choice when palbociclib in combination with an aromatase inhibitor is indicated. However, the expert also stated that real-world experience shows that some of these patients have chemotherapy. The clinical experts explained that in their opinion, the proportion of the eligible population having chemotherapy would be much less than the company's estimate of 30%. The committee concluded that the company submission had appropriately placed palbociclib in the treatment pathway, and that aromatase inhibitors are the comparator.\n\n# Patient experience\n\nThe committee heard from the patient and clinical experts that quality of life is much lower for people whose disease is treated with chemotherapy than with endocrine therapy, because of the side effects of chemotherapy. Endocrine therapies are therefore preferred when possible. Palbociclib, by increasing the effect of aromatase inhibitors, has the potential to reduce the number of people who need first-line chemotherapy, and delay such treatment in others. The committee heard from the patient expert that staying in a progression-free state for as long as possible and being able to continue with normal activities, including working, is very highly valued by patients and their families, and this benefit should not be underestimated. The committee noted that during consultation, 8\xa0UK clinicians in an advisory board, held by the company, advised that the quality-of-life difference between the progression-free and progressed states should be valued as highly as the difference between the progressed-disease state and death. The committee also took into account the consultation comments received emphasising how patients value delaying both disease progression and the need for chemotherapy. The committee agreed that people value delaying progression of the disease and an important consideration is delaying the time to chemotherapy.\n\n# Clinical effectiveness\n\n## Clinical trial evidence\n\nThe committee noted that the clinical-effectiveness evidence for palbociclib plus letrozole compared with letrozole alone came from 2\xa0studies: PALOMA‑1 and PALOMA‑2. PALOMA‑2 was a larger (666\xa0patients) placebo-controlled, double-blind trial, and PALOMA‑1 was a smaller (165\xa0patients) open-label study. The committee discussed the generalisability of the PALOMA trials to UK clinical practice. It noted that PALOMA‑1 contained no UK patients, but 7\xa0of the PALOMA‑2 sites were in the UK. The committee heard from the clinical experts that both trials had a greater proportion of people with metastatic disease when first diagnosed than is seen in UK practice (37% in PALOMA‑2 compared with about 5%\xa0to\xa010% in UK clinical practice). The committee noted that there was no significant difference in treatment response for people with metastatic disease at first diagnosis and were reassured by the clinical experts that a difference would not be expected. The committee agreed that the populations in both PALOMA trials were similar to the population seen in clinical practice in England. But the committee considered that, because PALOMA‑2 was a blinded larger trial, its results are likely to be more reliable for decision-making. The committee raised concerns that the higher incidence of haematological adverse events in the palbociclib arms of the trials would have resulted in some patients and investigators becoming unblinded to patient allocation during PALOMA‑2. The committee heard that to mitigate this, both investigator-assessed and blinded independent central review (BICR) of progression-free survival was carried out. The committee concluded that the BICR results would be more appropriate for decision-making.\n\n## PALOMA‑1 progression-free and overall survival data\n\nThe committee noted that in the overall intention-to-treat population, the BICR median progression-free survival reported in PALOMA‑1 was 25.7\xa0months for palbociclib plus letrozole, and 14.8\xa0months for letrozole alone. This was reported as statistically significant when using a 1‑sided p\xa0value (p=0.0286), but not if a 2‑sided p\xa0value had been used. The median overall survival from an interim analysis, which was available at the time of the first committee meeting, was 37.5\xa0months for palbociclib plus letrozole compared with 33.3\xa0months for letrozole alone. This was not a statistically significant difference. In response to consultation the company submitted the final analysis for overall survival from PALOMA‑1, which showed a median overall survival of 37.5\xa0months for palbociclib plus letrozole compared with 34.5\xa0months for letrozole alone. The committee noted a slightly smaller difference in median overall survival gain of 3\xa0months for palbociclib plus letrozole compared with letrozole alone than at the interim analysis (4.2\xa0months), but again there was no statistically significant difference between the treatment arms. The committee concluded that in PALOMA‑1 palbociclib improved progression-free survival, but no significant improvement in overall survival had been shown.\n\n## PALOMA‑2 progression-free and overall survival data\n\nThe committee noted that in the BICR intention-to-treat population, the median progression-free survival was 30.5\xa0months for palbociclib plus letrozole compared with 19.3\xa0months for letrozole alone (hazard ratio 0.653; confidence interval 0.505 to 0.844). The committee heard from the company that overall survival results from this trial are not available because the required number of events has not been reached, and the company remains blinded to the results. The committee concluded that in PALOMA‑2 palbociclib statistically significantly improved progression-free survival, but no data on overall survival are available.\n\n## Relationship between progression-free and overall survival\n\nThe committee noted that progression-free survival gains were seen in both trials. But an overall survival gain was seen only in PALOMA‑1 and it was not statistically significant. The committee noted the ERG's comment that final overall survival data from PALOMA‑1 should be considered the best available evidence on overall survival. It also noted the small number of patients in PALOMA‑1, and considered that the results are associated with a wide confidence interval. The clinical experts indicated that they would expect an improved progression-free survival with metastatic breast cancer to result in some benefit in overall survival. However, they judged that the situation is complex and difficult to predict because of the number of further lines of treatment that the person would have, and because the precise relationship between progression-free and overall survival is unclear. The committee agreed that data from PALOMA‑2, when available, will reduce the uncertainty around overall survival gain attributable to palbociclib plus letrozole. However the best available evidence at present is from PALOMA‑1, which showed a non-statistically significant survival gain of less than the progression-free survival gain. The committee concluded that palbociclib has a clear and important benefit in improving progression-free survival, and that it is likely that this would result in some improvement in overall survival. However, it reiterated that the size of this benefit remains uncertain.\n\n## Adverse effects of palbociclib\n\nThe committee noted that the trial evidence suggested a high incidence of haematological adverse events. It was aware that the marketing authorisation states that full blood counts must be done during treatment, so extra visits may be needed for monitoring. However, it heard from the clinical and patient experts that the adverse events are reversible and manageable. The clinical expert highlighted that many incidences of neutropenia observed in the trials were laboratory findings only and did not result in clinical infections. They expect that in clinical practice, many of these people will continue having palbociclib. In the trials people developing neutropenia may have discontinued treatment, because of protocol restrictions. The committee concluded that, although the incidence of neutropenia in particular was high, the adverse events were manageable and in clinical practice treatment discontinuation because of adverse events will be lower than in the trials.\n\n# Cost effectiveness\n\nThe committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. It accepted the structure of the economic model developed by the company and considered it appropriate for decision-making.\n\n## Data sources in the model\n\nThe committee noted that the company's original model used overall survival from PALOMA‑1, because this is the only source available, but it used progression-free survival data from PALOMA‑2. The ERG stated that it considers the mixing of the 2\xa0data sets to be methodologically flawed, because it assumes that progression-free survival and overall survival were independent of one another. Therefore, the ERG preferred to use the PALOMA‑1 time-to-event data throughout. The committee noted that in the revised analyses submitted during consultation, the company used progression-free survival data from PALOMA‑1 and also the updated final overall survival data from PALOMA‑1 (see section\xa04.4). The committee noted that in the revised analyses the company had accepted all amendments suggested in the ERG's exploratory base case, except the modelling of overall survival.\n\n## Modelling overall survival\n\nIn its revised analyses the company used 2\xa0different approaches for modelling overall survival. The company's 'lower bound' survival was based on a parametric curve (exponential) fitted to the individual patient data from the final analysis of PALOMA‑1. This method closely resembled the ERG's preferred approach. The company also calculated its 'upper bound' survival, by increasing the overall survival gain in PALOMA‑1 to match the modelled progression-free survival gain (that is, 11.2\xa0months). The committee recalled that the relationship between progression-free and overall survival is complex and difficult to predict, but that palbociclib would be expected to improve overall survival. It noted the company's comments that the lack of a statistically significant overall survival gain in PALOMA‑1 could be because overall survival data are confounded by randomness of response to post-progression treatments. The committee concluded that although it is possible that the overall survival gain might be better than that in PALOMA‑1, there is no evidence to support an assumption of overall survival gain equal to the progression-free survival gain without further overall survival data from PALOMA‑2.\n\n## Costs for post-progression states\n\nIn its original submission the company did not include any treatment-related costs beyond first-line therapy. It included only disease-related costs, estimated using package\xa02 care from NICE's clinical guideline on advanced breast cancer. After seeking advice from clinical nurse specialists, and making adjustments to reflect current NHS practice and variations in lines of treatment, the company incorporated an average disease-related cost of £573.86\xa0per cycle (28\xa0days) in the post-progression state. The ERG did not agree that treatment-related cost such as drug acquisition costs for second-line therapy and beyond could be ignored. It recommended more precise costing. The company presented revised analyses with higher estimated costs for post-progression states (£2,000; £1,395; and £1,140\xa0per cycle). The ERG estimated an average post-progression cost of £1,200\xa0per cycle for active treatment states, and £975\xa0per cycle for best supportive care. These estimates were based on a retrospective review of medical records for patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the UK (Kurosky et al. 2015), together with clinical advice. They also took into account the company's original estimates of disease-related costs. The CDF clinical lead also submitted average costs for second-, third- and fourth-line treatments, estimated in consultation with experts in the Chemotherapy Clinical Reference Group of NHS England. These estimates were presented as commercial in confidence because they included confidential pricing agreements and are therefore not presented here. The committee noted the different estimates and could not be sure which estimate could be considered the most plausible. However, the committee was reassured by the fact that, despite having used different sources, the estimates from the ERG and the CDF clinical lead are reasonably close. It therefore agreed that the ERG's estimates for post-progression costs are plausible.\n\n## Utility value for progression-free state\n\nIn its original base case, the company used different utility values for people in the progression-free state having palbociclib plus letrozole (0.74) or letrozole alone (0.71). These values were derived from the corresponding treatment arms of PALOMA‑2. Taking into account that the difference in the EQ‑5D values between the 2\xa0arms of PALOMA‑2 was not statistically significant, the ERG estimated an average utility value (0.72) by pooling EQ‑5D values for European patients from the first 21\xa0cycles in PALOMA‑2. The committee noted the company's comments that the ERG's preferred estimate undervalues progression-free survival, because people with progression-free disease can have a near-normal life. The company referred to NICE's technology appraisal guidance on everolimus with exemestane for treating advanced breast cancer after endocrine therapy. This used a utility value of 0.771 for people with hormone receptor-positive, HER2-negative disease that recurred or progressed after treatment with an aromatase inhibitor, who were having second-line treatment with everolimus plus exemestane. It argued that people on first-line treatment (as in this appraisal) should be assumed to have at least the same quality of life as accepted for those having second-line treatment after progression. The company also presented a scenario using a utility value of 0.75 for progression-free survival, a midpoint between 0.72 and\xa00.77.\n\nThe committee discussed the most appropriate source of utility values for use in economic modelling, particularly those gathered directly in the relevant trials compared with those sourced from elsewhere. It noted that there is a strong preference for people wanting to delay starting chemotherapy (see section\xa04.2). It also noted that because EQ‑5D measures the health state of people at points in time, it may not fully capture a person's preference to avoid future events. The committee was aware that EQ‑5D data from trials is recommended for use in the NICE reference case. It was, however, aware that there has been inconsistency in the utility values used for similar disease stages across different NICE appraisals for metastatic breast cancer. The committee concluded that it is difficult to precisely predict the quality of life of someone with progression-free disease who is taking endocrine therapy. It agreed to explore a range of utility values for progression-free disease (0.72 to 0.77) for its deliberation on the cost effectiveness of palbociclib.\n\n## Incremental cost-effectiveness ratios\n\nThe committee discussed the company's revised base case incorporating a confidential patient access scheme. It noted that the company had presented a range of incremental cost-effectiveness ratios (ICERs) using 2\xa0approaches to modelling overall survival, 3\xa0utility values for progression-free state (0.72, 0.75 and 0.77) and 3\xa0estimates for post-progression costs (£1,140; £1,395; and £2,000 per cycle). These ICERs were presented as commercial in confidence to maintain confidentiality around the patient access scheme. The committee agreed that after applying a discount to the list price as agreed in the patient access scheme, and using a more realistic estimation of the subsequent treatment costs, the ICERs would be within the range that can be considered cost effective.\n\n## Innovation\n\nThe committee discussed the innovative nature of palbociclib. It noted that the Medicines and Healthcare products Regulatory Agency recognises palbociclib as a promising innovative medicine. The committee agreed that there is a clinical need for better treatments for this patient group, and that it prolongs progression-free survival in this population. It recognised that this is important to patients and that no weight had been given in the cost-effectiveness analysis to the specific benefit of delaying chemotherapy with its attendant side effects, which patients consider important. The overall survival gain also remains an area of significant uncertainty, and could be greater than that shown in PALOMA‑1.\n\n## Conclusion\n\nThe committee noted that there are uncertainties in the calculation for the most plausible ICERs, including:\n\noverall survival modelling; the relationship between the overall survival and progression-free survival\n\n\n\nusing overall survival data from PALOMA‑1, which implied that overall survival gain is 27.5% of progression-free survival gain or\n\nassuming that overall survival gain is equal to the gain in progression-free survival\n\n\n\nthe utility value for progression-free disease\n\nthe cost of subsequent treatments.However the committee agreed that using a more realistic cost for progressive disease (closer to the ERG's estimate), and applying the discount agreed in the patient access scheme, results in ICERs that fall within the range considered a cost-effective use of NHS resources. Therefore, the committee recommended palbociclib in combination with an aromatase inhibitor as a cost-effective use of NHS resources for treating hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer in adults.\n\n## Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA495\n\nAppraisal title: Palbociclib with an aromatase inhibitor for previously untreated hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer\n\nSection\n\nKey conclusion\n\nPalbociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating previously untreated hormone receptor-positive, human epidermal growth factor receptor\xa02 (HER2)-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Palbociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\nThe committee concluded that palbociclib improves progression-free survival, but no significant improvement in overall survival has been shown.\n\nThe committee agreed that with the discount agreed in the patient access scheme, palbociclib is a cost-effective use of NHS resources and it can be recommended.\n\n, 4.4, 4.5, 4.16\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nNICE recommends endocrine therapy as first-line treatment for metastatic hormone receptor-positive and HER2-negative breast cancer but, if the symptoms are severe or the disease is rapidly progressing, people may need chemotherapy.\n\nPeople having treatment value delaying progression of the disease and an important consideration is delaying the time to chemotherapy.\n\n, 4.2\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nPalbociclib, by increasing the effect of aromatase inhibitors, may reduce the number of people who need first-line chemotherapy and delay such treatment in others.\n\nPalbociclib is recognised by the Medicines and Healthcare products Regulatory Agency as a promisingly innovative medicine. The committee agreed that there is a clinical need for better treatments for this patient group, and that it prolongs progression-free-survival.\n\n, 4.15\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nPalbociclib, in combination with an aromatase inhibitor, would be used for people who have not had previous treatment for metastatic breast cancer, and who would otherwise be offered an aromatase inhibitor alone.\n\n\n\nAdverse reactions\n\nAlthough the incidence of haematological adverse events in the palbociclib trials was high, they were reversible and manageable.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nClinical-effectiveness evidence for palbociclib plus letrozole compared with letrozole alone came from 2\xa0studies, PALOMA‑1 and PALOMA‑2. Because the PALOMA‑2 trial was a blinded larger trial, the committee considered that its results are likely to be more reliable for decision-making.\n\nFinal analysis for overall survival from PALOMA‑1 was submitted in response to consultation. However, overall survival results from PALOMA‑2 are not available because the required number of events has not been reached.\n\nData on progression-free survival were available from both trials.\n\nto 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe relevance to general clinical practice was not raised during this appraisal.\n\n–\n\nUncertainties generated by the evidence\n\nData from the trials showed that palbociclib improved progression-free survival, but no significant improvement in overall survival had been shown. An improved progression-free survival with metastatic breast cancer would be expected to have some benefit on overall survival. However, the size of benefit is uncertain.\n\nto 4.6\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo specific groups of people were presented for whom the technology is particularly clinically effective.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that palbociclib has a clear and important benefit for improving progression-free survival, and that it is likely that this would result in some improvement in overall survival. However, the size of benefit is uncertain.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee accepted the structure of the economic model developed by the company and considered it appropriate for decision-making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee concluded that it is possible that the overall survival gain may be better than that in PALOMA‑1 but, without further overall survival data from PALOMA‑2, an assumption of overall survival gain equal to the progression-free survival gain is not supported by any evidence.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nIn its original base case, the company used different utility values for people in the progression-free state having palbociclib plus letrozole (0.74) or letrozole alone (0.71). These values were derived from the corresponding treatment arms of PALOMA‑2. The ERG estimated an average utility value (0.72) by pooling EQ‑5D values for European patients from the first 21\xa0cycles in PALOMA‑2. The committee noted that because EQ‑5D measures the health state of people at points in time, it may not fully capture a person's preference to avoid future events. It was, however, aware that there has been inconsistency in the utility values used for similar disease stages across different NICE appraisals for metastatic breast cancer.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo specific groups of people were presented for whom the technology is particularly cost effective.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe approaches to modelling overall survival, the utility values for progression-free state and cost for post-progression disease states were the key drivers of the cost-effectiveness results.\n\nto 4.13\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee agreed that using a more realistic cost for progressive disease, and applying the discount agreed in the patient access scheme on the list price of the palbociclib, produced ICERs within the range considered a cost-effective use of NHS resources.\n\n(These ICERs incorporated a confidential patient access scheme, and were presented as commercial in confidence.)\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of palbociclib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\n\n\nEnd-of-life considerations\n\nNo end-of-life considerations were raised during the appraisal.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the appraisal.\n\n–"}
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https://www.nice.org.uk/guidance/ta495
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Evidence-based recommendations on palbociclib (Ibrance) as initial endocrine-based therapy for hormone-receptor positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic (secondary) breast cancer in adults.
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ae29c4ca740097ce203aeee78983dfb6dcaf362a
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Ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
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Ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
Evidence-based recommendations on ribociclib (Kisqali) as initial endocrine-based therapy for hormone-receptor positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic (secondary) breast cancer in adults.
# Recommendation
Ribociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating hormone receptor-positive, human epidermal growth factor receptor 2‑negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Ribociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.
Why the committee made this recommendation
Clinical trial evidence shows that ribociclib plus letrozole improves progression-free survival compared with letrozole alone. Although we do not know yet if this improvement leads to a survival benefit with ribociclib. But with the patient access scheme discount, ribociclib is a cost-effective use of NHS resources and it can be recommended.# The technology
# Marketing authorisation
Ribociclib (Kisqali, Novartis) in combination with an aromatase inhibitor is indicated for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy.
# Recommended dose and schedule
The recommended dose is 600 mg, taken orally, once daily for 21 consecutive days, followed by 7 days off treatment (28‑day cycle). Treatment should be continued as long as the patient is having clinical benefit from therapy or until unacceptable toxicity occurs. Ribociclib should be used together with 2.5 mg letrozole or another aromatase inhibitor. The aromatase inhibitor is taken orally, once daily, continuously throughout the 28‑day cycle.
Some adverse reactions may need to be managed by temporary dose interruptions or delays, dose reductions, or permanently stopping the treatment. See the summary of product characteristics for further details.
# Price
£2,950 for a 63‑tablet pack of 200‑mg tablets (excluding VAT; MIMS online, accessed November 2017). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ribociclib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Novartis, and reviews of this submission by the evidence review group (ERG) and the Decision Support Unit (DSU). See the committee papers for full details of the evidence.
# Clinical management
## Aromatase inhibitors are the appropriate comparator
The committee was aware that metastatic breast cancer is an incurable condition. NICE recommends endocrine therapy (such as aromatase inhibitors) as first-line treatment for people with metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. But if symptoms are severe or the disease is rapidly progressive, people may need chemotherapy. The committee noted that in the clinical trial (MONALEESA‑2) ribociclib was given in combination with letrozole (an aromatase inhibitor). The clinical experts explained that in clinical practice the available aromatase inhibitors (letrozole and anastrozole) are considered to be clinically equivalent, because they have similar clinical effectiveness and acquisition costs. The committee also heard that ribociclib plus an aromatase inhibitor would be used for people who have not had previous treatment for metastatic breast cancer, and who would otherwise be offered an aromatase inhibitor alone. It was aware of NICE's technology appraisal guidance on palbociclib for untreated HER-2 negative breast cancer, which is the same type of drug as ribociclib (a cyclin-dependent kinase 4 and 6 inhibitor). The committee noted that palbociclib is not a comparator for this appraisal because it is not established clinical practice in the NHS. The clinical expert explained that after disease progression most people would have several further lines of therapy, including chemotherapy. The committee concluded that the company had placed ribociclib appropriately in the treatment pathway, and that aromatase inhibitor therapy is the comparator.
## Patients value improvements in progression-free survival
The patient expert stated that staying progression-free for as long as possible and being able to continue with normal activities, including working, is very highly valued by patients and their families. The clinical experts emphasised that ribociclib plus letrozole increased the progression-free survival of patients in MONALEESA‑2. The patient and clinical experts explained that remaining progression-free delays the need for further treatments, including chemotherapy. Chemotherapy can be associated with significant side effects that reduce quality of life, and therefore delaying later-line treatments is considered very important to patients. The committee concluded that an increase in progression-free survival is highly valued by patients.
# Clinical evidence
## The clinical-effectiveness evidence is relevant to NHS practice
MONALEESA‑2 was a double blind, placebo-controlled, randomised trial that included 668 postmenopausal women with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. It compared ribociclib combined with letrozole against placebo plus letrozole. The ERG noted that the proportion of people in the trial who presented with advanced or metastatic disease at the time of first diagnosis of breast cancer (34%) was higher than expected in the NHS (10%). But overall the trial population reflects patients seen in the NHS. The committee concluded that the MONALEESA‑2 population is generalisable to NHS clinical practice.
## Ribociclib improves progression-free survival compared with letrozole alone
Progression-free survival in MONALEESA‑2 was assessed both by the investigators and by independent review. The ERG raised concerns that the higher incidence of neutropenia with ribociclib could have resulted in some patients and investigators becoming unblinded to patient allocation, therefore the independent review is the more objective outcome measure. The ERG noted that an independent progression-free assessment was not available for the most recent data cut-off (January 2017). At the independent review in June 2016 the median progression-free assessment had not been reached, but the hazard ratio was 0.597 (confidence interval 0.430 to 0.830). Using January 2017 data, investigator-assessed progression-free survival was 25.3 months for ribociclib and 16 months for letrozole (hazard ratio of 0.568, confidence interval 0.457 to 0.704). This suggests a statistically significant improvement in progression-free survival for ribociclib compared with letrozole. The committee concluded that ribociclib improves progression-free survival compared with letrozole alone.
## It is not known whether ribociclib improves overall survival
The overall survival data from MONALEESA‑2 are immature. Using January 2017 data, there were 50 (15%) and 65 (19.7%) deaths in the ribociclib and letrozole arms respectively. The median overall survival in MONALEESA‑2 could not be estimated for ribociclib, and was 33 months for letrozole; the hazard ratio of 0.746 (confidence interval 0.517 to 1.078) is not statistically significant. The committee concluded that there are insufficient data to allow them to decide whether ribociclib, compared with letrozole alone, improves overall survival.
# Adverse events
## Ribociclib has an acceptable adverse effects profile
In MONALEESA‑2 ribociclib was associated with an increased incidence of neutropenia in particular, but also other adverse events such as nausea and vomiting. The summary of product characteristics requires regular electrocardiogram assessments and liver function tests for people having ribociclib. The clinical experts explained that adverse events are more common when starting ribociclib treatment, and are usually resolved with dose reductions and interruptions. The committee acknowledged the risks associated with ribociclib and concluded that it has an acceptable adverse effects profile.
# The company's economic model
## The model uses a new approach in this disease area
The company's model is a patient-based state-transition model with 3 health states and death (an all-absorbing state):
progression-free survival on first-line treatment (PFS1)
progression-free survival on second-line treatment (PFS2)
progression.Because of the immaturity of the data, overall survival is modelled indirectly and is a function of the time spent in each state. The committee noted that this differs from many breast cancer economic models in NICE technology appraisals, which have used a partitioned survival approach, extrapolating progression-free survival and overall survival from clinical-trial data. It noted that the company's model uses a fixed post-progression state (PFS2), which is a new approach in this disease area. The committee acknowledged that the model may not be directly comparable with other breast cancer models.
## The model structure is appropriate for decision-making
The committee noted that some of the model's results are counterintuitive (for example, decreasing incremental survival gain for ribociclib resulted in a decrease in the incremental cost-effectiveness ratio ). Therefore after the first committee meeting the DSU was asked to examine and comment on the model, and to assess the evidence supporting the key assumptions and inputs. The DSU did 'black-box' testing of the model and concluded that the model structure is acceptable, and does not contain hidden errors. The committee concluded that the model structure is appropriate for decision-making.
# Progression-free survival state in second-line (PFS2)
## BOLERO-2 data is representative of disease progressing on first-line therapy
Data from MONALEESA‑2 were used to model survival in PFS1, but survival in PFS2 was modelled using data from the BOLERO-2 trial. BOLERO-2 was a placebo-controlled, randomised trial in 724 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole. It compared everolimus with exemestane against placebo with exemestane. The ERG and the DSU explained that a key assumption of the company's model is that patients in BOLERO-2 are representative of patients progressing in MONALEESA‑2. The DSU noted that both studies have similar populations in terms of Eastern Cooperative Oncology Group (ECOG) status, previous neoadjuvant or adjuvant chemotherapy, number of metastatic sites and age. All the patients in BOLERO-2 had previous treatment with an aromatase inhibitor. The committee noted that patients in BOLERO-2 had not had previous treatment with a CDK4/6 inhibitor, and it is not known whether this would affect progression-free or overall survival. The ERG and DSU agreed that BOLERO-2 is broadly representative of patients with progressive disease in MONALEESA‑2. The committee concluded that the use of BOLERO-2 data is appropriate.
# Relationship between progression-free and overall survival
## The size of the overall survival benefit is uncertain
The company's original base-case analysis assumed that the progression-free survival gain for ribociclib seen in MONALEESA‑2 translates into an equivalent overall survival gain (full-OS surrogacy). The clinical experts stated that they would expect improved progression-free survival to result in a benefit in overall survival, but the precise relationship between progression-free and overall survival is unknown. The ERG noted the interim survival analysis from the PALOMA-1 trial. This was an open-label trial of the CDK4/6 inhibitor palbociclib, given with letrozole, compared with letrozole alone in people with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. Only 38.5% of the progression-free survival gain for palbociclib was translated into an overall survival gain (partial-OS surrogacy). The ERG suggested that partial-OS surrogacy is more plausible than full-OS surrogacy. The DSU stated that progression-free survival gain is likely to result in an overall survival gain but there is no clear or predictable relationship between the two. The committee agreed that ribociclib improves progression-free survival, and it is likely that this would result in some improvement in overall survival, but the size of this benefit is uncertain. It noted that the partial-OS surrogacy assumption predicts an overall survival gain equal to 38.5% of the progression-free survival gain, based on interim survival results from PALOMA‑1. But more recent data from the trial suggests that only 27.5% of progression-free survival gain translates into an overall survival gain. The assumption of full surrogacy was made by the company in the face of immaturity of the survival data from MONALEESA‑2. The committee concluded that a degree of partial surrogacy is probably more likely than full surrogacy, however the magnitude of the relationship is highly uncertain.
# Modelling of time to treatment discontinuation and progression-free survival
## There is uncertainty about which extrapolations are the most appropriate
The company revised its base case in response to the DSU report and updated the extrapolation with the latest 2017 data for time to treatment discontinuation. The DSU noted the large difference between modelled progression-free survival and time to treatment discontinuation. The company stated that a difference was also observed between the Kaplan–Meier curves for progression-free survival and time to treatment discontinuation in MONALEESA‑2, so this was a real finding in the trial. The company used an exponential distribution and explained that for progression-free survival the exponential curve was the second best according to statistical goodness of fit, and that the choice of the curve was validated by clinical experts together with long-term validation using Kaplan–Meier curves for letrozole from the LEA, PALOMA-2 and ALLIANCE trials. The ERG critiqued the long-term validation and considered that the Weibull distribution is equally plausible for extrapolating progression-free survival in MONALEESA‑2. The DSU noted that studies referenced in NICE's technology appraisal guidance on palbociclib for untreated HER-2 negative breast cancer (Paridaens et al., 2008; Bergh et al., 2012; and Moridsen et al., 2003) report lower median overall survival than the LEA and ALLIANCE trials, and that it is difficult to know which survival estimate is relevant for validation. The DSU suggested that overall, the Weibull distribution seems to be more appropriate for the extrapolation of time to treatment discontinuation and progression-free survival because it results in the difference between the modelled mean time to treatment discontinuation and mean progression-free survival being smaller than when the exponential distribution is used. The Cancer Drug Fund clinical lead noted that extrapolation using the exponential curve appeared to give clinically reasonable results for progression-free survival, and that there is some justification in using the Weibull curve to model time to treatment discontinuation. The committee agreed that there are a number of ways to extrapolate progression-free survival and time to treatment discontinuation in the model. It therefore concluded that there is uncertainty about which extrapolations are the most appropriate.
# Utility values
## The utility values are appropriate for decision-making
The company's original base case used EQ‑5D 5-level data from MONALEESA‑2 to inform PFS1; the BOLERO-2 adjusted value of 0.774 to inform PFS2; and the Lloyd et al. 2006 value of 0.505 for the progression state. The company's revised base case, in line with a recent EQ-5D-5L NICE position statement, mapped the 5-level EQ‑5D data to 3‑level values for the PFS1 state. Because the mapped 3‑level utility is lower than the 5‑level value, the utility in PFS2 has to be lower than the original 0.774. The clinical experts agreed that the utility for PFS2 is likely to be smaller than the utility for PFS1. The DSU suggested a value of 0.69 for PFS2. The company accepted this value and used it in their revised base case. The clinical and patient experts explained that people who are progression-free on ribociclib live a nearly normal life, and therefore the PFS1 utility value could be higher than that used in the model. The committee concluded that the utilities in the company's revised base case are appropriate for decision-making, but noted that the utilities used may undervalue the quality of life for patients in the progression-free health state.
# Cost of subsequent therapies in the economic model
## A range of estimates was considered by the committee
Therapies in the progression health state were not modelled directly. The clinical experts stated that post second-line several treatments are available. The company's original base case assumed a monthly cost of £2,000 based on clinical expert opinion. The ERG noted that details of how this was estimated were not provided and that an additional management cost is included in the model. It suggested an estimate of £1,140, based on NICE's technology appraisal guidance on fulvestrant for locally advanced or metastatic breast cancer and adjusting for inflation. The DSU stated that assuming that the mean time on third-line therapy is 6.1 months (Systemic Anti-Cancer Therapy chemotherapy dataset and Kurosky et al. 2016), based on time patients could be treated using some of the third-line available treatments, both the company and the ERG are likely to be overestimating the cost of third-line treatments. The company's revised base case assumed a monthly cost of £1,500, which is between its original value of £2,000 and the ERG's value of £1,140. The Cancer Drugs Fund clinical lead, together with experts in the Chemotherapy Clinical Reference Group, also estimated the cost of subsequent treatments. These estimates were presented as commercial in confidence because they included confidential pricing agreements and are therefore not presented here. The committee noted that in the ongoing appraisal of palbociclib, the ERG calculated the average cost of subsequent therapies as £1,200 per month. It concluded that it would consider costs in the region of £1,140 to £1,200 in its decision-making.
# Ribociclib dose
## Assumptions about dose reduction over time are appropriate
Ribociclib is taken as three 200‑mg tablets (600 mg dose) once daily, for 21 days of the 28‑day cycle. A dose reduction of 400 mg to 200 mg is allowed for managing adverse events. The company assumed that patients who reduce their dose do not waste tablets. The clinical expert agreed that this would be the case in clinical practice. The ERG noted that wastage when treatment is stopped should be included, but that this has little impact on the cost effectiveness. The company incorporated wastage when treatment is stopped and explained that dose reductions based on individual participant data are more appropriate, because assuming a full dose does not reflect the MONALEESA‑2 data. The committee concluded that dose reduction of ribociclib is an appropriate assumption in the model.
# The company's revised base case
## Does not include all the committee's preferences
The company's revised base case included the following updates:
a patient access scheme
partial-OS surrogacy
exponential curves to extrapolate progression-free survival and time to treatment discontinuation
January 2017 data for progression-free survival and time to treatment discontinuation
cost of progression of £1,500
updated utilities
ribociclib dose reduction.The company's revised base case resulted in an ICER of less than £30,000 per quality-adjusted life year (QALY) gained. These ICERs were presented as commercial in confidence to maintain the confidentiality around the patient access scheme and therefore cannot be reported here. The committee noted its earlier conclusions that the relationship between progression-free survival and overall survival is uncertain (see section 3.10), that there is uncertainty in how to extrapolate progression-free survival and time to treatment discontinuation (section 3.11), and that a range of subsequent therapies' costs should be considered in its decision-making (section 3.13). It concluded that the company's base case does not include all the committee's preferences, and that scenario analyses are needed for the committee's decision-making.
# Cost-effectiveness estimate
## The cost-effectiveness estimates are broadly within the range considered a cost-effective use of NHS resources
The committee considered the company's revised scenario analyses. It emphasised that the survival data for MONALEESA‑2 are immature (see section 3.5), and that the relationship between progression-free survival and overall survival is unknown (see section 3.10). The committee agreed that the cost-effectiveness estimates are subject to high uncertainty given the assumptions about overall survival surrogacy (section 3.10), progression-free survival and time to treatment discontinuation extrapolation (section 3.11), and cost of subsequent treatments (section 3.13). It also noted that the company's model uses a new approach in this disease area (see section 3.7). The committee concluded that taking into account the uncertainties in the calculation of the cost-effectiveness estimates, it was persuaded that there were plausible cost-effectiveness estimates which were broadly in the range which could be considered a cost-effective use of NHS resources.
# Innovation
## There is a clinical need for better treatments for this patient group
The committee discussed the innovative nature of ribociclib. The clinical expert explained that CDK4/6 inhibitors offer a new effective treatment for people with this disease. The committee agreed that there is a clinical need for better treatments for this patient group. It noted that ribociclib prolongs progression-free survival, allowing people to live as near normal lives as possible and delaying chemotherapy. The committee recognised that no weight had been given in the cost-effectiveness analysis to the specific benefit of delaying chemotherapy with its attendant side effects, which patients consider important. The overall survival gain also remains an area of significant uncertainty, and this could be greater than that shown in PALOMA‑1.
# Conclusion
## Ribociclib is recommended
The committee concluded that there are uncertainties in the modelling, but the most plausible ICERs for ribociclib compared with letrozole are broadly within the range normally considered a cost-effective use of NHS resources. It noted the innovative nature of ribociclib and the importance of progression-free survival to patients with this disease. The committee recommended ribociclib as a cost-effective use of NHS resources for treating hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer.
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{'Recommendation': 'Ribociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating hormone receptor-positive, human epidermal growth factor receptor\xa02‑negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Ribociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\nWhy the committee made this recommendation\n\nClinical trial evidence shows that ribociclib plus letrozole improves progression-free survival compared with letrozole alone. Although we do not know yet if this improvement leads to a survival benefit with ribociclib. But with the patient access scheme discount, ribociclib is a cost-effective use of NHS resources and it can be recommended.', 'The technology': '# Marketing authorisation\n\nRibociclib (Kisqali, Novartis) in combination with an aromatase inhibitor is indicated for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor\xa02 (HER2)-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy.\n\n# Recommended dose and schedule\n\nThe recommended dose is 600\xa0mg, taken orally, once daily for 21\xa0consecutive days, followed by 7\xa0days off treatment (28‑day cycle). Treatment should be continued as long as the patient is having clinical benefit from therapy or until unacceptable toxicity occurs. Ribociclib should be used together with 2.5\xa0mg letrozole or another aromatase inhibitor. The aromatase inhibitor is taken orally, once daily, continuously throughout the 28‑day cycle.\n\nSome adverse reactions may need to be managed by temporary dose interruptions or delays, dose reductions, or permanently stopping the treatment. See the summary of product characteristics for further details.\n\n# Price\n\n£2,950 for a 63‑tablet pack of 200‑mg tablets (excluding VAT; MIMS online, accessed November 2017). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ribociclib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.', 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Novartis, and reviews of this submission by the evidence review group (ERG) and the Decision Support Unit (DSU). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Aromatase inhibitors are the appropriate comparator\n\nThe committee was aware that metastatic breast cancer is an incurable condition. NICE recommends endocrine therapy (such as aromatase inhibitors) as first-line treatment for people with metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. But if symptoms are severe or the disease is rapidly progressive, people may need chemotherapy. The committee noted that in the clinical trial (MONALEESA‑2) ribociclib was given in combination with letrozole (an aromatase inhibitor). The clinical experts explained that in clinical practice the available aromatase inhibitors (letrozole and anastrozole) are considered to be clinically equivalent, because they have similar clinical effectiveness and acquisition costs. The committee also heard that ribociclib plus an aromatase inhibitor would be used for people who have not had previous treatment for metastatic breast cancer, and who would otherwise be offered an aromatase inhibitor alone. It was aware of NICE's technology appraisal guidance on palbociclib for untreated HER-2 negative breast cancer, which is the same type of drug as ribociclib (a cyclin-dependent kinase\xa04 and\xa06 [CDK4/6] inhibitor). The committee noted that palbociclib is not a comparator for this appraisal because it is not established clinical practice in the NHS. The clinical expert explained that after disease progression most people would have several further lines of therapy, including chemotherapy. The committee concluded that the company had placed ribociclib appropriately in the treatment pathway, and that aromatase inhibitor therapy is the comparator.\n\n## Patients value improvements in progression-free survival\n\nThe patient expert stated that staying progression-free for as long as possible and being able to continue with normal activities, including working, is very highly valued by patients and their families. The clinical experts emphasised that ribociclib plus letrozole increased the progression-free survival of patients in MONALEESA‑2. The patient and clinical experts explained that remaining progression-free delays the need for further treatments, including chemotherapy. Chemotherapy can be associated with significant side effects that reduce quality of life, and therefore delaying later-line treatments is considered very important to patients. The committee concluded that an increase in progression-free survival is highly valued by patients.\n\n# Clinical evidence\n\n## The clinical-effectiveness evidence is relevant to NHS practice\n\nMONALEESA‑2 was a double blind, placebo-controlled, randomised trial that included 668\xa0postmenopausal women with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. It compared ribociclib combined with letrozole against placebo plus letrozole. The ERG noted that the proportion of people in the trial who presented with advanced or metastatic disease at the time of first diagnosis of breast cancer (34%) was higher than expected in the NHS (10%). But overall the trial population reflects patients seen in the NHS. The committee concluded that the MONALEESA‑2 population is generalisable to NHS clinical practice.\n\n## Ribociclib improves progression-free survival compared with letrozole alone\n\nProgression-free survival in MONALEESA‑2 was assessed both by the investigators and by independent review. The ERG raised concerns that the higher incidence of neutropenia with ribociclib could have resulted in some patients and investigators becoming unblinded to patient allocation, therefore the independent review is the more objective outcome measure. The ERG noted that an independent progression-free assessment was not available for the most recent data cut-off (January 2017). At the independent review in June 2016 the median progression-free assessment had not been reached, but the hazard ratio was 0.597 (confidence interval 0.430 to 0.830). Using January 2017 data, investigator-assessed progression-free survival was 25.3\xa0months for ribociclib and 16\xa0months for letrozole (hazard ratio of 0.568, confidence interval 0.457 to 0.704). This suggests a statistically significant improvement in progression-free survival for ribociclib compared with letrozole. The committee concluded that ribociclib improves progression-free survival compared with letrozole alone.\n\n## It is not known whether ribociclib improves overall survival\n\nThe overall survival data from MONALEESA‑2 are immature. Using January 2017 data, there were 50 (15%) and 65 (19.7%) deaths in the ribociclib and letrozole arms respectively. The median overall survival in MONALEESA‑2 could not be estimated for ribociclib, and was 33\xa0months for letrozole; the hazard ratio of 0.746 (confidence interval 0.517 to 1.078) is not statistically significant. The committee concluded that there are insufficient data to allow them to decide whether ribociclib, compared with letrozole alone, improves overall survival.\n\n# Adverse events\n\n## Ribociclib has an acceptable adverse effects profile\n\nIn MONALEESA‑2 ribociclib was associated with an increased incidence of neutropenia in particular, but also other adverse events such as nausea and vomiting. The summary of product characteristics requires regular electrocardiogram assessments and liver function tests for people having ribociclib. The clinical experts explained that adverse events are more common when starting ribociclib treatment, and are usually resolved with dose reductions and interruptions. The committee acknowledged the risks associated with ribociclib and concluded that it has an acceptable adverse effects profile.\n\n# The company's economic model\n\n## The model uses a new approach in this disease area\n\nThe company's model is a patient-based state-transition model with 3\xa0health states and death (an all-absorbing state):\n\nprogression-free survival on first-line treatment (PFS1)\n\nprogression-free survival on second-line treatment (PFS2)\n\nprogression.Because of the immaturity of the data, overall survival is modelled indirectly and is a function of the time spent in each state. The committee noted that this differs from many breast cancer economic models in NICE technology appraisals, which have used a partitioned survival approach, extrapolating progression-free survival and overall survival from clinical-trial data. It noted that the company's model uses a fixed post-progression state (PFS2), which is a new approach in this disease area. The committee acknowledged that the model may not be directly comparable with other breast cancer models.\n\n## The model structure is appropriate for decision-making\n\nThe committee noted that some of the model's results are counterintuitive (for example, decreasing incremental survival gain for ribociclib resulted in a decrease in the incremental cost-effectiveness ratio [ICER]). Therefore after the first committee meeting the DSU was asked to examine and comment on the model, and to assess the evidence supporting the key assumptions and inputs. The DSU did 'black-box' testing of the model and concluded that the model structure is acceptable, and does not contain hidden errors. The committee concluded that the model structure is appropriate for decision-making.\n\n# Progression-free survival state in second-line (PFS2)\n\n## BOLERO-2 data is representative of disease progressing on first-line therapy\n\nData from MONALEESA‑2 were used to model survival in PFS1, but survival in PFS2 was modelled using data from the BOLERO-2 trial. BOLERO-2 was a placebo-controlled, randomised trial in 724\xa0postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer refractory to letrozole or anastrozole. It compared everolimus with exemestane against placebo with exemestane. The ERG and the DSU explained that a key assumption of the company's model is that patients in BOLERO-2 are representative of patients progressing in MONALEESA‑2. The DSU noted that both studies have similar populations in terms of Eastern Cooperative Oncology Group (ECOG) status, previous neoadjuvant or adjuvant chemotherapy, number of metastatic sites and age. All the patients in BOLERO-2 had previous treatment with an aromatase inhibitor. The committee noted that patients in BOLERO-2 had not had previous treatment with a CDK4/6 inhibitor, and it is not known whether this would affect progression-free or overall survival. The ERG and DSU agreed that BOLERO-2 is broadly representative of patients with progressive disease in MONALEESA‑2. The committee concluded that the use of BOLERO-2 data is appropriate.\n\n# Relationship between progression-free and overall survival\n\n## The size of the overall survival benefit is uncertain\n\nThe company's original base-case analysis assumed that the progression-free survival gain for ribociclib seen in MONALEESA‑2 translates into an equivalent overall survival gain (full-OS surrogacy). The clinical experts stated that they would expect improved progression-free survival to result in a benefit in overall survival, but the precise relationship between progression-free and overall survival is unknown. The ERG noted the interim survival analysis from the PALOMA-1 trial. This was an open-label trial of the CDK4/6 inhibitor palbociclib, given with letrozole, compared with letrozole alone in people with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. Only 38.5% of the progression-free survival gain for palbociclib was translated into an overall survival gain (partial-OS surrogacy). The ERG suggested that partial-OS surrogacy is more plausible than full-OS surrogacy. The DSU stated that progression-free survival gain is likely to result in an overall survival gain but there is no clear or predictable relationship between the two. The committee agreed that ribociclib improves progression-free survival, and it is likely that this would result in some improvement in overall survival, but the size of this benefit is uncertain. It noted that the partial-OS surrogacy assumption predicts an overall survival gain equal to 38.5% of the progression-free survival gain, based on interim survival results from PALOMA‑1. But more recent data from the trial suggests that only 27.5% of progression-free survival gain translates into an overall survival gain. The assumption of full surrogacy was made by the company in the face of immaturity of the survival data from MONALEESA‑2. The committee concluded that a degree of partial surrogacy is probably more likely than full surrogacy, however the magnitude of the relationship is highly uncertain.\n\n# Modelling of time to treatment discontinuation and progression-free survival\n\n## There is uncertainty about which extrapolations are the most appropriate\n\nThe company revised its base case in response to the DSU report and updated the extrapolation with the latest 2017 data for time to treatment discontinuation. The DSU noted the large difference between modelled progression-free survival and time to treatment discontinuation. The company stated that a difference was also observed between the Kaplan–Meier curves for progression-free survival and time to treatment discontinuation in MONALEESA‑2, so this was a real finding in the trial. The company used an exponential distribution and explained that for progression-free survival the exponential curve was the second best according to statistical goodness of fit, and that the choice of the curve was validated by clinical experts together with long-term validation using Kaplan–Meier curves for letrozole from the LEA, PALOMA-2 and ALLIANCE trials. The ERG critiqued the long-term validation and considered that the Weibull distribution is equally plausible for extrapolating progression-free survival in MONALEESA‑2. The DSU noted that studies referenced in NICE's technology appraisal guidance on palbociclib for untreated HER-2 negative breast cancer (Paridaens et al., 2008; Bergh et al., 2012; and Moridsen et al., 2003) report lower median overall survival than the LEA and ALLIANCE trials, and that it is difficult to know which survival estimate is relevant for validation. The DSU suggested that overall, the Weibull distribution seems to be more appropriate for the extrapolation of time to treatment discontinuation and progression-free survival because it results in the difference between the modelled mean time to treatment discontinuation and mean progression-free survival being smaller than when the exponential distribution is used. The Cancer Drug Fund clinical lead noted that extrapolation using the exponential curve appeared to give clinically reasonable results for progression-free survival, and that there is some justification in using the Weibull curve to model time to treatment discontinuation. The committee agreed that there are a number of ways to extrapolate progression-free survival and time to treatment discontinuation in the model. It therefore concluded that there is uncertainty about which extrapolations are the most appropriate.\n\n# Utility values\n\n## The utility values are appropriate for decision-making\n\nThe company's original base case used EQ‑5D 5-level data from MONALEESA‑2 to inform PFS1; the BOLERO-2 adjusted value of 0.774 to inform PFS2; and the Lloyd et al. 2006 value of 0.505 for the progression state. The company's revised base case, in line with a recent EQ-5D-5L NICE position statement, mapped the 5-level EQ‑5D data to 3‑level values for the PFS1 state. Because the mapped 3‑level utility is lower than the 5‑level value, the utility in PFS2 has to be lower than the original 0.774. The clinical experts agreed that the utility for PFS2 is likely to be smaller than the utility for PFS1. The DSU suggested a value of 0.69 for PFS2. The company accepted this value and used it in their revised base case. The clinical and patient experts explained that people who are progression-free on ribociclib live a nearly normal life, and therefore the PFS1 utility value could be higher than that used in the model. The committee concluded that the utilities in the company's revised base case are appropriate for decision-making, but noted that the utilities used may undervalue the quality of life for patients in the progression-free health state.\n\n# Cost of subsequent therapies in the economic model\n\n## A range of estimates was considered by the committee\n\nTherapies in the progression health state were not modelled directly. The clinical experts stated that post second-line several treatments are available. The company's original base case assumed a monthly cost of £2,000 based on clinical expert opinion. The ERG noted that details of how this was estimated were not provided and that an additional management cost is included in the model. It suggested an estimate of £1,140, based on NICE's technology appraisal guidance on fulvestrant for locally advanced or metastatic breast cancer and adjusting for inflation. The DSU stated that assuming that the mean time on third-line therapy is 6.1 months (Systemic Anti-Cancer Therapy chemotherapy dataset and Kurosky et al. 2016), based on time patients could be treated using some of the third-line available treatments, both the company and the ERG are likely to be overestimating the cost of third-line treatments. The company's revised base case assumed a monthly cost of £1,500, which is between its original value of £2,000 and the ERG's value of £1,140. The Cancer Drugs Fund clinical lead, together with experts in the Chemotherapy Clinical Reference Group, also estimated the cost of subsequent treatments. These estimates were presented as commercial in confidence because they included confidential pricing agreements and are therefore not presented here. The committee noted that in the ongoing appraisal of palbociclib, the ERG calculated the average cost of subsequent therapies as £1,200 per month. It concluded that it would consider costs in the region of £1,140 to £1,200 in its decision-making.\n\n# Ribociclib dose\n\n## Assumptions about dose reduction over time are appropriate\n\nRibociclib is taken as three 200‑mg tablets (600\xa0mg dose) once daily, for 21\xa0days of the 28‑day cycle. A dose reduction of 400\xa0mg\xa0to 200\xa0mg is allowed for managing adverse events. The company assumed that patients who reduce their dose do not waste tablets. The clinical expert agreed that this would be the case in clinical practice. The ERG noted that wastage when treatment is stopped should be included, but that this has little impact on the cost effectiveness. The company incorporated wastage when treatment is stopped and explained that dose reductions based on individual participant data are more appropriate, because assuming a full dose does not reflect the MONALEESA‑2 data. The committee concluded that dose reduction of ribociclib is an appropriate assumption in the model.\n\n# The company's revised base case\n\n## Does not include all the committee's preferences\n\nThe company's revised base case included the following updates:\n\na patient access scheme\n\npartial-OS surrogacy\n\nexponential curves to extrapolate progression-free survival and time to treatment discontinuation\n\nJanuary 2017 data for progression-free survival and time to treatment discontinuation\n\ncost of progression of £1,500\n\nupdated utilities\n\nribociclib dose reduction.The company's revised base case resulted in an ICER of less than £30,000 per quality-adjusted life year (QALY) gained. These ICERs were presented as commercial in confidence to maintain the confidentiality around the patient access scheme and therefore cannot be reported here. The committee noted its earlier conclusions that the relationship between progression-free survival and overall survival is uncertain (see section 3.10), that there is uncertainty in how to extrapolate progression-free survival and time to treatment discontinuation (section 3.11), and that a range of subsequent therapies' costs should be considered in its decision-making (section 3.13). It concluded that the company's base case does not include all the committee's preferences, and that scenario analyses are needed for the committee's decision-making.\n\n# Cost-effectiveness estimate\n\n## The cost-effectiveness estimates are broadly within the range considered a cost-effective use of NHS resources\n\nThe committee considered the company's revised scenario analyses. It emphasised that the survival data for MONALEESA‑2 are immature (see section 3.5), and that the relationship between progression-free survival and overall survival is unknown (see section 3.10). The committee agreed that the cost-effectiveness estimates are subject to high uncertainty given the assumptions about overall survival surrogacy (section 3.10), progression-free survival and time to treatment discontinuation extrapolation (section 3.11), and cost of subsequent treatments (section 3.13). It also noted that the company's model uses a new approach in this disease area (see section 3.7). The committee concluded that taking into account the uncertainties in the calculation of the cost-effectiveness estimates, it was persuaded that there were plausible cost-effectiveness estimates which were broadly in the range which could be considered a cost-effective use of NHS resources.\n\n# Innovation\n\n## There is a clinical need for better treatments for this patient group\n\nThe committee discussed the innovative nature of ribociclib. The clinical expert explained that CDK4/6 inhibitors offer a new effective treatment for people with this disease. The committee agreed that there is a clinical need for better treatments for this patient group. It noted that ribociclib prolongs progression-free survival, allowing people to live as near normal lives as possible and delaying chemotherapy. The committee recognised that no weight had been given in the cost-effectiveness analysis to the specific benefit of delaying chemotherapy with its attendant side effects, which patients consider important. The overall survival gain also remains an area of significant uncertainty, and this could be greater than that shown in PALOMA‑1.\n\n# Conclusion\n\n## Ribociclib is recommended\n\nThe committee concluded that there are uncertainties in the modelling, but the most plausible ICERs for ribociclib compared with letrozole are broadly within the range normally considered a cost-effective use of NHS resources. It noted the innovative nature of ribociclib and the importance of progression-free survival to patients with this disease. The committee recommended ribociclib as a cost-effective use of NHS resources for treating hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer."}
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https://www.nice.org.uk/guidance/ta496
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Evidence-based recommendations on ribociclib (Kisqali) as initial endocrine-based therapy for hormone-receptor positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic (secondary) breast cancer in adults.
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cc927c12f913211fdc54fcdc1f725673784e2663
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nice
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Atrial fibrillation and heart valve disease: self-monitoring coagulation status using point-of-care coagulometers (the CoaguChek XS system)
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Atrial fibrillation and heart valve disease: self-monitoring coagulation status using point-of-care coagulometers (the CoaguChek XS system)
Evidence-based recommendations on the CoaguChek XS system for self-monitoring coagulation status in adults and children. The recommendations originally included the InRatio2 PT/INR, but this was withdrawn from the market in October 2016 and is not currently available.
# Recommendations
The CoaguChek XS system is recommended for self‑monitoring coagulation status in adults and children on long‑term vitamin K antagonist therapy who have atrial fibrillation or heart valve disease if:
the person prefers this form of testing and
the person or their carer is both physically and cognitively able to self‑monitor effectively.
This recommendation has been removed because the InRatio2 PT/INR monitor is no longer available.
Patients and carers should be trained in the effective use of the CoaguChek XS system and clinicians involved in their care should regularly review their ability to self‑monitor.
Equipment for self‑monitoring should be regularly checked using reliable quality control procedures, and by testing patients' equipment against a healthcare professional's coagulometer which is checked in line with an external quality assurance scheme. Ensure accurate patient records are kept and shared appropriately.
For people who may have difficulty with or who are unable to self‑monitor, such as children or people with disabilities, their carers should be considered to help with self‑monitoring.# The technologies
Three CE‑marked point‑of‑care coagulometers for self‑monitoring coagulation status were identified during scoping as being relevant to this assessment. One of these coagulometers, the ProTime microcoagulation system, was included in the assessment but has been removed from this guidance because it is no longer available to the NHS and its successor model is not intended for patient self‑monitoring. Additional details of the coagulometers included in the guidance are provided in section 4.# Clinical need and practice
# The problem addressed
The point‑of‑care coagulometers are designed to monitor the clotting tendency of blood in people on long‑term vitamin K antagonist therapy, such as those with atrial fibrillation or artificial heart valves who are at risk of thrombosis. The tests allow monitoring by 2 different methods of care: self‑testing and self‑managing. Both methods are based on the international normalised ratio (INR), which is a standardised unit for measuring the time it takes for blood to clot. Self‑testing refers to the user doing the INR test themselves and then contacting their healthcare professional with the reading for advice on any change to the dosage of the anticoagulant that may be needed. Self‑managing refers to the user doing the INR test themselves and then self‑adjusting the dosage of their anticoagulant medication by following an agreed care protocol. Together, these methods of care are referred to as self‑monitoring.
The use of these coagulometers may reduce the frequency of visits to hospital or clinics for patients and enable them to be monitored more regularly. This may improve health outcomes by enabling the dose of therapy to be adjusted more accurately, thereby avoiding adverse events that can result from an over‑ or under‑dose of long‑term vitamin K antagonist therapy, such as stroke and major haemorrhage.
The purpose of this assessment is to evaluate the clinical and cost effectiveness of using the CoaguChek XS system and the INRatio2 PT/INR monitor for self‑monitoring (self‑testing or self‑managing) coagulation status in people on long‑term vitamin K antagonist therapy who have atrial fibrillation or heart valve disease.
# The condition
There are a number of conditions that can result in people having an increased risk of thrombosis and consequently, receiving long‑term vitamin K antagonist therapy. These conditions include atrial fibrillation and heart valve disease. Guidance on self‑monitoring the coagulation status of people who have had a venous thromboembolism and are receiving long‑term vitamin K antagonist therapy is included in the NICE guideline on venous thromboembolic diseases and so this population is not included in the scope of this diagnostics assessment of self‑monitoring coagulometers.
## Atrial fibrillation
Atrial fibrillation is the most common heart arrhythmia and affects around 800,000 people in the UK. It can affect adults of any age but it is more common in older people; 0.5% of people aged 50–59 years and around 8% of people aged over 65 years are estimated to be affected. Atrial fibrillation is also more common in men than women, and is more common in people with other conditions, such as high blood pressure, atherosclerosis and heart valve problems.
Approximately 47% of people with atrial fibrillation currently receive vitamin K antagonist therapy. It is estimated that a further 30% of people with atrial fibrillation could receive this therapy but currently do not. People with atrial fibrillation are at a 5–6 times greater risk of stroke, with 12,500 strokes directly attributable to atrial fibrillation occurring every year in the UK. Treatment with warfarin reduces this risk by 50–70%.
## Heart valve disease
Valve disease can affect blood flow through the heart in 2 ways: valve stenosis, in which the valve does not open fully, and valve regurgitation (or incompetence) in which the valve does not close properly, allowing blood to leak backwards. Disease can occur in any of the 4 heart valves, although disorders of the aortic and mitral valves are more serious.
The main causes of heart valve disease are congenital heart disease and other diseases such as rheumatic fever, lupus, cardiomyopathy and endocarditis. Aortic stenosis is the most common type of valve disease and it affects around 1 in 20 adults over the age of 65 years in the UK.
Data from the UK heart valve registry indicate that approximately 0.2% of the UK population has prosthetic heart valves. Around 6500 adult heart valve replacements (using mechanical or biological valves) are carried out each year, of which around 5000 are aortic valve replacements.
Patients with mechanical heart valves (and some patients with bioprosthetic valves) are susceptible to thromboembolism and need lifelong anticoagulant therapy.
# The diagnostic and care pathways
Non‑vitamin K antagonist oral anticoagulants are an alternative to vitamin K antagonists and can be administered to reduce the risk of thrombosis or stroke. The non‑vitamin K antagonist oral anticoagulants have fewer food and drug interactions than vitamin K antagonists and they do not need therapeutic monitoring. However, they may be unsuitable for some people, such as people with mechanical heart valves, certain people with renal or liver dysfunction and those taking concurrent drugs that cannot be taken with the non‑vitamin K antagonist oral anticoagulants. The individual summary of product characteristics should be consulted for specific details when prescribing a non‑vitamin K antagonist oral anticoagulant. NICE technology appraisal guidance recommends 3 non‑vitamin K antagonist oral anticoagulants (see the NICE guidance on apixaban, rivaroxaban and dabigatran etexilate) for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation.
Guidelines on oral anticoagulation with warfarin, published by the British Committee for Standards in Haematology (Keeling et al. 2011), outline the process for INR monitoring for those receiving warfarin. The NICE clinical knowledge summary for oral anticoagulation states that INR can be most accurately measured in venous blood samples, but that capillary blood samples are also used because they are more convenient. People being tested should receive a written copy of their INR result including any necessary dose adjustments and a date for the next check.
The summary states that the INR should be measured:
daily, or on alternate days, until it is within the therapeutic range (usually between 2.0 and 3.0, ideally 2.5) on 2 consecutive occasions
then twice weekly for 1–2 weeks, followed by weekly measurements until the INR is stable within the therapeutic range
thereafter, depending on the stability of the INR, at longer intervals (for example, up to every 12 weeks, if agreed locally).
More frequent monitoring of the INR is recommended for patients at risk of overcoagulation or bleeding, or those having problems adhering to treatment. Intravenous drug users, and people with hepatitis B, hepatitis C, or HIV, may be referred to a specialist clinic according to local arrangements.
INR monitoring can be managed by local anticoagulant clinics in primary care, but sometimes clinics are based in secondary care, involving travel to hospital. The NICE anticoagulation commissioning guide (2013) states that anticoagulation therapy services can be delivered in a number of different ways, and that mixed models of provision may be needed across a local health region. This could include full service provision in secondary or primary care, shared provision, domiciliary provision and self‑management. Services may be managed by a range of healthcare professionals including nurses, pharmacists and general practitioners.# The diagnostic tests
# The interventions
## The CoaguChek XS system
The CoaguChek XS system (Roche Diagnostics) comprises a meter and specifically designed test strips that can analyse a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time and the international normalised ratio (INR). These measures indicate the rate at which the blood clots. If the INR is too low, there is a higher risk of blood clots that can lead to a heart attack or a stroke. If the INR is too high, there is a higher risk of bleeding, which in severe cases can be gastrointestinal or intracerebral bleeding.
A code chip, which contains calibration data and the expiry date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted and the blood sample is applied. The test result is displayed approximately 1 minute after applying the sample and the monitor automatically stores the result in its memory. The user is guided through the process by on‑screen graphical instructions.
The CoaguChek XS test strip contains a lyophilised reagent consisting of thromboplastin and a peptide substrate. When a blood sample is applied, thromboplastin activates coagulation, which leads to the formation of thrombin. The enzyme thrombin cleaves the peptide substrate, generating an electrochemical signal. Depending on the time elapsed before it first appears, this signal is then converted by means of an algorithm into customary coagulation units and the result is displayed on the screen. This can be displayed as prothrombin time in seconds, Quick value, or INR.
The CoaguChek XS system has a number of in‑built quality control functions including checks of the electric components when switched on, the test strip temperature during testing, and checks on the test strip batch such as the expiry date and quality of each strip. The CoaguChek XS test strips are packaged as single strips in resealable plastic containers in quantities of 24 and 48 test strips. The strips can be stored at room temperature or refrigerated between 2 and 8°C and can be used straight from the fridge. On manufacture, the CoaguChek XS test strips have a shelf‑life (expiration date) of 18 months.
The CoaguChek XS meter is supplied with 4 × AAA batteries, a CoaguChek Softclix finger pricker and 20 Softclix XL lancets, 6 test strips, a user manual and carry case. The system can carry out a minimum of 60 tests per set of batteries. The meter is 138 mm × 78 mm × 28 mm and weighs 127 g (without batteries).
An earlier model of the CoaguChek XS system is the CoaguChek S system. The CoaguChek XS system is reported to have the following advantages over the CoaguChek S system: the thromboplastin used in the prothrombin time test strips is a human recombinant thromboplastin, which is more sensitive and has a lower international sensitivity index of 1.0 compared with 1.6; test strips have inbuilt quality control that is automatically run with every test; test strips do not have to be refrigerated; a smaller blood sample can be used; and the meter is smaller and lighter. Another model of the CoaguChek XS system is the CoaguChek XS Plus system. The XS Plus model is intended for use by healthcare professionals only and is not indicated for individual INR self‑monitoring.
## The INRatio2 PT/INR monitor
The INRatio2 PT/INR monitor (Alere) does a modified version of the 1‑stage prothrombin time test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process. The system consists of a monitor and disposable test strips.
The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports prothrombin time and INR results. Instructions and test results are displayed on an LCD. The monitor can store the results so that past test results can be reviewed.
The test strip comprises 2 layers of transparent plastic laminated to each other that contain 1 sample well, 3 clot cells, and narrow channels connecting the sample well and the clot cells. The top side of the bottom layer is printed with 3 pairs of silver electrodes (1 pair per cell) that start from inside the clot cells to the end of the strip where they are connected to the monitor main circuitry. Test strips are individually foil wrapped, supplied in quantities of 12 or 48 strips and can be stored at room temperature for up to 12 months or until the expiration date.
The INRatio2 PT/INR monitor analyses fresh capillary blood and when the blood sample is applied to the sample well, it is drawn through the narrow channels by capillary action to the clot cells, where the impedance of the sample is measured by the monitor through the electrodes. Clot cells have reagents applied and the reagents are different for each channel. One channel contains the thromboplastin reagent for the prothrombin time test. The other 2 channels contain reagents that produce a low and high control time, regardless of the clotting time of the sample.
Initially, the electrode impedance is infinite but drops to a minimum value when the blood sample fills the clot cells. The time when this initial minimum impedance is achieved is registered by the monitor as the start of the coagulation. As the reaction progresses, the sample impedance increases to a maximum and then gradually drops as the clotting proceeds. The elapsed time, in seconds, from the start until the clotting end point is reached is the prothrombin time. The monitor software calculates the INR of the sample using prothrombin time and calibration coefficients.
The INRatio2 PT/INR monitor does a self‑test when it is turned on and each test strip has a code that is accepted by the monitor if the strip code is in the correct format. The monitor uses 4 × AA batteries or a mains adapter as a power source, and can connect to a printer or computer through the RS232 serial communication port.
# The comparator: INR testing
The comparator used in this assessment is INR testing in primary or secondary care using laboratory analysers or point‑of‑care tests.# Outcomes
The Diagnostics Advisory Committee (section 8) considered evidence from a number of sources (section 9).
# How outcomes were assessed
The assessment consisted of a systematic review of the evidence on test performance and clinical‑effectiveness data for the CoaguChek XS system, the INRatio2 PT/INR monitor, the ProTime microcoagulation system and comparator tests. The ProTime microcoagulation system was in the assessment but has been removed from this guidance because it is no longer available to the NHS and its successor model is not intended for patient self‑monitoring.
# Clinical effectiveness
The External Assessment Group conducted a systematic review of the evidence on the clinical effectiveness of self‑monitoring coagulation status in people on long‑term vitamin K antagonist therapy who have atrial fibrillation or heart valve disease.
Studies were included if they appeared relevant to the outcomes listed in the decision problem:
Intermediate outcomes:
time and values in therapeutic range
international normalised ratio (INR) values
test failure rate
time to test result.
Patient adherence to testing and treatment:
frequency of testing
frequency of visits to primary or secondary care clinics.
Clinical outcomes:
frequency of bleeds or blood clots
morbidity (for example, thromboembolic and cerebrovascular events) and mortality from INR testing and vitamin K antagonist therapy
adverse events from INR testing, false test results, vitamin K antagonist therapy and sequelae.
Patient‑reported outcomes:
anxiety associated with waiting time for results and not knowing current coagulation status and risk
acceptability of the tests
health‑related quality of life.
In total, 26 randomised controlled trials met the inclusion criteria and were included in this assessment. The CoaguChek system was used in 22 of the 26 trials: 9 trials used the CoaguChek S model, 4 trials used the CoaguChek XS model, 1 trial used the CoaguChek Plus model, and 2 trials used the CoaguChek model. It was unclear which model of the CoaguChek system was used in 6 of the 22 trials. In 2 of the remaining 4 trials either the CoaguChek S system or the INRatio monitor was used for INR measurement (results were not reported according to the type of point‑of‑care monitor, and the model of the INRatio monitor used in the trials was not reported). No trials that exclusively assessed the clinical effectiveness of the INRatio2 PT/INR monitor were identified. The ProTime microcoagulation system was used in the other 2 trials. In all 6 trials based in the UK, the CoaguChek system (either CoaguChek or version 'S') was used for the INR measurement.
The evidence on the clinical effectiveness of the coagulometers for monitoring coagulation status was summarised by the External Assessment Group in 3 categories: intermediate outcomes, clinical outcomes, and patient‑reported outcomes.
## Performance of point‑of‑care coagulometers
The External Assessment Group did not carry out a formal evaluation of the performance of the CoaguChek system or the INRatio2 PT/INR monitor with regard to INR measurement because it was outside the scope of this assessment. However, an objective 'true' INR remains to be defined and INR determined in the laboratory is regarded as the gold standard to which all other measurement methods should be compared. Information on the precision and accuracy of these point‑of‑care coagulometers was therefore gathered from the available literature.
A systematic review by Christensen and Larsen published in 2012 assessed the precision and accuracy of currently available point‑of‑care coagulometers including CoaguChek XS, INRatio and ProTime. The authors found that the precision of CoaguChek XS varied from a coefficient of variation of 1.4% to 5.9% based on data from 14 studies. The precision of INRatio and ProTime varied from 5.4% to 8.4% based on data from 6 studies. The coefficient of correlation for CoaguChek XS varied from 0.81 to 0.98, and that for INRatio varied from 0.73 to 0.95. The review concluded that the precision and accuracy of point‑of‑care coagulometers were generally acceptable compared with laboratory‑based INR testing. The same conclusions were drawn by the Canadian Agency for Drugs and Technologies in Health report published in 2012 on point‑of‑care testing. Similarly, the international guidelines prepared in 2005 by the International Self‑Monitoring Association for Oral Anticoagulation stated that 'Point‑of‑care instruments have been tested in a number of different clinical settings and their accuracy and precision are considered to be more than adequate for the monitoring of oral anticoagulation therapy in both adults and children'.
Six studies compared the performance of CoaguChek S with that of CoaguChek XS in relation to conventional INR measurement. The studies showed a good agreement between the 2 CoaguChek models and conventional laboratory‑based testing results. However, the CoaguChek XS showed more accurate and precise results than CoaguChek S in both adults and children, especially for higher INR values (>3.5).
## Evidence on intermediate outcomes
Eighteen trials (including 4 trials that used the CoaguChek XS system) reported INR time in therapeutic range although there was variation in the measures used for reporting this outcome, so pooling the data was not appropriate. Time in therapeutic range ranged from 52% to 80% for self‑monitoring and from 55% to 77% for standard care. In 15 of the 18 trials, time in therapeutic range was higher in self‑monitoring participants compared with those in standard care and, in 5 of these trials (including 2 trials using the CoaguChek XS system), the difference between intervention groups was statistically significant. Three of the UK‑based trials reported no statistically significant differences between self‑monitoring and standard care.
Twelve trials reported INR values in therapeutic range and there was variation in the measures used so pooling the data was not appropriate. In 8 of these trials, the proportion of INR values in therapeutic range ranged from 43.2% to 80.8% for self‑monitoring and from 22.3% to 72.0% for standard care. In 4 trials that reported the proportion of participants in therapeutic range, the values ranged from 53.0% to 72.9% for self‑monitoring and from 43.2% to 72.0% for standard care. Ten of the trials reported higher proportions of INR values in therapeutic range or larger proportions of participants in therapeutic range for self‑monitoring than for standard care.
Among participants with artificial heart valves, self‑monitoring resulted in a statistically significant higher INR time in therapeutic range compared with standard care. In 2 trials that included participants with atrial fibrillation, no time in therapeutic range differences were found between self‑monitoring and standard care.
One trial reported the time for each INR monitoring (that is, time from INR measurement to test results) and the total time spent for anticoagulant management during the 4‑month follow‑up period. The time spent for each INR measurement by self‑managed participants was statistically significantly lower (mean 5.3 minutes, standard deviation 2.6 minutes) compared with the time spent by participants receiving standard care (mean 158 minutes, SD 67.8 minutes, p<0.001). During the 4‑month follow‑up, the total time spent for anticoagulation monitoring by participants in standard care was statistically significantly higher (mean 614.9 minutes, SD 308.8 minutes) than the total time spent by participants who self‑managed their therapy (mean 99.6 minutes, SD 46.1 minutes, p<0.0001).
One trial reported more than 98% adherence with self‑testing and of those who did not adhere, 2 had difficulties doing the test or experienced disruption caused by hospitalisation, and 1 lost the CoaguChek meter. In another trial 75% (30/40) of participants did not report any problems with using the device and expressed willingness to continue with self‑monitoring. The remaining participants who did not adhere to the testing procedure (25%) reported difficulties with the technique or problems placing the fingertip blood drop on the right position on the test strip. This resulted in the need to use multiple strips to achieve a single reading.
## Evidence on clinical outcomes
Twenty one trials reported a total of 1472 major and minor bleeding events involving 8394 participants. 476 major bleeding events were reported in a total of 8202 participants and 13 of these 21 trials reported 994 minor bleeding events in a total of 5425 participants. No statistically significant differences were seen between self‑monitoring participants (self‑testing and self‑management) and those in standard care for any bleeding events (relative risk 0.95, 95% confidence interval 0.74 to 1.21, p=0.66), major bleeding events (RR 1.02, 95% CI 0.86 to 1.22, p=0.80) and minor bleeding events (RR 0.94, 95% CI 0.65 to 1.34, p=0.73). The results were not affected by removing the UK‑based trials or by restricting the included trials to those assessing the CoaguChek system. Similarly, sensitivity analyses restricted to trials using the CoaguChek XS system showed no differences from the all‑trials results. A sensitivity analysis restricted to trials at low risk of bias slightly changed the estimate of effect but did not substantially impact on the findings (RR 0.59, 95% CI 0.27 to 1.30, p=0.19).
The External Assessment Group did a subgroup analysis by type of anticoagulant management therapy. No difference between self‑management and standard care for any bleeding events (RR 0.94, 95% CI 0.68 to 1.30, p=0.69) was found but there was a statistically significant higher risk in self‑testing participants than in those receiving standard care (RR 1.15, 95% CI 1.03 to 1.28, p=0.02). No statistically significant differences in the risk of major bleeding were seen between self‑management (RR 1.09, 95% CI 0.81 to 1.46, p=0.58) or self‑testing (RR 0.99, 95% CI 0.80 to 1.23) compared with standard care. When only minor bleeding events were assessed, there was a statistically significant increased risk in self‑testing participants (23%) compared with those in standard care (RR 1.23, 95% CI 1.06 to 1.42, p=0.005) but not in those who were self‑managing (RR 0.84, 95% CI 0.53 to 1.35, p=0.47).
Of the 21 trials, 2 trials enrolled participants with atrial fibrillation, 6 trials enrolled participants with artificial heart valves and 13 trials enrolled participants with mixed indication. No statistically significant subgroup differences were found for bleeding events according to the type of clinical indication or the type of control standard care.
Twenty one trials reported 351 major and minor thromboembolic events in a total of 8394 participants. Self‑monitoring (self‑testing and self‑management) showed a statistically significant reduction in the risk of thromboembolic events by 42% (RR 0.58, 95% CI 0.40 to 0.84, p=0.004) compared with standard care. The risk reduction further increased to 48% when only major thromboembolic events were considered (RR 0.52, 95% CI 0.34 to 0.80, p=0.003). The risk of thromboembolic events substantially decreased when the analyses were restricted to non‑UK trials (RR 0.50, 95% CI 0.32, 0.76, p=0.001); to CoaguChek trials (RR 0.52, 95% CI 0.38, 0.71, p<0.0001); and to trials at low risk of bias (RR 0.38, 95% CI 0.16 to 0.92, p=0.03).
Self‑management halved the risk of thromboembolic events compared with standard care (RR 0.51, 95% CI 0.37 to 0.69, p<0.0001). In contrast, there was no statistically significant risk reduction for self‑testing compared with standard care (RR 0.99, 95% CI 0.75 to 1.31, p=0.56). The subgroup difference between self‑management and self‑testing was statistically significant (p=0.002). Self‑monitoring participants with artificial heart valves showed a statistically significant reduction in the number of thromboembolic events compared with those in standard care (RR 0.56, 95% CI 0.38 to 0.82, p=0.003). No statistically significant effect was shown among self‑monitoring participants with mixed clinical indication (atrial fibrillation, artificial heart valves, or other conditions) compared with participants receiving standard care.
Thirteen trials reported 422 deaths due to all‑cause mortality in a total of 6537 participants. The risk reduction for all‑cause mortality was not statistically significant between self‑monitoring (self‑testing and self‑management) and standard care (RR 0.83, 95% CI 0.63 to 1.10, p=0.20).
Risk of death reduced by 32% through self‑management (RR 0.68, 95% CI 0.46 to 1.01, p=0.06) but not through self‑testing (RR 0.97, 95% CI 0.78 to 1.19, p=0.74) even though the test for subgroup differences was not statistically significant (p=0.13). Self‑monitoring halved the risk of mortality in participants with artificial heart valves (RR 0.54, 95% CI 0.32 to 0.92, p=0.02) but not in those with mixed clinical indication for anticoagulant therapy (RR 0.95, 95% CI 0.78 to 1.16, p=0.61). The subgroup difference between participants with artificial heart valves and those with mixed indication with regard to the number of deaths was statistically significant (p=0.05). No data were available from trials that enrolled participants with atrial fibrillation. Statistically significantly fewer deaths were recorded among participants who self‑monitored their therapy compared with those who were routinely managed by their GP/doctor (RR 0.52, 95% CI 0.30 to 0.90, p=0.02).
## Evidence on patient‑reported outcomes
One trial (n=28) compared self‑management with self‑testing in children and reported that 1 parent did not favour self‑management because of the increased anxiety about INR measurements.
Four trials conducted a questionnaire survey to assess acceptability to participants of self‑testing and self‑management using point‑of‑care devices. These trials reported high rates of acceptance for both self‑management and self‑testing (77% to 98%).
One of these trials reported that 93% of participants rated their satisfaction with regard to self‑monitoring (using either the INRatio monitor or the CoaguChek S system) as high or good. When asked about the overall relative satisfaction with the device, 43% of participants favoured the INRatio monitor, 36% the CoaguChek S system, and 21% both devices in equal way. One trial conducted in children reported that most participants (13 out of 14 participating families, 92%) opted for the CoaguChek XS device.
An unpublished review from the National Thrombosis Service in the Netherlands reported the INR values from over 5000 patients on vitamin K antagonist therapy using either the CoaguChek XS system or the INRatio2 PT/INR monitor for self‑monitoring. The review reported that the INR values within therapeutic range were comparable between the monitors. It also reported that the choice of monitor appeared to have no clinically relevant effect on the time in therapeutic range or adverse outcomes in people on long‑term vitamin K antagonist therapy.
# Health‑related quality of life
Health‑related quality‑of‑life outcomes were reported in 9 trials using a variety of different measures. Four trials used Sawicki's questionnaire to measure quality of life, and substantially greater improvements in treatment satisfaction and self‑efficacy were reported in the self‑management arm compared with the standard care arm of the trials. All 4 trials reported a reduced level of distress and daily inconvenience although 1 trial reported an increased level of distress in participants who received education but did not directly monitor their anticoagulation therapy.
Two UK‑based trials reported no substantial differences in quality‑of‑life outcomes between self‑monitoring participants and those receiving standard care. One trial reported quality‑of‑life data using the UK SF‑36, the EuroQol scores and Lancaster's instrument. The other trial assessed themes that were adapted from the Lancaster tool, the SEIQol tool and a series of focus groups. Five common themes emerged from the interviews on self‑management: knowledge and management of condition and self‑empowerment, increased anxiety and obsession with health, self‑efficacy, relationship with healthcare professionals, and societal and economic cost. One trial, conducted in the Netherlands, measured quality of life in people with artificial heart valves by using the SF‑36v2. Substantial improvements in quality‑of‑life scores in the physical component summary were reported in people who self‑managed their therapy compared with those receiving standard care.
Another trial measured quality of life by means of the Health Utilities Index Mark 3. It reported a statistically significant gain in health utilities at the 2‑year follow‑up among self‑testing participants compared with those managed in high quality anticoagulant clinics (p<0.001). The same investigators also measured anticoagulant satisfaction using Duke Anticoagulation Satisfaction Scale. They found that the degree of satisfaction was higher in self‑testing participants compared with those in standard care (p=0.002).
One trial compared self‑management with self‑testing in children and provided quality‑of‑life data using the KIDCLOT PAC QL parent‑proxy (parents' quality of life and their assessment of child's quality of life) and the child teen KIDCLOT PAC QL. The 5 common themes identified were: awareness, communication, relationship between parent and child, flexibility and anxiety.
# Costs and cost effectiveness
The External Assessment Group conducted a systematic review to identify existing economic analyses for self‑monitoring coagulation status. The review also sought to identify potentially relevant evidence sources to inform parameter values for the de novo economic model developed by the External Assessment Group. The de novo economic model constructed aimed to assess the cost effectiveness of self‑monitoring coagulation status using the CoaguChek XS system, the INRatio2 PT/INR monitor or the ProTime microcoagulation system. The ProTime microcoagulation system was included in the assessment but has been removed from this guidance because it is no longer available to the NHS and its successor model is not intended for patient self‑monitoring.
## Systematic review of cost‑effectiveness evidence
The systematic review identified 12 relevant economic evaluations. All of these evaluations compared INR self‑monitoring strategies with standard care and were assessed against the NICE reference case by the External Assessment Group. The results of the studies included in the systematic review varied widely and showed that the cost effectiveness of self‑monitoring was dependent on a number of key factors.
The adopted perspective and the initial costs associated with self‑monitoring appeared to substantially affect the cost effectiveness. Self‑monitoring strategies appeared more favourable than standard care when a wider societal perspective was adopted, as a result of lower time costs associated with fewer health service contacts. The size of the estimates of effect applied to self‑monitoring in reducing thromboembolic and bleeding events compared with those applied to standard care also appeared to affect cost effectiveness. The 2 UK‑based evaluations applied effect estimates consistent with small or negligible differences between self‑management and usual care with respect to time in therapeutic range and adverse thromboembolic and haemorrhagic events. This resulted in a low probability of self‑monitoring being cost effective. Several studies that applied large effect estimates resulted in a high probability of self‑monitoring being cost effective.
The 2 UK‑based economic evaluations were based on data from the same trial. One evaluation adopted an NHS and wider societal perspective, and the other adopted an NHS and personal social services perspective. Self‑monitoring strategies appeared to increase the costs of INR monitoring in the short term and because these 2 evaluations applied small effect estimates, consistent with those seen in the largest UK‑based trial of patient self‑management, self‑monitoring of INR appeared unlikely to be cost effective. However, no UK‑based trials have been sufficiently powered to detect a statistically significant difference between standard INR monitoring and patient self‑monitoring in terms of major thromboembolic or haemorrhagic events. Therefore, the External Assessment Group carried out a meta‑analysis of relevant trials including evidence from a number of European trials in which standard care is similar to that provided in the UK in terms of approach, frequency of testing and the level of INR control achieved.
## Economic analysis
The External Assessment Group developed a de novo economic model designed to assess the cost effectiveness of self‑monitoring (self‑managing and self‑testing) coagulation status using 2 different point‑of‑care coagulometers: the CoaguChek XS system and the INRatio2 PT/INR monitor.
## Model structure
The structure of the Markov model was based on the review of published models of INR self‑monitoring and previous models evaluating the cost effectiveness of new anticoagulant drugs compared with warfarin therapy in people with atrial fibrillation. A further unpublished economic model of INR self‑monitoring was provided by the manufacturer of CoaguChek XS, and this model was also used to inform the structure of the new economic model.
The Markov model compared the alternative monitoring strategies for a hypothetical cohort of people with atrial fibrillation or an artificial heart valve, and was used to simulate the occurrence of thromboembolic and bleeding events over a 10‑year period. People with atrial fibrillation or an artificial heart valve represent the majority of people on long‑term vitamin K antagonist therapy. The model simulated transitions between the discrete health states, and accumulated costs and quality‑adjusted life years (QALYs) on a quarterly (3 month) cycle. Within each cycle, the simulated cohort was exposed to a risk of the adverse events as well as death from other causes. The adverse events included in the model were ischaemic stroke (minor, non‑disabling, and major, disabling or fatal), systemic embolism, minor haemorrhage, and major haemorrhage (intra‑cranial haemorrhage, including haemorrhagic stroke, gastrointestinal bleed, and others). A constraint was applied whereby the simulated cohort in the model could only experience 1 event per cycle.
## Model inputs
The model was populated using data derived from the systematic clinical effectiveness review, other additional focused reviews to inform key parameters (for instance baseline risks), routine sources of cost data, and where necessary some study‑specific cost estimates based on expert opinion.
## Costs
Data on the resource use and costs associated with the alternative monitoring strategies were informed by published literature, existing guidance, expert opinion, manufacturers' and suppliers' prices, and other routine sources of unit cost data. Some costs were informed by expert opinion where suitable data from other sources were not available.
## Health‑related quality of life
The baseline utility value for people with atrial fibrillation or mechanical heart valve who were stable was taken as the baseline EQ‑5D value from trial data, 0.738. This value was applied to 65–70 year old people and adjusted by the External Assessment Group to estimate age‑specific baseline utilities in the model.
Utilities associated with acute events were applied for the 3‑month period after the event. For post‑event states with associated ongoing morbidity, the appropriate health state utilities were applied for all subsequent cycles spent in these states. Half‑cycle corrections were applied, by assuming that people experienced events on average at the mid‑point of the cycle. Thus a patient starting off in the well state and experiencing a major stroke in a given cycle of the model would accrue 6 weeks at the utility value for well and 6 weeks at the utility value for major stroke.
## Base‑case analysis
For the purposes of decision‑making, the incremental cost‑effectiveness ratios (ICERs) per QALY gained were considered. The following assumptions were applied in the base‑case analysis:
% of standard care monitoring was done in primary care by practice nurses.
% of the cohort had atrial fibrillation and 40% had an artificial heart valve.
The average age of the cohort was 65 years, and 55% were male.
% of people who self‑monitored did self‑testing and 50% self‑managed.
The increase in the number of tests done per year with self‑monitoring was 23 (that is, 35 tests compared with 12 tests in standard care).
Relative treatment effects were estimated and applied separately for self‑testing and self‑management.
% of participants did not start self‑monitoring after training (training failure).
% of participants stopped self‑monitoring within a year of starting.
Self‑monitoring device costs were annuitized over 5 years.
% of devices were reused by another patient when a patient stopped self‑monitoring.
The results indicated that over a 10‑year period, introducing self‑monitoring would reduce the proportion of people experiencing a thromboembolic event by 2.5%, while slightly increasing the proportion having a major haemorrhagic event by 1.4%.
The predicted monitoring costs were higher with self‑monitoring compared with standard monitoring, but the total health and social care costs were similar and in some cases lower. The QALY gains were greater for self‑monitoring than standard monitoring. For all of the self‑monitoring coagulometers there was a QALY gain of 0.027 compared with standard monitoring. Self‑monitoring with the INRatio2 PT/INR monitor was £29 cheaper than standard monitoring. Self‑monitoring with the CoaguChek XS system was £37 more expensive than standard monitoring. Therefore, in the base‑case scenario, the self‑monitoring strategies compared favourably with standard care. The INRatio2 PT/INR monitor dominated standard monitoring in the analysis because it was less costly and more effective. The ICER for the CoaguChek XS system was £319 per QALY gained compared with standard monitoring. The lower cost of the INRatio2 PT/INR monitor and testing strips, coupled with the assumption of equivalent clinical effectiveness, meant that the INRatio2 PT/INR monitor also dominated the CoaguChek XS system. However, it should be noted that no direct evidence of clinical effectiveness was identified exclusively for the INRatio2 PT/INR monitor from the systematic review.
## Analysis of alternative scenarios
Several scenario analyses were done by the External Assessment Group:
exclusive self‑testing or self‑management compared with standard monitoring in primary and secondary care
exclusive primary or secondary care clinic testing compared with self‑monitoring in primary and secondary care
different pooled risk estimates applied.
For the exclusive self‑management strategy, the INRatio2 PT/INR monitor and the CoaguChek XS system dominated standard monitoring under the base‑case assumptions, whereas for the exclusive self‑testing strategy, the ICERs were above £2 million per QALY gained compared with standard monitoring. The results also showed that for a mixed self‑monitoring strategy (50% self‑testing, 50% self‑management), the CoaguChek XS system and the INRatio2 PT/INR monitor dominated standard monitoring when exclusively carried out in secondary care. When applying the pooled relative risk estimates for adverse events (derived from all self‑monitoring studies) to both self‑testing and self‑managing participants, the cost savings and QALY gains associated with self‑monitoring increased.
The External Assessment Group carried out alternative non‑base‑case scenarios, to assess the impact of using self‑monitoring to replace standard monitoring tests (that is, no increase in the number of tests done annually). It was assumed that there was no difference in clinical effectiveness between self‑management, self‑testing and standard care. Under most of these scenarios, standard monitoring was found to be less costly than self‑monitoring. However, self‑testing and self‑management with the INRatio2 PT/INR monitor and the CoaguChek XS system dominated standard monitoring when carried out exclusively in secondary care.
Subgroup analyses showed the cost effectiveness of self‑monitoring compared with standard care, stratified by indication (atrial fibrillation and artificial heart valves) and cohort age. Self‑monitoring in a '65 years old with atrial fibrillation' cohort was estimated to cost £2574 per QALY gained when using the INRatio2 PT/INR monitor and £4160 per QALY gained when using the CoaguChek XS system, compared with standard monitoring. For a '65 years old with artificial heart valve' cohort, self‑monitoring with the INRatio2 PT/INR monitor and the CoaguChek XS system was found to be more effective and less costly (dominant) compared with standard monitoring.
A further analysis was carried out for the atrial fibrillation cohort using the baseline risks seen for participants with better INR control in standard care, assuming a constant relative risk reduction for thromboembolic events associated with self‑monitoring. As the INR time in therapeutic range increased in the control group, and the baseline risk of thromboembolic events consequently dropped, the cost effectiveness of self‑monitoring also decreased. However, the ICERs for the CoaguChek XS system and the INRatio2 PT/INR monitor only rose above £20,000 per QALY gained when the baseline time in therapeutic range was set at greater than 72.6%.
## Sensitivity analyses
Deterministic sensitivity analysis showed that the model‑based findings were most sensitive to the baseline risk of thromboembolic events and the effectiveness of self‑monitoring for preventing these events. The ICERs for the self‑monitoring strategies rose above £30,000 per QALY gained when the baseline risk was set to 1.15% and the upper confidence limit for the relative risk of thromboembolic events associated with self‑management (RR 0.69) was applied. The same was found when the lower baseline risk of thromboembolic events was coupled with the upper confidence limit of the pooled relative risk for self‑monitoring (RR 0.89). It should be noted however that self‑management on its own remained cost saving under the former combined scenario.
A sensitivity analysis was also conducted to approximate the cost effectiveness of self‑monitoring for a cohort of children with an artificial heart valve on long‑term vitamin K antagonist therapy. For this analysis, the cohort age was set to 10, the baseline risk of thromboembolic events was reduced to 1.4%, and the standardised mortality ratio for all‑cause mortality after a stroke was set at 14.5. Under this scenario, self‑monitoring with the CoaguChek XS system and the INRatio2 PT/INR monitor dominated standard monitoring. However, it should be noted that the standardised mortality ratio estimated for an 18–55 year old cohort of people with artificial heart valves was applied because no robust data were identified to appropriately adjust the risk of death from all causes in children with an artificial heart valve.
Probabilistic sensitivity analyses of the base case were done to examine the uncertainty in the cost effectiveness of self‑monitoring. Self‑monitoring with the CoaguChek XS system and the INRatio2 PT/INR monitor were estimated to have an 80% and 81% probability of being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, respectively. However, it should be noted that there is no direct randomised controlled trial evidence to show the clinical effectiveness of the INRatio2 PT/INR monitor.# Considerations
The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of self‑monitoring coagulometers for self‑testing or self‑managing coagulation status in people on long‑term vitamin K antagonist therapy who have atrial fibrillation or heart valve disease.
The Committee considered the clinical evidence on the use of point‑of‑care coagulometers in people with atrial fibrillation or artificial heart valves. The Committee noted that 26 randomised controlled trials compared the use of point‑of‑care coagulometers for self‑monitoring with standard anticoagulation control. The Committee noted that self‑monitoring nearly halved the risk of thromboembolic events and substantially reduced the risk of mortality in people with artificial heart valves compared with standard monitoring. However, the Committee also noted that self‑monitoring did not result in a statistically significant reduction in the number of major and minor bleeding events compared with standard monitoring. The Committee discussed the heterogeneity in the trials and the applicability of the pooled results from the meta‑analysis of the trial data to the UK population. It noted that the meta‑analysis results showed low statistical heterogeneity and concluded that self‑monitoring offered clinical benefit because it was likely to result in a significant reduction in thromboembolic events. The Committee concluded that the pooled effect estimates from the meta‑analysis were likely to be applicable to the UK because there are no confounding biological differences between people receiving vitamin K antagonist therapy in the UK and those in other countries.
The Committee discussed that 22 of the 26 trials included in the assessment investigated the use of the CoaguChek system and considered the different versions of the CoaguChek systems used in these trials. The Committee noted that there are substantial technical differences between the CoaguChek S system and the CoaguChek XS system and heard from clinical specialists and the manufacturer that changes had been made to the different versions to improve reliability and accuracy. The Committee considered the performance of the CoaguChek S and XS systems compared with the gold standard of laboratory‑based INR testing and noted that the precision and accuracy of the 2 CoaguChek versions correlated with that of laboratory‑based measurements. The Committee concluded that results from the CoaguChek XS system were likely to be at least as good as those obtained from trials in which previous versions of the system were used. The Committee also noted that 4 of the 22 trials investigated the use of the CoaguChek XS system and that 2 of these trials demonstrated a significant improvement in time in therapeutic range. The Committee concluded that it was appropriate to pool the results of trials using different versions of the CoaguChek system and that these pooled results could demonstrate the clinical effectiveness of self‑monitoring using the CoaguChek XS version of the system.
The Committee considered the evidence for the 2 different self‑monitoring coagulometers: the CoaguChek XS system and the INRatio2 PT/INR monitor. The Committee noted that 22 of the 26 trials included in the assessment investigated the use of the CoaguChek system and noted that there was no direct randomised controlled trial evidence to show the clinical effectiveness of the INRatio2 PT/INR monitor. The Committee considered the evidence that showed the 2 coagulometers had a broadly similar performance in precision and accuracy with regard to time in therapeutic range measurement when compared with the gold standard of laboratory‑based INR testing and therefore concluded that it was appropriate to extrapolate the clinical‑effectiveness data from the CoaguChek system to the INRatio2 PT/INR monitor.
The Committee discussed the usability of the coagulometers and noted that small differences in devices can sometimes result in large differences in behaviour. The Committee considered the results of the systematic review by Christensen and Larsen (2012) and the unpublished review of over 5000 patients from the National Thrombosis Service in the Netherlands. It noted that although the results of the unpublished review suggested that any potential differences in usability between the 2 monitors did not affect their clinical effectiveness, the unpublished review could not be considered methodologically robust. The Committee concluded that based on the systematic review, any potential differences in the usability of the coagulometers did not appear to affect their ability to measure INR.
The Committee considered the differences in clinical outcomes between people who were self‑managing their anticoagulation control and those who were self‑testing. The Committee noted that there was a statistically significantly greater reduction in thromboembolic events among people who self‑managed compared with those who self‑tested. The Committee also noted that when only minor bleeding events were assessed, a statistically significantly increased risk was seen in self‑testing participants compared with those in standard care. All‑cause mortality was lower through self‑management but not through self‑testing. The Committee discussed possible reasons for the differences in results between self‑managing and self‑testing, and it heard from clinical specialists that people who self‑manage their coagulation control may behave differently to those who self‑test because they have greater responsibility for managing their coagulation control. The Committee noted that the largest trial in the assessment of self‑testing did not show a reduction in clinical adverse events but did show an increase in the time in therapeutic range (Matchar et al. 2010). The Committee also noted that this trial had a high standard of coagulation control in the control arm, which could explain why no statistically significant difference in clinical adverse events was detected between the self‑testing group and the standard care group. The Committee concluded that the high standard of coagulation control in the control arm of the trial may not reflect general UK clinical practice and so it was plausible that the increase in time in therapeutic range would lead to a statistically significant reduction in clinical adverse events if compared with UK standard coagulation control practice. The Committee concluded that self‑testing and self‑managing were likely to be clinically effective and that self‑testing was often a step towards self‑management in clinical practice.
The Committee considered the clinical evidence for using self‑monitoring in the population group with atrial fibrillation. The Committee noted that only 2 trials investigated self‑monitoring in people with atrial fibrillation and 19 trials investigated self‑monitoring in a mixed population that included people with atrial fibrillation. The Committee heard from clinical specialists that the clinical outcomes for people with atrial fibrillation are similar to those for people with artificial heart valves. The Committee also heard that people with artificial heart valves may be a younger population than people with atrial fibrillation. The Committee noted that it was not possible to isolate the data for people with atrial fibrillation from the mixed populations investigated in the 19 trials but concluded that it was likely that self‑monitoring would result in similar clinical benefits in people with atrial fibrillation to those achieved in people with artificial heart valves.
The Committee considered the cost‑effectiveness analysis carried out by the External Assessment Group on self‑monitoring. In the base‑case analysis, self‑monitoring with the CoaguChek XS system resulted in an incremental cost‑effectiveness ratio (ICER) of around £300 per quality‑adjusted life year (QALY) gained (based on the pooled effect estimates from the meta‑analysis) compared with standard monitoring. Self‑monitoring with the INRatio2 PT/INR monitor dominated (that is, was less expensive and more effective than) the CoaguChek XS system and standard care, although the Committee noted that there was no direct randomised controlled trial evidence for the clinical effectiveness of the INRatio2 PT/INR monitor so clinical effectiveness equivalent to the CoaguChek XS system was assumed in the base case. The Committee concluded that self‑monitoring with the CoaguChek XS system is cost effective in light of the reduction in thromboembolic events seen in the pooled results of the trial data. However, although the INRatio2 PT/INR monitor dominated standard monitoring in the base‑case analysis, the Committee did not consider this result to be as robust as that for the CoaguChek XS system because there was no direct evidence of clinical effectiveness for the INRatio2 PT/INR monitor that showed a reduction in thromboembolic events. The Committee noted the similar performance of the CoaguChek XS system and the InRatio2 PT/INR monitor compared with the gold standard of laboratory‑based INR testing and concluded therefore that self‑monitoring with the INRatio2 PT/INR monitor was likely to represent a cost‑effective use of NHS resources.
The Committee considered the cost effectiveness of self‑testing and self‑managing individually. The findings showed that self‑management alone is highly cost effective (dominant) but that self‑testing alone is not cost effective, compared with standard monitoring. The Committee noted that these findings were based on the contrasting pooled‑effect estimates obtained from the meta‑analysis of randomised controlled trials, based on thromboembolic events while self‑testing and self‑managing. The Committee discussed the impact of 1 large trial by Matchar et al. (2010) (see section 6.6) on the cost effectiveness of self‑testing and noted that although this trial did not show a reduction in clinical adverse events, it did show an increase in the time in therapeutic range. The Committee discussed the impact on the ICERs for self‑testing if the economic model was driven by time in therapeutic range rather than adverse events. The Committee concluded that self‑testing may be more cost effective if the model had been based on time in therapeutic range. The Committee also considered the costs of self‑managing and self‑testing and noted that self‑testing was more expensive because of higher administration costs. The Committee heard from the External Assessment Group that if the pooled‑effect estimates from self‑monitoring were applied to self‑testing, self‑testing would become cost effective even with the higher administration costs this incurred. The Committee concluded that it was likely that the increase in time in therapeutic range shown for self‑testing in the trial would lead to a reduction in adverse events compared with standard clinical practice in the UK. The Committee therefore concluded that it was likely that the clinical benefits of self‑testing had been underestimated in the economic analyses and that both self‑testing and self‑managing were cost effective.
The Committee considered the impact on people whose anticoagulation therapy is monitored by standard clinical practice. The Committee acknowledged the additional costs and inconvenience for patients of travelling to specialist clinics or hospital to be monitored. The Committee also noted the loss in productivity through absence from work or school to attend clinic appointments. The Committee acknowledged these costs were incurred outside the healthcare system and therefore not included in the reference case; however, it considered that self‑monitoring may reduce the costs and inconvenience incurred by the patient. The Committee also noted that monitoring anticoagulation therapy can have a substantial impact on the quality of life of patients and their families because of the anxiety associated with the risks of bleeding and the consequent behavioural changes such as the length of time they are willing to spend away from home or the distances they are willing to travel. The Committee concluded that the main benefits of self‑monitoring involve reducing the substantial burden associated with monitoring anticoagulation therapy for the patient and their families.
The Committee considered the different methods of self‑monitoring for people having long‑term vitamin K antagonist therapy. The Committee heard from a clinical specialist that computer algorithms may be used by some services to determine dose adjustments. The Committee noted that the cost of software licensing had not been included in the cost‑effectiveness analyses and it discussed the implications of computer‑based dosing for people who would self‑manage their coagulation status. The Committee heard that there were alternative methods to determine dose adjustments and that a lack of internet access should not restrict a person's access to self‑monitoring. The Committee considered an additional analysis by the External Assessment Group that investigated the impact of an additional cost for dose adjustment software on the base‑case ICERs for self‑managing. The Committee noted that the additional cost of software would need to be greater than £190 per patient per year to substantially affect the cost‑effectiveness of self‑managing with the coagulometers. The Committee concluded that the additional cost of software was unlikely to exceed this value and therefore, even with this potential additional cost, self‑managing with the point‑of‑care coagulometers would still represent a cost‑effective use of resources in the NHS.
The Committee considered the benefits for patients receiving vitamin K antagonist therapy of using point‑of‑care coagulometers. It heard from a patient expert on the Committee that self‑monitoring is important to psychological wellbeing because it provides a sense of control for the patient and removes the need to frequently attend clinics or hospitals, which serve as a constant reminder of their condition. The Committee also heard that self‑monitoring allows people to travel to visit, or act as a carer for, other family members, without having to worry about attending testing appointments or if testing facilities are available in other countries. The Committee also heard that the current variation in access to self‑testing strips on prescription for self‑monitoring was of concern to patients because it restricted their freedom to move GP practice or move house to a different area in case the testing strips would no longer be prescribed. The Committee concluded that the benefits of self‑monitoring for patients were not fully captured in the cost‑effectiveness analyses.
The Committee considered the similarities between self‑monitoring coagulation status and self‑managing diabetes. The Committee heard from a patient expert that some patients are used to self‑testing for conditions such as diabetes, hypertension and heart conditions. The Committee also heard from a clinical specialist that although there were similarities between self‑testing for different conditions, there were intrinsic differences between self‑testing for diabetes and coagulation. Vitamin K antagonists are more sensitive to diet and exercise, and act over a longer period of time than insulin. Therefore, the dose response for vitamin K antagonists is less predictable than for insulin and the risk of adverse events is perceived to be higher. The clinical specialist also reported that some patients were successfully self‑monitoring their coagulation status but not all people receiving vitamin K antagonist therapy will be able to self‑monitor and some may not wish to. The Committee noted that some groups of patients who may have difficulty with self‑monitoring, such as children or those with a disability, may be able to self‑test or self‑manage with the help of a carer. The Committee concluded that there are different considerations for self‑monitoring of coagulation status to those made for self‑testing for diabetes, and that the decision for a patient to self‑monitor should be made after a thorough discussion and subsequent agreement between the patient and the healthcare professional.
The Committee considered the impact of the increasing use of non‑vitamin K antagonist oral anticoagulant drugs, which do not involve monitoring because of their predictable dose response. It heard from clinical specialists that there are factors that may influence clinical decisions and affect the number of people receiving warfarin: people receiving warfarin who have stable INRs may be unlikely to switch to non‑vitamin K antagonist oral anticoagulants, and the non‑vitamin K antagonist oral anticoagulants may be unsuitable for some, such as people with mechanical heart valves, certain people with renal or liver dysfunction or those taking drugs that cannot be taken at the same time as the non‑vitamin K antagonist oral anticoagulants. The Committee concluded that, because the non‑vitamin K antagonist oral anticoagulants would not be suitable for all people who need anticoagulant therapy, and there are many people who will receive warfarin therapy rather than non‑vitamin K antagonist oral anticoagulant therapy, self‑monitoring coagulometers are still of clinical importance to the NHS and patients.
The Committee considered the need for quality control of individual patient coagulometers. The Committee heard from a clinical specialist that the National External Quality Assessment Service runs a scheme to ensure the accuracy of coagulometers used by healthcare professionals, and coagulometers used by patients could be checked against a professional coagulometer to ensure accuracy. The Committee concluded that this was a reliable method of ensuring accuracy of individual coagulometers.
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{'Recommendations': "The CoaguChek\xa0XS system is recommended for self‑monitoring coagulation status in adults and children on long‑term vitamin\xa0K antagonist therapy who have atrial fibrillation or heart valve disease if:\n\nthe person prefers this form of testing and\n\nthe person or their carer is both physically and cognitively able to self‑monitor effectively.\n\nThis recommendation has been removed because the InRatio2\xa0PT/INR monitor is no longer available.\n\nPatients and carers should be trained in the effective use of the CoaguChek\xa0XS system and clinicians involved in their care should regularly review their ability to self‑monitor.\n\nEquipment for self‑monitoring should be regularly checked using reliable quality control procedures, and by testing patients' equipment against a healthcare professional's coagulometer which is checked in line with an external quality assurance scheme. Ensure accurate patient records are kept and shared appropriately.\n\nFor people who may have difficulty with or who are unable to self‑monitor, such as children or people with disabilities, their carers should be considered to help with self‑monitoring.", 'The technologies': 'Three CE‑marked point‑of‑care coagulometers for self‑monitoring coagulation status were identified during scoping as being relevant to this assessment. One of these coagulometers, the ProTime microcoagulation system, was included in the assessment but has been removed from this guidance because it is no longer available to the NHS and its successor model is not intended for patient self‑monitoring. Additional details of the coagulometers included in the guidance are provided in section 4.', 'Clinical need and practice': '# The problem addressed\n\nThe point‑of‑care coagulometers are designed to monitor the clotting tendency of blood in people on long‑term vitamin\xa0K antagonist therapy, such as those with atrial fibrillation or artificial heart valves who are at risk of thrombosis. The tests allow monitoring by 2\xa0different methods of care: self‑testing and self‑managing. Both methods are based on the international normalised ratio (INR), which is a standardised unit for measuring the time it takes for blood to clot. Self‑testing refers to the user doing the INR test themselves and then contacting their healthcare professional with the reading for advice on any change to the dosage of the anticoagulant that may be needed. Self‑managing refers to the user doing the INR test themselves and then self‑adjusting the dosage of their anticoagulant medication by following an agreed care protocol. Together, these methods of care are referred to as self‑monitoring.\n\nThe use of these coagulometers may reduce the frequency of visits to hospital or clinics for patients and enable them to be monitored more regularly. This may improve health outcomes by enabling the dose of therapy to be adjusted more accurately, thereby avoiding adverse events that can result from an over‑ or under‑dose of long‑term vitamin\xa0K antagonist therapy, such as stroke and major haemorrhage.\n\nThe purpose of this assessment is to evaluate the clinical and cost effectiveness of using the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor for self‑monitoring (self‑testing or self‑managing) coagulation status in people on long‑term vitamin\xa0K antagonist therapy who have atrial fibrillation or heart valve disease.\n\n# The condition\n\nThere are a number of conditions that can result in people having an increased risk of thrombosis and consequently, receiving long‑term vitamin\xa0K antagonist therapy. These conditions include atrial fibrillation and heart valve disease. Guidance on self‑monitoring the coagulation status of people who have had a venous thromboembolism and are receiving long‑term vitamin\xa0K antagonist therapy is included in the NICE guideline on venous thromboembolic diseases and so this population is not included in the scope of this diagnostics assessment of self‑monitoring coagulometers.\n\n## Atrial fibrillation\n\nAtrial fibrillation is the most common heart arrhythmia and affects around 800,000\xa0people in the UK. It can affect adults of any age but it is more common in older people; 0.5% of people aged 50–59\xa0years and around 8% of people aged over 65\xa0years are estimated to be affected. Atrial fibrillation is also more common in men than women, and is more common in people with other conditions, such as high blood pressure, atherosclerosis and heart valve problems.\n\nApproximately 47% of people with atrial fibrillation currently receive vitamin\xa0K antagonist therapy. It is estimated that a further 30% of people with atrial fibrillation could receive this therapy but currently do not. People with atrial fibrillation are at a 5–6\xa0times greater risk of stroke, with 12,500\xa0strokes directly attributable to atrial fibrillation occurring every year in the UK. Treatment with warfarin reduces this risk by 50–70%.\n\n## Heart valve disease\n\nValve disease can affect blood flow through the heart in 2\xa0ways: valve stenosis, in which the valve does not open fully, and valve regurgitation (or incompetence) in which the valve does not close properly, allowing blood to leak backwards. Disease can occur in any of the 4\xa0heart valves, although disorders of the aortic and mitral valves are more serious.\n\nThe main causes of heart valve disease are congenital heart disease and other diseases such as rheumatic fever, lupus, cardiomyopathy and endocarditis. Aortic stenosis is the most common type of valve disease and it affects around 1\xa0in 20\xa0adults over the age of 65\xa0years in the UK.\n\nData from the UK heart valve registry indicate that approximately 0.2% of the UK population has prosthetic heart valves. Around 6500\xa0adult heart valve replacements (using mechanical or biological valves) are carried out each year, of which around 5000\xa0are aortic valve replacements.\n\nPatients with mechanical heart valves (and some patients with bioprosthetic valves) are susceptible to thromboembolism and need lifelong anticoagulant therapy.\n\n# The diagnostic and care pathways\n\nNon‑vitamin\xa0K antagonist oral anticoagulants are an alternative to vitamin\xa0K antagonists and can be administered to reduce the risk of thrombosis or stroke. The non‑vitamin\xa0K antagonist oral anticoagulants have fewer food and drug interactions than vitamin\xa0K antagonists and they do not need therapeutic monitoring. However, they may be unsuitable for some people, such as people with mechanical heart valves, certain people with renal or liver dysfunction and those taking concurrent drugs that cannot be taken with the non‑vitamin\xa0K antagonist oral anticoagulants. The individual summary of product characteristics should be consulted for specific details when prescribing a non‑vitamin\xa0K antagonist oral anticoagulant. NICE technology appraisal guidance recommends 3\xa0non‑vitamin\xa0K antagonist oral anticoagulants (see the NICE guidance on apixaban, rivaroxaban and dabigatran etexilate) for preventing stroke and systemic embolism in people with non‑valvular atrial fibrillation.\n\nGuidelines on oral anticoagulation with warfarin, published by the British Committee for Standards in Haematology (Keeling et al. 2011), outline the process for INR monitoring for those receiving warfarin. The NICE clinical knowledge summary for oral anticoagulation states that INR can be most accurately measured in venous blood samples, but that capillary blood samples are also used because they are more convenient. People being tested should receive a written copy of their INR result including any necessary dose adjustments and a date for the next check.\n\nThe summary states that the INR should be measured:\n\ndaily, or on alternate days, until it is within the therapeutic range (usually between 2.0\xa0and 3.0, ideally 2.5) on 2\xa0consecutive occasions\n\nthen twice weekly for 1–2\xa0weeks, followed by weekly measurements until the INR is stable within the therapeutic range\n\nthereafter, depending on the stability of the INR, at longer intervals (for example, up to every 12\xa0weeks, if agreed locally).\n\nMore frequent monitoring of the INR is recommended for patients at risk of overcoagulation or bleeding, or those having problems adhering to treatment. Intravenous drug users, and people with hepatitis B, hepatitis C, or HIV, may be referred to a specialist clinic according to local arrangements.\n\nINR monitoring can be managed by local anticoagulant clinics in primary care, but sometimes clinics are based in secondary care, involving travel to hospital. The NICE anticoagulation commissioning guide (2013) states that anticoagulation therapy services can be delivered in a number of different ways, and that mixed models of provision may be needed across a local health region. This could include full service provision in secondary or primary care, shared provision, domiciliary provision and self‑management. Services may be managed by a range of healthcare professionals including nurses, pharmacists and general practitioners.', 'The diagnostic tests': '# The interventions\n\n## The CoaguChek\xa0XS system\n\nThe CoaguChek\xa0XS system (Roche Diagnostics) comprises a meter and specifically designed test strips that can analyse a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time and the international normalised ratio (INR). These measures indicate the rate at which the blood clots. If the INR is too low, there is a higher risk of blood clots that can lead to a heart attack or a stroke. If the INR is too high, there is a higher risk of bleeding, which in severe cases can be gastrointestinal or intracerebral bleeding.\n\nA code chip, which contains calibration data and the expiry date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted and the blood sample is applied. The test result is displayed approximately 1\xa0minute after applying the sample and the monitor automatically stores the result in its memory. The user is guided through the process by on‑screen graphical instructions.\n\nThe CoaguChek\xa0XS test strip contains a lyophilised reagent consisting of thromboplastin and a peptide substrate. When a blood sample is applied, thromboplastin activates coagulation, which leads to the formation of thrombin. The enzyme thrombin cleaves the peptide substrate, generating an electrochemical signal. Depending on the time elapsed before it first appears, this signal is then converted by means of an algorithm into customary coagulation units and the result is displayed on the screen. This can be displayed as prothrombin time in seconds, Quick value, or INR.\n\nThe CoaguChek\xa0XS system has a number of in‑built quality control functions including checks of the electric components when switched on, the test strip temperature during testing, and checks on the test strip batch such as the expiry date and quality of each strip. The CoaguChek XS test strips are packaged as single strips in resealable plastic containers in quantities of 24\xa0and 48\xa0test strips. The strips can be stored at room temperature or refrigerated between 2\xa0and 8°C and can be used straight from the fridge. On manufacture, the CoaguChek XS test strips have a shelf‑life (expiration date) of 18\xa0months.\n\nThe CoaguChek\xa0XS meter is supplied with 4\xa0× AAA batteries, a CoaguChek\xa0Softclix finger pricker and 20\xa0Softclix XL lancets, 6\xa0test strips, a user manual and carry case. The system can carry out a minimum of 60\xa0tests per set of batteries. The meter is 138\xa0mm × 78\xa0mm × 28\xa0mm and weighs 127\xa0g (without batteries).\n\nAn earlier model of the CoaguChek\xa0XS system is the CoaguChek\xa0S system. The CoaguChek\xa0XS system is reported to have the following advantages over the CoaguChek\xa0S system: the thromboplastin used in the prothrombin time test strips is a human recombinant thromboplastin, which is more sensitive and has a lower international sensitivity index of 1.0\xa0compared with 1.6; test strips have inbuilt quality control that is automatically run with every test; test strips do not have to be refrigerated; a smaller blood sample can be used; and the meter is smaller and lighter. Another model of the CoaguChek\xa0XS system is the CoaguChek\xa0XS Plus system. The XS Plus model is intended for use by healthcare professionals only and is not indicated for individual INR self‑monitoring.\n\n## The INRatio2\xa0PT/INR monitor\n\nThe INRatio2\xa0PT/INR monitor (Alere) does a modified version of the 1‑stage prothrombin time test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process. The system consists of a monitor and disposable test strips.\n\nThe monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports prothrombin time and INR results. Instructions and test results are displayed on an LCD. The monitor can store the results so that past test results can be reviewed.\n\nThe test strip comprises 2\xa0layers of transparent plastic laminated to each other that contain 1\xa0sample well, 3\xa0clot cells, and narrow channels connecting the sample well and the clot cells. The top side of the bottom layer is printed with 3\xa0pairs of silver electrodes (1\xa0pair per cell) that start from inside the clot cells to the end of the strip where they are connected to the monitor main circuitry. Test strips are individually foil wrapped, supplied in quantities of 12\xa0or 48\xa0strips and can be stored at room temperature for up to 12\xa0months or until the expiration date.\n\nThe INRatio2\xa0PT/INR monitor analyses fresh capillary blood and when the blood sample is applied to the sample well, it is drawn through the narrow channels by capillary action to the clot cells, where the impedance of the sample is measured by the monitor through the electrodes. Clot cells have reagents applied and the reagents are different for each channel. One channel contains the thromboplastin reagent for the prothrombin time test. The other 2\xa0channels contain reagents that produce a low and high control time, regardless of the clotting time of the sample.\n\nInitially, the electrode impedance is infinite but drops to a minimum value when the blood sample fills the clot cells. The time when this initial minimum impedance is achieved is registered by the monitor as the start of the coagulation. As the reaction progresses, the sample impedance increases to a maximum and then gradually drops as the clotting proceeds. The elapsed time, in seconds, from the start until the clotting end point is reached is the prothrombin time. The monitor software calculates the INR of the sample using prothrombin time and calibration coefficients.\n\nThe INRatio2\xa0PT/INR monitor does a self‑test when it is turned on and each test strip has a code that is accepted by the monitor if the strip code is in the correct format. The monitor uses 4\xa0× AA batteries or a mains adapter as a power source, and can connect to a printer or computer through the RS232\xa0serial communication port.\n\n# The comparator: INR testing\n\nThe comparator used in this assessment is INR testing in primary or secondary care using laboratory analysers or point‑of‑care tests.', 'Outcomes': "The Diagnostics Advisory Committee (section\xa08) considered evidence from a number of sources (section\xa09).\n\n# How outcomes were assessed\n\nThe assessment consisted of a systematic review of the evidence on test performance and clinical‑effectiveness data for the CoaguChek\xa0XS system, the INRatio2\xa0PT/INR monitor, the ProTime microcoagulation system and comparator tests. The ProTime microcoagulation system was in the assessment but has been removed from this guidance because it is no longer available to the NHS and its successor model is not intended for patient self‑monitoring.\n\n# Clinical effectiveness\n\nThe External Assessment Group conducted a systematic review of the evidence on the clinical effectiveness of self‑monitoring coagulation status in people on long‑term vitamin\xa0K antagonist therapy who have atrial fibrillation or heart valve disease.\n\nStudies were included if they appeared relevant to the outcomes listed in the decision problem:\n\nIntermediate outcomes:\n\n\n\ntime and values in therapeutic range\n\ninternational normalised ratio (INR) values\n\ntest failure rate\n\ntime to test result.\n\n\n\nPatient adherence to testing and treatment:\n\n\n\nfrequency of testing\n\nfrequency of visits to primary or secondary care clinics.\n\n\n\nClinical outcomes:\n\n\n\nfrequency of bleeds or blood clots\n\nmorbidity (for example, thromboembolic and cerebrovascular events) and mortality from INR testing and vitamin\xa0K antagonist therapy\n\nadverse events from INR testing, false test results, vitamin\xa0K antagonist therapy and sequelae.\n\n\n\nPatient‑reported outcomes:\n\n\n\nanxiety associated with waiting time for results and not knowing current coagulation status and risk\n\nacceptability of the tests\n\nhealth‑related quality of life.\n\n\n\nIn total, 26\xa0randomised controlled trials met the inclusion criteria and were included in this assessment. The CoaguChek system was used in 22\xa0of the 26\xa0trials: 9\xa0trials used the CoaguChek\xa0S model, 4\xa0trials used the CoaguChek\xa0XS model, 1\xa0trial used the CoaguChek Plus model, and 2\xa0trials used the CoaguChek model. It was unclear which model of the CoaguChek system was used in 6\xa0of the 22\xa0trials. In 2\xa0of the remaining 4\xa0trials either the CoaguChek\xa0S system or the INRatio monitor was used for INR measurement (results were not reported according to the type of point‑of‑care monitor, and the model of the INRatio monitor used in the trials was not reported). No trials that exclusively assessed the clinical effectiveness of the INRatio2\xa0PT/INR monitor were identified. The ProTime microcoagulation system was used in the other 2\xa0trials. In all 6\xa0trials based in the UK, the CoaguChek system (either CoaguChek or version 'S') was used for the INR measurement.\n\nThe evidence on the clinical effectiveness of the coagulometers for monitoring coagulation status was summarised by the External Assessment Group in 3\xa0categories: intermediate outcomes, clinical outcomes, and patient‑reported outcomes.\n\n## Performance of point‑of‑care coagulometers\n\nThe External Assessment Group did not carry out a formal evaluation of the performance of the CoaguChek system or the INRatio2\xa0PT/INR monitor with regard to INR measurement because it was outside the scope of this assessment. However, an objective 'true' INR remains to be defined and INR determined in the laboratory is regarded as the gold standard to which all other measurement methods should be compared. Information on the precision and accuracy of these point‑of‑care coagulometers was therefore gathered from the available literature.\n\nA systematic review by Christensen and Larsen published in 2012\xa0assessed the precision and accuracy of currently available point‑of‑care coagulometers including CoaguChek\xa0XS, INRatio and ProTime. The authors found that the precision of CoaguChek\xa0XS varied from a coefficient of variation of 1.4% to 5.9% based on data from 14\xa0studies. The precision of INRatio and ProTime varied from 5.4% to 8.4% based on data from 6\xa0studies. The coefficient of correlation for CoaguChek\xa0XS varied from 0.81\xa0to 0.98, and that for INRatio varied from 0.73\xa0to 0.95. The review concluded that the precision and accuracy of point‑of‑care coagulometers were generally acceptable compared with laboratory‑based INR testing. The same conclusions were drawn by the Canadian Agency for Drugs and Technologies in Health report published in 2012\xa0on point‑of‑care testing. Similarly, the international guidelines prepared in 2005\xa0by the International Self‑Monitoring Association for Oral Anticoagulation stated that 'Point‑of‑care instruments have been tested in a number of different clinical settings and their accuracy and precision are considered to be more than adequate for the monitoring of oral anticoagulation therapy in both adults and children'.\n\nSix studies compared the performance of CoaguChek\xa0S with that of CoaguChek\xa0XS in relation to conventional INR measurement. The studies showed a good agreement between the 2\xa0CoaguChek models and conventional laboratory‑based testing results. However, the CoaguChek\xa0XS showed more accurate and precise results than CoaguChek\xa0S in both adults and children, especially for higher INR values (>3.5).\n\n## Evidence on intermediate outcomes\n\nEighteen trials (including 4\xa0trials that used the CoaguChek\xa0XS system) reported INR time in therapeutic range although there was variation in the measures used for reporting this outcome, so pooling the data was not appropriate. Time in therapeutic range ranged from 52% to 80% for self‑monitoring and from 55% to 77% for standard care. In 15\xa0of the 18\xa0trials, time in therapeutic range was higher in self‑monitoring participants compared with those in standard care and, in 5\xa0of these trials (including 2\xa0trials using the CoaguChek\xa0XS system), the difference between intervention groups was statistically significant. Three of the UK‑based trials reported no statistically significant differences between self‑monitoring and standard care.\n\nTwelve trials reported INR values in therapeutic range and there was variation in the measures used so pooling the data was not appropriate. In 8\xa0of these trials, the proportion of INR values in therapeutic range ranged from 43.2% to 80.8% for self‑monitoring and from 22.3% to 72.0% for standard care. In 4\xa0trials that reported the proportion of participants in therapeutic range, the values ranged from 53.0% to 72.9% for self‑monitoring and from 43.2% to 72.0% for standard care. Ten of the trials reported higher proportions of INR values in therapeutic range or larger proportions of participants in therapeutic range for self‑monitoring than for standard care.\n\nAmong participants with artificial heart valves, self‑monitoring resulted in a statistically significant higher INR time in therapeutic range compared with standard care. In 2\xa0trials that included participants with atrial fibrillation, no time in therapeutic range differences were found between self‑monitoring and standard care.\n\nOne trial reported the time for each INR monitoring (that is, time from INR measurement to test results) and the total time spent for anticoagulant management during the 4‑month follow‑up period. The time spent for each INR measurement by self‑managed participants was statistically significantly lower (mean 5.3\xa0minutes, standard deviation [SD] 2.6\xa0minutes) compared with the time spent by participants receiving standard care (mean 158\xa0minutes, SD 67.8\xa0minutes, p<0.001). During the 4‑month follow‑up, the total time spent for anticoagulation monitoring by participants in standard care was statistically significantly higher (mean 614.9\xa0minutes, SD 308.8\xa0minutes) than the total time spent by participants who self‑managed their therapy (mean 99.6\xa0minutes, SD 46.1\xa0minutes, p<0.0001).\n\nOne trial reported more than 98% adherence with self‑testing and of those who did not adhere, 2\xa0had difficulties doing the test or experienced disruption caused by hospitalisation, and 1\xa0lost the CoaguChek meter. In another trial 75% (30/40) of participants did not report any problems with using the device and expressed willingness to continue with self‑monitoring. The remaining participants who did not adhere to the testing procedure (25%) reported difficulties with the technique or problems placing the fingertip blood drop on the right position on the test strip. This resulted in the need to use multiple strips to achieve a single reading.\n\n## Evidence on clinical outcomes\n\nTwenty one trials reported a total of 1472\xa0major and minor bleeding events involving 8394\xa0participants. 476\xa0major bleeding events were reported in a total of 8202\xa0participants and 13\xa0of these 21\xa0trials reported 994\xa0minor bleeding events in a total of 5425\xa0participants. No statistically significant differences were seen between self‑monitoring participants (self‑testing and self‑management) and those in standard care for any bleeding events (relative risk [RR] 0.95, 95% confidence interval [CI] 0.74\xa0to 1.21, p=0.66), major bleeding events (RR 1.02, 95% CI 0.86\xa0to 1.22, p=0.80) and minor bleeding events (RR 0.94, 95% CI 0.65\xa0to 1.34, p=0.73). The results were not affected by removing the UK‑based trials or by restricting the included trials to those assessing the CoaguChek system. Similarly, sensitivity analyses restricted to trials using the CoaguChek\xa0XS system showed no differences from the all‑trials results. A sensitivity analysis restricted to trials at low risk of bias slightly changed the estimate of effect but did not substantially impact on the findings (RR 0.59, 95% CI 0.27\xa0to 1.30, p=0.19).\n\nThe External Assessment Group did a subgroup analysis by type of anticoagulant management therapy. No difference between self‑management and standard care for any bleeding events (RR 0.94, 95% CI 0.68\xa0to 1.30, p=0.69) was found but there was a statistically significant higher risk in self‑testing participants than in those receiving standard care (RR 1.15, 95% CI 1.03\xa0to 1.28, p=0.02). No statistically significant differences in the risk of major bleeding were seen between self‑management (RR 1.09, 95% CI 0.81\xa0to 1.46, p=0.58) or self‑testing (RR 0.99, 95% CI 0.80\xa0to 1.23) compared with standard care. When only minor bleeding events were assessed, there was a statistically significant increased risk in self‑testing participants (23%) compared with those in standard care (RR 1.23, 95% CI 1.06\xa0to 1.42, p=0.005) but not in those who were self‑managing (RR 0.84, 95% CI 0.53\xa0to 1.35, p=0.47).\n\nOf the 21\xa0trials, 2\xa0trials enrolled participants with atrial fibrillation, 6\xa0trials enrolled participants with artificial heart valves and 13\xa0trials enrolled participants with mixed indication. No statistically significant subgroup differences were found for bleeding events according to the type of clinical indication or the type of control standard care.\n\nTwenty one trials reported 351\xa0major and minor thromboembolic events in a total of 8394\xa0participants. Self‑monitoring (self‑testing and self‑management) showed a statistically significant reduction in the risk of thromboembolic events by 42% (RR 0.58, 95% CI 0.40\xa0to 0.84, p=0.004) compared with standard care. The risk reduction further increased to 48% when only major thromboembolic events were considered (RR 0.52, 95% CI 0.34\xa0to 0.80, p=0.003). The risk of thromboembolic events substantially decreased when the analyses were restricted to non‑UK trials (RR 0.50, 95% CI 0.32, 0.76, p=0.001); to CoaguChek trials (RR 0.52, 95% CI 0.38, 0.71, p<0.0001); and to trials at low risk of bias (RR 0.38, 95% CI 0.16\xa0to 0.92, p=0.03).\n\nSelf‑management halved the risk of thromboembolic events compared with standard care (RR 0.51, 95% CI 0.37\xa0to 0.69, p<0.0001). In contrast, there was no statistically significant risk reduction for self‑testing compared with standard care (RR 0.99, 95% CI 0.75\xa0to 1.31, p=0.56). The subgroup difference between self‑management and self‑testing was statistically significant (p=0.002). Self‑monitoring participants with artificial heart valves showed a statistically significant reduction in the number of thromboembolic events compared with those in standard care (RR 0.56, 95% CI 0.38\xa0to 0.82, p=0.003). No statistically significant effect was shown among self‑monitoring participants with mixed clinical indication (atrial fibrillation, artificial heart valves, or other conditions) compared with participants receiving standard care.\n\nThirteen trials reported 422\xa0deaths due to all‑cause mortality in a total of 6537\xa0participants. The risk reduction for all‑cause mortality was not statistically significant between self‑monitoring (self‑testing and self‑management) and standard care (RR 0.83, 95% CI 0.63\xa0to 1.10, p=0.20).\n\nRisk of death reduced by 32% through self‑management (RR 0.68, 95% CI 0.46\xa0to 1.01, p=0.06) but not through self‑testing (RR 0.97, 95% CI 0.78\xa0to 1.19, p=0.74) even though the test for subgroup differences was not statistically significant (p=0.13). Self‑monitoring halved the risk of mortality in participants with artificial heart valves (RR 0.54, 95% CI 0.32\xa0to 0.92, p=0.02) but not in those with mixed clinical indication for anticoagulant therapy (RR 0.95, 95% CI 0.78\xa0to 1.16, p=0.61). The subgroup difference between participants with artificial heart valves and those with mixed indication with regard to the number of deaths was statistically significant (p=0.05). No data were available from trials that enrolled participants with atrial fibrillation. Statistically significantly fewer deaths were recorded among participants who self‑monitored their therapy compared with those who were routinely managed by their GP/doctor (RR 0.52, 95% CI 0.30\xa0to 0.90, p=0.02).\n\n## Evidence on patient‑reported outcomes\n\nOne trial (n=28) compared self‑management with self‑testing in children and reported that 1\xa0parent did not favour self‑management because of the increased anxiety about INR measurements.\n\nFour trials conducted a questionnaire survey to assess acceptability to participants of self‑testing and self‑management using point‑of‑care devices. These trials reported high rates of acceptance for both self‑management and self‑testing (77% to 98%).\n\nOne of these trials reported that 93% of participants rated their satisfaction with regard to self‑monitoring (using either the INRatio monitor or the CoaguChek\xa0S system) as high or good. When asked about the overall relative satisfaction with the device, 43% of participants favoured the INRatio monitor, 36% the CoaguChek\xa0S system, and 21% both devices in equal way. One trial conducted in children reported that most participants (13\xa0out of 14\xa0participating families, 92%) opted for the CoaguChek\xa0XS device.\n\nAn unpublished review from the National Thrombosis Service in the Netherlands reported the INR values from over 5000\xa0patients on vitamin\xa0K antagonist therapy using either the CoaguChek\xa0XS system or the INRatio2\xa0PT/INR monitor for self‑monitoring. The review reported that the INR values within therapeutic range were comparable between the monitors. It also reported that the choice of monitor appeared to have no clinically relevant effect on the time in therapeutic range or adverse outcomes in people on long‑term vitamin K antagonist therapy.\n\n# Health‑related quality of life\n\nHealth‑related quality‑of‑life outcomes were reported in 9\xa0trials using a variety of different measures. Four trials used Sawicki's questionnaire to measure quality of life, and substantially greater improvements in treatment satisfaction and self‑efficacy were reported in the self‑management arm compared with the standard care arm of the trials. All 4\xa0trials reported a reduced level of distress and daily inconvenience although 1\xa0trial reported an increased level of distress in participants who received education but did not directly monitor their anticoagulation therapy.\n\nTwo UK‑based trials reported no substantial differences in quality‑of‑life outcomes between self‑monitoring participants and those receiving standard care. One trial reported quality‑of‑life data using the UK SF‑36, the EuroQol scores and Lancaster's instrument. The other trial assessed themes that were adapted from the Lancaster tool, the SEIQol tool and a series of focus groups. Five common themes emerged from the interviews on self‑management: knowledge and management of condition and self‑empowerment, increased anxiety and obsession with health, self‑efficacy, relationship with healthcare professionals, and societal and economic cost. One trial, conducted in the Netherlands, measured quality of life in people with artificial heart valves by using the SF‑36v2. Substantial improvements in quality‑of‑life scores in the physical component summary were reported in people who self‑managed their therapy compared with those receiving standard care.\n\nAnother trial measured quality of life by means of the Health Utilities Index Mark 3. It reported a statistically significant gain in health utilities at the 2‑year follow‑up among self‑testing participants compared with those managed in high quality anticoagulant clinics (p<0.001). The same investigators also measured anticoagulant satisfaction using Duke Anticoagulation Satisfaction Scale. They found that the degree of satisfaction was higher in self‑testing participants compared with those in standard care (p=0.002).\n\nOne trial compared self‑management with self‑testing in children and provided quality‑of‑life data using the KIDCLOT PAC QL parent‑proxy (parents' quality of life and their assessment of child's quality of life) and the child teen KIDCLOT PAC QL. The 5\xa0common themes identified were: awareness, communication, relationship between parent and child, flexibility and anxiety.\n\n# Costs and cost effectiveness\n\nThe External Assessment Group conducted a systematic review to identify existing economic analyses for self‑monitoring coagulation status. The review also sought to identify potentially relevant evidence sources to inform parameter values for the de novo economic model developed by the External Assessment Group. The de novo economic model constructed aimed to assess the cost effectiveness of self‑monitoring coagulation status using the CoaguChek\xa0XS system, the INRatio2\xa0PT/INR monitor or the ProTime microcoagulation system. The ProTime microcoagulation system was included in the assessment but has been removed from this guidance because it is no longer available to the NHS and its successor model is not intended for patient self‑monitoring.\n\n## Systematic review of cost‑effectiveness evidence\n\nThe systematic review identified 12\xa0relevant economic evaluations. All of these evaluations compared INR self‑monitoring strategies with standard care and were assessed against the NICE reference case by the External Assessment Group. The results of the studies included in the systematic review varied widely and showed that the cost effectiveness of self‑monitoring was dependent on a number of key factors.\n\nThe adopted perspective and the initial costs associated with self‑monitoring appeared to substantially affect the cost effectiveness. Self‑monitoring strategies appeared more favourable than standard care when a wider societal perspective was adopted, as a result of lower time costs associated with fewer health service contacts. The size of the estimates of effect applied to self‑monitoring in reducing thromboembolic and bleeding events compared with those applied to standard care also appeared to affect cost effectiveness. The 2\xa0UK‑based evaluations applied effect estimates consistent with small or negligible differences between self‑management and usual care with respect to time in therapeutic range and adverse thromboembolic and haemorrhagic events. This resulted in a low probability of self‑monitoring being cost effective. Several studies that applied large effect estimates resulted in a high probability of self‑monitoring being cost effective.\n\nThe 2\xa0UK‑based economic evaluations were based on data from the same trial. One evaluation adopted an NHS and wider societal perspective, and the other adopted an NHS and personal social services perspective. Self‑monitoring strategies appeared to increase the costs of INR monitoring in the short term and because these 2\xa0evaluations applied small effect estimates, consistent with those seen in the largest UK‑based trial of patient self‑management, self‑monitoring of INR appeared unlikely to be cost effective. However, no UK‑based trials have been sufficiently powered to detect a statistically significant difference between standard INR monitoring and patient self‑monitoring in terms of major thromboembolic or haemorrhagic events. Therefore, the External Assessment Group carried out a meta‑analysis of relevant trials including evidence from a number of European trials in which standard care is similar to that provided in the UK in terms of approach, frequency of testing and the level of INR control achieved.\n\n## Economic analysis\n\nThe External Assessment Group developed a de novo economic model designed to assess the cost effectiveness of self‑monitoring (self‑managing and self‑testing) coagulation status using 2\xa0different point‑of‑care coagulometers: the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor.\n\n## Model structure\n\nThe structure of the Markov model was based on the review of published models of INR self‑monitoring and previous models evaluating the cost effectiveness of new anticoagulant drugs compared with warfarin therapy in people with atrial fibrillation. A further unpublished economic model of INR self‑monitoring was provided by the manufacturer of CoaguChek\xa0XS, and this model was also used to inform the structure of the new economic model.\n\nThe Markov model compared the alternative monitoring strategies for a hypothetical cohort of people with atrial fibrillation or an artificial heart valve, and was used to simulate the occurrence of thromboembolic and bleeding events over a 10‑year period. People with atrial fibrillation or an artificial heart valve represent the majority of people on long‑term vitamin\xa0K antagonist therapy. The model simulated transitions between the discrete health states, and accumulated costs and quality‑adjusted life years (QALYs) on a quarterly (3\xa0month) cycle. Within each cycle, the simulated cohort was exposed to a risk of the adverse events as well as death from other causes. The adverse events included in the model were ischaemic stroke (minor, non‑disabling, and major, disabling or fatal), systemic embolism, minor haemorrhage, and major haemorrhage (intra‑cranial haemorrhage, including haemorrhagic stroke, gastrointestinal bleed, and others). A constraint was applied whereby the simulated cohort in the model could only experience 1\xa0event per cycle.\n\n## Model inputs\n\nThe model was populated using data derived from the systematic clinical effectiveness review, other additional focused reviews to inform key parameters (for instance baseline risks), routine sources of cost data, and where necessary some study‑specific cost estimates based on expert opinion.\n\n## Costs\n\nData on the resource use and costs associated with the alternative monitoring strategies were informed by published literature, existing guidance, expert opinion, manufacturers' and suppliers' prices, and other routine sources of unit cost data. Some costs were informed by expert opinion where suitable data from other sources were not available.\n\n## Health‑related quality of life\n\nThe baseline utility value for people with atrial fibrillation or mechanical heart valve who were stable was taken as the baseline EQ‑5D value from trial data, 0.738. This value was applied to 65–70\xa0year old people and adjusted by the External Assessment Group to estimate age‑specific baseline utilities in the model.\n\nUtilities associated with acute events were applied for the 3‑month period after the event. For post‑event states with associated ongoing morbidity, the appropriate health state utilities were applied for all subsequent cycles spent in these states. Half‑cycle corrections were applied, by assuming that people experienced events on average at the mid‑point of the cycle. Thus a patient starting off in the well state and experiencing a major stroke in a given cycle of the model would accrue 6\xa0weeks at the utility value for well and 6\xa0weeks at the utility value for major stroke.\n\n## Base‑case analysis\n\nFor the purposes of decision‑making, the incremental cost‑effectiveness ratios (ICERs) per QALY gained were considered. The following assumptions were applied in the base‑case analysis:\n\n% of standard care monitoring was done in primary care by practice nurses.\n\n% of the cohort had atrial fibrillation and 40% had an artificial heart valve.\n\nThe average age of the cohort was 65\xa0years, and 55% were male.\n\n% of people who self‑monitored did self‑testing and 50% self‑managed.\n\nThe increase in the number of tests done per year with self‑monitoring was 23\xa0(that is, 35\xa0tests compared with 12\xa0tests in standard care).\n\nRelative treatment effects were estimated and applied separately for self‑testing and self‑management.\n\n% of participants did not start self‑monitoring after training (training failure).\n\n% of participants stopped self‑monitoring within a year of starting.\n\nSelf‑monitoring device costs were annuitized over 5\xa0years.\n\n% of devices were reused by another patient when a patient stopped self‑monitoring.\n\nThe results indicated that over a 10‑year period, introducing self‑monitoring would reduce the proportion of people experiencing a thromboembolic event by 2.5%, while slightly increasing the proportion having a major haemorrhagic event by 1.4%.\n\nThe predicted monitoring costs were higher with self‑monitoring compared with standard monitoring, but the total health and social care costs were similar and in some cases lower. The QALY gains were greater for self‑monitoring than standard monitoring. For all of the self‑monitoring coagulometers there was a QALY gain of 0.027\xa0compared with standard monitoring. Self‑monitoring with the INRatio2\xa0PT/INR monitor was £29\xa0cheaper than standard monitoring. Self‑monitoring with the CoaguChek\xa0XS system was £37\xa0more expensive than standard monitoring. Therefore, in the base‑case scenario, the self‑monitoring strategies compared favourably with standard care. The INRatio2\xa0PT/INR monitor dominated standard monitoring in the analysis because it was less costly and more effective. The ICER for the CoaguChek\xa0XS system was £319\xa0per QALY gained compared with standard monitoring. The lower cost of the INRatio2\xa0PT/INR monitor and testing strips, coupled with the assumption of equivalent clinical effectiveness, meant that the INRatio2\xa0PT/INR monitor also dominated the CoaguChek\xa0XS system. However, it should be noted that no direct evidence of clinical effectiveness was identified exclusively for the INRatio2\xa0PT/INR monitor from the systematic review.\n\n## Analysis of alternative scenarios\n\nSeveral scenario analyses were done by the External Assessment Group:\n\nexclusive self‑testing or self‑management compared with standard monitoring in primary and secondary care\n\nexclusive primary or secondary care clinic testing compared with self‑monitoring in primary and secondary care\n\ndifferent pooled risk estimates applied.\n\nFor the exclusive self‑management strategy, the INRatio2\xa0PT/INR monitor and the CoaguChek\xa0XS system dominated standard monitoring under the base‑case assumptions, whereas for the exclusive self‑testing strategy, the ICERs were above £2\xa0million per QALY gained compared with standard monitoring. The results also showed that for a mixed self‑monitoring strategy (50% self‑testing, 50% self‑management), the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor dominated standard monitoring when exclusively carried out in secondary care. When applying the pooled relative risk estimates for adverse events (derived from all self‑monitoring studies) to both self‑testing and self‑managing participants, the cost savings and QALY gains associated with self‑monitoring increased.\n\nThe External Assessment Group carried out alternative non‑base‑case scenarios, to assess the impact of using self‑monitoring to replace standard monitoring tests (that is, no increase in the number of tests done annually). It was assumed that there was no difference in clinical effectiveness between self‑management, self‑testing and standard care. Under most of these scenarios, standard monitoring was found to be less costly than self‑monitoring. However, self‑testing and self‑management with the INRatio2\xa0PT/INR monitor and the CoaguChek\xa0XS system dominated standard monitoring when carried out exclusively in secondary care.\n\nSubgroup analyses showed the cost effectiveness of self‑monitoring compared with standard care, stratified by indication (atrial fibrillation and artificial heart valves) and cohort age. Self‑monitoring in a '65\xa0years old with atrial fibrillation' cohort was estimated to cost £2574\xa0per QALY gained when using the INRatio2\xa0PT/INR monitor and £4160\xa0per QALY gained when using the CoaguChek\xa0XS system, compared with standard monitoring. For a '65\xa0years old with artificial heart valve' cohort, self‑monitoring with the INRatio2\xa0PT/INR monitor and the CoaguChek\xa0XS system was found to be more effective and less costly (dominant) compared with standard monitoring.\n\nA further analysis was carried out for the atrial fibrillation cohort using the baseline risks seen for participants with better INR control in standard care, assuming a constant relative risk reduction for thromboembolic events associated with self‑monitoring. As the INR time in therapeutic range increased in the control group, and the baseline risk of thromboembolic events consequently dropped, the cost effectiveness of self‑monitoring also decreased. However, the ICERs for the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor only rose above £20,000\xa0per QALY gained when the baseline time in therapeutic range was set at greater than 72.6%.\n\n## Sensitivity analyses\n\nDeterministic sensitivity analysis showed that the model‑based findings were most sensitive to the baseline risk of thromboembolic events and the effectiveness of self‑monitoring for preventing these events. The ICERs for the self‑monitoring strategies rose above £30,000\xa0per QALY gained when the baseline risk was set to 1.15% and the upper confidence limit for the relative risk of thromboembolic events associated with self‑management (RR 0.69) was applied. The same was found when the lower baseline risk of thromboembolic events was coupled with the upper confidence limit of the pooled relative risk for self‑monitoring (RR 0.89). It should be noted however that self‑management on its own remained cost saving under the former combined scenario.\n\nA sensitivity analysis was also conducted to approximate the cost effectiveness of self‑monitoring for a cohort of children with an artificial heart valve on long‑term vitamin\xa0K antagonist therapy. For this analysis, the cohort age was set to 10, the baseline risk of thromboembolic events was reduced to 1.4%, and the standardised mortality ratio for all‑cause mortality after a stroke was set at 14.5. Under this scenario, self‑monitoring with the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor dominated standard monitoring. However, it should be noted that the standardised mortality ratio estimated for an 18–55\xa0year old cohort of people with artificial heart valves was applied because no robust data were identified to appropriately adjust the risk of death from all causes in children with an artificial heart valve.\n\nProbabilistic sensitivity analyses of the base case were done to examine the uncertainty in the cost effectiveness of self‑monitoring. Self‑monitoring with the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor were estimated to have an 80% and 81% probability of being cost effective if the maximum acceptable ICER was £20,000\xa0per QALY gained, respectively. However, it should be noted that there is no direct randomised controlled trial evidence to show the clinical effectiveness of the INRatio2\xa0PT/INR monitor.", 'Considerations': "The Diagnostics Advisory Committee reviewed the evidence available on the clinical and cost effectiveness of self‑monitoring coagulometers for self‑testing or self‑managing coagulation status in people on long‑term vitamin\xa0K antagonist therapy who have atrial fibrillation or heart valve disease.\n\nThe Committee considered the clinical evidence on the use of point‑of‑care coagulometers in people with atrial fibrillation or artificial heart valves. The Committee noted that 26\xa0randomised controlled trials compared the use of point‑of‑care coagulometers for self‑monitoring with standard anticoagulation control. The Committee noted that self‑monitoring nearly halved the risk of thromboembolic events and substantially reduced the risk of mortality in people with artificial heart valves compared with standard monitoring. However, the Committee also noted that self‑monitoring did not result in a statistically significant reduction in the number of major and minor bleeding events compared with standard monitoring. The Committee discussed the heterogeneity in the trials and the applicability of the pooled results from the meta‑analysis of the trial data to the UK population. It noted that the meta‑analysis results showed low statistical heterogeneity and concluded that self‑monitoring offered clinical benefit because it was likely to result in a significant reduction in thromboembolic events. The Committee concluded that the pooled effect estimates from the meta‑analysis were likely to be applicable to the UK because there are no confounding biological differences between people receiving vitamin\xa0K antagonist therapy in the UK and those in other countries.\n\nThe Committee discussed that 22\xa0of the 26\xa0trials included in the assessment investigated the use of the CoaguChek system and considered the different versions of the CoaguChek systems used in these trials. The Committee noted that there are substantial technical differences between the CoaguChek\xa0S system and the CoaguChek\xa0XS system and heard from clinical specialists and the manufacturer that changes had been made to the different versions to improve reliability and accuracy. The Committee considered the performance of the CoaguChek\xa0S and XS systems compared with the gold standard of laboratory‑based INR testing and noted that the precision and accuracy of the 2\xa0CoaguChek versions correlated with that of laboratory‑based measurements. The Committee concluded that results from the CoaguChek\xa0XS system were likely to be at least as good as those obtained from trials in which previous versions of the system were used. The Committee also noted that 4\xa0of the 22\xa0trials investigated the use of the CoaguChek\xa0XS system and that 2\xa0of these trials demonstrated a significant improvement in time in therapeutic range. The Committee concluded that it was appropriate to pool the results of trials using different versions of the CoaguChek system and that these pooled results could demonstrate the clinical effectiveness of self‑monitoring using the CoaguChek\xa0XS version of the system.\n\nThe Committee considered the evidence for the 2\xa0different self‑monitoring coagulometers: the CoaguChek\xa0XS system and the INRatio2\xa0PT/INR monitor. The Committee noted that 22\xa0of the 26\xa0trials included in the assessment investigated the use of the CoaguChek system and noted that there was no direct randomised controlled trial evidence to show the clinical effectiveness of the INRatio2\xa0PT/INR monitor. The Committee considered the evidence that showed the 2\xa0coagulometers had a broadly similar performance in precision and accuracy with regard to time in therapeutic range measurement when compared with the gold standard of laboratory‑based INR testing and therefore concluded that it was appropriate to extrapolate the clinical‑effectiveness data from the CoaguChek system to the INRatio2\xa0PT/INR monitor.\n\nThe Committee discussed the usability of the coagulometers and noted that small differences in devices can sometimes result in large differences in behaviour. The Committee considered the results of the systematic review by Christensen and Larsen (2012) and the unpublished review of over 5000\xa0patients from the National Thrombosis Service in the Netherlands. It noted that although the results of the unpublished review suggested that any potential differences in usability between the 2 monitors did not affect their clinical effectiveness, the unpublished review could not be considered methodologically robust. The Committee concluded that based on the systematic review, any potential differences in the usability of the coagulometers did not appear to affect their ability to measure INR.\n\nThe Committee considered the differences in clinical outcomes between people who were self‑managing their anticoagulation control and those who were self‑testing. The Committee noted that there was a statistically significantly greater reduction in thromboembolic events among people who self‑managed compared with those who self‑tested. The Committee also noted that when only minor bleeding events were assessed, a statistically significantly increased risk was seen in self‑testing participants compared with those in standard care. All‑cause mortality was lower through self‑management but not through self‑testing. The Committee discussed possible reasons for the differences in results between self‑managing and self‑testing, and it heard from clinical specialists that people who self‑manage their coagulation control may behave differently to those who self‑test because they have greater responsibility for managing their coagulation control. The Committee noted that the largest trial in the assessment of self‑testing did not show a reduction in clinical adverse events but did show an increase in the time in therapeutic range (Matchar et al. 2010). The Committee also noted that this trial had a high standard of coagulation control in the control arm, which could explain why no statistically significant difference in clinical adverse events was detected between the self‑testing group and the standard care group. The Committee concluded that the high standard of coagulation control in the control arm of the trial may not reflect general UK clinical practice and so it was plausible that the increase in time in therapeutic range would lead to a statistically significant reduction in clinical adverse events if compared with UK standard coagulation control practice. The Committee concluded that self‑testing and self‑managing were likely to be clinically effective and that self‑testing was often a step towards self‑management in clinical practice.\n\nThe Committee considered the clinical evidence for using self‑monitoring in the population group with atrial fibrillation. The Committee noted that only 2\xa0trials investigated self‑monitoring in people with atrial fibrillation and 19\xa0trials investigated self‑monitoring in a mixed population that included people with atrial fibrillation. The Committee heard from clinical specialists that the clinical outcomes for people with atrial fibrillation are similar to those for people with artificial heart valves. The Committee also heard that people with artificial heart valves may be a younger population than people with atrial fibrillation. The Committee noted that it was not possible to isolate the data for people with atrial fibrillation from the mixed populations investigated in the 19\xa0trials but concluded that it was likely that self‑monitoring would result in similar clinical benefits in people with atrial fibrillation to those achieved in people with artificial heart valves.\n\nThe Committee considered the cost‑effectiveness analysis carried out by the External Assessment Group on self‑monitoring. In the base‑case analysis, self‑monitoring with the CoaguChek\xa0XS system resulted in an incremental cost‑effectiveness ratio (ICER) of around £300\xa0per quality‑adjusted life year (QALY) gained (based on the pooled effect estimates from the meta‑analysis) compared with standard monitoring. Self‑monitoring with the INRatio2\xa0PT/INR monitor dominated (that is, was less expensive and more effective than) the CoaguChek\xa0XS system and standard care, although the Committee noted that there was no direct randomised controlled trial evidence for the clinical effectiveness of the INRatio2\xa0PT/INR monitor so clinical effectiveness equivalent to the CoaguChek\xa0XS system was assumed in the base case. The Committee concluded that self‑monitoring with the CoaguChek\xa0XS system is cost effective in light of the reduction in thromboembolic events seen in the pooled results of the trial data. However, although the INRatio2\xa0PT/INR monitor dominated standard monitoring in the base‑case analysis, the Committee did not consider this result to be as robust as that for the CoaguChek\xa0XS system because there was no direct evidence of clinical effectiveness for the INRatio2\xa0PT/INR monitor that showed a reduction in thromboembolic events. The Committee noted the similar performance of the CoaguChek\xa0XS system and the InRatio2\xa0PT/INR monitor compared with the gold standard of laboratory‑based INR testing and concluded therefore that self‑monitoring with the INRatio2\xa0PT/INR monitor was likely to represent a cost‑effective use of NHS resources.\n\nThe Committee considered the cost effectiveness of self‑testing and self‑managing individually. The findings showed that self‑management alone is highly cost effective (dominant) but that self‑testing alone is not cost effective, compared with standard monitoring. The Committee noted that these findings were based on the contrasting pooled‑effect estimates obtained from the meta‑analysis of randomised controlled trials, based on thromboembolic events while self‑testing and self‑managing. The Committee discussed the impact of 1\xa0large trial by Matchar et al. (2010) (see section 6.6) on the cost effectiveness of self‑testing and noted that although this trial did not show a reduction in clinical adverse events, it did show an increase in the time in therapeutic range. The Committee discussed the impact on the ICERs for self‑testing if the economic model was driven by time in therapeutic range rather than adverse events. The Committee concluded that self‑testing may be more cost effective if the model had been based on time in therapeutic range. The Committee also considered the costs of self‑managing and self‑testing and noted that self‑testing was more expensive because of higher administration costs. The Committee heard from the External Assessment Group that if the pooled‑effect estimates from self‑monitoring were applied to self‑testing, self‑testing would become cost effective even with the higher administration costs this incurred. The Committee concluded that it was likely that the increase in time in therapeutic range shown for self‑testing in the trial would lead to a reduction in adverse events compared with standard clinical practice in the UK. The Committee therefore concluded that it was likely that the clinical benefits of self‑testing had been underestimated in the economic analyses and that both self‑testing and self‑managing were cost effective.\n\nThe Committee considered the impact on people whose anticoagulation therapy is monitored by standard clinical practice. The Committee acknowledged the additional costs and inconvenience for patients of travelling to specialist clinics or hospital to be monitored. The Committee also noted the loss in productivity through absence from work or school to attend clinic appointments. The Committee acknowledged these costs were incurred outside the healthcare system and therefore not included in the reference case; however, it considered that self‑monitoring may reduce the costs and inconvenience incurred by the patient. The Committee also noted that monitoring anticoagulation therapy can have a substantial impact on the quality of life of patients and their families because of the anxiety associated with the risks of bleeding and the consequent behavioural changes such as the length of time they are willing to spend away from home or the distances they are willing to travel. The Committee concluded that the main benefits of self‑monitoring involve reducing the substantial burden associated with monitoring anticoagulation therapy for the patient and their families.\n\nThe Committee considered the different methods of self‑monitoring for people having long‑term vitamin\xa0K antagonist therapy. The Committee heard from a clinical specialist that computer algorithms may be used by some services to determine dose adjustments. The Committee noted that the cost of software licensing had not been included in the cost‑effectiveness analyses and it discussed the implications of computer‑based dosing for people who would self‑manage their coagulation status. The Committee heard that there were alternative methods to determine dose adjustments and that a lack of internet access should not restrict a person's access to self‑monitoring. The Committee considered an additional analysis by the External Assessment Group that investigated the impact of an additional cost for dose adjustment software on the base‑case ICERs for self‑managing. The Committee noted that the additional cost of software would need to be greater than £190\xa0per patient per year to substantially affect the cost‑effectiveness of self‑managing with the coagulometers. The Committee concluded that the additional cost of software was unlikely to exceed this value and therefore, even with this potential additional cost, self‑managing with the point‑of‑care coagulometers would still represent a cost‑effective use of resources in the NHS.\n\nThe Committee considered the benefits for patients receiving vitamin\xa0K antagonist therapy of using point‑of‑care coagulometers. It heard from a patient expert on the Committee that self‑monitoring is important to psychological wellbeing because it provides a sense of control for the patient and removes the need to frequently attend clinics or hospitals, which serve as a constant reminder of their condition. The Committee also heard that self‑monitoring allows people to travel to visit, or act as a carer for, other family members, without having to worry about attending testing appointments or if testing facilities are available in other countries. The Committee also heard that the current variation in access to self‑testing strips on prescription for self‑monitoring was of concern to patients because it restricted their freedom to move GP practice or move house to a different area in case the testing strips would no longer be prescribed. The Committee concluded that the benefits of self‑monitoring for patients were not fully captured in the cost‑effectiveness analyses.\n\nThe Committee considered the similarities between self‑monitoring coagulation status and self‑managing diabetes. The Committee heard from a patient expert that some patients are used to self‑testing for conditions such as diabetes, hypertension and heart conditions. The Committee also heard from a clinical specialist that although there were similarities between self‑testing for different conditions, there were intrinsic differences between self‑testing for diabetes and coagulation. Vitamin\xa0K antagonists are more sensitive to diet and exercise, and act over a longer period of time than insulin. Therefore, the dose response for vitamin\xa0K antagonists is less predictable than for insulin and the risk of adverse events is perceived to be higher. The clinical specialist also reported that some patients were successfully self‑monitoring their coagulation status but not all people receiving vitamin\xa0K antagonist therapy will be able to self‑monitor and some may not wish to. The Committee noted that some groups of patients who may have difficulty with self‑monitoring, such as children or those with a disability, may be able to self‑test or self‑manage with the help of a carer. The Committee concluded that there are different considerations for self‑monitoring of coagulation status to those made for self‑testing for diabetes, and that the decision for a patient to self‑monitor should be made after a thorough discussion and subsequent agreement between the patient and the healthcare professional.\n\nThe Committee considered the impact of the increasing use of non‑vitamin\xa0K antagonist oral anticoagulant drugs, which do not involve monitoring because of their predictable dose response. It heard from clinical specialists that there are factors that may influence clinical decisions and affect the number of people receiving warfarin: people receiving warfarin who have stable INRs may be unlikely to switch to non‑vitamin\xa0K antagonist oral anticoagulants, and the non‑vitamin\xa0K antagonist oral anticoagulants may be unsuitable for some, such as people with mechanical heart valves, certain people with renal or liver dysfunction or those taking drugs that cannot be taken at the same time as the non‑vitamin\xa0K antagonist oral anticoagulants. The Committee concluded that, because the non‑vitamin\xa0K antagonist oral anticoagulants would not be suitable for all people who need anticoagulant therapy, and there are many people who will receive warfarin therapy rather than non‑vitamin\xa0K antagonist oral anticoagulant therapy, self‑monitoring coagulometers are still of clinical importance to the NHS and patients.\n\nThe Committee considered the need for quality control of individual patient coagulometers. The Committee heard from a clinical specialist that the National External Quality Assessment Service runs a scheme to ensure the accuracy of coagulometers used by healthcare professionals, and coagulometers used by patients could be checked against a professional coagulometer to ensure accuracy. The Committee concluded that this was a reliable method of ensuring accuracy of individual coagulometers."}
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https://www.nice.org.uk/guidance/dg14
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Evidence-based recommendations on the CoaguChek XS system for self-monitoring coagulation status in adults and children. The recommendations originally included the InRatio2 PT/INR, but this was withdrawn from the market in October 2016 and is not currently available.
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5f64499c3d07dddec5497551998b6b9c474521c9
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nice
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Transvaginal mesh repair of anterior or posterior vaginal wall prolapse
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Transvaginal mesh repair of anterior or posterior vaginal wall prolapse
Evidence-based recommendations on transvaginal mesh repair of anterior or posterior vaginal wall prolapse. This involves inserting a mesh to replace tissue that has weakened and caused the pelvic organs to drop down (prolapse) into the vagina.
# Recommendations
Current evidence on the safety of transvaginal mesh repair of anterior or posterior vaginal wall prolapse shows there are serious but well-recognised safety concerns. Evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.
All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.
Further research should include details of patient selection, long-term outcomes including complications, type of mesh used and method of fixation, and quality of life.# Indications and current treatments
Vaginal wall prolapse is a protrusion of 1 or more pelvic organs (such as the bladder or the rectum) through the vaginal fascia. The vaginal wall then moves from its normal position (prolapses), into or outside the vagina. Vaginal wall prolapse can affect a woman's quality of life because of its local physical effects (pressure, bulging, heaviness or discomfort). It can also affect urinary, bowel or sexual function. There are different types of vaginal wall prolapse depending on the organs and sites involved. These include anterior vaginal wall prolapse (including prolapse of the urethra or bladder ) and posterior vaginal wall prolapse (including prolapse of the rectum or small bowel ). A woman can present with prolapse of 1 or both of these sites.
Current treatment options for vaginal wall prolapse include pelvic floor muscle training, use of mechanical devices (ring or shelf pessaries) and surgery, including anterior or posterior colporrhaphy and site-specific defect repair such as paravaginal repair.
The aims of using mesh to repair vaginal wall prolapse are to add extra support and to reduce the risk of recurrence, particularly for women with recurrent prolapse or with congenital connective tissue disorders (such as Ehlers–Danlos syndrome or Marfan's syndrome).# The procedure
Transvaginal mesh repair of anterior or posterior vaginal wall prolapse involves removing some of the stretched tissue if needed, and tightening the underlying tissue (colporrhaphy). Mesh is used to support the repair.
The procedure is usually done with the patient under general anaesthesia. Anterior colporrhaphy involves dissection of the vaginal mucosa through a midline incision in the anterior vaginal wall to expose the bladder and pubocervical fascia. The fascia is then plicated (folded), some excess tissue may be removed and the incision is closed. Posterior colporrhaphy involves a vaginal incision and plication of the levator ani. Other site-specific procedures, such as paravaginal repair, may also be done using methods similar to colporrhaphy.
The technique for inserting mesh varies. Mesh is usually placed using an open technique, although trocar introducers can also be used without direct visualisation. The mesh is usually positioned and sutured over the fascial defect as an 'inlay'.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.
In a randomised controlled trial (RCT) of 865 women with anterior or posterior vaginal wall prolapse treated by synthetic mesh augmented repair or standard repair alone, there were no statistically significant differences in prolapse symptom scores (5.3 versus 4.9 respectively, p=0.37). There were also no statistically significant differences in symptomatic prolapse (85% compared with 82% respectively, p=0.30) or the proportion of women reporting 'something coming down' (34% compared with 31% respectively, p=0.59) at 2‑year follow‑up. The quality-of-life scores were also similar. In an RCT of 735 women with anterior or posterior vaginal wall prolapse treated by biological graft augmented repair or standard repair alone, there were no statistically significant differences in prolapse symptom scores (5.5 compared with 4.9 respectively, p=0.43) or symptomatic prolapse (82% compared with 81% respectively, p=0.85). The proportion of women reporting 'something coming down' was statistically significantly higher in the graft augmented repair group (40% compared with 31% in the standard repair alone group, p=0.04) at 2‑year follow‑up. The quality-of-life scores were similar between the 2 groups.
In a systematic review of 4,023 patients, there was a statistically significantly lower risk of awareness of prolapse in women treated by transvaginal permanent mesh repair compared with native tissue repair (relative risk 0.66, 95% confidence interval 0.54 to 0.81; n=1,614, 12 RCTs) at 1- to 3‑year follow‑up.
In the RCT of 865 women with anterior or posterior vaginal wall prolapse treated by synthetic mesh augmented repair or standard repair alone, there were no statistically significant differences in the proportions of women with an overall Pelvic Organ Prolapse Quantification (POP‑Q) score of 2b, 3 or 4 (16% compared with 14% respectively, p=0.52) at 1‑year follow‑up. In the RCT of 735 women with anterior or posterior vaginal wall prolapse treated by biological graft augmented repair or standard repair alone, the proportions of women with an overall POP‑Q score of 2b, 3 or 4 were 18% (54/298) and 16% (47/303) respectively at 1‑year follow‑up (p=0.47). In the systematic review of 4,023 patients, women who had a transvaginal mesh repair were less likely to have a stage 2 or worse anterior compartment prolapse on examination than those having a native tissue repair (RR 0.45, 95% CI 0.36 to 0.55, 13 RCTs, n=1,406, I2=35%) at 1- to 3‑year follow‑up. The risk of recurrent prolapse was lower in the transvaginal permanent mesh group than in the native tissue repair group (RR 0.40, 95% CI 0.30 to 0.53, 21 studies, n=2,494, I2=73%).
In the systematic review of 4,023 patients, those who had a transvaginal mesh repair were less likely to have repeat surgery for prolapse (RR 0.53, 95% CI 0.31 to 0.88, 12 RCTs, n=1,675) at 1‑ to 3‑year follow‑up than those who had native tissue repair. In a population-based cohort study of 27,809 patients who had mesh or native tissue repair, surgery for recurrent prolapse was reported in similar proportions of patients: 5% of patients in both groups at 1‑year follow‑up, and 10% (95% CI 9 to 12%) in the mesh group at 5‑year follow‑up compared with 9% (95% CI 9 to 10%) in the native tissue group. In the RCT of 865 patients who had synthetic mesh or standard repair, further prolapse surgery was needed in a similar proportion of patients (4% compared with 5% respectively) at 2‑year follow‑up. In the RCT of 735 patients who had biological graft or standard repair, further prolapse surgery was needed in 5% of patients in both groups (15/300 and 15/299) at 2‑year follow‑up.
The specialist advisers listed anatomical success, restoration of bladder, bowel and sexual function, and long-term success as the key efficacy outcomes.
Sixteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.
Immediate postoperative complications were reported in 4% (20/278) of patients who had anterior prolapse repair with mesh and 4% (343/7643) of patients who had repair without mesh in a cohort study of 18,986 patients. Late postoperative complications were more common in patients who had a mesh repair compared with those who had a non-mesh repair (adjusted incidence rate ratio 3.15, 95% confidence interval 2.46 to 4.04) in the same study.
Mesh complications were reported in 12% (51/434) of patients who had a synthetic mesh repair at 2‑year follow‑up in a randomised controlled trial (RCT) of 865 patients. Surgical removal of the mesh was needed in 9% (37/434) of patients in the same study. Mesh complications were reported in less than 1% (2/368) of patients who had a biological graft repair and less than 1% (2/367) of patients who had a standard repair in an RCT of 735 patients. Surgical removal was needed in 3 of the 4 patients. Surgery for mesh complications was reported in 6% of patients who had a mesh repair in a cohort study of 27,809 patients.
Mesh exposure was reported in 12% (134/2,097) of patients who had a transvaginal permanent mesh repair in a systematic review of 4,023 patients at 1‑ to 3‑year review. Surgery for mesh exposure was reported in 8% (100/1,227) of patients in the same review. The overall rate of graft erosion (by meta-analysis of 110 studies) was 10% (95% CI 10 to 11%) of procedures in a systematic review of 126 studies. Mesh erosion was reported in 5% (32/677) of patients and vesicovaginal fistula with mesh extrusion was reported in less than 1% of patients (2/677) in a case series of 677 patients.
Serious adverse effects of any kind (excluding mesh complications) were reported in 8% (34/435) of patients who had a synthetic mesh repair and 7% (31/430) of patients who had a standard repair (p=0.73) at 1‑year follow‑up in the RCT of 865 patients. Serious adverse effects of any kind (excluding mesh complications) were reported in 10% (36/368) of patients who had a biological graft repair and 6% (23/367) of patients who had a standard repair (p=0.08) at 1‑year follow‑up in the RCT of 735 patients.
Bladder injury was more common in women who had a transvaginal permanent mesh repair than those who had a native tissue repair (relative risk 3.92, 95% CI 1.62 to 9.50, 11 RCTs, n=1,514, I2=0%, moderate-quality evidence) in the systematic review of 4,023 patients. Bowel injury was reported in 1 study in the same systematic review, and there was no evidence of a difference between the 2 groups (RR 3.26, 95% CI 0.13 to 78.81, n=169). Bladder injury and rectal damage were reported in 2% (11/677) and 1% (5/677) of patients respectively in a case series of 677 patients. In 2 patients, urinary tract injury was not recognised at the time of surgery and led to stone formation. One patient needed a laparotomy and removal of the mesh with resection of the bladder wall. Ureteric trauma was reported in 1 patient in the same study; this was treated by ureteroneocystotomy.
Bleeding more than 500 ml was reported in 2% (15/677) of patients in the case series of 677 patients. Vaginal or pelvic haematoma was reported in 6% (37/677) of patients in a case series of 677 patients. In 10 patients, major vaginal haematomas led to urinary retention or transformed into an abscess. Several of them needed to be drained transcutaneously. Perineal haematoma was reported in 3% (17/677) of patients in the same study.
Pelvic abscess was reported in 1% (4/677) of patients in the case series of 677 patients. One patient, with a history of intrauterine device inserted 30 years ago, had necrotising fasciitis. The patient developed signs of systemic toxicity 6 days after the prolapse repair. She was treated by fasciotomy and debridement but died after 18 days.
De novo stress urinary incontinence was more common in patients who had a transvaginal permanent mesh repair than in those who had a native tissue repair (RR 1.39, 95% CI 1.06 to 1.82, 12 RCTs, n=1,512, I2=0%, low-quality evidence) in the systematic review of 4,023 patients. Incontinence surgery admissions were more common after anterior repair with mesh than after anterior repair without mesh (adjusted incidence rate ratio 3.20, 95% CI 2.06 to 4.96) in a cohort study of 18,986 patients.
Urinary retention within 90 days was more common in patients who had a mesh repair than in those who had a repair without mesh (8% compared with 6%, risk ratio 1.33, 95% CI 1.18 to 1.51) in a cohort study of 27,991 patients.
The overall rate of dyspareunia (by meta-analysis of 70 studies) was 9% (95% CI 8 to 10%) of procedures in the systematic review of 126 studies. Pain and dyspareunia was reported in 2% (16/677) of patients in the case series of 677 patients.
As well as safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not describe any additional anecdotal or theoretical adverse events.
Sixteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information
For related NICE guidance, see the NICE website.
# Information for patients
NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2757-9
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{'Recommendations': 'Current evidence on the safety of transvaginal mesh repair of anterior or posterior vaginal wall prolapse shows there are serious but well-recognised safety concerns. Evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.\n\nAll adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nFurther research should include details of patient selection, long-term outcomes including complications, type of mesh used and method of fixation, and quality of life.', 'Indications and current treatments': "Vaginal wall prolapse is a protrusion of 1 or more pelvic organs (such as the bladder or the rectum) through the vaginal fascia. The vaginal wall then moves from its normal position (prolapses), into or outside the vagina. Vaginal wall prolapse can affect a woman's quality of life because of its local physical effects (pressure, bulging, heaviness or discomfort). It can also affect urinary, bowel or sexual function. There are different types of vaginal wall prolapse depending on the organs and sites involved. These include anterior vaginal wall prolapse (including prolapse of the urethra [urethrocele] or bladder [cystocele]) and posterior vaginal wall prolapse (including prolapse of the rectum [rectocele] or small bowel [enterocele]). A woman can present with prolapse of 1 or both of these sites.\n\nCurrent treatment options for vaginal wall prolapse include pelvic floor muscle training, use of mechanical devices (ring or shelf pessaries) and surgery, including anterior or posterior colporrhaphy and site-specific defect repair such as paravaginal repair.\n\nThe aims of using mesh to repair vaginal wall prolapse are to add extra support and to reduce the risk of recurrence, particularly for women with recurrent prolapse or with congenital connective tissue disorders (such as Ehlers–Danlos syndrome or Marfan's syndrome).", 'The procedure': "Transvaginal mesh repair of anterior or posterior vaginal wall prolapse involves removing some of the stretched tissue if needed, and tightening the underlying tissue (colporrhaphy). Mesh is used to support the repair.\n\nThe procedure is usually done with the patient under general anaesthesia. Anterior colporrhaphy involves dissection of the vaginal mucosa through a midline incision in the anterior vaginal wall to expose the bladder and pubocervical fascia. The fascia is then plicated (folded), some excess tissue may be removed and the incision is closed. Posterior colporrhaphy involves a vaginal incision and plication of the levator ani. Other site-specific procedures, such as paravaginal repair, may also be done using methods similar to colporrhaphy.\n\nThe technique for inserting mesh varies. Mesh is usually placed using an open technique, although trocar introducers can also be used without direct visualisation. The mesh is usually positioned and sutured over the fascial defect as an 'inlay'.", 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 865\xa0women with anterior or posterior vaginal wall prolapse treated by synthetic mesh augmented repair or standard repair alone, there were no statistically significant differences in prolapse symptom scores (5.3 versus 4.9 respectively, p=0.37). There were also no statistically significant differences in symptomatic prolapse (85% [291/341] compared with 82% [283/347] respectively, p=0.30) or the proportion of women reporting 'something coming down' (34% [116/342] compared with 31% [106/347] respectively, p=0.59) at 2‑year follow‑up. The quality-of-life scores were also similar. In an RCT of 735\xa0women with anterior or posterior vaginal wall prolapse treated by biological graft augmented repair or standard repair alone, there were no statistically significant differences in prolapse symptom scores (5.5 compared with 4.9 respectively, p=0.43) or symptomatic prolapse (82% [245/299] compared with 81% [242/298] respectively, p=0.85). The proportion of women reporting 'something coming down' was statistically significantly higher in the graft augmented repair group (40% [120/299] compared with 31% [91/298] in the standard repair alone group, p=0.04) at 2‑year follow‑up. The quality-of-life scores were similar between the 2\xa0groups.\n\nIn a systematic review of 4,023\xa0patients, there was a statistically significantly lower risk of awareness of prolapse in women treated by transvaginal permanent mesh repair compared with native tissue repair (relative risk [RR] 0.66, 95% confidence interval [CI] 0.54 to 0.81; n=1,614, 12\xa0RCTs) at 1- to 3‑year follow‑up.\n\nIn the RCT of 865\xa0women with anterior or posterior vaginal wall prolapse treated by synthetic mesh augmented repair or standard repair alone, there were no statistically significant differences in the proportions of women with an overall Pelvic Organ Prolapse Quantification (POP‑Q) score of\xa02b, 3\xa0or\xa04 (16% [54/336] compared with 14% [47/338] respectively, p=0.52) at 1‑year follow‑up. In the RCT of 735\xa0women with anterior or posterior vaginal wall prolapse treated by biological graft augmented repair or standard repair alone, the proportions of women with an overall POP‑Q score of\xa02b, 3\xa0or\xa04 were 18% (54/298) and 16% (47/303) respectively at 1‑year follow‑up (p=0.47). In the systematic review of 4,023\xa0patients, women who had a transvaginal mesh repair were less likely to have a stage\xa02 or worse anterior compartment prolapse on examination than those having a native tissue repair (RR 0.45, 95% CI 0.36 to 0.55, 13\xa0RCTs, n=1,406, I2=35%) at 1- to 3‑year follow‑up. The risk of recurrent prolapse was lower in the transvaginal permanent mesh group than in the native tissue repair group (RR 0.40, 95% CI 0.30 to 0.53, 21\xa0studies, n=2,494, I2=73%).\n\nIn the systematic review of 4,023\xa0patients, those who had a transvaginal mesh repair were less likely to have repeat surgery for prolapse (RR 0.53, 95% CI 0.31 to 0.88, 12\xa0RCTs, n=1,675) at 1‑ to 3‑year follow‑up than those who had native tissue repair. In a population-based cohort study of 27,809\xa0patients who had mesh or native tissue repair, surgery for recurrent prolapse was reported in similar proportions of patients: 5% of patients in both groups at 1‑year follow‑up, and 10% (95% CI 9 to 12%) in the mesh group at 5‑year follow‑up compared with 9% (95% CI 9 to 10%) in the native tissue group. In the RCT of 865\xa0patients who had synthetic mesh or standard repair, further prolapse surgery was needed in a similar proportion of patients (4% [15/343] compared with 5% [16/348] respectively) at 2‑year follow‑up. In the RCT of 735\xa0patients who had biological graft or standard repair, further prolapse surgery was needed in 5% of patients in both groups (15/300 and 15/299) at 2‑year follow‑up.\n\nThe specialist advisers listed anatomical success, restoration of bladder, bowel and sexual function, and long-term success as the key efficacy outcomes.\n\nSixteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.\n\nImmediate postoperative complications were reported in 4% (20/278) of patients who had anterior prolapse repair with mesh and 4% (343/7643) of patients who had repair without mesh in a cohort study of 18,986\xa0patients. Late postoperative complications were more common in patients who had a mesh repair compared with those who had a non-mesh repair (adjusted incidence rate ratio 3.15, 95% confidence interval [CI] 2.46 to 4.04) in the same study.\n\nMesh complications were reported in 12% (51/434) of patients who had a synthetic mesh repair at 2‑year follow‑up in a randomised controlled trial (RCT) of 865\xa0patients. Surgical removal of the mesh was needed in 9% (37/434) of patients in the same study. Mesh complications were reported in less than 1% (2/368) of patients who had a biological graft repair and less than 1% (2/367) of patients who had a standard repair in an RCT of 735\xa0patients. Surgical removal was needed in 3\xa0of the 4\xa0patients. Surgery for mesh complications was reported in 6% of patients who had a mesh repair in a cohort study of 27,809\xa0patients.\n\nMesh exposure was reported in 12% (134/2,097) of patients who had a transvaginal permanent mesh repair in a systematic review of 4,023\xa0patients at 1‑ to 3‑year review. Surgery for mesh exposure was reported in 8% (100/1,227) of patients in the same review. The overall rate of graft erosion (by meta-analysis of 110\xa0studies) was 10% (95% CI 10 to 11%) of procedures in a systematic review of 126\xa0studies. Mesh erosion was reported in 5% (32/677) of patients and vesicovaginal fistula with mesh extrusion was reported in less than 1% of patients (2/677) in a case series of 677\xa0patients.\n\nSerious adverse effects of any kind (excluding mesh complications) were reported in 8% (34/435) of patients who had a synthetic mesh repair and 7% (31/430) of patients who had a standard repair (p=0.73) at 1‑year follow‑up in the RCT of 865\xa0patients. Serious adverse effects of any kind (excluding mesh complications) were reported in 10% (36/368) of patients who had a biological graft repair and 6% (23/367) of patients who had a standard repair (p=0.08) at 1‑year follow‑up in the RCT of 735\xa0patients.\n\nBladder injury was more common in women who had a transvaginal permanent mesh repair than those who had a native tissue repair (relative risk [RR] 3.92, 95% CI 1.62 to 9.50, 11\xa0RCTs, n=1,514, I2=0%, moderate-quality evidence) in the systematic review of 4,023\xa0patients. Bowel injury was reported in 1\xa0study in the same systematic review, and there was no evidence of a difference between the 2\xa0groups (RR 3.26, 95% CI 0.13 to 78.81, n=169). Bladder injury and rectal damage were reported in 2% (11/677) and 1% (5/677) of patients respectively in a case series of 677\xa0patients. In 2\xa0patients, urinary tract injury was not recognised at the time of surgery and led to stone formation. One patient needed a laparotomy and removal of the mesh with resection of the bladder wall. Ureteric trauma was reported in 1\xa0patient in the same study; this was treated by ureteroneocystotomy.\n\nBleeding more than 500\xa0ml was reported in 2% (15/677) of patients in the case series of 677\xa0patients. Vaginal or pelvic haematoma was reported in 6% (37/677) of patients in a case series of 677\xa0patients. In 10\xa0patients, major vaginal haematomas led to urinary retention or transformed into an abscess. Several of them needed to be drained transcutaneously. Perineal haematoma was reported in 3% (17/677) of patients in the same study.\n\nPelvic abscess was reported in 1% (4/677) of patients in the case series of 677\xa0patients. One patient, with a history of intrauterine device inserted 30\xa0years ago, had necrotising fasciitis. The patient developed signs of systemic toxicity 6\xa0days after the prolapse repair. She was treated by fasciotomy and debridement but died after 18\xa0days.\n\nDe novo stress urinary incontinence was more common in patients who had a transvaginal permanent mesh repair than in those who had a native tissue repair (RR 1.39, 95% CI 1.06 to 1.82, 12\xa0RCTs, n=1,512, I2=0%, low-quality evidence) in the systematic review of 4,023\xa0patients. Incontinence surgery admissions were more common after anterior repair with mesh than after anterior repair without mesh (adjusted incidence rate ratio 3.20, 95% CI 2.06 to 4.96) in a cohort study of 18,986\xa0patients.\n\nUrinary retention within 90\xa0days was more common in patients who had a mesh repair than in those who had a repair without mesh (8% compared with 6%, risk ratio 1.33, 95% CI 1.18 to 1.51) in a cohort study of 27,991\xa0patients.\n\nThe overall rate of dyspareunia (by meta-analysis of 70\xa0studies) was 9% (95% CI 8 to 10%) of procedures in the systematic review of 126\xa0studies. Pain and dyspareunia was reported in 2% (16/677) of patients in the case series of 677\xa0patients.\n\nAs well as safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not describe any additional anecdotal or theoretical adverse events.\n\nSixteen commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Further information': 'For related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2757-9'}
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https://www.nice.org.uk/guidance/ipg599
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Evidence-based recommendations on transvaginal mesh repair of anterior or posterior vaginal wall prolapse. This involves inserting a mesh to replace tissue that has weakened and caused the pelvic organs to drop down (prolapse) into the vagina.
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c312f6f50254d4ea57a9f796fe5376c4fe25730d
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nice
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Naltrexone–bupropion for managing overweight and obesity
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Naltrexone–bupropion for managing overweight and obesity
Evidence-based recommendations on naltrexone–bupropion (Mysimba) for managing overweight and obesity in adults.
# Recommendations
Naltrexone–bupropion is not recommended within its marketing authorisation for managing overweight and obesity in adults alongside a reduced-calorie diet and increased physical activity.
This recommendation is not intended to affect treatment with naltrexone–bupropion that was started in the NHS before this guidance was published. Adults having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Obesity is very common in England, affecting about 30% of the population. Current management for overweight and obesity is lifestyle measures alone, lifestyle measures with orlistat or bariatric surgery.
Clinical trial evidence shows that naltrexone–bupropion with lifestyle measures is more effective than lifestyle measures alone, but its long-term effectiveness is unknown.
The estimate of cost effectiveness for naltrexone–bupropion with lifestyle measures, compared with lifestyle measures alone, is highly uncertain because of uncertainties in the modelling assumptions. Large numbers of people could be eligible for treatment which could potentially be long-term, leading to high overall costs for naltrexone–bupropion. Therefore, in these circumstances more certainty is needed that naltrexone–bupropion will provide value for the NHS.# The technology
# Marketing authorisation
Adjunct to a reduced-calorie diet and increased physical activity, Naltrexone–bupropion (Mysimba) is indicated for the management of weight in adult patients (aged 18 and over) with an initial BMI of
kg/m2 or more (obese) or
from 27 kg/m2 to 30 kg/m2 (overweight) in the presence of one or more weight-related co-morbidities (such as type 2 diabetes, dyslipidaemia, or controlled hypertension).Treatment should be stopped after 16 weeks if the patient has not lost at least 5% of their initial body weight.
# Recommended dose and schedule
Administered orally in a prolonged-release tablet. Dose is escalated over a 4‑week period to a total dose of 32 mg naltrexone and 360 mg bupropion: week 1, 1 tablet in the morning; week 2, 1 tablet morning and evening; week 3, 2 tablets in the morning and 1 in the evening; from week 4, 2 tablets morning and evening.
# Price
Acquisition cost (excluding VAT) £73.00 per pack of 112 tablets (source: company's submission). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Orexigen Therapeutics and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Current management and comparators
## Weight management services are tiered but access to these services varies greatly across England
The clinical expert explained that weight management should follow current guidelines such as NICE's clinical guideline on obesity: identification, assessment and management. The prevalence of the condition is high in England with about 30% of the population defined as obese. Weight management services are tiered: tier 1 (healthy lifestyle promotions), tier 2 (lifestyle weight management programmes), tier 3 (weight management services including adjunct drug treatment) and tier 4 (bariatric surgery). The committee heard from the clinical experts that the type and quality of care and access to these services varies greatly across England. In some parts of the country, the already patchy tier 3 services are being de-commissioned, with most people not having access to multi-disciplinary weight management services. A disproportionately low number of bariatric surgeries are currently being done in the NHS. Only around 0.1% of people eligible for bariatric surgery actually have it. The patient expert stressed that limited access to services can be demoralising for patients, and there is a need for more comprehensive and equitable services across the country.
## Orlistat is not widely used and new pharmacological treatment options to manage overweight and obesity are needed
The clinical experts explained that orlistat is the only drug treatment currently available, after lifestyle measures alone have failed. Its use is limited by undesirable side-effects, leading to poor adherence and outcomes and so most people do not want to take it, or stop treatment after a short time. The patient expert also highlighted that orlistat causes unpleasant and socially unacceptable gastrointestinal side-effects. The committee heard from the clinical experts that there is therefore a high unmet clinical need for novel pharmacological approaches to treatment. Naltrexone–bupropion provides a new treatment option with a novel mechanism of action that does not have the same side-effects as orlistat and may be better tolerated. The committee concluded that orlistat is not widely used in clinical practice and that there is a need for new pharmacological treatment options to manage overweight and obesity.
## Pharmacological treatment is only effective when it is given with lifestyle interventions
The committee heard from the clinical expert that any pharmacological treatment for weight management should be part of an integrated care pathway that includes lifestyle management. All pharmacological interventions for obesity are much less effective without adjunct lifestyle measures. The expert commented that naltrexone–bupropion should first be available in tier 3 services where comprehensive lifestyle management and monitoring would be available, but it is highly likely that it would become available in primary care in the future. The committee recognised that adjunct lifestyle measures alongside pharmacological treatment are important for treatment success and the population that may have access to naltrexone–bupropion is likely to be large, given the high prevalence of obesity (see section 3.1).
## Standard management is the relevant comparator
The committee heard from the clinical experts, and from consultees after consultation on the appraisal consultation document that standard management (lifestyle measures) is the relevant comparator because orlistat is not often used in clinical practice. The committee accepted that orlistat should not be considered the only comparator for the reasons discussed in section 3.2. It concluded that standard management was therefore the main comparator in the appraisal.
# Duration of treatment
## Treatment for obesity is likely to be recurrent or ongoing
The patient expert explained that people who are overweight or obese can be caught in a cycle of weight loss and regain, which can be psychologically distressing. The clinical expert noted that when people stop treatment they do not continue to lose weight and many will regain weight. The clinical expert also noted that long-term treatment with naltrexone–bupropion is likely to be necessary for many people, to maximise the likelihood of maintaining weight loss. The committee concluded that this would likely lead to long-term or recurrent treatment with naltrexone–bupropion for many people.
# Analysis
## A full intention-to-treat analysis is more appropriate
The committee had concerns over the use of a modified intention-to-treat (ITT) analysis and noted this included people who had at least one post-baseline measurement of weight while on the study drug. This removed around 20% of people from the analysis, whereas the full ITT population included as many people as possible from the point of randomisation into the trial (including all people who dropped out, whether or not a post-baseline weight measurement was taken). The ERG explained that a modified ITT analysis could bias results in favour of naltrexone–bupropion, because drop-out before the first assessment point could have been as a result of people stopping treatment because of intolerance or adverse events related to the study drug. The committee agreed that the full ITT analysis was more appropriate for decision-making.
# Trial results
## Trials showed that naltrexone–bupropion is more effective than placebo
The committee considered the key clinical evidence presented by the company, which came from 4 contrave obesity research (COR) trials done in the US. All were double-blind randomised trials with either placebo or naltrexone–bupropion given as an adjunct to standard care (lifestyle measures):
COR‑I included people who were obese or overweight. At week 56, the modified ITT results showed a mean percentage reduction in weight with naltrexone–bupropion of 6.1% compared with 1.3% with placebo.
COR‑II included people who were obese or overweight. At week 28, the modified ITT results showed a mean percentage reduction in weight of 6.6% with naltrexone–bupropion compared with 2.1% with placebo.
COR‑BMOD included people who were obese or overweight but everyone had an intensive standard management regimen. At week 56, the modified ITT results showed a mean percentage reduction in weight of 9.7% with naltrexone–bupropion compared with 5.5% with placebo.
COR‑DM included people who were obese or overweight and who had type 2 diabetes. At week 56, the modified ITT results showed a mean percentage reduction in weight with naltrexone–bupropion of 5.1% compared with 1.8% with placebo. The committee considered that the trials were all good quality but were of short duration. The company presented the results for the modified ITT population and the committee was aware of the limitations of this analysis (see section 3.6). The committee noted that in the full ITT analysis in the clarification response, naltrexone–bupropion was also more effective than placebo in all 4 of the COR trials. It also noted that there was a smaller effect in the trial of people with type 2 diabetes (COR‑DM). The clinical expert explained that a smaller effect has been shown in obesity drug trials of patients with type 2 diabetes and the reason is not fully understood. The committee concluded that the results showed naltrexone–bupropion to be more effective than placebo in all the COR trials but that the long-term effectiveness of naltrexone–bupropion was unknown.
## Non-intensive standard management alongside pharmacological treatment is more likely in UK practice
The committee noted that the trials were done in the US but heard from the clinical expert that the characteristics of participants in the trials are similar to those likely to be seen in practice in England. The trials had more female than male participants, which reflects the population in England who are more likely to engage with the health service to lose weight. The committee considered the generalisability of adjunctive standard management regimens in the trials. The clinical expert explained that the intensive regimen in COR‑BMOD was unlikely to reflect standard practice in England, because of the variation in care in some regions (see section 3.1). The regimens in the other COR trials would be more representative of practice in England, where people have general counselling on lifestyle measures. The committee concluded that standard care in the trials, other than COR‑BMOD, is applicable to practice in England.
## People who are overweight are not well represented in the trials
The marketing authorisation for naltrexone–bupropion is for people who are overweight (BMI of 27 kg/m2 to 30 kg/m2) with a comorbidity, and for those who are obese (BMI over 30 kg/m2). The committee noted that only a small percentage of patients in the trials were overweight. It heard from the clinical expert that this is representative of the clinical population most likely to be seen by the health service in England, because people who are obese are more likely to seek help. Therefore, the committee concluded that the appraisal should focus on people who are obese because there is very limited data to inform a decision on people who are overweight.
# Company's economic model
## Using a discrete event simulation model was reasonable
The company presented a discrete event simulation (DES) model that compared naltrexone–bupropion plus standard management with orlistat plus standard management and standard management alone. Because standard management was the main comparator in the appraisal (see section 3.4), the most relevant analyses were those comparing naltrexone–bupropion plus standard management with standard management alone. The committee agreed with the ERG that a DES approach was reasonable, but was concerned that the initial model did not reflect the full treatment pathway for people with obesity. After consultation, the company incorporated a transition to bariatric surgery, which may be a subsequent treatment option for some people (see section 3.1) but it was unable to capture episodes of retreatment which the committee had concluded is a likely scenario for many people (see section 3.5). The company noted that there were limited clinical data to inform such a scenario in the model and the committee accepted this reasoning.
## The model was implemented correctly and is appropriate for decision-making
The ERG had concerns about how the initial economic model was implemented using Discrete Integrated Condition Event (DICE) methodology in Excel, which caused extremely slow run times. It was also concerned that not enough simulations were run to produce stable deterministic and probabilistic results and that the probabilistic analyses did not cover all the main input parameters. The company recognised the limitations of implementing the model in Excel and using DICE. After consultation, the company re-implemented the DES model in Visual Basic for Applications, increased the number of simulations, and extended the probabilistic analyses to explore the main input parameters. The committee heard from the ERG that the revised model ran more efficiently and that the ERG was able to reproduce similar results. The ERG believed that the company's validation of the model, comparing the old and new implementations in terms of the incremental cost-effectiveness ratio (ICER) and other outcomes, gave confidence in the results. The committee concluded it was satisfied that the model was fit for purpose and the results are appropriate for decision-making.
# Model assumptions
## The baseline characteristics reflect the population under consideration
The company's initial model used sources other than the trials to estimate some of the baseline characteristics, such as proportions of current smokers and people with type 2 diabetes. The ERG preferred the COR trials as its sources for the baseline characteristics. The committee recalled its earlier conclusion that the trial population was representative of the population seen in practice in England (see section 3.8) and therefore agreed with the ERG that the baseline characteristics in the model should reflect those in the COR trials. In response to consultation, the company incorporated the committee's preference and the committee was satisfied that the model reflected a population that would be seen in England.
## Using data from the COR-I and COR-DM trials and a full ITT analysis to inform time-to-treatment discontinuation is appropriate
The company's estimates for time-to-treatment discontinuation (TTD) were based initially on the results from the pooled COR trials and the indirect treatment comparison with orlistat, which also used the modified ITT population. The committee reiterated its views about the inappropriateness of using a modified ITT population (see section 3.6). The ERG commented that it is inappropriate to pool the data because of statistical and clinical heterogeneity between the trials. COR‑II had an earlier assessment point than the other trials (28 weeks rather than 56 weeks) and COR‑BMOD had a more intensive standard care regimen. Because such intensive standard management is unlikely to be seen in practice (section 3.8), the committee agreed with the ERG's view that COR‑BMOD should be considered separately to the other regimens and that it was inappropriate to pool data from the COR trials because of statistical and clinical heterogeneity. The committee also noted that to derive the TTD for orlistat, the estimates for naltrexone–bupropion TTD were scaled to orlistat treatment at an earlier assessment point. It heard from the ERG that scaling could lead to bias in favour of naltrexone–bupropion and it preferred to remove the scaling and use the full ITT analysis. The committee agreed with the ERG's reasoning that applying a scaling factor may lead to bias. In its response to consultation, the company accepted the committee's preference to use only the COR‑I and COR‑DM trials to inform TTD and removed the scaling factor for naltrexone–bupropion to orlistat. The company also used the full ITT analysis to estimate TTD. The committee was satisfied that the TTD estimates are appropriate for decision-making.
## It is difficult to predict and model weight regain trajectory after stopping treatment
The company's model was based on a previous one by Ara et al. (2012). The ERG explained that the company had deviated from the assumptions used in Ara et al. The company assumed that after stopping all treatment, people regained weight to a predicted BMI (that is, the BMI predicted for the person if they had not lost weight after having naltrexone–bupropion in the trial) rather than returning to their baseline weight. In their response to the appraisal consultation document, the company maintained its preference for its original approach because it follows evidence from the natural history model synthesised by Ara et al. that there is a correlation for age and BMI, and it did not want to deviate from evidence that other factors can influence BMI. The committee heard that the ERG agreed with the company in part, but because it found conflicting and implausible predictions for patients whose condition responded and those whose condition did not respond it preferred to apply the conservative option of a return to a baseline BMI. The committee heard from the ERG that a return to a baseline BMI significantly increased the ICER for naltrexone–bupropion in the company's initial model, and therefore the company's assumption could favour naltrexone–bupropion. The clinical expert explained that it is difficult to predict what an individual's future BMI would be after treatment had stopped but that, irrespective of treatment for obesity, there is a natural increase in BMI with time. The committee concluded there is uncertainty on the most appropriate BMI trajectory after treatment has stopped and it is difficult to model. It also concluded that the effect of this on the modelling results was unclear but that the company's approach was likely to favour naltrexone–bupropion.
# Cost-effectiveness results
## Naltrexone–bupropion may not be an appropriate use of NHS resources
The committee noted that the ICER for naltrexone–bupropion with standard management compared with standard management alone is £23,750 per quality-adjusted life year (QALY) gained. It also noted that the model showed a small incremental benefit for naltrexone–bupropion (a QALY gain of 0.0434). Because of the small QALY gain, the committee expected that the ICER would be very sensitive to changes in the QALY estimate. It noted the company estimated that an additional 0.009 incremental QALY benefit would reduce the ICER to below £20,000 per QALY gained, and it considered that this showed the sensitivity of the ICER to small changes in the QALYs. The committee considered that the ICER was uncertain for a number of reasons. It recalled that the model was unable to capture episodes of retreatment, which the committee had concluded is a likely scenario for many people (see section 3.5), and it was unclear how this would affect the ICER. It also recalled that there is uncertainty about how to model weight regain after treatment has stopped (see section 3.14) and that the effect of different approaches on the modelling results was unclear, but the company's approach was likely to favour naltrexone–bupropion (see section 3.14). The committee concluded that the combination of these factors means that there is considerable uncertainty about the true ICER for naltrexone–bupropion.
The committee referred to section 6.3.3 of NICE's guide to the methods of technology appraisal. This states that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of the technology as an effective use of NHS resources take into account a number of factors including the degree of certainty around the ICER. The committee concluded that there is substantial uncertainty around the ICER for the reasons outlined in section 3.15.
The committee also referred to section 6.2.14 of the guide, which states that the committee 'will want to be increasingly certain of the cost effectiveness of a technology as the impact of the adoption of the technology on NHS resources increases. Therefore, the committee may require more robust evidence on the effectiveness and cost effectiveness of technologies that are expected to have a large impact on NHS resources.' The committee recalled the high prevalence of obesity (see section 3.1) and that, as a consequence, there was potential for the impact of introducing the treatment to be large. The committee recognised the high unmet need for pharmacological treatments but, recognising the potentially large impact on NHS resources, it took a cautious approach in making its recommendations. Because of the uncertainty around the ICER, the potentially large patient population and long duration of treatment, the committee needed to be certain that naltrexone–bupropion will provide value to the NHS. Therefore, it was unable to recommend naltrexone–bupropion as a cost-effective treatment for use in the NHS.
The committee was aware that the company believed that the cost effectiveness of naltrexone–bupropion was inherently underestimated because its model captured only 3 obesity-related diseases (myocardial infarction, stroke and type 2 diabetes), whereas weight is a known risk factor for many other diseases. Also, the company's model did not include the increased risk of death after a myocardial infarction or stroke or the relationship between BMI and mortality risk beyond the first 15 years of the time horizon. The committee accepted that the effects of these on the cost-effectiveness estimates were unknown and ideally would have been included in the company's model. However, the committee was not persuaded that this would change its conclusions about the cost effectiveness of naltrexone–bupropion.
# Other considerations
## Naltrexone–bupropion is considered an innovative technology
The committee recalled that naltrexone–bupropion offers a different mechanism of action to current treatment (orlistat) and may be better tolerated than orlistat (see section 3.2). The committee accepted that naltrexone–bupropion could be considered innovative but, for the reasons discussed in sections 3.15 to 3.18, it was unable to recommend naltrexone–bupropion for use in the NHS.
# Conclusion
The committee noted that the ICER for naltrexone–bupropion with standard management compared with standard management alone was £23,750 per QALY gained. It identified a number of uncertainties around the modelling assumptions and considered that there is considerable uncertainty about the true ICER for naltrexone–bupropion. It noted that the patient population is potentially very large and treatment is long-term. Because of the uncertainty about the true ICER and the potentially high impact on NHS resources, the committee needed to be certain that naltrexone–bupropion will provide value to the NHS. Therefore it was unable to recommend naltrexone–bupropion as a cost-effective treatment for use in the NHS.
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{'Recommendations': 'Naltrexone–bupropion is not recommended within its marketing authorisation for managing overweight and obesity in adults alongside a reduced-calorie diet and increased physical activity.\n\nThis recommendation is not intended to affect treatment with naltrexone–bupropion that was started in the NHS before this guidance was published. Adults having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nObesity is very common in England, affecting about 30% of the population. Current management for overweight and obesity is lifestyle measures alone, lifestyle measures with orlistat or bariatric surgery.\n\nClinical trial evidence shows that naltrexone–bupropion with lifestyle measures is more effective than lifestyle measures alone, but its long-term effectiveness is unknown.\n\nThe estimate of cost effectiveness for naltrexone–bupropion with lifestyle measures, compared with lifestyle measures alone, is highly uncertain because of uncertainties in the modelling assumptions. Large numbers of people could be eligible for treatment which could potentially be long-term, leading to high overall costs for naltrexone–bupropion. Therefore, in these circumstances more certainty is needed that naltrexone–bupropion will provide value for the NHS.', 'The technology': "# Marketing authorisation\n\nAdjunct to a reduced-calorie diet and increased physical activity, Naltrexone–bupropion (Mysimba) is indicated for the management of weight in adult patients (aged 18 and over) with an initial BMI of\n\nkg/m2 or more (obese) or\n\nfrom 27\xa0kg/m2 to 30\xa0kg/m2 (overweight) in the presence of one or more weight-related co-morbidities (such as type\xa02 diabetes, dyslipidaemia, or controlled hypertension).Treatment should be stopped after 16\xa0weeks if the patient has not lost at least 5% of their initial body weight.\n\n# Recommended dose and schedule\n\nAdministered orally in a prolonged-release tablet. Dose is escalated over a 4‑week period to a total dose of 32\xa0mg naltrexone and 360\xa0mg bupropion: week\xa01, 1\xa0tablet in the morning; week\xa02, 1\xa0tablet morning and evening; week\xa03, 2\xa0tablets in the morning and 1\xa0in the evening; from week\xa04, 2\xa0tablets morning and evening.\n\n# Price\n\nAcquisition cost (excluding VAT) £73.00 per pack of 112\xa0tablets (source: company's submission). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Orexigen Therapeutics and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Current management and comparators\n\n## Weight management services are tiered but access to these services varies greatly across England\n\nThe clinical expert explained that weight management should follow current guidelines such as NICE's clinical guideline on obesity: identification, assessment and management. The prevalence of the condition is high in England with about 30% of the population defined as obese. Weight management services are tiered: tier\xa01 (healthy lifestyle promotions), tier\xa02 (lifestyle weight management programmes), tier\xa03 (weight management services including adjunct drug treatment) and tier\xa04 (bariatric surgery). The committee heard from the clinical experts that the type and quality of care and access to these services varies greatly across England. In some parts of the country, the already patchy tier\xa03 services are being de-commissioned, with most people not having access to multi-disciplinary weight management services. A disproportionately low number of bariatric surgeries are currently being done in the NHS. Only around 0.1% of people eligible for bariatric surgery actually have it. The patient expert stressed that limited access to services can be demoralising for patients, and there is a need for more comprehensive and equitable services across the country.\n\n## Orlistat is not widely used and new pharmacological treatment options to manage overweight and obesity are needed\n\nThe clinical experts explained that orlistat is the only drug treatment currently available, after lifestyle measures alone have failed. Its use is limited by undesirable side-effects, leading to poor adherence and outcomes and so most people do not want to take it, or stop treatment after a short time. The patient expert also highlighted that orlistat causes unpleasant and socially unacceptable gastrointestinal side-effects. The committee heard from the clinical experts that there is therefore a high unmet clinical need for novel pharmacological approaches to treatment. Naltrexone–bupropion provides a new treatment option with a novel mechanism of action that does not have the same side-effects as orlistat and may be better tolerated. The committee concluded that orlistat is not widely used in clinical practice and that there is a need for new pharmacological treatment options to manage overweight and obesity.\n\n## Pharmacological treatment is only effective when it is given with lifestyle interventions\n\nThe committee heard from the clinical expert that any pharmacological treatment for weight management should be part of an integrated care pathway that includes lifestyle management. All pharmacological interventions for obesity are much less effective without adjunct lifestyle measures. The expert commented that naltrexone–bupropion should first be available in tier\xa03 services where comprehensive lifestyle management and monitoring would be available, but it is highly likely that it would become available in primary care in the future. The committee recognised that adjunct lifestyle measures alongside pharmacological treatment are important for treatment success and the population that may have access to naltrexone–bupropion is likely to be large, given the high prevalence of obesity (see section\xa03.1).\n\n## Standard management is the relevant comparator\n\nThe committee heard from the clinical experts, and from consultees after consultation on the appraisal consultation document that standard management (lifestyle measures) is the relevant comparator because orlistat is not often used in clinical practice. The committee accepted that orlistat should not be considered the only comparator for the reasons discussed in section\xa03.2. It concluded that standard management was therefore the main comparator in the appraisal.\n\n# Duration of treatment\n\n## Treatment for obesity is likely to be recurrent or ongoing\n\nThe patient expert explained that people who are overweight or obese can be caught in a cycle of weight loss and regain, which can be psychologically distressing. The clinical expert noted that when people stop treatment they do not continue to lose weight and many will regain weight. The clinical expert also noted that long-term treatment with naltrexone–bupropion is likely to be necessary for many people, to maximise the likelihood of maintaining weight loss. The committee concluded that this would likely lead to long-term or recurrent treatment with naltrexone–bupropion for many people.\n\n# Analysis\n\n## A full intention-to-treat analysis is more appropriate\n\nThe committee had concerns over the use of a modified intention-to-treat (ITT) analysis and noted this included people who had at least one post-baseline measurement of weight while on the study drug. This removed around 20% of people from the analysis, whereas the full ITT population included as many people as possible from the point of randomisation into the trial (including all people who dropped out, whether or not a post-baseline weight measurement was taken). The ERG explained that a modified ITT analysis could bias results in favour of naltrexone–bupropion, because drop-out before the first assessment point could have been as a result of people stopping treatment because of intolerance or adverse events related to the study drug. The committee agreed that the full ITT analysis was more appropriate for decision-making.\n\n# Trial results\n\n## Trials showed that naltrexone–bupropion is more effective than placebo\n\nThe committee considered the key clinical evidence presented by the company, which came from 4\xa0contrave obesity research (COR) trials done in the US. All were double-blind randomised trials with either placebo or naltrexone–bupropion given as an adjunct to standard care (lifestyle measures):\n\nCOR‑I included people who were obese or overweight. At week\xa056, the modified ITT results showed a mean percentage reduction in weight with naltrexone–bupropion of 6.1% compared with 1.3% with placebo.\n\nCOR‑II included people who were obese or overweight. At week\xa028, the modified ITT results showed a mean percentage reduction in weight of 6.6% with naltrexone–bupropion compared with 2.1% with placebo.\n\nCOR‑BMOD included people who were obese or overweight but everyone had an intensive standard management regimen. At week\xa056, the modified ITT results showed a mean percentage reduction in weight of 9.7% with naltrexone–bupropion compared with 5.5% with placebo.\n\nCOR‑DM included people who were obese or overweight and who had type\xa02 diabetes. At week\xa056, the modified ITT results showed a mean percentage reduction in weight with naltrexone–bupropion of 5.1% compared with 1.8% with placebo. The committee considered that the trials were all good quality but were of short duration. The company presented the results for the modified ITT population and the committee was aware of the limitations of this analysis (see section\xa03.6). The committee noted that in the full ITT analysis in the clarification response, naltrexone–bupropion was also more effective than placebo in all\xa04 of the COR trials. It also noted that there was a smaller effect in the trial of people with type\xa02 diabetes (COR‑DM). The clinical expert explained that a smaller effect has been shown in obesity drug trials of patients with type\xa02 diabetes and the reason is not fully understood. The committee concluded that the results showed naltrexone–bupropion to be more effective than placebo in all the COR trials but that the long-term effectiveness of naltrexone–bupropion was unknown.\n\n## Non-intensive standard management alongside pharmacological treatment is more likely in UK practice\n\nThe committee noted that the trials were done in the US but heard from the clinical expert that the characteristics of participants in the trials are similar to those likely to be seen in practice in England. The trials had more female than male participants, which reflects the population in England who are more likely to engage with the health service to lose weight. The committee considered the generalisability of adjunctive standard management regimens in the trials. The clinical expert explained that the intensive regimen in COR‑BMOD was unlikely to reflect standard practice in England, because of the variation in care in some regions (see section\xa03.1). The regimens in the other COR trials would be more representative of practice in England, where people have general counselling on lifestyle measures. The committee concluded that standard care in the trials, other than COR‑BMOD, is applicable to practice in England.\n\n## People who are overweight are not well represented in the trials\n\nThe marketing authorisation for naltrexone–bupropion is for people who are overweight (BMI of 27\xa0kg/m2 to 30\xa0kg/m2) with a comorbidity, and for those who are obese (BMI over 30\xa0kg/m2). The committee noted that only a small percentage of patients in the trials were overweight. It heard from the clinical expert that this is representative of the clinical population most likely to be seen by the health service in England, because people who are obese are more likely to seek help. Therefore, the committee concluded that the appraisal should focus on people who are obese because there is very limited data to inform a decision on people who are overweight.\n\n# Company's economic model\n\n## Using a discrete event simulation model was reasonable\n\nThe company presented a discrete event simulation (DES) model that compared naltrexone–bupropion plus standard management with orlistat plus standard management and standard management alone. Because standard management was the main comparator in the appraisal (see section\xa03.4), the most relevant analyses were those comparing naltrexone–bupropion plus standard management with standard management alone. The committee agreed with the ERG that a DES approach was reasonable, but was concerned that the initial model did not reflect the full treatment pathway for people with obesity. After consultation, the company incorporated a transition to bariatric surgery, which may be a subsequent treatment option for some people (see section\xa03.1) but it was unable to capture episodes of retreatment which the committee had concluded is a likely scenario for many people (see section\xa03.5). The company noted that there were limited clinical data to inform such a scenario in the model and the committee accepted this reasoning.\n\n## The model was implemented correctly and is appropriate for decision-making\n\nThe ERG had concerns about how the initial economic model was implemented using Discrete Integrated Condition Event (DICE) methodology in Excel, which caused extremely slow run times. It was also concerned that not enough simulations were run to produce stable deterministic and probabilistic results and that the probabilistic analyses did not cover all the main input parameters. The company recognised the limitations of implementing the model in Excel and using DICE. After consultation, the company re-implemented the DES model in Visual Basic for Applications, increased the number of simulations, and extended the probabilistic analyses to explore the main input parameters. The committee heard from the ERG that the revised model ran more efficiently and that the ERG was able to reproduce similar results. The ERG believed that the company's validation of the model, comparing the old and new implementations in terms of the incremental cost-effectiveness ratio (ICER) and other outcomes, gave confidence in the results. The committee concluded it was satisfied that the model was fit for purpose and the results are appropriate for decision-making.\n\n# Model assumptions\n\n## The baseline characteristics reflect the population under consideration\n\nThe company's initial model used sources other than the trials to estimate some of the baseline characteristics, such as proportions of current smokers and people with type\xa02 diabetes. The ERG preferred the COR trials as its sources for the baseline characteristics. The committee recalled its earlier conclusion that the trial population was representative of the population seen in practice in England (see section\xa03.8) and therefore agreed with the ERG that the baseline characteristics in the model should reflect those in the COR trials. In response to consultation, the company incorporated the committee's preference and the committee was satisfied that the model reflected a population that would be seen in England.\n\n## Using data from the COR-I and COR-DM trials and a full ITT analysis to inform time-to-treatment discontinuation is appropriate\n\nThe company's estimates for time-to-treatment discontinuation (TTD) were based initially on the results from the pooled COR trials and the indirect treatment comparison with orlistat, which also used the modified ITT population. The committee reiterated its views about the inappropriateness of using a modified ITT population (see section\xa03.6). The ERG commented that it is inappropriate to pool the data because of statistical and clinical heterogeneity between the trials. COR‑II had an earlier assessment point than the other trials (28\xa0weeks rather than 56\xa0weeks) and COR‑BMOD had a more intensive standard care regimen. Because such intensive standard management is unlikely to be seen in practice (section\xa03.8), the committee agreed with the ERG's view that COR‑BMOD should be considered separately to the other regimens and that it was inappropriate to pool data from the COR trials because of statistical and clinical heterogeneity. The committee also noted that to derive the TTD for orlistat, the estimates for naltrexone–bupropion TTD were scaled to orlistat treatment at an earlier assessment point. It heard from the ERG that scaling could lead to bias in favour of naltrexone–bupropion and it preferred to remove the scaling and use the full ITT analysis. The committee agreed with the ERG's reasoning that applying a scaling factor may lead to bias. In its response to consultation, the company accepted the committee's preference to use only the COR‑I and COR‑DM trials to inform TTD and removed the scaling factor for naltrexone–bupropion to orlistat. The company also used the full ITT analysis to estimate TTD. The committee was satisfied that the TTD estimates are appropriate for decision-making.\n\n## It is difficult to predict and model weight regain trajectory after stopping treatment\n\nThe company's model was based on a previous one by Ara et al. (2012). The ERG explained that the company had deviated from the assumptions used in Ara et al. The company assumed that after stopping all treatment, people regained weight to a predicted BMI (that is, the BMI predicted for the person if they had not lost weight after having naltrexone–bupropion in the trial) rather than returning to their baseline weight. In their response to the appraisal consultation document, the company maintained its preference for its original approach because it follows evidence from the natural history model synthesised by Ara et al. that there is a correlation for age and BMI, and it did not want to deviate from evidence that other factors can influence BMI. The committee heard that the ERG agreed with the company in part, but because it found conflicting and implausible predictions for patients whose condition responded and those whose condition did not respond it preferred to apply the conservative option of a return to a baseline BMI. The committee heard from the ERG that a return to a baseline BMI significantly increased the ICER for naltrexone–bupropion in the company's initial model, and therefore the company's assumption could favour naltrexone–bupropion. The clinical expert explained that it is difficult to predict what an individual's future BMI would be after treatment had stopped but that, irrespective of treatment for obesity, there is a natural increase in BMI with time. The committee concluded there is uncertainty on the most appropriate BMI trajectory after treatment has stopped and it is difficult to model. It also concluded that the effect of this on the modelling results was unclear but that the company's approach was likely to favour naltrexone–bupropion.\n\n# Cost-effectiveness results\n\n## Naltrexone–bupropion may not be an appropriate use of NHS resources\n\nThe committee noted that the ICER for naltrexone–bupropion with standard management compared with standard management alone is £23,750 per quality-adjusted life year (QALY) gained. It also noted that the model showed a small incremental benefit for naltrexone–bupropion (a QALY gain of 0.0434). Because of the small QALY gain, the committee expected that the ICER would be very sensitive to changes in the QALY estimate. It noted the company estimated that an additional 0.009 incremental QALY benefit would reduce the ICER to below £20,000 per QALY gained, and it considered that this showed the sensitivity of the ICER to small changes in the QALYs. The committee considered that the ICER was uncertain for a number of reasons. It recalled that the model was unable to capture episodes of retreatment, which the committee had concluded is a likely scenario for many people (see section\xa03.5), and it was unclear how this would affect the ICER. It also recalled that there is uncertainty about how to model weight regain after treatment has stopped (see section\xa03.14) and that the effect of different approaches on the modelling results was unclear, but the company's approach was likely to favour naltrexone–bupropion (see section 3.14). The committee concluded that the combination of these factors means that there is considerable uncertainty about the true ICER for naltrexone–bupropion.\n\nThe committee referred to section 6.3.3 of NICE's guide to the methods of technology appraisal. This states that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of the technology as an effective use of NHS resources take into account a number of factors including the degree of certainty around the ICER. The committee concluded that there is substantial uncertainty around the ICER for the reasons outlined in section\xa03.15.\n\nThe committee also referred to section 6.2.14 of the guide, which states that the committee 'will want to be increasingly certain of the cost effectiveness of a technology as the impact of the adoption of the technology on NHS resources increases. Therefore, the committee may require more robust evidence on the effectiveness and cost effectiveness of technologies that are expected to have a large impact on NHS resources.' The committee recalled the high prevalence of obesity (see section\xa03.1) and that, as a consequence, there was potential for the impact of introducing the treatment to be large. The committee recognised the high unmet need for pharmacological treatments but, recognising the potentially large impact on NHS resources, it took a cautious approach in making its recommendations. Because of the uncertainty around the ICER, the potentially large patient population and long duration of treatment, the committee needed to be certain that naltrexone–bupropion will provide value to the NHS. Therefore, it was unable to recommend naltrexone–bupropion as a cost-effective treatment for use in the NHS.\n\nThe committee was aware that the company believed that the cost effectiveness of naltrexone–bupropion was inherently underestimated because its model captured only 3\xa0obesity-related diseases (myocardial infarction, stroke and type\xa02 diabetes), whereas weight is a known risk factor for many other diseases. Also, the company's model did not include the increased risk of death after a myocardial infarction or stroke or the relationship between BMI and mortality risk beyond the first 15\xa0years of the time horizon. The committee accepted that the effects of these on the cost-effectiveness estimates were unknown and ideally would have been included in the company's model. However, the committee was not persuaded that this would change its conclusions about the cost effectiveness of naltrexone–bupropion.\n\n# Other considerations\n\n## Naltrexone–bupropion is considered an innovative technology\n\nThe committee recalled that naltrexone–bupropion offers a different mechanism of action to current treatment (orlistat) and may be better tolerated than orlistat (see section\xa03.2). The committee accepted that naltrexone–bupropion could be considered innovative but, for the reasons discussed in sections\xa03.15 to 3.18, it was unable to recommend naltrexone–bupropion for use in the NHS.\n\n# Conclusion\n\nThe committee noted that the ICER for naltrexone–bupropion with standard management compared with standard management alone was £23,750 per QALY gained. It identified a number of uncertainties around the modelling assumptions and considered that there is considerable uncertainty about the true ICER for naltrexone–bupropion. It noted that the patient population is potentially very large and treatment is long-term. Because of the uncertainty about the true ICER and the potentially high impact on NHS resources, the committee needed to be certain that naltrexone–bupropion will provide value to the NHS. Therefore it was unable to recommend naltrexone–bupropion as a cost-effective treatment for use in the NHS."}
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https://www.nice.org.uk/guidance/ta494
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Evidence-based recommendations on naltrexone–bupropion (Mysimba) for managing overweight and obesity in adults.
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b9a2b3a6fa2ec4de2d5f3a408ec6526751b0b3b1
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nice
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Processed nerve allografts to repair peripheral nerve discontinuities
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Processed nerve allografts to repair peripheral nerve discontinuities
Evidence-based recommendations on processed nerve allografts to repair peripheral nerve discontinuities. This involves using a specially treated nerve (an allograft) taken from a human donor after death to bridge the gap in the nerve.
# Recommendations
Current evidence on the safety and efficacy of processed nerve allografts to repair peripheral nerve discontinuities is adequate to support the use of this procedure for digital nerves provided that standard arrangements are in place for clinical governance, consent and audit.
The evidence on the safety of processed nerve allografts to repair peripheral nerve discontinuities in other sites raises no major safety concerns. However, current evidence on its efficacy in these sites is limited in quantity. Therefore, for indications other than digital nerve repair, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to do processed nerve allografts to repair peripheral nerve discontinuities in sites other than the digital nerves should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy on mixed nerve repair and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having processed nerve allografts to repair peripheral nerve discontinuities (see section 7.1).
This procedure should only be done by surgeons with training and experience in peripheral nerve repair.
Patient selection should take into consideration the site, type of nerve (motor, sensory, mixed) and the size of the defect.
NICE encourages further research into processed nerve allografts to repair peripheral nerve discontinuities. This should include information on the type of nerve repaired, the anatomical site, the size of the defect, patient reported outcome measures, functional outcomes, time to recovery and long-term outcomes (12 months to 18 months).# Indications and current treatments
Peripheral nerve damage can be caused by trauma or surgery, and can lead to reduced sensation and mobility of the affected limb or region. If direct repair is not possible because the section of nerve discontinuity is too long, grafts or artificial nerve conduits can be used.
Autologous nerve grafting (using another nerve from the same patient) is used most frequently (usually using the sural nerve from the leg). However, this can be associated with donor site morbidity. Untreated allografts (using a nerve from a donor) have also been used. However, postoperative immunosuppressive treatment is needed with untreated allografts.# The procedure
Acellular processed nerve allografts are nerves from deceased human donors that have had their immunogenic components removed using tissue processing techniques. They are stored frozen until implantation and are available in different sizes. Immunosuppressive treatment is not needed.
The procedure is done under general anaesthesia. The injured nerve is exposed, and the nerve ends are cleared of necrotic tissues and resected to allow for tension-free alignment with the graft. The graft is sutured to the exposed nerve ends. After grafting, limb splinting may be needed for several weeks to allow optimal nerve regeneration. The typical length of an allograft implant is 1 cm to 3 cm.
The aim of the procedure is to bridge the peripheral nerve discontinuity to allow axonal regeneration and growth through the allograft towards the distal nerve.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a randomised controlled trial (RCT) of 23 patients needing digital nerve repair comparing processed nerve allograft (PNA) with treated bovine graft at 12‑month follow-up, static 2‑point discrimination assessment (s2PD, which tests the ability to discern the difference between 1 and 2 static pressure points) was statistically significantly better in the PNA group (n=5) than the bovine graft group (n=7; 5±1 mm versus 8±5 mm, p0.05) at 12‑month follow-up. In a non-randomised comparative study of 153 patients needing digital nerve repair comparing PNA repair (n=72) with tension-free suture nerve repair (n=81), s2PD scores (excellent plus good, defined as the ability to distinguish between 2 static pressure points at a maximum distance of 15 mm) were not statistically significantly different between the PNA group (67% ) and the tension-free suture group (64% ) at 6‑month follow-up (p=0.749). In a case series of 17 patients with digital nerve injuries treated by PNA grafting, s2PD was excellent or good in 78% (14/18) of digits repaired, at a mean follow-up of 15 months. In the RCT of 23 patients, Semmes–Weinstein monofilament test (testing of pressure threshold using a monofilament; range: 2.833=normal sensation to 6.650=residual sensation) was statistically significantly better in the PNA group than the treated bovine graft group (3.6±0.7 versus 4.4±1.4, p<0.05) at 12‑month follow-up. In the same study, thermal sensation was totally improved from baseline at 12‑month follow-up and not statistically significantly different between the treatment (PNA group: from 7% to 100% and bovine graft group: from 33% to 100% ).
In a case series of 64 patients needing nerve repair in the upper extremity and treated by grafting using PNA, there was meaningful recovery in 75% (48/64) of all patients. Univariate analysis showed that distal sites of injuries have a statistically significantly higher likelihood of recovery than proximal upper limb sites (odds ratio 5.606, 95% confidence interval 1.663 to 18.903; p<0.05). In the same study, discontinuities smaller than 30 mm had a statistically significantly greater likelihood of meaningful repair than those greater than 50 mm (OR 14.333, 95% CI 2.143 to 95.848; p<0.05). In a case series of 26 patients with lingual nerve and inferior alveolar nerve discontinuities treated by PNA grafting, meaningful sensory recovery was assessed using a neurosensory test improvement tool (ranging from normal=best, through mild, moderate and severe to complete=worse). At 12‑month follow-up, neurosensory test improvement scores were normal in 52% (12/23), mild in 9% (2/23), moderate in 26% (6/23) and severe in 13% (3/23) of patients. In the same study, neurosensory improvement was reported in 86% (12/14) of patients with discontinuities 8 mm to 20 mm in length and 89% (8/9) of patients with discontinuities 30 mm to 70 mm in length.
In the RCT of 23 patients, disability of the arm, shoulder and hand score (DASH: 0=no disability, 100=most severe disability) was not statistically significantly different between the PNA group (5±6.5) and the bovine graft group (8±6.3) at 12‑month follow-up (p=0.318).
In a case series of 108 patients needing nerve repair, there was no sensory recovery because of graft failure in 5% (4/76) of patients at last follow-up and surgical revision was needed.
In the RCT of 23 patients, at 12‑month follow-up, pain measured using a visual analogue scale (VAS, 0=no pain, 10=extreme pain) had improved from baseline in both groups (PNA group: from 4.7±3.4 to 0.5±0.6; treated bovine graft: from 4.4±2.1 to 0.9±1.0) but there was no statistically significant difference between the groups (p=0.432). In another case series of 26 patients needing PNA after resection of neuromas of the foot and ankle, mean ordinal pain score (0=no pain to 10=worse pain) statistically significantly reduced from 7.5 points at baseline to 4.9 points at a mean 66‑week follow-up (difference 2.6, range +2.0 to -8.0; p=0.016). In the same study, patient reported outcome measurement information system scores were used to assess the impact of pain on patients' behaviour and daily function (reported as T‑scores with a population mean of 50 and a standard deviation of 10). Pain behaviour T‑score decreased by 7.3 (range+2.0 to -22.0) from 63.0 at baseline (percentile decrease of 24%, p<0.003). Pain interference T‑score decreased by 11.3 (range +2.0 to -27.0) from 68.0 at baseline (mean percentile change of 31%, p<0.003). In a case series of 17 patients with digital nerve injury treated by grafting with PNA, pain (measured using a VAS: 0=no pain, 10=extreme pain) worsened in 1 patient (VAS score increased from 5 at baseline to 8 at 15‑month follow).
In the non-randomised comparative study of 153 patients, difference in satisfaction rate was not statistically significantly different between the PNA group and the tension-free suture group (2.02%, 95% CI -6.07 to 10.87) at 6‑month follow-up.
The specialist advisers listed key efficacy outcomes as re-innervation of target organs, nerve regeneration rate, clinical sensory and motor outcome scales, and patient reported outcomes.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Tenolysis was needed in 3% (2/78) of patients at 6‑month follow-up in a non-randomised comparative study of 153 patients needing digital nerve repair comparing processed nerve allograft (PNA) repair (n=72) with tension-free suture nerve repair (n=81).
Neuroma was reported after 1 nerve repair of 132 nerves in a case series of 108 patients needing nerve repair.
Local infection that improved after treatment (not specified) was reported in 1 patient in a case series of 15 patients treated by PNA grafting.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: immunological reaction or rejection, and inflammatory reaction to preservatives. They considered that the following were theoretical adverse events: immunological reaction or rejection, inflammatory reaction to preservatives and sub-optimal results because of preference in using the allograft when patients could be treated by more established interventions.# Further information
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
Patient commentary was not sought because the procedure is only being done in research setting in the UK.
For related NICE guidance, see the NICE website.
# Information for patients
NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2731-9
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{'Recommendations': "Current evidence on the safety and efficacy of processed nerve allografts to repair peripheral nerve discontinuities is adequate to support the use of this procedure for digital nerves provided that standard arrangements are in place for clinical governance, consent and audit.\n\nThe evidence on the safety of processed nerve allografts to repair peripheral nerve discontinuities in other sites raises no major safety concerns. However, current evidence on its efficacy in these sites is limited in quantity. Therefore, for indications other than digital nerve repair, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do processed nerve allografts to repair peripheral nerve discontinuities in sites other than the digital nerves should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy on mixed nerve repair and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having processed nerve allografts to repair peripheral nerve discontinuities (see section\xa07.1).\n\nThis procedure should only be done by surgeons with training and experience in peripheral nerve repair.\n\nPatient selection should take into consideration the site, type of nerve (motor, sensory, mixed) and the size of the defect.\n\nNICE encourages further research into processed nerve allografts to repair peripheral nerve discontinuities. This should include information on the type of nerve repaired, the anatomical site, the size of the defect, patient reported outcome measures, functional outcomes, time to recovery and long-term outcomes (12\xa0months to 18\xa0months).", 'Indications and current treatments': 'Peripheral nerve damage can be caused by trauma or surgery, and can lead to reduced sensation and mobility of the affected limb or region. If direct repair is not possible because the section of nerve discontinuity is too long, grafts or artificial nerve conduits can be used.\n\nAutologous nerve grafting (using another nerve from the same patient) is used most frequently (usually using the sural nerve from the leg). However, this can be associated with donor site morbidity. Untreated allografts (using a nerve from a donor) have also been used. However, postoperative immunosuppressive treatment is needed with untreated allografts.', 'The procedure': 'Acellular processed nerve allografts are nerves from deceased human donors that have had their immunogenic components removed using tissue processing techniques. They are stored frozen until implantation and are available in different sizes. Immunosuppressive treatment is not needed.\n\nThe procedure is done under general anaesthesia. The injured nerve is exposed, and the nerve ends are cleared of necrotic tissues and resected to allow for tension-free alignment with the graft. The graft is sutured to the exposed nerve ends. After grafting, limb splinting may be needed for several weeks to allow optimal nerve regeneration. The typical length of an allograft implant is 1\xa0cm to 3\xa0cm.\n\nThe aim of the procedure is to bridge the peripheral nerve discontinuity to allow axonal regeneration and growth through the allograft towards the distal nerve.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 23\xa0patients needing digital nerve repair comparing processed nerve allograft (PNA) with treated bovine graft at 12‑month follow-up, static 2‑point discrimination assessment (s2PD, which tests the ability to discern the difference between 1\xa0and 2\xa0static pressure points) was statistically significantly better in the PNA group (n=5) than the bovine graft group (n=7; 5±1\xa0mm versus 8±5\xa0mm, p<0.05). In the same study, moving 2‑point discrimination assessment (m2PD) was not statistically significantly different between the PNA group and the bovine graft group (5±1\xa0mm versus 7±5\xa0mm, p>0.05) at 12‑month follow-up. In a non-randomised comparative study of 153\xa0patients needing digital nerve repair comparing PNA repair (n=72) with tension-free suture nerve repair (n=81), s2PD scores (excellent plus good, defined as the ability to distinguish between 2\xa0static pressure points at a maximum distance of 15\xa0mm) were not statistically significantly different between the PNA group (67% [48/72]) and the tension-free suture group (64% [52/81]) at 6‑month follow-up (p=0.749). In a case series of 17\xa0patients with digital nerve injuries treated by PNA grafting, s2PD was excellent or good in 78% (14/18) of digits repaired, at a mean follow-up of 15\xa0months. In the RCT of 23\xa0patients, Semmes–Weinstein monofilament test (testing of pressure threshold using a monofilament; range: 2.833=normal sensation to 6.650=residual sensation) was statistically significantly better in the PNA group than the treated bovine graft group (3.6±0.7 versus 4.4±1.4, p<0.05) at 12‑month follow-up. In the same study, thermal sensation was totally improved from baseline at 12‑month follow-up and not statistically significantly different between the treatment (PNA group: from 7% [1/14] to 100% [6/6] and bovine graft group: from 33% [3/9] to 100% [7/7]).\n\nIn a case series of 64\xa0patients needing nerve repair in the upper extremity and treated by grafting using PNA, there was meaningful recovery in 75% (48/64) of all patients. Univariate analysis showed that distal sites of injuries have a statistically significantly higher likelihood of recovery than proximal upper limb sites (odds ratio [OR] 5.606, 95% confidence interval [CI] 1.663 to 18.903; p<0.05). In the same study, discontinuities smaller than 30\xa0mm had a statistically significantly greater likelihood of meaningful repair than those greater than 50\xa0mm (OR 14.333, 95%\xa0CI 2.143 to 95.848; p<0.05). In a case series of 26\xa0patients with lingual nerve and inferior alveolar nerve discontinuities treated by PNA grafting, meaningful sensory recovery was assessed using a neurosensory test improvement tool (ranging from normal=best, through mild, moderate and severe to complete=worse). At 12‑month follow-up, neurosensory test improvement scores were normal in 52% (12/23), mild in 9% (2/23), moderate in 26% (6/23) and severe in 13% (3/23) of patients. In the same study, neurosensory improvement was reported in 86% (12/14) of patients with discontinuities 8\xa0mm to 20\xa0mm in length and 89% (8/9) of patients with discontinuities 30\xa0mm to 70\xa0mm in length.\n\nIn the RCT of 23\xa0patients, disability of the arm, shoulder and hand score (DASH: 0=no disability, 100=most severe disability) was not statistically significantly different between the PNA group (5±6.5) and the bovine graft group (8±6.3) at 12‑month follow-up (p=0.318).\n\nIn a case series of 108\xa0patients needing nerve repair, there was no sensory recovery because of graft failure in 5% (4/76) of patients at last follow-up and surgical revision was needed.\n\nIn the RCT of 23\xa0patients, at 12‑month follow-up, pain measured using a visual analogue scale (VAS, 0=no pain, 10=extreme pain) had improved from baseline in both groups (PNA group: from 4.7±3.4 to 0.5±0.6; treated bovine graft: from 4.4±2.1 to 0.9±1.0) but there was no statistically significant difference between the groups (p=0.432). In another case series of 26\xa0patients needing PNA after resection of neuromas of the foot and ankle, mean ordinal pain score (0=no pain to 10=worse pain) statistically significantly reduced from 7.5\xa0points at baseline to 4.9\xa0points at a mean 66‑week follow-up (difference\xa02.6, range +2.0 to -8.0; p=0.016). In the same study, patient reported outcome measurement information system scores were used to assess the impact of pain on patients' behaviour and daily function (reported as T‑scores with a population mean of\xa050 and a standard deviation of\xa010). Pain behaviour T‑score decreased by\xa07.3 (range+2.0 to -22.0) from 63.0\xa0at baseline (percentile decrease of 24%, p<0.003). Pain interference T‑score decreased by\xa011.3 (range +2.0 to -27.0) from 68.0\xa0at baseline (mean percentile change of 31%, p<0.003). In a case series of 17\xa0patients with digital nerve injury treated by grafting with PNA, pain (measured using a VAS: 0=no pain, 10=extreme pain) worsened in 1\xa0patient (VAS score increased from 5\xa0at baseline to 8\xa0at 15‑month follow).\n\nIn the non-randomised comparative study of 153\xa0patients, difference in satisfaction rate was not statistically significantly different between the PNA group and the tension-free suture group (2.02%, 95% CI -6.07 to 10.87) at 6‑month follow-up.\n\nThe specialist advisers listed key efficacy outcomes as re-innervation of target organs, nerve regeneration rate, clinical sensory and motor outcome scales, and patient reported outcomes.", 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nTenolysis was needed in 3% (2/78) of patients at 6‑month follow-up in a non-randomised comparative study of 153\xa0patients needing digital nerve repair comparing processed nerve allograft (PNA) repair (n=72) with tension-free suture nerve repair (n=81).\n\nNeuroma was reported after 1\xa0nerve repair of 132\xa0nerves in a case series of 108\xa0patients needing nerve repair.\n\nLocal infection that improved after treatment (not specified) was reported in 1\xa0patient in a case series of 15\xa0patients treated by PNA grafting.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: immunological reaction or rejection, and inflammatory reaction to preservatives. They considered that the following were theoretical adverse events: immunological reaction or rejection, inflammatory reaction to preservatives and sub-optimal results because of preference in using the allograft when patients could be treated by more established interventions.', 'Further information': "This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\nPatient commentary was not sought because the procedure is only being done in research setting in the UK.\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2731-9"}
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https://www.nice.org.uk/guidance/ipg597
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Evidence-based recommendations on processed nerve allografts to repair peripheral nerve discontinuities. This involves using a specially treated nerve (an allograft) taken from a human donor after death to bridge the gap in the nerve.
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671220c0646874599c577a736aa8f2c22bda4744
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nice
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Hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea
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Hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea
Evidence-based recommendations on hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea in adults. This involves implanting a device under the skin in the chest and connecting it to a nerve under the tongue (hypoglossal nerve).
# Recommendations
Current evidence on the safety and efficacy of hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to do hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea using NICE's interventional procedure outcomes audit tool.
Patient selection and the procedure should be done by clinicians with special expertise in the management of obstructive sleep apnoea.
Further research including the use of observational data from registries should provide information on patient selection, safety outcomes, quality of life, long-term outcomes and the position of the procedure in the treatment pathway. NICE may update the guidance on publication of further evidence.# Indications and current treatments
Obstructive sleep apnoea (OSA) is characterised by repeated episodes of apnoea and hypopnoea during sleep, loud snoring and excessive daytime sleepiness. The main cause is collapse of the upper airway during sleep. OSA has a big impact on quality of life and increases the risk of having a stroke and developing conditions such as hypertension and atrial fibrillation.
OSA may be improved by lifestyle changes such as weight loss, avoiding alcohol or sedative medication, and change of sleeping position. The most common treatment for severe OSA is continuous positive airway pressure, applied through a face mask during sleep. Surgical interventions include tonsillectomy, adenoidectomy, uvulopalatopharyngoplasty and, rarely, tracheostomy and bariatric surgery.# The procedure
Hypoglossal nerve stimulation aims to treat obstructive sleep apnoea by preventing the tongue prolapsing backwards and causing upper airway obstruction during sleep. It works by delivering an electrical current to the hypoglossal nerve. This contracts the genioglossus muscle, the major muscle responsible for tongue protrusion, and all other intrinsic muscles of the tongue. Using general anaesthesia, a neurostimulator is implanted in an infraclavicular subcutaneous pocket and a stimulating lead is placed on the main trunk of the hypoglossal nerve. The neurostimulator delivers electrical pulses to the hypoglossal nerve. With some devices, stimulation can be synchronised with respiration using sensing leads that measure changes in breathing. The respiratory-sensing leads are positioned between the external and internal intercostal muscle. The stimulator is programmed and controlled wirelessly to adapt to specific patient needs.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.
In a systematic review and meta-analysis of 200 patients, there was a statistically significant decrease in the apnoea–hypopnoea index (AHI; a normal AHI is less than 5 events per hour). At 3-, 6-, and 12‑month follow-up the mean differences from baseline were -23.94 (95% confidence interval -31.45 to -16.43, 34 patients), -25.60 (95% CI -31.18 to -20.01, 60 patients) and -17.51 (95% CI -20.69 to -14.34, 170 patients) respectively (p<0.001 for all time points).
In a randomised controlled therapy-withdrawal trial of 46 'responders' from a prospective case series of 126 patients (23 therapy-maintenance responders compared with 23 therapy-withdrawal responders), there was a statistically significant increase in the mean AHI from 7.6 at 1‑year follow-up (before randomisation into the trial) to 25.8 at 1 week after randomisation, in the group in which the device was turned off for 1 week (p<0.001). There was no statistical difference in mean AHI within the therapy-maintenance group, who continued to use the device (7.2 compared with 8.9). At 18‑month follow-up, the mean AHI scores were 9.6 in the therapy-maintenance group and 10.7 in the group who had the device turned off for 1 week (p<0.05 for the differences compared with baseline within groups). There was a statistically significant difference between the therapy-withdrawal group and the therapy-maintenance group for change in mean AHI, from assessment at 1 year to assessment at the end of the therapy-withdrawal study (p<0.001).
In the systematic review and meta-analysis of 200 patients, there was a statistically significant decrease in the oxygen desaturation index (defined as the number of times per hour of sleep that the blood oxygen level drops by 4 or more percentage points from baseline). At 3-, 6-, and 12‑month follow-up the mean differences from baseline were -10.04 (CI -16.31 to -3.78, 34 patients), -11.68 (95% CI -17.16 to -6.19, 60 patients) and -13.73 (95% CI -16.87 to -10.58, 170 patients) respectively (p<0.01 at 3 months and p<0.001 at 6 and 12 months).
In the systematic review and meta-analysis of 200 patients, there was a statistically significant decrease in the Epworth sleepiness scale (scores range from 0 to 24 with higher scores indicating more daytime sleepiness). At 3-, 6-, and 12‑month follow-up the mean differences from baseline were -4.17 (CI -6.45 to -1.90, 34 patients), -3.82 (95% CI -5.37 to -2.27, 60 patients) and -4.42 (95% CI -5.39 to -3.44, 170 patients) respectively (p<0.001 for all time points).
In a follow-up study of 95 patients from the prospective case series of 126 patients, there was a statistically significant increase in the mean functional outcomes of sleep questionnaire score (FOSQ, ranging from 5 to 20 with higher scores indicating better subjective sleep quality) from 14.6±3.0 at baseline to 17.5±2.9 at 4‑year follow-up (p<0.05).
In the follow-up study of 95 patients from the prospective case series of 126 patients, the rates of bed-partner reported 'no snoring' or 'soft snoring' were 17% (18/108) at baseline and 85% at 4‑year follow-up.
In a prospective case series of 46 patients, there was a statistically significant improvement in the mean sleep apnoea quality of life index from 4.3±1.0 at baseline to 4.7±1.2 at 6‑month follow-up (p=0.019).
The specialist advisers listed the key efficacy outcomes as: reduction in severity of obstructive sleep apnoea, improved sleep and reduced daytime sleepiness.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.
Transient ipsilateral hemi-tongue paresis was reported in 15% (2/13) of patients in a prospective case series of 13 patients from a systematic review and meta-analysis of 200 patients.
Tongue abrasion was reported in 26% (33/126) of patients in a follow-up study of 95 patients from a prospective case series of 126 patients within 4 years of the procedure.
Bleeding was reported in 1 patient within 30 days of implantation in a prospective case series of 46 patients. This was caused by a hypertensive crisis and surgical intervention was needed; hypertension was treated with medication. In the same study, haematoma was reported in 7% (3/46) of patients. One of the 2 cases classified as non-serious occurred within 30 days of implantation and the other occurred more than 30 days after implantation. The third case was classified as a serious event and occurred within 30 days of implantation.
Rupture of a vein was reported in 6% (2/31) of patients during cervical tunnelling in a prospective case series of 31 patients; 1 of the patients needed 1 further cervical incision.
Seroma at an incision site was reported in 10% (2/20) of patients after the procedure in a retrospective case series of 20 patients. One seroma occurred at the sensing‑lead incision 1 week after surgery and the other occurred at the implantable pulse‑generator incision 4 weeks after surgery. Both resolved uneventfully with percutaneous needle drainage.
Headache was reported in 6% (8/126) of patients in the prospective case series of 126 patients within 1 year of the procedure.
Infection was reported in 1 patient in a prospective case series of 22 patients from the systematic review and meta-analysis of 200 patients; the device was removed.
Dry mouth was reported in 13% (16/126) of patients in the prospective case series of 126 patients within 3 years of the procedure.
Discomfort due to electrical stimulation was reported in 58% (73/126) of patients in the prospective case series of 126 patients within 4 years of the procedure. In the same study, discomfort related to incisions was reported in 29% (37/126) of patients and discomfort not related to incisions was reported in 27% (34/126) of patients within 4 years of the procedure.
Paraesthesia was reported in 13% (6/46) of patients (within 30 days of implantation in 5 patients, and more than 30 days after implantation in 1 patient) in the prospective case series of 46 patients.
Device migration more than 30 days after implantation was reported in 1 patient in the prospective case series of 46 patients. Cuff dislodgement was reported in 2 patients in a prospective case series of 31 patients, and in 1 patient in a prospective case series of 21 patients, from the systematic review and meta-analysis of 200 patients; all 3 patients needed a new procedure to replace it.
Device removal was reported in 4 patients in the prospective case series of 31 patients, and in 2 patients in the prospective case series of 21 patients, from the systematic review and meta-analysis of 200 patients. Device removal was also reported in 3 patients, 1 to 4 years after the procedure, in the prospective case series of 126 patients. The reasons for removal were insomnia, septic sternoclavicular joint adjacent to the device and non-response to therapy. Device removal for cosmetic reasons was reported in 1 patient in a case series of 60 patients.
Leads breaking was reported in 15% (2/13) of patients in the prospective case series of 13 patients from the systematic review and meta-analysis of 200 patients.
Defective implanted pulse‑generator connector was reported in 1 patient in the prospective case series of 13 patients from the systematic review and meta-analysis of 200 patients.
Other complications reported in the systematic review and meta-analysis of 200 patients included postoperative pain and stiffness, sore throat, stitch abscess, local swelling, fever and lack of tongue response to stimulation.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, the specialist advisers did not list any anecdotal adverse events. They considered that the following were theoretical adverse events: fatigue of the upper airway dilator muscles leading to worsening sleep apnoea, and hypoglossal nerve damage.# Further information
For related NICE guidance, see the NICE website.
No patient commentary was sought because the procedure is not currently done in the UK. The Sleep Apnoea Trust Association provided feedback on this procedure.
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).
# Information for patients
NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2733-3
|
{'Recommendations': "Current evidence on the safety and efficacy of hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information to support shared decision-making. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea using NICE's interventional procedure outcomes audit tool.\n\nPatient selection and the procedure should be done by clinicians with special expertise in the management of obstructive sleep apnoea.\n\nFurther research including the use of observational data from registries should provide information on patient selection, safety outcomes, quality of life, long-term outcomes and the position of the procedure in the treatment pathway. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Obstructive sleep apnoea (OSA) is characterised by repeated episodes of apnoea and hypopnoea during sleep, loud snoring and excessive daytime sleepiness. The main cause is collapse of the upper airway during sleep. OSA has a big impact on quality of life and increases the risk of having a stroke and developing conditions such as hypertension and atrial fibrillation.\n\nOSA may be improved by lifestyle changes such as weight loss, avoiding alcohol or sedative medication, and change of sleeping position. The most common treatment for severe OSA is continuous positive airway pressure, applied through a face mask during sleep. Surgical interventions include tonsillectomy, adenoidectomy, uvulopalatopharyngoplasty and, rarely, tracheostomy and bariatric surgery.', 'The procedure': 'Hypoglossal nerve stimulation aims to treat obstructive sleep apnoea by preventing the tongue prolapsing backwards and causing upper airway obstruction during sleep. It works by delivering an electrical current to the hypoglossal nerve. This contracts the genioglossus muscle, the major muscle responsible for tongue protrusion, and all other intrinsic muscles of the tongue. Using general anaesthesia, a neurostimulator is implanted in an infraclavicular subcutaneous pocket and a stimulating lead is placed on the main trunk of the hypoglossal nerve. The neurostimulator delivers electrical pulses to the hypoglossal nerve. With some devices, stimulation can be synchronised with respiration using sensing leads that measure changes in breathing. The respiratory-sensing leads are positioned between the external and internal intercostal muscle. The stimulator is programmed and controlled wirelessly to adapt to specific patient needs.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.\n\nIn a systematic review and meta-analysis of 200\xa0patients, there was a statistically significant decrease in the apnoea–hypopnoea index (AHI; a normal AHI is less than 5\xa0events per hour). At 3-, 6-, and 12‑month follow-up the mean differences from baseline were -23.94 (95% confidence interval [CI] -31.45 to -16.43, 34\xa0patients), -25.60 (95% CI -31.18 to -20.01, 60\xa0patients) and -17.51 (95% CI -20.69 to -14.34, 170\xa0patients) respectively (p<0.001 for all time points).\n\nIn a randomised controlled therapy-withdrawal trial of 46\xa0'responders' from a prospective case series of 126 patients (23\xa0therapy-maintenance responders compared with 23 therapy-withdrawal responders), there was a statistically significant increase in the mean AHI from 7.6 at 1‑year follow-up (before randomisation into the trial) to 25.8 at 1\xa0week after randomisation, in the group in which the device was turned off for 1\xa0week (p<0.001). There was no statistical difference in mean AHI within the therapy-maintenance group, who continued to use the device (7.2\xa0compared with 8.9). At 18‑month follow-up, the mean AHI scores were 9.6 in the therapy-maintenance group and 10.7\xa0in the group who had the device turned off for 1\xa0week (p<0.05 for the differences compared with baseline within groups). There was a statistically significant difference between the therapy-withdrawal group and the therapy-maintenance group for change in mean AHI, from assessment at 1\xa0year to assessment at the end of the therapy-withdrawal study (p<0.001).\n\nIn the systematic review and meta-analysis of 200\xa0patients, there was a statistically significant decrease in the oxygen desaturation index (defined as the number of times per hour of sleep that the blood oxygen level drops by 4\xa0or more percentage points from baseline). At 3-, 6-, and 12‑month follow-up the mean differences from baseline were -10.04 (CI -16.31 to -3.78, 34\xa0patients), -11.68 (95% CI -17.16 to -6.19, 60\xa0patients) and -13.73 (95% CI -16.87 to -10.58, 170\xa0patients) respectively (p<0.01 at 3\xa0months and p<0.001 at 6\xa0and 12\xa0months).\n\nIn the systematic review and meta-analysis of 200\xa0patients, there was a statistically significant decrease in the Epworth sleepiness scale (scores range from 0\xa0to\xa024 with higher scores indicating more daytime sleepiness). At 3-, 6-, and 12‑month follow-up the mean differences from baseline were -4.17 (CI -6.45 to -1.90, 34\xa0patients), -3.82 (95% CI -5.37 to -2.27, 60\xa0patients) and -4.42 (95% CI -5.39 to -3.44, 170\xa0patients) respectively (p<0.001 for all time points).\n\nIn a follow-up study of 95 patients from the prospective case series of 126 patients, there was a statistically significant increase in the mean functional outcomes of sleep questionnaire score (FOSQ, ranging from 5\xa0to\xa020 with higher scores indicating better subjective sleep quality) from 14.6±3.0 at baseline to 17.5±2.9 at 4‑year follow-up (p<0.05).\n\nIn the follow-up study of 95\xa0patients from the prospective case series of 126\xa0patients, the rates of bed-partner reported 'no snoring' or 'soft snoring' were 17% (18/108) at baseline and 85% at 4‑year follow-up.\n\nIn a prospective case series of 46\xa0patients, there was a statistically significant improvement in the mean sleep apnoea quality of life index from 4.3±1.0 at baseline to 4.7±1.2 at 6‑month follow-up (p=0.019).\n\nThe specialist advisers listed the key efficacy outcomes as: reduction in severity of obstructive sleep apnoea, improved sleep and reduced daytime sleepiness.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see NICE's interventional procedure overview.\n\nTransient ipsilateral hemi-tongue paresis was reported in 15% (2/13) of patients in a prospective case series of 13\xa0patients from a systematic review and meta-analysis of 200\xa0patients.\n\nTongue abrasion was reported in 26% (33/126) of patients in a follow-up study of 95\xa0patients from a prospective case series of 126\xa0patients within 4\xa0years of the procedure.\n\nBleeding was reported in 1\xa0patient within 30\xa0days of implantation in a prospective case series of 46\xa0patients. This was caused by a hypertensive crisis and surgical intervention was needed; hypertension was treated with medication. In the same study, haematoma was reported in 7% (3/46) of patients. One of the 2\xa0cases classified as non-serious occurred within 30\xa0days of implantation and the other occurred more than 30\xa0days after implantation. The third case was classified as a serious event and occurred within 30\xa0days of implantation.\n\nRupture of a vein was reported in 6% (2/31) of patients during cervical tunnelling in a prospective case series of 31\xa0patients; 1\xa0of the patients needed 1\xa0further cervical incision.\n\nSeroma at an incision site was reported in 10% (2/20) of patients after the procedure in a retrospective case series of 20\xa0patients. One seroma occurred at the sensing‑lead incision 1\xa0week after surgery and the other occurred at the implantable pulse‑generator incision 4\xa0weeks after surgery. Both resolved uneventfully with percutaneous needle drainage.\n\nHeadache was reported in 6% (8/126) of patients in the prospective case series of 126\xa0patients within 1\xa0year of the procedure.\n\nInfection was reported in 1\xa0patient in a prospective case series of 22\xa0patients from the systematic review and meta-analysis of 200\xa0patients; the device was removed.\n\nDry mouth was reported in 13% (16/126) of patients in the prospective case series of 126\xa0patients within 3\xa0years of the procedure.\n\nDiscomfort due to electrical stimulation was reported in 58% (73/126) of patients in the prospective case series of 126\xa0patients within 4\xa0years of the procedure. In the same study, discomfort related to incisions was reported in 29% (37/126) of patients and discomfort not related to incisions was reported in 27% (34/126) of patients within 4\xa0years of the procedure.\n\nParaesthesia was reported in 13% (6/46) of patients (within 30\xa0days of implantation in 5\xa0patients, and more than 30\xa0days after implantation in 1\xa0patient) in the prospective case series of 46\xa0patients.\n\nDevice migration more than 30\xa0days after implantation was reported in 1\xa0patient in the prospective case series of 46\xa0patients. Cuff dislodgement was reported in 2\xa0patients in a prospective case series of 31\xa0patients, and in 1\xa0patient in a prospective case series of 21\xa0patients, from the systematic review and meta-analysis of 200\xa0patients; all 3\xa0patients needed a new procedure to replace it.\n\nDevice removal was reported in 4\xa0patients in the prospective case series of 31\xa0patients, and in 2\xa0patients in the prospective case series of 21\xa0patients, from the systematic review and meta-analysis of 200\xa0patients. Device removal was also reported in 3\xa0patients, 1\xa0to 4\xa0years after the procedure, in the prospective case series of 126\xa0patients. The reasons for removal were insomnia, septic sternoclavicular joint adjacent to the device and non-response to therapy. Device removal for cosmetic reasons was reported in 1\xa0patient in a case series of 60\xa0patients.\n\nLeads breaking was reported in 15% (2/13) of patients in the prospective case series of 13\xa0patients from the systematic review and meta-analysis of 200\xa0patients.\n\nDefective implanted pulse‑generator connector was reported in 1\xa0patient in the prospective case series of 13\xa0patients from the systematic review and meta-analysis of 200\xa0patients.\n\nOther complications reported in the systematic review and meta-analysis of 200\xa0patients included postoperative pain and stiffness, sore throat, stitch abscess, local swelling, fever and lack of tongue response to stimulation.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, the specialist advisers did not list any anecdotal adverse events. They considered that the following were theoretical adverse events: fatigue of the upper airway dilator muscles leading to worsening sleep apnoea, and hypoglossal nerve damage.", 'Further information': "For related NICE guidance, see the NICE website.\n\nNo patient commentary was sought because the procedure is not currently done in the UK. The Sleep Apnoea Trust Association provided feedback on this procedure.\n\nThis guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed NICE's interventional procedure outcomes audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2733-3"}
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https://www.nice.org.uk/guidance/ipg598
|
Evidence-based recommendations on hypoglossal nerve stimulation for moderate to severe obstructive sleep apnoea in adults. This involves implanting a device under the skin in the chest and connecting it to a nerve under the tongue (hypoglossal nerve).
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342d045411384803e27064f9df9db0a87ac3ec68
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nice
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Vismodegib for treating basal cell carcinoma
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Vismodegib for treating basal cell carcinoma
Evidence-based recommendations on vismodegib (Erivedge) for treating basal cell carcinoma in adults.
# Recommendations
Vismodegib is not recommended within its marketing authorisation for treating symptomatic metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that is inappropriate for surgery or radiotherapy, in adults.
This recommendation is not intended to affect treatment with vismodegib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that is inappropriate for surgery or radiotherapy, is best supportive care.
Clinical trial evidence shows that overall survival data in people with locally advanced basal cell carcinoma are limited. Only a small number of people with metastatic basal cell carcinoma were included in trials. There are also no trials directly comparing vismodegib with best supportive care. The results of an analysis comparing the treatments suggests that vismodegib may provide some benefit, but the methods used are not good enough for decision-making.
The most likely estimate of cost effectiveness for vismodegib compared with best supportive care is much higher than £30,000 per quality-adjusted life year (QALY) gained. The economic assessment may not have fully captured the quality-of-life benefits of vismodegib, but taking this into account would not lower the estimate of cost effectiveness to an acceptable level.
Vismodegib cannot be recommended because of the uncertainty in the evidence and because it is not cost effective.# The technology
Vismodegib (Erivedge, Roche)
Marketing authorisation
Vismodegib is indicated for the treatment of 'adult patients with:
symptomatic metastatic basal cell carcinoma
locally advanced basal cell carcinoma inappropriate for surgery or radiotherapy'.
Recommended dose and schedule
The recommended dose is 1×150‑mg capsule taken once daily. Treatment should be continued until disease progression or unacceptable toxicity.
Price
Vismodegib is available at the list price of £6,285 for 28 capsules, each containing 150 mg (£224.50 per capsule; excluding VAT, British national formulary).
The company has agreed a patient access scheme with the Department of Health. If vismodegib had been recommended, this scheme would provide a simple discount to the list price of vismodegib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 4) considered evidence submitted by Roche Products and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical need
## People with advanced basal cell carcinoma that is inappropriate for surgery and radiotherapy would welcome treatment options
The committee understood that surgery and radiotherapy are the standard of care for treating locally advanced and metastatic basal cell carcinoma (BCC), also collectively termed 'advanced BCC'. When these are inappropriate there are no other active treatments available and best supportive care is the only option. The experts stated that this group of patients is typically older and relatively frail, with a number of comorbidities, and vismodegib has been an important treatment option since its availability on the Cancer Drugs Fund. The committee concluded that other treatment options would be welcomed.
## Effective treatments for advanced basal cell carcinoma that improve quality of life would be valued
The committee heard that advanced BCC is not tracked in the national cancer registries so definitive UK mortality and morbidity data are not readily available. However, clinical experience indicates that patients with locally advanced BCC are likely to have a similar life expectancy to the general population. There is increased mortality in some patients with metastatic BCC, but the clinical experts agreed that death is unlikely to be a result of the primary tumour. However, 1 clinical expert highlighted the burden of disease in this population. They explained that people with advanced BCC that is inappropriate for surgery and radiotherapy often develop large disfiguring lesions because of extensive tissue destruction, particularly on the face and neck. As a result, they have significant psychological stress and can become socially isolated. Additionally, wounds bleed, are painful and need regular dressing. The expert noted that a subgroup of people with Gorlin syndrome, an inherited condition, can develop a large number of tumours. People with Gorlin syndrome tend to develop BCC early in life and will therefore face the lifelong impact of multiple surgeries because the condition cannot be treated by radiotherapy. The committee heard that vismodegib can improve appearance, reduce pain and bleeding and subsequently improve nutrition, social interaction and overall quality of life. The committee concluded that patients would value access to effective treatments that improve quality of life.
# Clinical evidence
## The main evidence is from the single-arm, non-randomised, phase II STEVIE trial
The committee discussed the evidence from the ERIVANCE (n=104) and STEVIE (n=1,215) trials, including the baseline characteristics of the patients:
Both trials included substantially more patients with locally advanced BCC than with metastatic BCC. The clinical experts advised that this reflects clinical practice, in which metastatic BCC is much less common than locally advanced BCC.
The median age of people in the trials differed. The clinical experts explained that the population in ERIVANCE was substantially younger (median age 62 years) than expected in UK clinical practice (approximately 70 years) and that the population in STEVIE, with a median age of 72 years, was more representative.
The clinical experts stated that there were more patients with Gorlin syndrome in ERIVANCE and STEVIE than would be expected in the UK clinical practice. The committee also noted that patients with Gorlin syndrome had a lower median age, a better baseline performance score and a higher median number of target lesions than those without Gorlin syndrome. This may affect the overall results if not adjusted for.The committee concluded that STEVIE more closely reflected UK clinical practice than ERIVANCE, and that it should be the basis for decision-making.
## The clinical benefit of vismodegib is uncertain
The committee discussed the results from STEVIE, noting that the objective response rate was 68.5% (95% confidence interval 65.7 to 71.3) in the locally advanced BCC population and 36.9% (95% CI 26.6 to 71.2) in the metastatic BCC population. Median progression-free survival for patients with locally advanced BCC was 23.2 months (95% CI 21.4 to 26.0) and 13.1 months (95% CI 12.0 to 17.7) for patients with metastatic BCC. Results for health-related quality of life, measured using the Skindex-16 questionnaire, indicated that there was no clinically meaningful improvement for metastatic BCC and only clinically meaningful improvement in emotion scores for locally advanced BCC. The committee was aware of the observational nature of this evidence, the higher proportion of patients with Gorlin syndrome than in clinical practice, the lack of long-term data and that data on metastatic BCC were based on very small numbers of patients. The experts agreed that benefits in patients with metastatic BCC were less clear, and are likely to be seen in a small proportion of people with metastatic BCC. But they highlighted that patients with locally advanced BCC had experienced important benefits from vismodegib in practice. The committee noted that overall survival data were immature and were not presented for the locally advanced BCC population. Overall survival data from ERIVANCE were presented for the metastatic BCC population but the committee had previously concluded that this trial was not generalisable to UK clinical practice and also it included only 33 patients with metastatic BCC. The committee noted that vismodegib was not expected to have important overall survival benefits because the condition does not directly affect mortality. The committee concluded that although the clinically relevant benefits associated with vismodegib are plausible, the evidence presented was associated with substantial uncertainty and there were no direct comparative data with best supportive care.
# Adverse events
## Common side effects with vismodegib are manageable
All patients in ERIVANCE and 98% of patients in STEVIE had an adverse event. The committee noted that there were 110 deaths reported in STEVIE, and that 7 of these related to vismodegib, but it acknowledged that all patients in the study had significant pre-existing risk factors or comorbidities at baseline (as stated by the company). The committee remained concerned about the vismodegib-related deaths in the trial; it heard from the clinical experts that further analysis of the STEVIE safety data is awaited, but in practice vismodegib is generally well tolerated. The committee also noted that adverse events was the most frequent reason reported for discontinuing treatment. The most frequent adverse events reported in both trials were muscle spasms, alopecia, dysgeusia (distortion of sense of taste) and weight loss. One clinical expert stated that although muscle spasms were initially a concern, vismodegib is licensed at a dose that does not affect muscles seriously. Lack of nutrition and weight loss because of dysgeusia are manageable. The committee concluded that the most frequent side effects with vismodegib are manageable, but further analysis of safety data would be informative.
# Estimating effectiveness using a landmark approach
## The company's approach to estimating relative treatment effectiveness is uncertain
The committee was aware that the company did a 6‑month landmark analysis comparing vismodegib with best supportive care because there were no trials directly comparing the treatments. The committee noted that data from people who did not respond to treatment ('non-responders') in STEVIE were used to estimate a hazard ratio for people who did respond to treatment ('responders') compared with non-responders. The company then adjusted this hazard ratio to reflect the hazard ratio for non-responders compared with the intention-to-treat patients, as a proxy for vismodegib compared with best supportive care at the 6‑month landmark. The committee had concerns about this use of the non-responder data, considering that this population would have already had vismodegib. It considered the other limitations around the company's landmark approach, highlighted by the ERG:
The ERG stated that adjusting the hazard ratio as described above resulted in it being a time-varying hazard ratio, but evidence of a time-varying treatment effect was not presented. The company stated that this was done to account for the proportion of non-responders changing over time but it acknowledged the methodological limitations of this approach. The ERG explored the effect of using an unadjusted hazard ratio, and the committee preferred this approach.
The ERG stated that the choice of landmark should be made prospectively, based on a clinically meaningful time point. It noted that the company's 6‑month landmark, although not implausible, was chosen retrospectively and other possible landmarks, apart from a 3month exploratory landmark, which the ERG agreed was not appropriate, were not explored. A clinical expert stated that patients typically have a response within 3 months of treatment but the committee considered that further exploration around the landmark would have increased its confidence in the analysis. However, in response to the consultation, the company stated that this was not possible because of the lack of data available.
The ERG noted that the definition of non-responder varied by the outcome assessed, and explored using a consistent definition; the committee agreed that this was more appropriate.
The ERG stated that the company used a common treatment effect hazard ratio for advanced BCC to reflect the uncertainty in the hazard ratios, but the ERG considered this approach to be flawed because locally advanced BCC and metastatic BCC are clinically and prognostically different and should therefore be analysed separately. The clinical experts agreed, and the committee noted that the conditions were also defined independently in the marketing authorisation. The committee agreed that using a common treatment effect hazard ratio was not appropriate. However, the committee was aware of the very small numbers of patients with metastatic BCC. It considered that combined results from the cost-effectiveness model, based on the proportion of patients with locally advanced BCC and metastatic BCC in STEVIE, may be more robust for its decision-making. The company adjusted the hazard ratios for age and Eastern Cooperative Oncology Group (ECOG) status. The ERG stated that this was not based on a systematic selection process and that other baseline characteristics such as Gorlin syndrome, nerve infiltration and tumour location are important covariates but were not included in the landmark analyses. The ERG explored adjusting for Gorlin syndrome; the committee agreed with this and also considered that further covariate adjustment would have been informative. The committee also noted that the hazard ratios derived from the 6-month landmark varied considerably between people with locally advanced BCC and metastatic BCC. For people with metastatic BCC, the hazard ratio for progression-free survival was less than 1, suggesting that people who do not respond to treatment have better progression-free survival than those who do. The committee heard from the clinical experts that this is implausible. For people with locally advanced BCC, the hazard ratio for overall survival was 2.035; the committee questioned the plausibility of this estimate, because it heard from the clinical experts that vismodegib was unlikely to directly affect survival.Having fully considered the landmark analysis, the committee stated that the data were at high risk of bias. It questioned the availability of real-world data to supplement this analysis. It heard that there are US and French registries but data from these are not mature. Nonetheless, the committee considered that these data would have been helpful to support the company's comparison of vismodegib and best supportive care. The committee concluded that the results of the landmark analysis were not sufficiently robust for its decision-making.
# Subgroup analysis
## The group of people with Gorlin syndrome was too small for separate consideration
The company did a post hoc analysis of the Gorlin syndrome subgroup, as requested by the ERG during the clarification stage. The results, although not statistically significant, suggested that people with Gorlin syndrome have a higher response rate and longer duration of response with vismodegib than people without Gorlin syndrome. The ERG explained that these responses could be linked to the lower age and better baseline performance score of people with Gorlin syndrome, which were not adjusted for in the analysis. The committee was aware of the very small numbers of patients in this subgroup and concluded that it would not be appropriate to consider it separately.
# Modelling clinical outcomes in the company's economic model
## Limitations of the landmark approach are carried through to the economic model
Having established that the company's landmark analysis was associated with considerable uncertainty, the committee noted that the company's model used the 6‑month landmark analysis results from STEVIE. The resulting incremental cost-effectiveness ratios (ICERs) were therefore highly uncertain. However, the committee agreed that it would consider the results presented. It recalled that the ERG's suggested amendments to the company's landmark analysis were appropriate and it would consider results incorporating these changes:
adjusting for Gorlin syndrome in addition to age and ECOG status
using a consistent definition for non-responders across outcomes (that is, people with stable disease excluding those who have progressed or died before the landmark from the analysis)
using unadjusted hazard ratios.
## The log-logistic model is a better fit to estimate time to treatment discontinuation
The committee noted that the company generally selected the best-fitting model by comparing with the observed Kaplan–Meier data and using the Akaike Information Criterion and Bayesian Information Criterion. However, for time to treatment discontinuation the Weibull curve was chosen despite the log-logistic curve being a better fit. The company stated that this was because the locally advanced BCC and metastatic BCC time to treatment discontinuation log-logistic curves cross in the model. However, the ERG explained that this is caused by the company's approach to modelling the time to treatment discontinuation curves and was not related to the fit of the log-logistic curves. In response to consultation, the company stated that to prevent the locally advanced BCC time to treatment discontinuation log-logistic curve from crossing, it had to be capped to the progression-free survival curve from year 5, suggesting that patients who remained on treatment from year 5 could only discontinue because of progression or death. It considered this to be clinically implausible. The ERG suggested that because only 7% of patients remained on treatment after year 5, and the uncertainty in the long-term predictions of the economic analysis, the log-logistic curve, which is a better fit, would still be preferred. The committee agreed with this and also considered that the smoother drop in the tail of the log-logistic curve more accurately reflected the typically slow progression of the disease. For people with metastatic BCC, the company did not provide any rationale for choosing Weibull over the better fitting log-logistic model, despite the time to treatment discontinuation Weibull curve also crossing. The committee concluded that the log-logistic distribution was a better fit for extrapolating time to treatment discontinuation.
## The overall survival extrapolations are associated with high levels of uncertainty
The committee noted that there was an unusual plateau at the end of the overall survival Kaplan–Meier curve for patients with locally advanced BCC and metastatic BCC. The ERG highlighted that no patients with locally advanced BCC or metastatic BCC would die for 18 or 16 months, respectively, before the end of follow-up, which was 44 months for people with locally advanced BCC and 38 months for people with metastatic BCC. The committee heard from the ERG that this is unlikely considering that by 26 months, people in STEVIE would have been 74 years on average. The committee agreed it was particularly implausible that no patients with metastatic BCC would die for 16 months because the estimated mortality for people with metastatic BCC is 1 to 2 years after diagnosis. The committee concluded that because of the uncertainty around the overall survival data, the extrapolated tails of the overall survival curves would be associated with a high level of uncertainty regardless of the distribution used.
## The overall survival curves do not accurately reflect mortality for people with advanced BCC compared with the average UK population
The committee noted that the overall survival curves suggested an increased mortality risk in people with locally advanced BCC compared with the average age- and sex-matched UK population. However, a clinical expert explained that they would expect the overall survival curve for vismodegib to be close to an age and sex-matched background survival curve for the average UK population because mortality is rarely directly attributable to locally advanced BCC. Additionally, the committee agreed that mortality with metastatic BCC was underestimated by the assumption in the model that people with metastatic BCC would survive for more than 10 years. The committee was aware that the company explored capping the survival curve for vismodegib by the background mortality curve. The ERG explained that this method implies that the benefit between vismodegib and best supportive care diminishes over time and stops after both curves have crossed the background mortality curve (around at month 150). The committee agreed that this was a realistic scenario. On balance, the committee concluded there was substantial uncertainty associated with the evidence around overall survival.
# Utilities in the economic model
## The utility estimates are uncertain
The committee noted that no algorithm existed for mapping the Skindex-‑16 and MD Anderson Symptom Inventory data, collected during STEVIE, to EQ-5D. Therefore, health state utilities in the base-case analysis were derived from mapping SF‑36 data from ERIVANCE to EQ‑5D. The committee noted that the population baseline age in ERIVANCE (median 62 years) did not reflect patients in STEVIE (median 72 years) or those in UK clinical practice (approximately 70 years). It also heard from the ERG that the assessment of response or progression differed between ERIVANCE and STEVIE and that the underlying SF‑36 data seem to carry a high degree of uncertainty. This is because despite there being mainly non-statistically significant changes in quality of life over time in ERIVANCE measured with the SF‑36, the mapped EQ‑5D utility values suggest a decrease in quality of life over time. The company highlighted that quality-of-life benefits may not be fully captured because the SF‑36 lacks sensitivity. However, the committee recalled that it contains domains on social functioning, anxiety and depression. Nonetheless the committee acknowledged that the results may not fully reflect the feedback from the clinical experts that the main benefit of vismodegib is on the quality of life of patients. After the first committee meeting, the company submitted a scenario analysis to illustrate the potential underestimation of health-related quality of life in the economic analysis. However, the committee considered that this was purely an academic exercise because of the lack of data to inform a most plausible utility value. The ERG also highlighted that the model did not capture disutility from treatment-related adverse events. The committee recognised that the quality-of-life benefits may have been underestimated in the model, but was mindful that in the absence of robust evidence vismodegib's effect on quality of life is uncertain.
# Resource use and costs
## The company's assumptions about best supportive care are implausible
The company assumed that 67% of patients who progress after having vismodegib never have best supportive care, and that post-progression best supportive care for people who have had vismodegib differs from post-progression best supportive care for those who have not had vismodegib. The clinical experts explained that an initial delay in restarting best supportive care after vismodegib was plausible because these patients may initially only need monitoring or a less intensive regimen of best supportive care because they will have a lower disease burden. However, all patients will eventually go on to have best supportive care as their disease progresses, and this regimen will be the same irrespective of previous vismodegib treatment. The committee also heard from the clinical experts that the length of the delay in re-starting best supportive care after vismodegib varies in clinical practice, and depends on the location and type of the BCC. One clinical expert cited a 1- to 2‑year delay; another stated that a delay of 4 to 6 years is plausible after a good response to treatment and with a slow growing tumour. However, as vismodegib has only been available for 4 years, the committee considered that it would be unrealistic to assume a longer delay. On balance, the committee concluded that it would consider results assuming a delay of 3 years after progression before re-starting best supportive care, and this would include the same treatment as people on best supportive care whose disease has progressed.
# Cost-effectiveness analyses
## The committee considered the results that included its preferred assumptions
The committee's preferred assumptions were:
removing the half-cycle correction from the model
removing the company's adjustment to the hazard ratios derived by the landmark approach to reflect a hazard ratio for non-responders compared with the intention-to-treat population, instead of a non-responders compared with a responders hazard ratio
changing from a Weibull to a log-logistic time to treatment discontinuation curve in the locally advanced BCC and metastatic BCC models
capping the overall survival vismodegib curve by the background mortality curve
assuming that 67% of people on vismodegib who have progressed are initially monitored after progression but then move to best supportive care at 3 years (see section 3.12)
assuming that people on vismodegib moving to best supportive care have the same treatment regimen as people on best supportive care whose disease has progressed.The ERG also presented 2 further scenarios: assuming no survival benefit with vismodegib, and assuming a survival benefit with vismodegib incorporated using the committee's preferred hazard ratio adjusted for age, ECOG and Gorlin syndrome.
## Vismodegib is not cost effective
The committee noted that although vismodegib was unlikely to have a direct impact on survival, it could not rule out survival benefits altogether. However, it considered this was likely to be a small benefit and potentially only in a small population. The committee was mindful of the lack of evidence of a survival benefit (see section 3.2 and section 3.3) and considered that the overall survival benefit assumption incorporated in the model was too optimistic. The committee considered the ICERs based on both assumptions but considered that the true ICER was closer to the estimate assuming no survival benefit with vismodegib. Additionally, the committee recalled its consideration that even though locally advanced BCC and metastatic BCC are distinct conditions it would consider the results of the combined analyses including both populations so as not to disadvantage the very small numbers of patients with metastatic BCC. The committee noted that the combined ICERs were £96,548 per quality-adjusted life year (QALY) gained when a survival benefit was assumed and £4,694,943 per QALY gained when no survival benefit was assumed. It recalled that the economic assessment may not have fully captured the quality-of-life benefits of vismodegib, but taking this into account would not lower the estimate of cost effectiveness to an acceptable level. The committee was also aware that a confidential patient access scheme for vismodegib was available but noted that the ICERs remained substantially above a level that could be considered a cost-effective use of NHS resources.
# Cancer Drugs Fund
## Vismodegib does not meet the criteria to be included in the Cancer Drugs Fund
The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee agreed that there is substantial uncertainty about the clinical benefit of vismodegib in terms of overall survival and that this was a key driver of the results in the model, but it did not consider that data collection for around 2 years would sufficiently reduce the uncertainty around this. Importantly, the committee did not see any plausible potential for vismodegib to satisfy the criteria for routine use based on its confidential patient access scheme price. It therefore concluded that vismodegib did not meet the criteria to be included in the Cancer Drugs Fund.
# Other factors
## The committee did not identify any other factors that affected its recommendations
No equality or social value judgement issues were identified.
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of the technology.
The committee discussed the company's comments about the innovative nature of vismodegib. It heard from the clinical expert that vismodegib is the only treatment option available for advanced BCC that is inappropriate for surgery and radiotherapy. It delays disease progression and improves quality of life. The committee recalled its consideration that the model may not have fully captured the quality-of-life benefits associated with vismodegib. However, the committee considered that accounting for this would not lower the ICERs to an acceptable level, especially considering the uncertainties in the evidence. The committee concluded that vismodegib may be associated with benefits, but more robust comparative data are needed to support its long-term efficacy profile.
|
{'Recommendations': 'Vismodegib is not recommended within its marketing authorisation for treating symptomatic metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that is inappropriate for surgery or radiotherapy, in adults.\n\nThis recommendation is not intended to affect treatment with vismodegib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that is inappropriate for surgery or radiotherapy, is best supportive care.\n\nClinical trial evidence shows that overall survival data in people with locally advanced basal cell carcinoma are limited. Only a small number of people with metastatic basal cell carcinoma were included in trials. There are also no trials directly comparing vismodegib with best supportive care. The results of an analysis comparing the treatments suggests that vismodegib may provide some benefit, but the methods used are not good enough for decision-making.\n\nThe most likely estimate of cost effectiveness for vismodegib compared with best supportive care is much higher than £30,000 per quality-adjusted life year (QALY) gained. The economic assessment may not have fully captured the quality-of-life benefits of vismodegib, but taking this into account would not lower the estimate of cost effectiveness to an acceptable level.\n\nVismodegib cannot be recommended because of the uncertainty in the evidence and because it is not cost effective.', 'The technology': "Vismodegib (Erivedge, Roche)\n\nMarketing authorisation\n\nVismodegib is indicated for the treatment of 'adult patients with:\n\nsymptomatic metastatic basal cell carcinoma\n\nlocally advanced basal cell carcinoma inappropriate for surgery or radiotherapy'.\n\nRecommended dose and schedule\n\nThe recommended dose is 1×150‑mg capsule taken once daily. Treatment should be continued until disease progression or unacceptable toxicity.\n\nPrice\n\nVismodegib is available at the list price of £6,285 for 28\xa0capsules, each containing 150\xa0mg (£224.50 per capsule; excluding VAT, British national formulary).\n\nThe company has agreed a patient access scheme with the Department of Health. If vismodegib had been recommended, this scheme would provide a simple discount to the list price of vismodegib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa04) considered evidence submitted by Roche Products and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical need\n\n## People with advanced basal cell carcinoma that is inappropriate for surgery and radiotherapy would welcome treatment options\n\nThe committee understood that surgery and radiotherapy are the standard of care for treating locally advanced and metastatic basal cell carcinoma (BCC), also collectively termed 'advanced BCC'. When these are inappropriate there are no other active treatments available and best supportive care is the only option. The experts stated that this group of patients is typically older and relatively frail, with a number of comorbidities, and vismodegib has been an important treatment option since its availability on the Cancer Drugs Fund. The committee concluded that other treatment options would be welcomed.\n\n## Effective treatments for advanced basal cell carcinoma that improve quality of life would be valued\n\nThe committee heard that advanced BCC is not tracked in the national cancer registries so definitive UK mortality and morbidity data are not readily available. However, clinical experience indicates that patients with locally advanced BCC are likely to have a similar life expectancy to the general population. There is increased mortality in some patients with metastatic BCC, but the clinical experts agreed that death is unlikely to be a result of the primary tumour. However, 1 clinical expert highlighted the burden of disease in this population. They explained that people with advanced BCC that is inappropriate for surgery and radiotherapy often develop large disfiguring lesions because of extensive tissue destruction, particularly on the face and neck. As a result, they have significant psychological stress and can become socially isolated. Additionally, wounds bleed, are painful and need regular dressing. The expert noted that a subgroup of people with Gorlin syndrome, an inherited condition, can develop a large number of tumours. People with Gorlin syndrome tend to develop BCC early in life and will therefore face the lifelong impact of multiple surgeries because the condition cannot be treated by radiotherapy. The committee heard that vismodegib can improve appearance, reduce pain and bleeding and subsequently improve nutrition, social interaction and overall quality of life. The committee concluded that patients would value access to effective treatments that improve quality of life.\n\n# Clinical evidence\n\n## The main evidence is from the single-arm, non-randomised, phase\xa0II STEVIE trial\n\nThe committee discussed the evidence from the ERIVANCE (n=104) and STEVIE (n=1,215) trials, including the baseline characteristics of the patients:\n\nBoth trials included substantially more patients with locally advanced BCC than with metastatic BCC. The clinical experts advised that this reflects clinical practice, in which metastatic BCC is much less common than locally advanced BCC.\n\nThe median age of people in the trials differed. The clinical experts explained that the population in ERIVANCE was substantially younger (median age 62\xa0years) than expected in UK clinical practice (approximately 70\xa0years) and that the population in STEVIE, with a median age of 72\xa0years, was more representative.\n\nThe clinical experts stated that there were more patients with Gorlin syndrome in ERIVANCE and STEVIE than would be expected in the UK clinical practice. The committee also noted that patients with Gorlin syndrome had a lower median age, a better baseline performance score and a higher median number of target lesions than those without Gorlin syndrome. This may affect the overall results if not adjusted for.The committee concluded that STEVIE more closely reflected UK clinical practice than ERIVANCE, and that it should be the basis for decision-making.\n\n## The clinical benefit of vismodegib is uncertain\n\nThe committee discussed the results from STEVIE, noting that the objective response rate was 68.5% (95% confidence interval [CI] 65.7 to 71.3) in the locally advanced BCC population and 36.9% (95% CI 26.6 to 71.2) in the metastatic BCC population. Median progression-free survival for patients with locally advanced BCC was 23.2\xa0months (95% CI 21.4 to 26.0) and 13.1\xa0months (95% CI 12.0 to 17.7) for patients with metastatic BCC. Results for health-related quality of life, measured using the Skindex-16 questionnaire, indicated that there was no clinically meaningful improvement for metastatic BCC and only clinically meaningful improvement in emotion scores for locally advanced BCC. The committee was aware of the observational nature of this evidence, the higher proportion of patients with Gorlin syndrome than in clinical practice, the lack of long-term data and that data on metastatic BCC were based on very small numbers of patients. The experts agreed that benefits in patients with metastatic BCC were less clear, and are likely to be seen in a small proportion of people with metastatic BCC. But they highlighted that patients with locally advanced BCC had experienced important benefits from vismodegib in practice. The committee noted that overall survival data were immature and were not presented for the locally advanced BCC population. Overall survival data from ERIVANCE were presented for the metastatic BCC population but the committee had previously concluded that this trial was not generalisable to UK clinical practice and also it included only 33\xa0patients with metastatic BCC. The committee noted that vismodegib was not expected to have important overall survival benefits because the condition does not directly affect mortality. The committee concluded that although the clinically relevant benefits associated with vismodegib are plausible, the evidence presented was associated with substantial uncertainty and there were no direct comparative data with best supportive care.\n\n# Adverse events\n\n## Common side effects with vismodegib are manageable\n\nAll patients in ERIVANCE and 98% of patients in STEVIE had an adverse event. The committee noted that there were 110\xa0deaths reported in STEVIE, and that 7\xa0of these related to vismodegib, but it acknowledged that all patients in the study had significant pre-existing risk factors or comorbidities at baseline (as stated by the company). The committee remained concerned about the vismodegib-related deaths in the trial; it heard from the clinical experts that further analysis of the STEVIE safety data is awaited, but in practice vismodegib is generally well tolerated. The committee also noted that adverse events was the most frequent reason reported for discontinuing treatment. The most frequent adverse events reported in both trials were muscle spasms, alopecia, dysgeusia (distortion of sense of taste) and weight loss. One clinical expert stated that although muscle spasms were initially a concern, vismodegib is licensed at a dose that does not affect muscles seriously. Lack of nutrition and weight loss because of dysgeusia are manageable. The committee concluded that the most frequent side effects with vismodegib are manageable, but further analysis of safety data would be informative.\n\n# Estimating effectiveness using a landmark approach\n\n## The company's approach to estimating relative treatment effectiveness is uncertain\n\nThe committee was aware that the company did a 6‑month landmark analysis comparing vismodegib with best supportive care because there were no trials directly comparing the treatments. The committee noted that data from people who did not respond to treatment ('non-responders') in STEVIE were used to estimate a hazard ratio for people who did respond to treatment ('responders') compared with non-responders. The company then adjusted this hazard ratio to reflect the hazard ratio for non-responders compared with the intention-to-treat patients, as a proxy for vismodegib compared with best supportive care at the 6‑month landmark. The committee had concerns about this use of the non-responder data, considering that this population would have already had vismodegib. It considered the other limitations around the company's landmark approach, highlighted by the ERG:\n\nThe ERG stated that adjusting the hazard ratio as described above resulted in it being a time-varying hazard ratio, but evidence of a time-varying treatment effect was not presented. The company stated that this was done to account for the proportion of non-responders changing over time but it acknowledged the methodological limitations of this approach. The ERG explored the effect of using an unadjusted hazard ratio, and the committee preferred this approach.\n\nThe ERG stated that the choice of landmark should be made prospectively, based on a clinically meaningful time point. It noted that the company's 6‑month landmark, although not implausible, was chosen retrospectively and other possible landmarks, apart from a 3month exploratory landmark, which the ERG agreed was not appropriate, were not explored. A clinical expert stated that patients typically have a response within 3\xa0months of treatment but the committee considered that further exploration around the landmark would have increased its confidence in the analysis. However, in response to the consultation, the company stated that this was not possible because of the lack of data available.\n\nThe ERG noted that the definition of non-responder varied by the outcome assessed, and explored using a consistent definition; the committee agreed that this was more appropriate.\n\nThe ERG stated that the company used a common treatment effect hazard ratio for advanced BCC to reflect the uncertainty in the hazard ratios, but the ERG considered this approach to be flawed because locally advanced BCC and metastatic BCC are clinically and prognostically different and should therefore be analysed separately. The clinical experts agreed, and the committee noted that the conditions were also defined independently in the marketing authorisation. The committee agreed that using a common treatment effect hazard ratio was not appropriate. However, the committee was aware of the very small numbers of patients with metastatic BCC. It considered that combined results from the cost-effectiveness model, based on the proportion of patients with locally advanced BCC and metastatic BCC in STEVIE, may be more robust for its decision-making. The company adjusted the hazard ratios for age and Eastern Cooperative Oncology Group (ECOG) status. The ERG stated that this was not based on a systematic selection process and that other baseline characteristics such as Gorlin syndrome, nerve infiltration and tumour location are important covariates but were not included in the landmark analyses. The ERG explored adjusting for Gorlin syndrome; the committee agreed with this and also considered that further covariate adjustment would have been informative. The committee also noted that the hazard ratios derived from the 6-month landmark varied considerably between people with locally advanced BCC and metastatic BCC. For people with metastatic BCC, the hazard ratio for progression-free survival was less than 1, suggesting that people who do not respond to treatment have better progression-free survival than those who do. The committee heard from the clinical experts that this is implausible. For people with locally advanced BCC, the hazard ratio for overall survival was 2.035; the committee questioned the plausibility of this estimate, because it heard from the clinical experts that vismodegib was unlikely to directly affect survival.Having fully considered the landmark analysis, the committee stated that the data were at high risk of bias. It questioned the availability of real-world data to supplement this analysis. It heard that there are US and French registries but data from these are not mature. Nonetheless, the committee considered that these data would have been helpful to support the company's comparison of vismodegib and best supportive care. The committee concluded that the results of the landmark analysis were not sufficiently robust for its decision-making.\n\n# Subgroup analysis\n\n## The group of people with Gorlin syndrome was too small for separate consideration\n\nThe company did a post hoc analysis of the Gorlin syndrome subgroup, as requested by the ERG during the clarification stage. The results, although not statistically significant, suggested that people with Gorlin syndrome have a higher response rate and longer duration of response with vismodegib than people without Gorlin syndrome. The ERG explained that these responses could be linked to the lower age and better baseline performance score of people with Gorlin syndrome, which were not adjusted for in the analysis. The committee was aware of the very small numbers of patients in this subgroup and concluded that it would not be appropriate to consider it separately.\n\n# Modelling clinical outcomes in the company's economic model\n\n## Limitations of the landmark approach are carried through to the economic model\n\nHaving established that the company's landmark analysis was associated with considerable uncertainty, the committee noted that the company's model used the 6‑month landmark analysis results from STEVIE. The resulting incremental cost-effectiveness ratios (ICERs) were therefore highly uncertain. However, the committee agreed that it would consider the results presented. It recalled that the ERG's suggested amendments to the company's landmark analysis were appropriate and it would consider results incorporating these changes:\n\nadjusting for Gorlin syndrome in addition to age and ECOG status\n\nusing a consistent definition for non-responders across outcomes (that is, people with stable disease excluding those who have progressed or died before the landmark from the analysis)\n\nusing unadjusted hazard ratios.\n\n## The log-logistic model is a better fit to estimate time to treatment discontinuation\n\nThe committee noted that the company generally selected the best-fitting model by comparing with the observed Kaplan–Meier data and using the Akaike Information Criterion and Bayesian Information Criterion. However, for time to treatment discontinuation the Weibull curve was chosen despite the log-logistic curve being a better fit. The company stated that this was because the locally advanced BCC and metastatic BCC time to treatment discontinuation log-logistic curves cross in the model. However, the ERG explained that this is caused by the company's approach to modelling the time to treatment discontinuation curves and was not related to the fit of the log-logistic curves. In response to consultation, the company stated that to prevent the locally advanced BCC time to treatment discontinuation log-logistic curve from crossing, it had to be capped to the progression-free survival curve from year\xa05, suggesting that patients who remained on treatment from year\xa05 could only discontinue because of progression or death. It considered this to be clinically implausible. The ERG suggested that because only 7% of patients remained on treatment after year\xa05, and the uncertainty in the long-term predictions of the economic analysis, the log-logistic curve, which is a better fit, would still be preferred. The committee agreed with this and also considered that the smoother drop in the tail of the log-logistic curve more accurately reflected the typically slow progression of the disease. For people with metastatic BCC, the company did not provide any rationale for choosing Weibull over the better fitting log-logistic model, despite the time to treatment discontinuation Weibull curve also crossing. The committee concluded that the log-logistic distribution was a better fit for extrapolating time to treatment discontinuation.\n\n## The overall survival extrapolations are associated with high levels of uncertainty\n\nThe committee noted that there was an unusual plateau at the end of the overall survival Kaplan–Meier curve for patients with locally advanced BCC and metastatic BCC. The ERG highlighted that no patients with locally advanced BCC or metastatic BCC would die for 18\xa0or 16\xa0months, respectively, before the end of follow-up, which was 44\xa0months for people with locally advanced BCC and 38\xa0months for people with metastatic BCC. The committee heard from the ERG that this is unlikely considering that by 26\xa0months, people in STEVIE would have been 74\xa0years on average. The committee agreed it was particularly implausible that no patients with metastatic BCC would die for 16\xa0months because the estimated mortality for people with metastatic BCC is 1\xa0to 2\xa0years after diagnosis. The committee concluded that because of the uncertainty around the overall survival data, the extrapolated tails of the overall survival curves would be associated with a high level of uncertainty regardless of the distribution used.\n\n## The overall survival curves do not accurately reflect mortality for people with advanced BCC compared with the average UK population\n\nThe committee noted that the overall survival curves suggested an increased mortality risk in people with locally advanced BCC compared with the average age- and sex-matched UK population. However, a clinical expert explained that they would expect the overall survival curve for vismodegib to be close to an age and sex-matched background survival curve for the average UK population because mortality is rarely directly attributable to locally advanced BCC. Additionally, the committee agreed that mortality with metastatic BCC was underestimated by the assumption in the model that people with metastatic BCC would survive for more than 10\xa0years. The committee was aware that the company explored capping the survival curve for vismodegib by the background mortality curve. The ERG explained that this method implies that the benefit between vismodegib and best supportive care diminishes over time and stops after both curves have crossed the background mortality curve (around at month\xa0150). The committee agreed that this was a realistic scenario. On balance, the committee concluded there was substantial uncertainty associated with the evidence around overall survival.\n\n# Utilities in the economic model\n\n## The utility estimates are uncertain\n\nThe committee noted that no algorithm existed for mapping the Skindex-‑16 and MD\xa0Anderson Symptom Inventory data, collected during STEVIE, to EQ-5D. Therefore, health state utilities in the base-case analysis were derived from mapping SF‑36 data from ERIVANCE to EQ‑5D. The committee noted that the population baseline age in ERIVANCE (median 62\xa0years) did not reflect patients in STEVIE (median 72\xa0years) or those in UK clinical practice (approximately 70\xa0years). It also heard from the ERG that the assessment of response or progression differed between ERIVANCE and STEVIE and that the underlying SF‑36 data seem to carry a high degree of uncertainty. This is because despite there being mainly non-statistically significant changes in quality of life over time in ERIVANCE measured with the SF‑36, the mapped EQ‑5D utility values suggest a decrease in quality of life over time. The company highlighted that quality-of-life benefits may not be fully captured because the SF‑36 lacks sensitivity. However, the committee recalled that it contains domains on social functioning, anxiety and depression. Nonetheless the committee acknowledged that the results may not fully reflect the feedback from the clinical experts that the main benefit of vismodegib is on the quality of life of patients. After the first committee meeting, the company submitted a scenario analysis to illustrate the potential underestimation of health-related quality of life in the economic analysis. However, the committee considered that this was purely an academic exercise because of the lack of data to inform a most plausible utility value. The ERG also highlighted that the model did not capture disutility from treatment-related adverse events. The committee recognised that the quality-of-life benefits may have been underestimated in the model, but was mindful that in the absence of robust evidence vismodegib's effect on quality of life is uncertain.\n\n# Resource use and costs\n\n## The company's assumptions about best supportive care are implausible\n\nThe company assumed that 67% of patients who progress after having vismodegib never have best supportive care, and that post-progression best supportive care for people who have had vismodegib differs from post-progression best supportive care for those who have not had vismodegib. The clinical experts explained that an initial delay in restarting best supportive care after vismodegib was plausible because these patients may initially only need monitoring or a less intensive regimen of best supportive care because they will have a lower disease burden. However, all patients will eventually go on to have best supportive care as their disease progresses, and this regimen will be the same irrespective of previous vismodegib treatment. The committee also heard from the clinical experts that the length of the delay in re-starting best supportive care after vismodegib varies in clinical practice, and depends on the location and type of the BCC. One clinical expert cited a 1-\xa0to 2‑year delay; another stated that a delay of 4\xa0to 6\xa0years is plausible after a good response to treatment and with a slow growing tumour. However, as vismodegib has only been available for 4\xa0years, the committee considered that it would be unrealistic to assume a longer delay. On balance, the committee concluded that it would consider results assuming a delay of 3\xa0years after progression before re-starting best supportive care, and this would include the same treatment as people on best supportive care whose disease has progressed.\n\n# Cost-effectiveness analyses\n\n## The committee considered the results that included its preferred assumptions\n\nThe committee's preferred assumptions were:\n\nremoving the half-cycle correction from the model\n\nremoving the company's adjustment to the hazard ratios derived by the landmark approach to reflect a hazard ratio for non-responders compared with the intention-to-treat population, instead of a non-responders compared with a responders hazard ratio\n\nchanging from a Weibull to a log-logistic time to treatment discontinuation curve in the locally advanced BCC and metastatic BCC models\n\ncapping the overall survival vismodegib curve by the background mortality curve\n\nassuming that 67% of people on vismodegib who have progressed are initially monitored after progression but then move to best supportive care at 3 years (see section\xa03.12)\n\nassuming that people on vismodegib moving to best supportive care have the same treatment regimen as people on best supportive care whose disease has progressed.The ERG also presented 2\xa0further scenarios: assuming no survival benefit with vismodegib, and assuming a survival benefit with vismodegib incorporated using the committee's preferred hazard ratio adjusted for age, ECOG and Gorlin syndrome.\n\n## Vismodegib is not cost effective\n\nThe committee noted that although vismodegib was unlikely to have a direct impact on survival, it could not rule out survival benefits altogether. However, it considered this was likely to be a small benefit and potentially only in a small population. The committee was mindful of the lack of evidence of a survival benefit (see section\xa03.2 and section\xa03.3) and considered that the overall survival benefit assumption incorporated in the model was too optimistic. The committee considered the ICERs based on both assumptions but considered that the true ICER was closer to the estimate assuming no survival benefit with vismodegib. Additionally, the committee recalled its consideration that even though locally advanced BCC and metastatic BCC are distinct conditions it would consider the results of the combined analyses including both populations so as not to disadvantage the very small numbers of patients with metastatic BCC. The committee noted that the combined ICERs were £96,548 per quality-adjusted life year (QALY) gained when a survival benefit was assumed and £4,694,943 per QALY gained when no survival benefit was assumed. It recalled that the economic assessment may not have fully captured the quality-of-life benefits of vismodegib, but taking this into account would not lower the estimate of cost effectiveness to an acceptable level. The committee was also aware that a confidential patient access scheme for vismodegib was available but noted that the ICERs remained substantially above a level that could be considered a cost-effective use of NHS resources.\n\n# Cancer Drugs Fund\n\n## Vismodegib does not meet the criteria to be included in the Cancer Drugs Fund\n\nThe committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee agreed that there is substantial uncertainty about the clinical benefit of vismodegib in terms of overall survival and that this was a key driver of the results in the model, but it did not consider that data collection for around 2\xa0years would sufficiently reduce the uncertainty around this. Importantly, the committee did not see any plausible potential for vismodegib to satisfy the criteria for routine use based on its confidential patient access scheme price. It therefore concluded that vismodegib did not meet the criteria to be included in the Cancer Drugs Fund.\n\n# Other factors\n\n## The committee did not identify any other factors that affected its recommendations\n\nNo equality or social value judgement issues were identified.\n\nThe Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of the technology.\n\nThe committee discussed the company's comments about the innovative nature of vismodegib. It heard from the clinical expert that vismodegib is the only treatment option available for advanced BCC that is inappropriate for surgery and radiotherapy. It delays disease progression and improves quality of life. The committee recalled its consideration that the model may not have fully captured the quality-of-life benefits associated with vismodegib. However, the committee considered that accounting for this would not lower the ICERs to an acceptable level, especially considering the uncertainties in the evidence. The committee concluded that vismodegib may be associated with benefits, but more robust comparative data are needed to support its long-term efficacy profile."}
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https://www.nice.org.uk/guidance/ta489
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Evidence-based recommendations on vismodegib (Erivedge) for treating basal cell carcinoma in adults.
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ef15145df33b5c2a8f16ff325892f476524cbe4d
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Trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane
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Trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane
Evidence-based recommendations on trastuzumab emtansine (Kadcyla) for human epidermal growth factor receptor 2 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who have had trastuzumab and a taxane.
# Recommendations
Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for treating human epidermal growth factor receptor 2 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Trastuzumab emtansine is recommended only if the company provides it with the discount agreed in the patient access scheme.
# The technology
Description of the technology
Trastuzumab emtansine (Kadcyla; Roche) is an antibody‑drug conjugate consisting of trastuzumab linked to maytansine, which is a cytotoxic agent. Because the antibody targets human epidermal growth factor receptor 2 (HER2), and HER2 is overexpressed in breast cancer cells, the conjugate delivers the toxin directly to the cancer cells.
Marketing authorisation
Trastuzumab emtansine, as a single agent, has a UK marketing authorisation 'for the treatment of adult patients with HER2‑positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
received prior therapy for locally advanced or metastatic disease or
developed disease recurrence during or within 6 months of completing adjuvant therapy'.
Adverse reactions
The summary of product characteristics includes the following adverse reactions for trastuzumab emtansine: increase in serum transaminases, left ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, decreased platelet counts, an immune response to trastuzumab emtansine, and reactions secondary to the accidental administration of trastuzumab emtansine around infusion sites. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Trastuzumab emtansine is administered as an intravenous infusion. The recommended dose is 3.6 mg/kg bodyweight every 3 weeks (21‑day cycle). Patients should have treatment until the disease progresses or unacceptable toxicity occurs.
Price
The list price for trastuzumab emtansine is £1,641.01 for a 100‑mg vial and £2,625.62 for a 160‑mg vial (excluding VAT, British national formulary online, accessed February 2017). The company estimates that the average cost of a course of treatment is £91,614, using the list price, and based on a 3‑weekly dose of 3.6 mg/kg, a patient weight of 70.1 kg and an average length of treatment of 14.5 months.
The pricing arrangement considered during guidance development was one in which Roche had agreed a complex patient access scheme with the Department of Health. In October 2017 Roche agreed a simple discount patient access scheme with the Department of Health. The discount to the list price is applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). The appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance 371 (TA371) on trastuzumab emtansine for the treatment of HER2‑positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. The committee also considered the updated cost-effectiveness analyses submitted by Roche after consultation and their critique by the ERG.
Sections 4.1 to 4.26 reflect the committee's consideration of the evidence submitted in December 2013 for the original appraisal and the subsequent responses to consultation received during the development of TA371. The company included 2 randomised controlled trials in its original submission: EMILIA and TH3RESA. Both trials were international, open-label trials evaluating the safety and efficacy of trastuzumab emtansine (3.6 mg/kg every 3 weeks) for human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer. EMILIA compared trastuzumab emtansine with lapatinib plus capecitabine, and TH3RESA compared it with the clinician's choice of treatment. The company used 4 additional randomised controlled trials, together with EMILIA, in a mixed treatment comparison of trastuzumab emtansine and the other comparators listed in the scope. Sections 4.27 to 4.35 reflect the committee's consideration of the evidence submitted for the Cancer Drugs Fund reconsideration. The new evidence included additional follow-up data from EMILIA, which was used to model overall survival. New cost-effectiveness analyses were done using a complex patient access scheme. The patient access scheme considered by the committee was subsequently replaced by a commercial access agreement between Roche and NHS England. The commercial access agreement provides similar reductions in the total costs of treatment to the latest patient access scheme offer, and a simpler operational approach. The details of the agreement are commercial in confidence.
See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence, and the history for full details of the evidence used in NICE's original technology appraisal guidance on trastuzumab emtansine.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of trastuzumab emtansine, having considered evidence on the nature of human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer and the value placed on the benefits of trastuzumab emtansine by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical effectiveness (NICE technology appraisal guidance 371)
The committee discussed with patient experts the nature of the condition and the perceived benefits of trastuzumab emtansine for patients. It heard that metastatic breast cancer is a debilitating condition that can affect women of all ages and leads to premature death. The committee heard from the patient experts that patients and their families often highly value what may seem to others even relatively short extensions to life, as long as the person's quality of life is maintained. The committee noted that patients are particularly concerned about unpleasant side effects associated with treatment. The clinical experts explained that trastuzumab emtansine is both an effective treatment and also well tolerated, with fewer side effects than some of the other options. The committee recognised that patients value the availability of more treatment options and that trastuzumab emtansine would be welcomed by patients and their families.
The committee discussed with the clinical experts the current clinical management of HER2‑positive metastatic breast cancer. It was aware that NICE recommends trastuzumab plus paclitaxel as a first-line treatment for people who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate (see NICE's guidance on the use of trastuzumab for the treatment of advanced breast cancer). After disease progression, NICE recommends second- and third-line treatment with non-targeted therapies such as capecitabine or vinorelbine, which can be combined with continued trastuzumab therapy if disease progression is within the central nervous system alone (see NICE's guideline on advanced breast cancer). The committee heard from the clinical experts that trastuzumab plus chemotherapy has become the standard first-line treatment in clinical practice, but more recently in England patients may receive pertuzumab in addition to trastuzumab and docetaxel, which is funded by the Cancer Drugs Fund. It further heard that after disease progression on trastuzumab (that is, in the second-line setting) clinical practice varies, but most patients will continue trastuzumab plus chemotherapy (capecitabine or vinorelbine) or receive lapatinib plus capecitabine. The committee noted that continued trastuzumab therapy was not offered by all cancer centres, and that lapatinib plus capecitabine was available in England through the Cancer Drugs Fund. The committee heard from the clinical experts that contrary to NICE guidance, single-agent chemotherapy (for example, capecitabine or vinorelbine) is not routinely used for patients whose disease progressed on first-line treatment. The committee concluded that local access to treatments and the availability of treatments through the Cancer Drugs Fund led to some variation in clinical practice so that no single pathway of care could be defined.
The committee considered the likely position of trastuzumab emtansine in the treatment pathway of HER2‑positive, unresectable, locally advanced or metastatic breast cancer and the key comparators for trastuzumab emtansine in clinical practice. It noted that the clinical experts expect that trastuzumab emtansine would be used as second-line therapy (that is, instead of continued trastuzumab plus chemotherapy or lapatinib plus capecitabine) because trastuzumab emtansine has been shown to be more clinically effective than the alternative second‑line agent, lapatinib plus capecitabine, in EMILIA. The committee concluded that based on current clinical practice, trastuzumab plus capecitabine, trastuzumab plus vinorelbine and lapatinib plus capecitabine were relevant comparators at this stage of the disease.
The committee discussed which sources of trial data were appropriate for the second-line setting, in which trastuzumab emtansine is likely to be used. The committee was aware that 36% of patients in EMILIA and 0% of patients in TH3RESA received trastuzumab emtansine as second-line therapy for locally advanced or metastatic disease. Given these proportions, the committee concluded that EMILIA was the most relevant source of clinical evidence for its decision-making in this appraisal.
The committee discussed whether the results from EMILIA were generalisable to clinical practice, noting that patients in England may receive pertuzumab plus trastuzumab plus docetaxel in the first-line setting. It heard from the company that 9.5% of patients in EMILIA had previously received pertuzumab therapy (10.3% of patients in the trastuzumab emtansine group, 8.7% of patients in the lapatinib plus capecitabine group) but the committee considered this proportion too small to determine whether the effect of trastuzumab emtansine differed in patients who had previously received pertuzumab. In addition, the committee heard from the clinical experts that there was no evidence on whether or not pertuzumab can modify the effect of subsequent treatment with trastuzumab emtansine. However, the clinical experts indicated that trastuzumab emtansine demonstrated a clinical benefit after trastuzumab, and that trastuzumab and pertuzumab have similar mechanisms of action, so the effect of trastuzumab emtansine would not be expected to differ after trastuzumab or after pertuzumab plus trastuzumab. The committee concluded that it was currently unknown whether previous pertuzumab would alter the clinical effectiveness of subsequent treatment with trastuzumab emtansine, but there was no positive evidence that this was the case.
The committee also noted the evidence review group's (ERG's) concern that none of the patients in EMILIA had an Eastern Cooperative Oncology Group (ECOG) performance status of 2, whereas in clinical practice around one third of patients would have an ECOG performance status of 2. The committee appreciated that patients enrolled in clinical trials may be younger and with better performance status than those in routine clinical practice, and so might have better outcomes. The committee agreed that the population in EMILIA was otherwise reasonably representative of patients in the UK. It concluded that the results of EMILIA were suitable for assessing the clinical effectiveness of trastuzumab emtansine in clinical practice.
The committee considered the clinical effectiveness of trastuzumab emtansine as a second-line treatment. It was aware that in EMILIA, patients in the trastuzumab emtansine group had improved survival compared with patients in the lapatinib plus capecitabine group, irrespective of the line of therapy. However, the committee noted that subgroup analyses suggested a lesser benefit in patients who received second‑line treatment (in whom the difference in effect was not statistically significant) than in the overall population. The committee was aware that the analysis may not have been powered to show a difference in treatment effect in the subgroup. In addition, the committee heard from the clinical experts that there is no biologically plausible reason for the effect to differ according to the number of previous treatments patients had received. The committee concluded that the subgroup analysis was not reliable enough to inform a decision about the clinical effectiveness of trastuzumab emtansine as a second-line treatment.
The committee took note of the patient expert's concern about the tolerability of treatment and discussed the adverse events in EMILIA that led patients to stop treatment, which it considered to be a reasonable proxy for tolerability. The committee understood that fewer patients stopped treatment because of an adverse event in the trastuzumab emtansine group than in the lapatinib plus capecitabine group (5.9% and 17% of patients respectively). It also heard from the company that the most common adverse event that resulted in patients stopping trastuzumab emtansine was a decreased platelet count (2% of patients). The committee concluded that trastuzumab emtansine had been shown to have a satisfactory adverse event profile in EMILIA.
The committee considered the Bayesian mixed treatment comparison used by the company to estimate hazard ratios for trastuzumab emtansine relative to the comparators for which no head-to-head evidence existed. The committee agreed that CEREBEL, an open-label trial comparing the incidence of central nervous system metastases in patients with HER2‑positive metastatic breast cancer treated with lapatinib plus capecitabine or trastuzumab plus capecitabine, and the study by Martin et al. (2011), should be included in the base-case analysis to use all available evidence and that the ERG's random effects model would better reflect the heterogeneity between the trials than the company's fixed effect model.
# Cost effectiveness (NICE technology appraisal guidance 371)
The committee considered the company's economic model used to estimate the cost effectiveness of trastuzumab emtansine and how it captured the main aspects of the condition. It noted that the company used a 3‑state model and chose a time horizon of 10 years for its base case. The committee agreed that the model structure was consistent with other models used for the same disease. The committee noted that the ERG preferred a 15‑year time horizon because a small proportion of patients were still alive at 10 years and data for these patients would not be included in a model with a 10‑year horizon. The committee agreed that in principle a lifetime time horizon should be used to capture all long-term costs and health effects. It concluded that the company's model was appropriate to estimate the cost effectiveness of trastuzumab emtansine, but that a 15‑year time horizon should be used.
The committee considered the utility values used in the company's model. It noted that in the progression-free state, the company applied a higher utility value for trastuzumab emtansine than for its comparators. The company considered that the favourable side effect profile of trastuzumab emtansine supports using a distinct utility value for trastuzumab emtansine. The committee questioned whether utility values should differ for each treatment because the clinical experts indicated that most adverse events resolve within a few weeks, whereas in the model the utility values were applied throughout the entire progression-free state. In addition, the committee considered that applying a higher utility value for trastuzumab emtansine could result in treatment benefit being double-counted and overestimated, because the utility decrements for adverse events already capture part of this benefit. In response to the appraisal consultation document for NICE technology appraisal guidance 371, the company clarified that the utility decrements for adverse events were not applied separately in the model, but were incorporated into the utility values in the progression-free state, and therefore were applied only once. The committee heard from the ERG that, although the modelling of adverse events had limitations, the benefit of trastuzumab emtansine from reducing adverse events was not double-counted in the model. The committee acknowledged the additional evidence submitted by the company in response to the appraisal consultation document. It noted that the evidence suggested that in EMILIA, patients who received trastuzumab emtansine felt better and reported being less troubled by side effects than those who received lapatinib plus capecitabine. The committee was aware that EMILIA was an open-label trial, which may have introduced bias in the outcomes reported by patients, but noted the additional evidence on wellbeing and side effects presented by the company. The committee concluded that a marginally higher utility value for trastuzumab emtansine in the progression-free state could be accepted in this appraisal.
The committee noted that in its cost-effectiveness analysis, the company assumed clinical equivalence between capecitabine and vinorelbine, and between trastuzumab plus capecitabine and trastuzumab plus vinorelbine. The committee discussed with the clinical experts whether this assumption was clinically plausible. The clinical experts indicated that any chemotherapy would produce additional benefit when combined with trastuzumab. They stated that the precise clinical difference between capecitabine and vinorelbine had not been established in clinical trials, although in their opinion it would be reasonable to assume no difference. The committee concluded that, although it would be preferable to base the comparison on data from well-conducted clinical trials, the assumption of no difference between capecitabine- and vinorelbine-based regimens in the model could be justified for this appraisal.
The committee considered the adverse events associated with trastuzumab emtansine in relation to the economic modelling. It noted that the model incorporated utility decrements for only 3 adverse events and costs for 2 adverse events. The committee was concerned that this did not capture many adverse events associated with trastuzumab emtansine, including decreased platelet counts. The committee was aware that when the ERG included the costs of the adverse events that occurred frequently in EMILIA, this had little impact on the cost-effectiveness estimates. However, it concluded that the model should have incorporated both the decrease in utility and the increased costs associated with adverse events.
The committee considered the cost-effectiveness results for trastuzumab emtansine. It noted the company's suggestion that lapatinib plus capecitabine should be excluded from the analysis because the incremental cost-effectiveness ratio (ICER) for lapatinib plus capecitabine compared with capecitabine alone was £49,800 per quality-adjusted life year (QALY) gained, which the company considered to be above the acceptable maximum ICER normally regarded by NICE to represent cost-effective treatments. The committee was aware that excluding a technology based on its cost effectiveness in relation to a maximum ICER does not comply with the NICE reference case, which recommends a fully incremental cost–utility analysis. The committee agreed that there was no reason on this occasion to depart from the NICE reference case. It concluded that the cost effectiveness of trastuzumab emtansine should be evaluated in an incremental analysis comparing all technologies including lapatinib plus capecitabine.
The committee discussed the most plausible ICERs for trastuzumab emtansine without the patient access scheme. It agreed that lapatinib plus capecitabine, trastuzumab plus capecitabine and trastuzumab plus vinorelbine were in routine use in clinical practice in the NHS and should be included in the analysis. It also agreed that the analysis should use a 15‑year time horizon and incorporate the decrease in utility and increased costs associated with treating adverse events. The committee noted that in both the company's and ERG's base case, trastuzumab plus capecitabine and trastuzumab plus vinorelbine were more costly and less effective than lapatinib plus capecitabine (that is, they were dominated). The company's base-case ICER for trastuzumab emtansine compared with lapatinib plus capecitabine was £167,200 per QALY gained. The committee noted that the ERG's base-case ICER was very similar at £166,400 per QALY gained. At its first meeting, the committee agreed that the most plausible ICER was above the ICER range that would normally be considered a cost-effective use of NHS resources.
At its second meeting, the committee considered the revised cost-effectiveness results incorporating the patient access scheme submitted in response to the appraisal consultation document (which are commercial in confidence). It expressed disappointment that the patient access scheme did not reduce the ICER to a level close to one that could be accepted as a cost-effective use of NHS resources. The committee concluded that the size of the discount in the patient access scheme meant that it was still unable to recommend trastuzumab emtansine for treating HER2‑positive, unresectable, locally advanced or metastatic breast cancer after trastuzumab and a taxane.
The committee considered whether trastuzumab emtansine represents an innovative treatment. It acknowledged that trastuzumab emtansine is a novel antibody–drug conjugate combining the HER2-targeted anti-tumour activity of trastuzumab with a cytotoxic agent. It also noted that trastuzumab emtansine prolonged survival, with less toxicity than lapatinib plus capecitabine. However, the committee considered that all benefits of a substantial nature relating to treatment with trastuzumab emtansine had been captured in the QALY calculation, including the favourable adverse event profile and increased progression-free and overall survival.
The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The committee considered the criterion for short life expectancy. It agreed that the best estimate of expected survival using current standard NHS treatment was demonstrated in the control groups of the trials. The committee noted that in EMILIA, the median overall survival of patients in the lapatinib plus capecitabine group was 25.1 months. The committee noted the company's response to the appraisal consultation document suggesting that lapatinib plus capecitabine should not be considered a comparator in the context of life-extending treatments at the end of life because it is only available through the Cancer Drugs Fund. The committee was aware that it should be guided by established practice in the NHS when identifying the appropriate comparators, irrespective of how these are funded. The committee noted that lapatinib plus capecitabine was the comparator treatment in EMILIA, and after discussion with clinical experts the committee agreed that lapatinib plus capecitabine was a clinically relevant comparator in the second-line setting. Lapatinib plus capecitabine was also the relevant comparator for trastuzumab emtansine in the incremental cost-effectiveness analysis. After further consideration, the committee did not change its view that the evaluation of expected survival with current standard of care should be based on that of patients receiving lapatinib plus capecitabine. However, the committee did note the comment from the company that if lapatinib plus capecitabine is to be a comparator, evidence on survival from sources other than EMILIA should be taken into account. Specifically, the comment highlighted that in a clinical trial of lapatinib plus capecitabine compared with capecitabine alone (Cameron et al. 2010) the median survival with lapatinib plus capecitabine was 75 weeks (18.8 months). The committee considered evidence from this trial, together with other trials for lapatinib plus capecitabine in patients with advanced breast cancer. It noted that patients who received lapatinib plus capecitabine in EMILIA appeared to have lived longer than those who received it in other trials, in which median survival on this treatment generally fell below 24 months. However, the committee did not have details of the patient characteristics at baseline in these trials, so it could not compare them directly with EMILIA or determine the extent to which they were generalisable to clinical practice. The committee also noted that the mean survival with lapatinib plus capecitabine estimated by the company in its cost-effectiveness analysis was 30.4 months. The committee found it difficult to evaluate this conflicting evidence, but after review of the reported median survival from several trials of lapatinib plus capecitabine, it was prepared to accept that trastuzumab emtansine fulfilled this criterion. It also accepted that trastuzumab emtansine fulfilled the other 2 end-of-life criteria, namely a small patient population (approximately 1,200) and a survival gain of at least 3 months. The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for end-of-life consideration.
Based on the considerations in section 4.19, the committee discussed whether trastuzumab emtansine represents a cost-effective use of NHS resources. It agreed that, even taking into account additional weights applied to QALY benefits for a life-extending treatment at the end of life, the ICER incorporating the patient access scheme remained well above the range that could be considered a cost-effective use of NHS resources. The committee concluded that trastuzumab emtansine could not be recommended for treating HER2-positive, unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane.
# Pharmaceutical Price Regulation Scheme (PPRS)
The committee met after an appeal against the final appraisal determination for this appraisal, which was upheld. The appeal panel had concluded that 'the 2014 PPRS should have been taken into account, or, alternatively and sufficiently for this appeal, that the possibility of the PPRS being relevant had not been sufficiently considered and its irrelevance established'. The committee noted that, after this appeal, NICE had sought a view from the Department of Health about whether it should take account of the payment mechanism set out in the 2014 PPRS agreement in its technology appraisals. In the Department of Health's view, 'the 2014 PPRS does not place obligations on, nor create expectations of, NICE other than where these are explicitly stated in that agreement'. The Department of Health noted paragraph 4.9 of the PPRS which states that 'the basic cost-effectiveness threshold used by NICE will be retained at a level consistent with the current range and not changed for the duration of the scheme', and stated that 'the PPRS contains no other provisions which require NICE to adopt a particular approach or method for technology appraisals, or to make an adjustment to its considerations to take account of the payment arrangements set out in the scheme agreement'. The committee understood that, in response to the appeal decision, NICE developed a position statement about the relevance of the 'PPRS payment mechanism' of the 2014 PPRS to assessing the cost effectiveness of new branded medicines. This took into account the views obtained from the Department of Health. It was subsequently refined in a targeted consultation with the Department of Health, the Association of the British Pharmaceutical Industry (ABPI), and NHS England. The NICE position statement concluded that 'the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee noted the response from the ABPI, an association with 57 pharmaceutical company members, which stated that the ABPI had no comments on the substance of the position statement, and welcomed the statement. The committee also noted the ABPI comment that: 'Indeed, any other interpretation may increase the risk of legal challenge from other companies'. The committee was, however, aware that the company continued to believe that it was 'unfair to disregard the consideration of PPRS payments within the appraisal process' and was 'deeply disappointed' by the conclusion of the position statement. Company representatives at the meeting stated that the company's opinion was that the NICE position statement should state that 'the 2014 PPRS payment mechanism should, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines', and that it should apply to all technology appraisals, not just to the appraisal of trastuzumab emtansine. The committee concluded that the 2 sole negotiators for the PPRS, that is the Department of the Health and the ABPI, fully supported the NICE position statement, but that the company disagreed with it.
The committee discussed what the NICE position statement meant for its consideration of cost effectiveness. It noted the company's suggestion that the failure of NICE to identify a solution was not sufficient reason for the committee to disregard the impact of the 2014 PPRS on its appraisal of trastuzumab emtansine. The company representatives stated that the company's view was that the committee should disregard the NICE position statement, and either accept the 'pragmatic solution' suggested in the company's formal response (see section 4.25), or itself devise some other mechanism to incorporate the PPRS into its evaluation of cost effectiveness. The committee reminded itself that its role was limited to making recommendations to NICE about the clinical and cost effectiveness of treatments for use within the NHS, in line with the guide to the methods of technology appraisal (2013). This states that the committee should not recommend treatments that are not cost effective. It also recalled paragraph 6.2.14 of the guide, which states that: 'The potential budget impact of the adoption of a new technology does not determine the appraisal committee's decision'. The committee concluded that it was not responsible for devising new methods for estimating cost effectiveness and, further, it had neither the remit nor the expertise to do so. Furthermore, it understood that the position statement had been issued as guidance to all NICE technology appraisal committees to ensure consistency of decision-making. It therefore took the view that the NICE position statement should not be disregarded without clear and coherent reasons for doing so.
The committee discussed whether the PPRS could potentially be relevant to assessing opportunity costs that underlie a NICE appraisal; that is, would NHS adoption of trastuzumab emtansine, or other branded medicines that were not cost effective, come without additional cost to society, and without reducing spending on other more cost-effective treatments. It noted that the rationale for the NICE position statement was that it was not clear how payments made under the 2014 scheme were being applied in providing NHS services. The payments were not mandated to be allocated to local drug budgets and so would not automatically or routinely allow local commissioners or NHS England to revise their assessment of the opportunity costs of branded medicines. The committee also noted NHS England's question and answer document for the NHS on the Pharmaceutical Price Regulation Scheme (PPRS), which states that 'the agreement makes no provision for what happens to the PPRS payments, so there is no commitment for the Department of Health to make any additional payments to the NHS'. Moreover, the committee was aware that any rebates for drug costs are paid quarterly, so even if the PPRS payments were repaid to the NHS, and directly to local commissioners, who have finite budgets, decisions would have to be made to temporarily reduce funding other health services until the PPRS payments are received, which would incur opportunity cost. In addition, there would be no rebate for administration or other follow-on medical costs incurred from introducing a new technology. The committee also understood that, under the terms of the 2014 PPRS, when the allowed growth rate is exceeded, companies will make a cash payment of a percentage applied to sales covered by the PPRS payment during the relevant quarter (excluding products launched after 1 January 2014), and that percentage will be equal for all companies. Therefore, the committee considered that the opportunity cost would not only be borne by the NHS, but also by other companies who have joined the 2014 PPRS, and would have to contribute a larger share to the rebate based on how much the allowed spend was exceeded because of trastuzumab emtansine prescribing. The committee concluded that, as it stands, the 2014 PPRS does not remove the opportunity cost from funding treatments that are not considered to be cost effective according to the normal methods of technology appraisals, and that the precise and full costs of introducing a new technology into the NHS were not covered or rebated through the PPRS.
The committee noted that the essence of the position statement was that NICE did not consider that the 2014 PPRS enabled rebates to be transparently attributed to the acquisition cost of individual branded medicines at the time of the appraisal, and so could not identify a way in which the 2014 PPRS could fit within NICE's framework of appraising cost effectiveness. However, the statement did provide for potential exceptions to the general position of NICE. The committee referred to the guidance in the guide to the methods of technology appraisal (2013) on considering prices for technologies in cost-effectiveness analyses. Specifically, it noted paragraph 5.5.2 which states that the public list prices for technologies should be used in the reference case analysis or alternatively, and when nationally available, price reductions, provided that these are transparent and consistently available across the NHS, and the period for which the specified price is available is guaranteed. Because of the role of the committee and the basis for the position statement, the committee concluded that it would only be able to apply the exception provided for in the position statement if the PPRS mechanism could be shown to reduce the cost of the technology to the NHS, and still be in keeping with paragraph 5.5.2 of the guide.
The committee discussed the company's proposal that the committee issues positive guidance on trastuzumab emtansine conditional on the following:
The company remains within the 2014 PPRS scheme.
The spend level within the 2014 PPRS scheme remains above the agreed growth levels.
Guidance is reviewed at the start of the 2019 PPRS scheme.The committee noted that the company's proposal did not show how the PPRS rebate mechanism can be applied directly to the cost to the NHS of trastuzumab emtansine, in a way that could be incorporated into a cost-effectiveness analysis. It also heard from NICE that accepting this proposal would potentially be unlawful for a number of reasons. Firstly, the committee would be overriding current guidance on the assessment of the cost effectiveness of health technologies and, by not applying its published methods of technology appraisal, this implies that NICE would not be fulfilling its statutory functions. This would also be incongruous with the 2014 PPRS itself, which states that 'the basic cost-effectiveness threshold used by NICE will be retained at a level consistent with the current range and not changed for the duration of the scheme', indicating that NICE should continue to assess cost effectiveness. Secondly, accepting the proposal would potentially impact on the financial position of other pharmaceutical companies, with the potential legal implications referred to in the ABPI's response to consultation on the NICE position statement (see section 4.21). Thirdly, there is already a mechanism within the existing process for companies to propose special pricing arrangements to be taken into account in technology appraisals; patient access schemes. These have to be approved by the Department of Health, which is also responsible for the 2014 PPRS. The committee noted that the company could have used this mechanism to apply a price discount in line with what it believed would be the true cost of trastuzumab emtansine to the NHS, in the context of the 2014 PPRS. Accepting the company's proposal would, therefore, transcend the existing framework. In summary, the committee was not satisfied that the company's proposal demonstrated that the impact of the PPRS rebate could be traced back to the opportunity cost of trastuzumab emtansine within the existing NICE guide to the methods of technology appraisal (2013), and NICE's statutory functions. Because of this, the committee concluded that the company's proposal did not represent an exception that might lead it to depart from the general position in the NICE statement.
In conclusion, the committee did not hear anything that it could consider to be reasonable grounds to disregard the NICE position statement in this appraisal. The committee agreed that it may consider the 2014 PPRS if specific proposals are put forward, if these fit within the methods and processes of technology appraisal and are consistent with NICE's statutory functions. However, it did not consider that such proposals had been put forward in this appraisal. Therefore, the committee concluded that the 2014 PPRS did not affect its previous recommendations about trastuzumab emtansine.
# Cancer Drugs Fund reconsideration
This appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2‑positive, unresectable, locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. In its revised submission, the company included:
an additional 2 years' follow-up data from EMILIA, which was used to model overall survival
a complex patient access scheme in which the NHS would pay for trastuzumab emtansine up to the first 14 months of treatment for each patient, and the company would pay for trastuzumab emtansine for any patients remaining on treatment beyond 14 months (which was subsequently amended after the first committee meeting) and
an updated model incorporating new data and using some of the committee's preferred assumptions (see sections 4.10 to 4.20):
extending the model time horizon from 10 to 15 years
incorporating the follow-up costs of left ventricular ejection fraction monitoring
correcting the utility values for adverse events (although the ERG suggested that these may still be incorrect)
using the actual dose of trastuzumab emtansine and lapatinib plus capecitabine rather than the planned dose
revising the parameters for the probabilistic sensitivity analysis and
estimating the post-progression treatment costs.
## Clinical management of HER2‑positive advanced breast cancer
The committee heard from the clinical experts that trastuzumab emtansine is an effective treatment, which improves overall survival by several months compared with other HER2‑directed treatments. The clinical experts recognised that trastuzumab emtansine is not suitable for everyone, but noted that it is particularly well tolerated in many people compared with other treatments. The committee heard that the other treatment options have a worse toxicity and side effect profile than trastuzumab emtansine. It also heard that, on average, after 6 months of capecitabine treatment people start to have major side effects, which reduce treatment effectiveness and cause people to stop treatment. This also applies to the combination therapies, trastuzumab plus capecitabine and lapatinib plus capecitabine. People whose disease responds well to trastuzumab emtansine have improved quality of life as well as longer life. The clinical experts noted that they can assess whether trastuzumab emtansine is effective or limited by toxicity within 3 cycles. Treatment normally continues until disease progression. The clinical experts stated that the next line of treatment after trastuzumab emtansine would depend on the person's treatment history, but options were limited at this stage, and often this would be palliative care.
## Patient experience
The patient experts described the benefits of treatment with trastuzumab emtansine. They stated that as well as the treatment stopping the progression of the condition, quality of life is better with trastuzumab emtansine than with other treatments. They noted that the side effects are minimal so they no longer need to be admitted to hospital or confined to bed after treatment. The patient experts stated that trastuzumab emtansine has removed some of the fear associated with their disease and has given them quality time with family and friends. They also emphasised that trastuzumab emtansine has helped them to live their lives fully and continue working, 2 factors that are very important and highly valued by patients, especially because many are relatively young women with caring responsibilities. They stated that if the drug were not available there would be no other suitable treatments for them.
The committee acknowledged the comments from patients after consultation, in particular that 115,000 people have signed a Breast Cancer Now petition urging NICE and Roche to ensure that trastuzumab emtansine remains available for patients in England. The committee appreciated how important it is for effective treatments for breast cancer to be available, but noted that its role was to consider the clinical and cost effectiveness of this technology at the price set by the company (including any nationally agreed access arrangements). Nevertheless, the committee acknowledged that it was relevant that the treatment had been provided to patients in the NHS in England for 3 years so that patients and clinicians would view a negative recommendation as 'taking away' an existing NHS funded treatment. Although it could be argued that the opportunity cost issues are not the same for a previously funded drug as for one that requires new NHS investment, the NICE methods guide does not have any specific mechanisms or advice which apply to this situation.
## Comparators
The committee noted that the company had excluded some of the comparators listed in the original appraisal from the incremental analysis in the revised submission. The committee assumed that vinorelbine had been excluded because it was expected to be dominated (less effective and more costly) by capecitabine. The company also excluded lapatinib plus capecitabine from the cost-effectiveness analysis because lapatinib was removed from the Cancer Drugs Fund in January 2015. The company stated that it has independent audit data to suggest that lapatinib plus capecitabine no longer represents current practice in England. The committee heard that lapatinib was removed from the Cancer Drugs Fund because the evaluation score (which considers clinical effectiveness, toxicity and drug cost for the Cancer Drugs Fund) for lapatinib plus capecitabine was considered to be too low to keep it in the Fund. The committee heard from the Cancer Drugs Fund clinical lead that drugs that had been removed from the Cancer Drugs Fund were no longer commissioned in England. The committee noted that lapatinib plus capecitabine was removed after trastuzumab emtansine became available. Since then, trastuzumab emtansine has become part of NHS clinical practice, and has replaced the comparator treatments listed in the original scope. The committee noted the company's opinion that trastuzumab plus capecitabine should be considered as the main comparator for trastuzumab emtansine. Responses from other consultees and commentators supported this view. The committee heard from the clinical expert and the Cancer Drugs Fund clinical lead that if trastuzumab emtansine were not available, trastuzumab plus capecitabine was likely to be offered to patients with HER2-positive advanced breast cancer who had relapsed after first-line trastuzumab-based therapy. The committee noted that trastuzumab plus capecitabine does not have a marketing authorisation for this indication but was aware that according to section 6.2 of the NICE guide to the methods of technology appraisal, comparators without a marketing authorisation for the relevant indication can be considered as comparators by the committee if they are part of established practice in the NHS. It also noted that based on the results of the network meta-analysis, trastuzumab plus capecitabine showed similar clinical effectiveness to lapatinib plus capecitabine. Overall the committee concluded that based on what it had heard from experts at the committee meeting and in light of the consultation comments, trastuzumab plus capecitabine is the most relevant comparator.
## The company's revised economic model
The committee considered the company's updated economic model submitted for the Cancer Drugs Fund reconsideration and the subsequent updates in response to the ERG's critique. It also considered the ERG's exploratory analyses. It acknowledged that the final version of the model from the company took into account the ERG's concerns about the plausibility of the methods used in the probabilistic sensitivity analysis in the model. The company:
used patient-level data to calculate vial use
excluded an additional adjustment for wastage
updated the patient access scheme and
updated the probabilistic sensitivity analysis in line with the ERG's suggestions.The committee heard from the ERG that the patient access scheme and other amendments had been accurately incorporated in the model. The committee agreed that the company's changes were plausible. It also noted that the updated probabilistic sensitivity analysis in the final version was validated by the ERG. In general the ERG was satisfied with the updated analysis, but it also tested alternative prior distributions to determine the sensitivity of the economic model. As a result, the cost-effectiveness results presented by the company and the ERG were very similar.
## Calculation of treatment costs
The committee considered the company's economic model and the ERG's critique. The committee noted that the company initially estimated average vial use using the average dose from EMILIA, but also used patient-level data to calculate vial use after a request from the ERG. The committee noted that using patient-level data increased the ICER compared with the company's base case, but it recognised that this did not account for dose reductions or treatment breaks. The committee heard that there is vial sharing in oncology centres that have centralised intravenous drug preparation. This reduces the amount of wastage, but cannot stop it completely. The committee noted that the company's revised economic model assumed no wastage because it used patient-level data to calculate vial use, although the previous version of the model assumed that 50% of any drug remaining in a vial after the dose is drawn up is re-used and 50% is wasted. The committee concluded that some wastage needs to be included in the calculation of trastuzumab emtansine treatment costs, because assuming no wastage is not plausible.
## End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the updated median overall survival in the EMILIA intention-to-treat population was 25.9 months for people randomised to lapatinib plus capecitabine (it was 25.1 months at the time of the original appraisal), and 29.9 months for those randomised to trastuzumab emtansine. The committee recognised that during NICE's original appraisal of trastuzumab emtansine, evidence from other trials of lapatinib plus capecitabine in advanced breast cancer was also considered. The original appraisal committee noted that patients who received lapatinib plus capecitabine in EMILIA appeared to live longer than those who received it in other trials, in which median survival generally fell below 24 months. The committee also considered the evidence submitted by the company for life expectancy with trastuzumab plus capecitabine. It heard from the company that there are limited data available on the life expectancy of patients with metastatic breast cancer receiving trastuzumab with capecitabine as second-line treatment. However, data from the CEREBEL study (Pivot et al. 2015) suggests that it is likely to be around 24 months. The committee took into account that patients with metastatic disease who are eligible for trastuzumab emtansine had already progressed on first-line therapy and were in the advanced stages of the disease. Therefore the committee agreed to uphold the end-of-life decision from the original appraisal. It was aware that it was now looking at a different comparator from the one on which the original decision had been made (lapatinib plus capecitabine), but judged that any difference in survival between lapatinib plus capecitabine and trastuzumab and capecitabine was likely to be marginal, taking into account the results of the network meta-analysis (see section 4.31). The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for a life-extending, end-of-life treatment for HER2-positive advanced breast cancer.
## Conclusions
The committee noted that the updated evidence available since the original appraisal confirms that trastuzumab emtansine is clinically effective, with a statistically significant survival benefit compared with lapatinib plus capecitabine. Despite only indirect evidence of its effectiveness compared with trastuzumab plus capecitabine, there was no reason to consider that the relative benefits would not be comparable. Based on what the committee heard from experts at the committee meeting and in light of the consultation comments, it concluded that trastuzumab plus capecitabine is the most relevant comparator. Based on the clinical and cost-effectiveness analyses, including the updated complex patient access scheme, the most plausible ICER for trastuzumab emtansine compared with trastuzumab plus capecitabine was within the range that would normally be considered cost effective if the end-of-life criteria apply. The committee therefore concluded that trastuzumab emtansine could be recommended for use in the NHS for treating HER2-positive advanced breast cancer.
# Summary of appraisal committee's key conclusions
TA458
Appraisal title: Trastuzumab emtansine for treating HER2‑positive advanced breast cancer after trastuzumab and a taxane
Section
Key conclusion (Cancer Drugs Fund reconsideration of TA371)
Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for treating human epidermal growth factor receptor 2 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Trastuzumab emtansine is recommended only if the company provides it in line with the commercial access agreement with NHS England.
The updated evidence available since the original appraisal confirms that trastuzumab emtansine is clinically effective, with a statistically significant survival benefit compared with lapatinib plus capecitabine. Despite only indirect evidence of its effectiveness compared with trastuzumab plus capecitabine, there was no reason to consider that the benefits would not be comparable. Based on the clinical and cost-effectiveness analyses, including an updated complex patient access scheme (that was subsequently replaced by a commercial access agreement), the most plausible ICER for trastuzumab emtansine compared with trastuzumab plus capecitabine was within the range that would normally be considered cost effective if the end-of-life criteria apply.
Cancer Drugs Fund reconsideration of TA371
The company's revised submission included:
an additional 2 years follow-up data from EMILIA, which was used to model overall survival and
a complex patient access scheme.
After consultation an updated model was submitted, in which the company:
used patient-level data to calculate vial use
excluded an additional adjustment for wastage and
updated the patient access scheme and
updated the probabilistic sensitivity analysis in line with the ERG's suggestions.
The committee considered that based on what it heard from experts at the committee meeting and in light of the consultation comments, trastuzumab plus capecitabine is the only relevant comparator.
It also recognised that during NICE's original appraisal on trastuzumab emtansine, the original appraisal committee noted that patients who received lapatinib plus capecitabine in EMILIA appeared to live longer than those who received it in other trials, in which median survival generally fell below 24 months. The committee also considered the evidence submitted by the company for life expectancy with trastuzumab plus capecitabine. It heard from the company that data from the CEREBEL study (Pivot et al. 2015) suggests that it is likely to be around 24 months. The committee took into account that patients with metastatic disease eligible for trastuzumab emtansine had already progressed on first-line therapy, and were in the advanced stages of the disease. Therefore the committee agreed to uphold the end-of-life decision from the original appraisal. The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for a life-extending, end-of-life treatment for HER2‑positive advanced breast cancer.
Taking into account all factors, including the end-of-life criteria and the commercial access agreement that replaced the updated complex patient access scheme, trastuzumab emtansine could be recommended for use in the NHS for treating HER2-positive advanced breast cancer.
The complex patient access scheme was subsequently replaced by a commercial access agreement. See section 2 for further details.
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{'Recommendations': 'Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for treating human epidermal growth factor receptor\xa02 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease or developed disease recurrence during or within 6\xa0months of completing adjuvant therapy. Trastuzumab emtansine is recommended only if the company provides it with the discount agreed in the patient access scheme.\n\n', 'The technology': "Description of the technology\n\nTrastuzumab emtansine (Kadcyla; Roche) is an antibody‑drug conjugate consisting of trastuzumab linked to maytansine, which is a cytotoxic agent. Because the antibody targets human epidermal growth factor receptor\xa02 (HER2), and HER2 is overexpressed in breast cancer cells, the conjugate delivers the toxin directly to the cancer cells.\n\nMarketing authorisation\n\nTrastuzumab emtansine, as a single agent, has a UK marketing authorisation 'for the treatment of adult patients with HER2‑positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:\n\nreceived prior therapy for locally advanced or metastatic disease or\n\ndeveloped disease recurrence during or within 6\xa0months of completing adjuvant therapy'.\n\nAdverse reactions\n\nThe summary of product characteristics includes the following adverse reactions for trastuzumab emtansine: increase in serum transaminases, left ventricular dysfunction, infusion-related reactions, hypersensitivity reactions, decreased platelet counts, an immune response to trastuzumab emtansine, and reactions secondary to the accidental administration of trastuzumab emtansine around infusion sites. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nTrastuzumab emtansine is administered as an intravenous infusion. The recommended dose is 3.6\xa0mg/kg bodyweight every 3\xa0weeks (21‑day cycle). Patients should have treatment until the disease progresses or unacceptable toxicity occurs.\n\nPrice\n\nThe list price for trastuzumab emtansine is £1,641.01 for a 100‑mg vial and £2,625.62 for a 160‑mg vial (excluding VAT, British national formulary online, accessed February 2017). The company estimates that the average cost of a course of treatment is £91,614, using the list price, and based on a 3‑weekly dose of 3.6\xa0mg/kg, a patient weight of 70.1\xa0kg and an average length of treatment of 14.5\xa0months.\n\nThe pricing arrangement considered during guidance development was one in which Roche had agreed a complex patient access scheme with the Department of Health. In October 2017 Roche agreed a simple discount patient access scheme with the Department of Health. The discount to the list price is applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Roche and a review of this submission by the evidence review group (ERG). The appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance 371 (TA371) on trastuzumab emtansine for the treatment of HER2‑positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. The committee also considered the updated cost-effectiveness analyses submitted by Roche after consultation and their critique by the ERG.\n\nSections\xa04.1 to\xa04.26 reflect the committee's consideration of the evidence submitted in December 2013 for the original appraisal and the subsequent responses to consultation received during the development of TA371. The company included 2\xa0randomised controlled trials in its original submission: EMILIA and TH3RESA. Both trials were international, open-label trials evaluating the safety and efficacy of trastuzumab emtansine (3.6\xa0mg/kg every 3\xa0weeks) for human epidermal growth factor receptor\xa02 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer. EMILIA compared trastuzumab emtansine with lapatinib plus capecitabine, and TH3RESA compared it with the clinician's choice of treatment. The company used 4\xa0additional randomised controlled trials, together with EMILIA, in a mixed treatment comparison of trastuzumab emtansine and the other comparators listed in the scope. Sections\xa04.27 to\xa04.35 reflect the committee's consideration of the evidence submitted for the Cancer Drugs Fund reconsideration. The new evidence included additional follow-up data from EMILIA, which was used to model overall survival. New cost-effectiveness analyses were done using a complex patient access scheme. The patient access scheme considered by the committee was subsequently replaced by a commercial access agreement between Roche and NHS England. The commercial access agreement provides similar reductions in the total costs of treatment to the latest patient access scheme offer, and a simpler operational approach. The details of the agreement are commercial in confidence.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence, and the history for full details of the evidence used in NICE's original technology appraisal guidance on trastuzumab emtansine.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of trastuzumab emtansine, having considered evidence on the nature of human epidermal growth factor receptor\xa02 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer and the value placed on the benefits of trastuzumab emtansine by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness (NICE technology appraisal guidance 371)\n\nThe committee discussed with patient experts the nature of the condition and the perceived benefits of trastuzumab emtansine for patients. It heard that metastatic breast cancer is a debilitating condition that can affect women of all ages and leads to premature death. The committee heard from the patient experts that patients and their families often highly value what may seem to others even relatively short extensions to life, as long as the person's quality of life is maintained. The committee noted that patients are particularly concerned about unpleasant side effects associated with treatment. The clinical experts explained that trastuzumab emtansine is both an effective treatment and also well tolerated, with fewer side effects than some of the other options. The committee recognised that patients value the availability of more treatment options and that trastuzumab emtansine would be welcomed by patients and their families.\n\nThe committee discussed with the clinical experts the current clinical management of HER2‑positive metastatic breast cancer. It was aware that NICE recommends trastuzumab plus paclitaxel as a first-line treatment for people who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate (see NICE's guidance on the use of trastuzumab for the treatment of advanced breast cancer). After disease progression, NICE recommends second- and third-line treatment with non-targeted therapies such as capecitabine or vinorelbine, which can be combined with continued trastuzumab therapy if disease progression is within the central nervous system alone (see NICE's guideline on advanced breast cancer). The committee heard from the clinical experts that trastuzumab plus chemotherapy has become the standard first-line treatment in clinical practice, but more recently in England patients may receive pertuzumab in addition to trastuzumab and docetaxel, which is funded by the Cancer Drugs Fund. It further heard that after disease progression on trastuzumab (that is, in the second-line setting) clinical practice varies, but most patients will continue trastuzumab plus chemotherapy (capecitabine or vinorelbine) or receive lapatinib plus capecitabine. The committee noted that continued trastuzumab therapy was not offered by all cancer centres, and that lapatinib plus capecitabine was available in England through the Cancer Drugs Fund. The committee heard from the clinical experts that contrary to NICE guidance, single-agent chemotherapy (for example, capecitabine or vinorelbine) is not routinely used for patients whose disease progressed on first-line treatment. The committee concluded that local access to treatments and the availability of treatments through the Cancer Drugs Fund led to some variation in clinical practice so that no single pathway of care could be defined.\n\nThe committee considered the likely position of trastuzumab emtansine in the treatment pathway of HER2‑positive, unresectable, locally advanced or metastatic breast cancer and the key comparators for trastuzumab emtansine in clinical practice. It noted that the clinical experts expect that trastuzumab emtansine would be used as second-line therapy (that is, instead of continued trastuzumab plus chemotherapy or lapatinib plus capecitabine) because trastuzumab emtansine has been shown to be more clinically effective than the alternative second‑line agent, lapatinib plus capecitabine, in EMILIA. The committee concluded that based on current clinical practice, trastuzumab plus capecitabine, trastuzumab plus vinorelbine and lapatinib plus capecitabine were relevant comparators at this stage of the disease.\n\nThe committee discussed which sources of trial data were appropriate for the second-line setting, in which trastuzumab emtansine is likely to be used. The committee was aware that 36% of patients in EMILIA and 0% of patients in TH3RESA received trastuzumab emtansine as second-line therapy for locally advanced or metastatic disease. Given these proportions, the committee concluded that EMILIA was the most relevant source of clinical evidence for its decision-making in this appraisal.\n\nThe committee discussed whether the results from EMILIA were generalisable to clinical practice, noting that patients in England may receive pertuzumab plus trastuzumab plus docetaxel in the first-line setting. It heard from the company that 9.5% of patients in EMILIA had previously received pertuzumab therapy (10.3% of patients in the trastuzumab emtansine group, 8.7% of patients in the lapatinib plus capecitabine group) but the committee considered this proportion too small to determine whether the effect of trastuzumab emtansine differed in patients who had previously received pertuzumab. In addition, the committee heard from the clinical experts that there was no evidence on whether or not pertuzumab can modify the effect of subsequent treatment with trastuzumab emtansine. However, the clinical experts indicated that trastuzumab emtansine demonstrated a clinical benefit after trastuzumab, and that trastuzumab and pertuzumab have similar mechanisms of action, so the effect of trastuzumab emtansine would not be expected to differ after trastuzumab or after pertuzumab plus trastuzumab. The committee concluded that it was currently unknown whether previous pertuzumab would alter the clinical effectiveness of subsequent treatment with trastuzumab emtansine, but there was no positive evidence that this was the case.\n\nThe committee also noted the evidence review group's (ERG's) concern that none of the patients in EMILIA had an Eastern Cooperative Oncology Group (ECOG) performance status of 2, whereas in clinical practice around one third of patients would have an ECOG performance status of 2. The committee appreciated that patients enrolled in clinical trials may be younger and with better performance status than those in routine clinical practice, and so might have better outcomes. The committee agreed that the population in EMILIA was otherwise reasonably representative of patients in the UK. It concluded that the results of EMILIA were suitable for assessing the clinical effectiveness of trastuzumab emtansine in clinical practice.\n\nThe committee considered the clinical effectiveness of trastuzumab emtansine as a second-line treatment. It was aware that in EMILIA, patients in the trastuzumab emtansine group had improved survival compared with patients in the lapatinib plus capecitabine group, irrespective of the line of therapy. However, the committee noted that subgroup analyses suggested a lesser benefit in patients who received second‑line treatment (in whom the difference in effect was not statistically significant) than in the overall population. The committee was aware that the analysis may not have been powered to show a difference in treatment effect in the subgroup. In addition, the committee heard from the clinical experts that there is no biologically plausible reason for the effect to differ according to the number of previous treatments patients had received. The committee concluded that the subgroup analysis was not reliable enough to inform a decision about the clinical effectiveness of trastuzumab emtansine as a second-line treatment.\n\nThe committee took note of the patient expert's concern about the tolerability of treatment and discussed the adverse events in EMILIA that led patients to stop treatment, which it considered to be a reasonable proxy for tolerability. The committee understood that fewer patients stopped treatment because of an adverse event in the trastuzumab emtansine group than in the lapatinib plus capecitabine group (5.9% and 17% of patients respectively). It also heard from the company that the most common adverse event that resulted in patients stopping trastuzumab emtansine was a decreased platelet count (2% of patients). The committee concluded that trastuzumab emtansine had been shown to have a satisfactory adverse event profile in EMILIA.\n\nThe committee considered the Bayesian mixed treatment comparison used by the company to estimate hazard ratios for trastuzumab emtansine relative to the comparators for which no head-to-head evidence existed. The committee agreed that CEREBEL, an open-label trial comparing the incidence of central nervous system metastases in patients with HER2‑positive metastatic breast cancer treated with lapatinib plus capecitabine or trastuzumab plus capecitabine, and the study by Martin et al. (2011), should be included in the base-case analysis to use all available evidence and that the ERG's random effects model would better reflect the heterogeneity between the trials than the company's fixed effect model.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0371)\n\nThe committee considered the company's economic model used to estimate the cost effectiveness of trastuzumab emtansine and how it captured the main aspects of the condition. It noted that the company used a 3‑state model and chose a time horizon of 10\xa0years for its base case. The committee agreed that the model structure was consistent with other models used for the same disease. The committee noted that the ERG preferred a 15‑year time horizon because a small proportion of patients were still alive at 10\xa0years and data for these patients would not be included in a model with a 10‑year horizon. The committee agreed that in principle a lifetime time horizon should be used to capture all long-term costs and health effects. It concluded that the company's model was appropriate to estimate the cost effectiveness of trastuzumab emtansine, but that a 15‑year time horizon should be used.\n\nThe committee considered the utility values used in the company's model. It noted that in the progression-free state, the company applied a higher utility value for trastuzumab emtansine than for its comparators. The company considered that the favourable side effect profile of trastuzumab emtansine supports using a distinct utility value for trastuzumab emtansine. The committee questioned whether utility values should differ for each treatment because the clinical experts indicated that most adverse events resolve within a few weeks, whereas in the model the utility values were applied throughout the entire progression-free state. In addition, the committee considered that applying a higher utility value for trastuzumab emtansine could result in treatment benefit being double-counted and overestimated, because the utility decrements for adverse events already capture part of this benefit. In response to the appraisal consultation document for NICE technology appraisal guidance\xa0371, the company clarified that the utility decrements for adverse events were not applied separately in the model, but were incorporated into the utility values in the progression-free state, and therefore were applied only once. The committee heard from the ERG that, although the modelling of adverse events had limitations, the benefit of trastuzumab emtansine from reducing adverse events was not double-counted in the model. The committee acknowledged the additional evidence submitted by the company in response to the appraisal consultation document. It noted that the evidence suggested that in EMILIA, patients who received trastuzumab emtansine felt better and reported being less troubled by side effects than those who received lapatinib plus capecitabine. The committee was aware that EMILIA was an open-label trial, which may have introduced bias in the outcomes reported by patients, but noted the additional evidence on wellbeing and side effects presented by the company. The committee concluded that a marginally higher utility value for trastuzumab emtansine in the progression-free state could be accepted in this appraisal.\n\nThe committee noted that in its cost-effectiveness analysis, the company assumed clinical equivalence between capecitabine and vinorelbine, and between trastuzumab plus capecitabine and trastuzumab plus vinorelbine. The committee discussed with the clinical experts whether this assumption was clinically plausible. The clinical experts indicated that any chemotherapy would produce additional benefit when combined with trastuzumab. They stated that the precise clinical difference between capecitabine and vinorelbine had not been established in clinical trials, although in their opinion it would be reasonable to assume no difference. The committee concluded that, although it would be preferable to base the comparison on data from well-conducted clinical trials, the assumption of no difference between capecitabine- and vinorelbine-based regimens in the model could be justified for this appraisal.\n\nThe committee considered the adverse events associated with trastuzumab emtansine in relation to the economic modelling. It noted that the model incorporated utility decrements for only 3\xa0adverse events and costs for 2\xa0adverse events. The committee was concerned that this did not capture many adverse events associated with trastuzumab emtansine, including decreased platelet counts. The committee was aware that when the ERG included the costs of the adverse events that occurred frequently in EMILIA, this had little impact on the cost-effectiveness estimates. However, it concluded that the model should have incorporated both the decrease in utility and the increased costs associated with adverse events.\n\nThe committee considered the cost-effectiveness results for trastuzumab emtansine. It noted the company's suggestion that lapatinib plus capecitabine should be excluded from the analysis because the incremental cost-effectiveness ratio (ICER) for lapatinib plus capecitabine compared with capecitabine alone was £49,800 per quality-adjusted life year (QALY) gained, which the company considered to be above the acceptable maximum ICER normally regarded by NICE to represent cost-effective treatments. The committee was aware that excluding a technology based on its cost effectiveness in relation to a maximum ICER does not comply with the NICE reference case, which recommends a fully incremental cost–utility analysis. The committee agreed that there was no reason on this occasion to depart from the NICE reference case. It concluded that the cost effectiveness of trastuzumab emtansine should be evaluated in an incremental analysis comparing all technologies including lapatinib plus capecitabine.\n\nThe committee discussed the most plausible ICERs for trastuzumab emtansine without the patient access scheme. It agreed that lapatinib plus capecitabine, trastuzumab plus capecitabine and trastuzumab plus vinorelbine were in routine use in clinical practice in the NHS and should be included in the analysis. It also agreed that the analysis should use a 15‑year time horizon and incorporate the decrease in utility and increased costs associated with treating adverse events. The committee noted that in both the company's and ERG's base case, trastuzumab plus capecitabine and trastuzumab plus vinorelbine were more costly and less effective than lapatinib plus capecitabine (that is, they were dominated). The company's base-case ICER for trastuzumab emtansine compared with lapatinib plus capecitabine was £167,200 per QALY gained. The committee noted that the ERG's base-case ICER was very similar at £166,400 per QALY gained. At its first meeting, the committee agreed that the most plausible ICER was above the ICER range that would normally be considered a cost-effective use of NHS resources.\n\nAt its second meeting, the committee considered the revised cost-effectiveness results incorporating the patient access scheme submitted in response to the appraisal consultation document (which are commercial in confidence). It expressed disappointment that the patient access scheme did not reduce the ICER to a level close to one that could be accepted as a cost-effective use of NHS resources. The committee concluded that the size of the discount in the patient access scheme meant that it was still unable to recommend trastuzumab emtansine for treating HER2‑positive, unresectable, locally advanced or metastatic breast cancer after trastuzumab and a taxane.\n\nThe committee considered whether trastuzumab emtansine represents an innovative treatment. It acknowledged that trastuzumab emtansine is a novel antibody–drug conjugate combining the HER2-targeted anti-tumour activity of trastuzumab with a cytotoxic agent. It also noted that trastuzumab emtansine prolonged survival, with less toxicity than lapatinib plus capecitabine. However, the committee considered that all benefits of a substantial nature relating to treatment with trastuzumab emtansine had been captured in the QALY calculation, including the favourable adverse event profile and increased progression-free and overall survival.\n\nThe committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe committee considered the criterion for short life expectancy. It agreed that the best estimate of expected survival using current standard NHS treatment was demonstrated in the control groups of the trials. The committee noted that in EMILIA, the median overall survival of patients in the lapatinib plus capecitabine group was 25.1\xa0months. The committee noted the company's response to the appraisal consultation document suggesting that lapatinib plus capecitabine should not be considered a comparator in the context of life-extending treatments at the end of life because it is only available through the Cancer Drugs Fund. The committee was aware that it should be guided by established practice in the NHS when identifying the appropriate comparators, irrespective of how these are funded. The committee noted that lapatinib plus capecitabine was the comparator treatment in EMILIA, and after discussion with clinical experts the committee agreed that lapatinib plus capecitabine was a clinically relevant comparator in the second-line setting. Lapatinib plus capecitabine was also the relevant comparator for trastuzumab emtansine in the incremental cost-effectiveness analysis. After further consideration, the committee did not change its view that the evaluation of expected survival with current standard of care should be based on that of patients receiving lapatinib plus capecitabine. However, the committee did note the comment from the company that if lapatinib plus capecitabine is to be a comparator, evidence on survival from sources other than EMILIA should be taken into account. Specifically, the comment highlighted that in a clinical trial of lapatinib plus capecitabine compared with capecitabine alone (Cameron et al. 2010) the median survival with lapatinib plus capecitabine was 75\xa0weeks (18.8\xa0months). The committee considered evidence from this trial, together with other trials for lapatinib plus capecitabine in patients with advanced breast cancer. It noted that patients who received lapatinib plus capecitabine in EMILIA appeared to have lived longer than those who received it in other trials, in which median survival on this treatment generally fell below 24\xa0months. However, the committee did not have details of the patient characteristics at baseline in these trials, so it could not compare them directly with EMILIA or determine the extent to which they were generalisable to clinical practice. The committee also noted that the mean survival with lapatinib plus capecitabine estimated by the company in its cost-effectiveness analysis was 30.4\xa0months. The committee found it difficult to evaluate this conflicting evidence, but after review of the reported median survival from several trials of lapatinib plus capecitabine, it was prepared to accept that trastuzumab emtansine fulfilled this criterion. It also accepted that trastuzumab emtansine fulfilled the other 2\xa0end-of-life criteria, namely a small patient population (approximately 1,200) and a survival gain of at least 3\xa0months. The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for end-of-life consideration.\n\nBased on the considerations in section\xa04.19, the committee discussed whether trastuzumab emtansine represents a cost-effective use of NHS resources. It agreed that, even taking into account additional weights applied to QALY benefits for a life-extending treatment at the end of life, the ICER incorporating the patient access scheme remained well above the range that could be considered a cost-effective use of NHS resources. The committee concluded that trastuzumab emtansine could not be recommended for treating HER2-positive, unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane.\n\n# Pharmaceutical Price Regulation Scheme (PPRS)\n\nThe committee met after an appeal against the final appraisal determination for this appraisal, which was upheld. The appeal panel had concluded that 'the 2014 PPRS should have been taken into account, or, alternatively and sufficiently for this appeal, that the possibility of the PPRS being relevant had not been sufficiently considered and its irrelevance established'. The committee noted that, after this appeal, NICE had sought a view from the Department of Health about whether it should take account of the payment mechanism set out in the 2014 PPRS agreement in its technology appraisals. In the Department of Health's view, 'the 2014 PPRS does not place obligations on, nor create expectations of, NICE other than where these are explicitly stated in that agreement'. The Department of Health noted paragraph\xa04.9 of the PPRS which states that 'the basic cost-effectiveness threshold used by NICE will be retained at a level consistent with the current range and not changed for the duration of the scheme', and stated that 'the PPRS contains no other provisions which require NICE to adopt a particular approach or method for technology appraisals, or to make an adjustment to its considerations to take account of the payment arrangements set out in the scheme agreement'. The committee understood that, in response to the appeal decision, NICE developed a position statement about the relevance of the 'PPRS payment mechanism' of the 2014 PPRS to assessing the cost effectiveness of new branded medicines. This took into account the views obtained from the Department of Health. It was subsequently refined in a targeted consultation with the Department of Health, the Association of the British Pharmaceutical Industry (ABPI), and NHS England. The NICE position statement concluded that 'the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee noted the response from the ABPI, an association with 57\xa0pharmaceutical company members, which stated that the ABPI had no comments on the substance of the position statement, and welcomed the statement. The committee also noted the ABPI comment that: 'Indeed, any other interpretation may increase the risk of legal challenge from other companies'. The committee was, however, aware that the company continued to believe that it was 'unfair to disregard the consideration of PPRS payments within the appraisal process' and was 'deeply disappointed' by the conclusion of the position statement. Company representatives at the meeting stated that the company's opinion was that the NICE position statement should state that 'the 2014 PPRS payment mechanism should, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines', and that it should apply to all technology appraisals, not just to the appraisal of trastuzumab emtansine. The committee concluded that the 2\xa0sole negotiators for the PPRS, that is the Department of the Health and the ABPI, fully supported the NICE position statement, but that the company disagreed with it.\n\nThe committee discussed what the NICE position statement meant for its consideration of cost effectiveness. It noted the company's suggestion that the failure of NICE to identify a solution was not sufficient reason for the committee to disregard the impact of the 2014 PPRS on its appraisal of trastuzumab emtansine. The company representatives stated that the company's view was that the committee should disregard the NICE position statement, and either accept the 'pragmatic solution' suggested in the company's formal response (see section\xa04.25), or itself devise some other mechanism to incorporate the PPRS into its evaluation of cost effectiveness. The committee reminded itself that its role was limited to making recommendations to NICE about the clinical and cost effectiveness of treatments for use within the NHS, in line with the guide to the methods of technology appraisal (2013). This states that the committee should not recommend treatments that are not cost effective. It also recalled paragraph\xa06.2.14 of the guide, which states that: 'The potential budget impact of the adoption of a new technology does not determine the appraisal committee's decision'. The committee concluded that it was not responsible for devising new methods for estimating cost effectiveness and, further, it had neither the remit nor the expertise to do so. Furthermore, it understood that the position statement had been issued as guidance to all NICE technology appraisal committees to ensure consistency of decision-making. It therefore took the view that the NICE position statement should not be disregarded without clear and coherent reasons for doing so.\n\nThe committee discussed whether the PPRS could potentially be relevant to assessing opportunity costs that underlie a NICE appraisal; that is, would NHS adoption of trastuzumab emtansine, or other branded medicines that were not cost effective, come without additional cost to society, and without reducing spending on other more cost-effective treatments. It noted that the rationale for the NICE position statement was that it was not clear how payments made under the 2014 scheme were being applied in providing NHS services. The payments were not mandated to be allocated to local drug budgets and so would not automatically or routinely allow local commissioners or NHS England to revise their assessment of the opportunity costs of branded medicines. The committee also noted NHS England's question and answer document for the NHS on the Pharmaceutical Price Regulation Scheme (PPRS), which states that 'the agreement makes no provision for what happens to the PPRS payments, so there is no commitment for the Department of Health to make any additional payments to the NHS'. Moreover, the committee was aware that any rebates for drug costs are paid quarterly, so even if the PPRS payments were repaid to the NHS, and directly to local commissioners, who have finite budgets, decisions would have to be made to temporarily reduce funding other health services until the PPRS payments are received, which would incur opportunity cost. In addition, there would be no rebate for administration or other follow-on medical costs incurred from introducing a new technology. The committee also understood that, under the terms of the 2014 PPRS, when the allowed growth rate is exceeded, companies will make a cash payment of a percentage applied to sales covered by the PPRS payment during the relevant quarter (excluding products launched after 1\xa0January 2014), and that percentage will be equal for all companies. Therefore, the committee considered that the opportunity cost would not only be borne by the NHS, but also by other companies who have joined the 2014 PPRS, and would have to contribute a larger share to the rebate based on how much the allowed spend was exceeded because of trastuzumab emtansine prescribing. The committee concluded that, as it stands, the 2014 PPRS does not remove the opportunity cost from funding treatments that are not considered to be cost effective according to the normal methods of technology appraisals, and that the precise and full costs of introducing a new technology into the NHS were not covered or rebated through the PPRS.\n\nThe committee noted that the essence of the position statement was that NICE did not consider that the 2014 PPRS enabled rebates to be transparently attributed to the acquisition cost of individual branded medicines at the time of the appraisal, and so could not identify a way in which the 2014 PPRS could fit within NICE's framework of appraising cost effectiveness. However, the statement did provide for potential exceptions to the general position of NICE. The committee referred to the guidance in the guide to the methods of technology appraisal (2013) on considering prices for technologies in cost-effectiveness analyses. Specifically, it noted paragraph\xa05.5.2 which states that the public list prices for technologies should be used in the reference case analysis or alternatively, and when nationally available, price reductions, provided that these are transparent and consistently available across the NHS, and the period for which the specified price is available is guaranteed. Because of the role of the committee and the basis for the position statement, the committee concluded that it would only be able to apply the exception provided for in the position statement if the PPRS mechanism could be shown to reduce the cost of the technology to the NHS, and still be in keeping with paragraph\xa05.5.2 of the guide.\n\nThe committee discussed the company's proposal that the committee issues positive guidance on trastuzumab emtansine conditional on the following:\n\nThe company remains within the 2014 PPRS scheme.\n\nThe spend level within the 2014 PPRS scheme remains above the agreed growth levels.\n\nGuidance is reviewed at the start of the 2019 PPRS scheme.The committee noted that the company's proposal did not show how the PPRS rebate mechanism can be applied directly to the cost to the NHS of trastuzumab emtansine, in a way that could be incorporated into a cost-effectiveness analysis. It also heard from NICE that accepting this proposal would potentially be unlawful for a number of reasons. Firstly, the committee would be overriding current guidance on the assessment of the cost effectiveness of health technologies and, by not applying its published methods of technology appraisal, this implies that NICE would not be fulfilling its statutory functions. This would also be incongruous with the 2014 PPRS itself, which states that 'the basic cost-effectiveness threshold used by NICE will be retained at a level consistent with the current range and not changed for the duration of the scheme', indicating that NICE should continue to assess cost effectiveness. Secondly, accepting the proposal would potentially impact on the financial position of other pharmaceutical companies, with the potential legal implications referred to in the ABPI's response to consultation on the NICE position statement (see section\xa04.21). Thirdly, there is already a mechanism within the existing process for companies to propose special pricing arrangements to be taken into account in technology appraisals; patient access schemes. These have to be approved by the Department of Health, which is also responsible for the 2014 PPRS. The committee noted that the company could have used this mechanism to apply a price discount in line with what it believed would be the true cost of trastuzumab emtansine to the NHS, in the context of the 2014 PPRS. Accepting the company's proposal would, therefore, transcend the existing framework. In summary, the committee was not satisfied that the company's proposal demonstrated that the impact of the PPRS rebate could be traced back to the opportunity cost of trastuzumab emtansine within the existing NICE guide to the methods of technology appraisal (2013), and NICE's statutory functions. Because of this, the committee concluded that the company's proposal did not represent an exception that might lead it to depart from the general position in the NICE statement.\n\nIn conclusion, the committee did not hear anything that it could consider to be reasonable grounds to disregard the NICE position statement in this appraisal. The committee agreed that it may consider the 2014 PPRS if specific proposals are put forward, if these fit within the methods and processes of technology appraisal and are consistent with NICE's statutory functions. However, it did not consider that such proposals had been put forward in this appraisal. Therefore, the committee concluded that the 2014 PPRS did not affect its previous recommendations about trastuzumab emtansine.\n\n# Cancer Drugs Fund reconsideration\n\nThis appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2‑positive, unresectable, locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. In its revised submission, the company included:\n\nan additional 2\xa0years' follow-up data from EMILIA, which was used to model overall survival\n\na complex patient access scheme in which the NHS would pay for trastuzumab emtansine up to the first 14\xa0months of treatment for each patient, and the company would pay for trastuzumab emtansine for any patients remaining on treatment beyond 14\xa0months (which was subsequently amended after the first committee meeting) and\n\nan updated model incorporating new data and using some of the committee's preferred assumptions (see sections\xa04.10 to\xa04.20):\n\n\n\nextending the model time horizon from 10 to 15\xa0years\n\nincorporating the follow-up costs of left ventricular ejection fraction monitoring\n\ncorrecting the utility values for adverse events (although the ERG suggested that these may still be incorrect)\n\nusing the actual dose of trastuzumab emtansine and lapatinib plus capecitabine rather than the planned dose\n\nrevising the parameters for the probabilistic sensitivity analysis and\n\nestimating the post-progression treatment costs.\n\n\n\n## Clinical management of HER2‑positive advanced breast cancer\n\nThe committee heard from the clinical experts that trastuzumab emtansine is an effective treatment, which improves overall survival by several months compared with other HER2‑directed treatments. The clinical experts recognised that trastuzumab emtansine is not suitable for everyone, but noted that it is particularly well tolerated in many people compared with other treatments. The committee heard that the other treatment options have a worse toxicity and side effect profile than trastuzumab emtansine. It also heard that, on average, after 6\xa0months of capecitabine treatment people start to have major side effects, which reduce treatment effectiveness and cause people to stop treatment. This also applies to the combination therapies, trastuzumab plus capecitabine and lapatinib plus capecitabine. People whose disease responds well to trastuzumab emtansine have improved quality of life as well as longer life. The clinical experts noted that they can assess whether trastuzumab emtansine is effective or limited by toxicity within 3\xa0cycles. Treatment normally continues until disease progression. The clinical experts stated that the next line of treatment after trastuzumab emtansine would depend on the person's treatment history, but options were limited at this stage, and often this would be palliative care.\n\n## Patient experience\n\nThe patient experts described the benefits of treatment with trastuzumab emtansine. They stated that as well as the treatment stopping the progression of the condition, quality of life is better with trastuzumab emtansine than with other treatments. They noted that the side effects are minimal so they no longer need to be admitted to hospital or confined to bed after treatment. The patient experts stated that trastuzumab emtansine has removed some of the fear associated with their disease and has given them quality time with family and friends. They also emphasised that trastuzumab emtansine has helped them to live their lives fully and continue working, 2\xa0factors that are very important and highly valued by patients, especially because many are relatively young women with caring responsibilities. They stated that if the drug were not available there would be no other suitable treatments for them.\n\nThe committee acknowledged the comments from patients after consultation, in particular that 115,000\xa0people have signed a Breast Cancer Now petition urging NICE and Roche to ensure that trastuzumab emtansine remains available for patients in England. The committee appreciated how important it is for effective treatments for breast cancer to be available, but noted that its role was to consider the clinical and cost effectiveness of this technology at the price set by the company (including any nationally agreed access arrangements). Nevertheless, the committee acknowledged that it was relevant that the treatment had been provided to patients in the NHS in England for 3\xa0years so that patients and clinicians would view a negative recommendation as 'taking away' an existing NHS funded treatment. Although it could be argued that the opportunity cost issues are not the same for a previously funded drug as for one that requires new NHS investment, the NICE methods guide does not have any specific mechanisms or advice which apply to this situation.\n\n## Comparators\n\nThe committee noted that the company had excluded some of the comparators listed in the original appraisal from the incremental analysis in the revised submission. The committee assumed that vinorelbine had been excluded because it was expected to be dominated (less effective and more costly) by capecitabine. The company also excluded lapatinib plus capecitabine from the cost-effectiveness analysis because lapatinib was removed from the Cancer Drugs Fund in January 2015. The company stated that it has independent audit data to suggest that lapatinib plus capecitabine no longer represents current practice in England. The committee heard that lapatinib was removed from the Cancer Drugs Fund because the evaluation score (which considers clinical effectiveness, toxicity and drug cost for the Cancer Drugs Fund) for lapatinib plus capecitabine was considered to be too low to keep it in the Fund. The committee heard from the Cancer Drugs Fund clinical lead that drugs that had been removed from the Cancer Drugs Fund were no longer commissioned in England. The committee noted that lapatinib plus capecitabine was removed after trastuzumab emtansine became available. Since then, trastuzumab emtansine has become part of NHS clinical practice, and has replaced the comparator treatments listed in the original scope. The committee noted the company's opinion that trastuzumab plus capecitabine should be considered as the main comparator for trastuzumab emtansine. Responses from other consultees and commentators supported this view. The committee heard from the clinical expert and the Cancer Drugs Fund clinical lead that if trastuzumab emtansine were not available, trastuzumab plus capecitabine was likely to be offered to patients with HER2-positive advanced breast cancer who had relapsed after first-line trastuzumab-based therapy. The committee noted that trastuzumab plus capecitabine does not have a marketing authorisation for this indication but was aware that according to section\xa06.2 of the NICE guide to the methods of technology appraisal, comparators without a marketing authorisation for the relevant indication can be considered as comparators by the committee if they are part of established practice in the NHS. It also noted that based on the results of the network meta-analysis, trastuzumab plus capecitabine showed similar clinical effectiveness to lapatinib plus capecitabine. Overall the committee concluded that based on what it had heard from experts at the committee meeting and in light of the consultation comments, trastuzumab plus capecitabine is the most relevant comparator.\n\n## The company's revised economic model\n\nThe committee considered the company's updated economic model submitted for the Cancer Drugs Fund reconsideration and the subsequent updates in response to the ERG's critique. It also considered the ERG's exploratory analyses. It acknowledged that the final version of the model from the company took into account the ERG's concerns about the plausibility of the methods used in the probabilistic sensitivity analysis in the model. The company:\n\nused patient-level data to calculate vial use\n\nexcluded an additional adjustment for wastage\n\nupdated the patient access scheme and\n\nupdated the probabilistic sensitivity analysis in line with the ERG's suggestions.The committee heard from the ERG that the patient access scheme and other amendments had been accurately incorporated in the model. The committee agreed that the company's changes were plausible. It also noted that the updated probabilistic sensitivity analysis in the final version was validated by the ERG. In general the ERG was satisfied with the updated analysis, but it also tested alternative prior distributions to determine the sensitivity of the economic model. As a result, the cost-effectiveness results presented by the company and the ERG were very similar.\n\n## Calculation of treatment costs\n\nThe committee considered the company's economic model and the ERG's critique. The committee noted that the company initially estimated average vial use using the average dose from EMILIA, but also used patient-level data to calculate vial use after a request from the ERG. The committee noted that using patient-level data increased the ICER compared with the company's base case, but it recognised that this did not account for dose reductions or treatment breaks. The committee heard that there is vial sharing in oncology centres that have centralised intravenous drug preparation. This reduces the amount of wastage, but cannot stop it completely. The committee noted that the company's revised economic model assumed no wastage because it used patient-level data to calculate vial use, although the previous version of the model assumed that 50% of any drug remaining in a vial after the dose is drawn up is re-used and 50% is wasted. The committee concluded that some wastage needs to be included in the calculation of trastuzumab emtansine treatment costs, because assuming no wastage is not plausible.\n\n## End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the updated median overall survival in the EMILIA intention-to-treat population was 25.9\xa0months for people randomised to lapatinib plus capecitabine (it was 25.1\xa0months at the time of the original appraisal), and 29.9\xa0months for those randomised to trastuzumab emtansine. The committee recognised that during NICE's original appraisal of trastuzumab emtansine, evidence from other trials of lapatinib plus capecitabine in advanced breast cancer was also considered. The original appraisal committee noted that patients who received lapatinib plus capecitabine in EMILIA appeared to live longer than those who received it in other trials, in which median survival generally fell below 24\xa0months. The committee also considered the evidence submitted by the company for life expectancy with trastuzumab plus capecitabine. It heard from the company that there are limited data available on the life expectancy of patients with metastatic breast cancer receiving trastuzumab with capecitabine as second-line treatment. However, data from the CEREBEL study (Pivot et al. 2015) suggests that it is likely to be around 24\xa0months. The committee took into account that patients with metastatic disease who are eligible for trastuzumab emtansine had already progressed on first-line therapy and were in the advanced stages of the disease. Therefore the committee agreed to uphold the end-of-life decision from the original appraisal. It was aware that it was now looking at a different comparator from the one on which the original decision had been made (lapatinib plus capecitabine), but judged that any difference in survival between lapatinib plus capecitabine and trastuzumab and capecitabine was likely to be marginal, taking into account the results of the network meta-analysis (see section\xa04.31). The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for a life-extending, end-of-life treatment for HER2-positive advanced breast cancer.\n\n## Conclusions\n\nThe committee noted that the updated evidence available since the original appraisal confirms that trastuzumab emtansine is clinically effective, with a statistically significant survival benefit compared with lapatinib plus capecitabine. Despite only indirect evidence of its effectiveness compared with trastuzumab plus capecitabine, there was no reason to consider that the relative benefits would not be comparable. Based on what the committee heard from experts at the committee meeting and in light of the consultation comments, it concluded that trastuzumab plus capecitabine is the most relevant comparator. Based on the clinical and cost-effectiveness analyses, including the updated complex patient access scheme, the most plausible ICER for trastuzumab emtansine compared with trastuzumab plus capecitabine was within the range that would normally be considered cost effective if the end-of-life criteria apply. The committee therefore concluded that trastuzumab emtansine could be recommended for use in the NHS for treating HER2-positive advanced breast cancer.\n\n# Summary of appraisal committee's key conclusions\n\nTA458\n\nAppraisal title: Trastuzumab emtansine for treating HER2‑positive advanced breast cancer after trastuzumab and a taxane\n\nSection\n\nKey conclusion (Cancer Drugs Fund reconsideration of TA371)\n\nTrastuzumab emtansine is recommended, within its marketing authorisation, as an option for treating human epidermal growth factor receptor\xa02 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Trastuzumab emtansine is recommended only if the company provides it in line with the commercial access agreement with NHS England.\n\nThe updated evidence available since the original appraisal confirms that trastuzumab emtansine is clinically effective, with a statistically significant survival benefit compared with lapatinib plus capecitabine. Despite only indirect evidence of its effectiveness compared with trastuzumab plus capecitabine, there was no reason to consider that the benefits would not be comparable. Based on the clinical and cost-effectiveness analyses, including an updated complex patient access scheme (that was subsequently replaced by a commercial access agreement), the most plausible ICER for trastuzumab emtansine compared with trastuzumab plus capecitabine was within the range that would normally be considered cost effective if the end-of-life criteria apply.\n\n\n\n, 4.35\n\nCancer Drugs Fund reconsideration of TA371\n\nThe company's revised submission included:\n\nan additional 2\xa0years follow-up data from EMILIA, which was used to model overall survival and\n\na complex patient access scheme.\n\nAfter consultation an updated model was submitted, in which the company:\n\nused patient-level data to calculate vial use\n\nexcluded an additional adjustment for wastage and\n\nupdated the patient access scheme and\n\nupdated the probabilistic sensitivity analysis in line with the ERG's suggestions.\n\nThe committee considered that based on what it heard from experts at the committee meeting and in light of the consultation comments, trastuzumab plus capecitabine is the only relevant comparator.\n\nIt also recognised that during NICE's original appraisal on trastuzumab emtansine, the original appraisal committee noted that patients who received lapatinib plus capecitabine in EMILIA appeared to live longer than those who received it in other trials, in which median survival generally fell below 24\xa0months. The committee also considered the evidence submitted by the company for life expectancy with trastuzumab plus capecitabine. It heard from the company that data from the CEREBEL study (Pivot et al. 2015) suggests that it is likely to be around 24\xa0months. The committee took into account that patients with metastatic disease eligible for trastuzumab emtansine had already progressed on first-line therapy, and were in the advanced stages of the disease. Therefore the committee agreed to uphold the end-of-life decision from the original appraisal. The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for a life-extending, end-of-life treatment for HER2‑positive advanced breast cancer.\n\nTaking into account all factors, including the end-of-life criteria and the commercial access agreement that replaced the updated complex patient access scheme, trastuzumab emtansine could be recommended for use in the NHS for treating HER2-positive advanced breast cancer.\n\n, 4.32, 4.34, 4.35\n\n The complex patient access scheme was subsequently replaced by a commercial access agreement. See section\xa02 for further details."}
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https://www.nice.org.uk/guidance/ta458
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Evidence-based recommendations on trastuzumab emtansine (Kadcyla) for human epidermal growth factor receptor 2 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who have had trastuzumab and a taxane.
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nice
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Tests in secondary care to identify people at high risk of ovarian cancer
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Tests in secondary care to identify people at high risk of ovarian cancer
Evidence-based recommendations on tests in secondary care to identify people at high risk of ovarian cancer. The tests are the IOTA ADNEX model, Overa (MIA2G), RMI I (at thresholds other than 250), ROMA and IOTA Simple Rules.
# Recommendations
There is currently not enough evidence to recommend the routine adoption of the IOTA ADNEX model, Overa (MIA2G), RMI I (at thresholds other than 200 or 250), ROMA or IOTA Simple Rules in secondary care in the NHS to help decide whether to refer people with suspected ovarian cancer to a specialist multidisciplinary team (MDT).
The NICE guideline on ovarian cancer recommends that people with an RMI I of 250 or more are referred to a specialist MDT. Evidence suggests that there is no substantial change in accuracy if the threshold for RMI I is lowered to 200.
The IOTA ADNEX model, Overa (MIA2G), RMI I (at thresholds other than 250), ROMA and IOTA Simple Rules show promise. Further research is recommended on test accuracy and the impact of the test results on clinical decision-making (see section 6 for detailed research recommendations).# Clinical need and practice
# The problem addressed
Tests and risk scores are used in secondary care to help determine if a person referred with suspected ovarian cancer is likely to have an ovarian malignancy. Results inform decisions about whether they should be referred to a specialist multidisciplinary team (MDT) for further assessment and treatment. Currently, serum biomarker CA125 and pelvic ultrasound scans are widely used in secondary care, as part of the risk of malignancy index 1 (RMI I) score, in deciding whether a referral to a specialist MDT is needed. However, not all ovarian malignancies show elevated CA125 levels (particularly early stage ovarian cancer). Also elevated levels of CA125 are not always indicative of ovarian cancer, because they may be raised from other causes, such as endometriosis, fibroids, pregnancy, pelvic inflammatory disease, liver disease or heart failure. Tests and risk scores included in this assessment (ADNEX, Overa , RMI I at thresholds other than 250, ROMA and Simple Rules) may be better able to distinguish between benign and malignant ovarian tumours, and increase the proportion of people with a correct referral from secondary care to a specialist MDT.
Increasing the proportion of people with ovarian cancer who get a correct referral to a specialist MDT is likely to improve patient outcomes. Also, improved testing could lead to more accurate recognition of people referred to secondary care with suspected ovarian cancer who do not have the condition. This could reduce inappropriate referrals to specialist care for further assessment and treatment, as well as the costs and anxiety that this can cause.
# The condition
Ovarian cancer starts in cells in, or near, the ovaries. Primary ovarian tumours are classified based on the tissue that they develop from, with 3 main types: epithelial ovarian tumours, sex cord-stromal tumours of the ovary and germ cell tumours of the ovary. Each subtype of tumour can be benign, malignant or intermediate (borderline malignant). About 90% of primary ovarian cancers are malignant epithelial tumours. Non-epithelial ovarian cancers make up a higher proportion of ovarian cancer in people who are premenopausal.
Data from Cancer Research UK (ovarian cancer statistics) suggests:
There were about 7,400 new cases of ovarian cancer in the UK in 2014, accounting for 2% of all new cancer cases.
The incidence of ovarian cancer increases with age, with more than half of cases between 2012 and 2014 happening in people aged 65 years and over.
There were about 50 new cases in people under 19 years in this time period, about 600 new cases in people under 40 years and about 1,400 new cases in people under 50 years.
# The diagnostics and care pathways
## Diagnosis
The NICE guideline on ovarian cancer includes recommendations on criteria and tests to use in primary care when deciding whether to refer someone to secondary care with suspected ovarian cancer. Recommendations from this guideline have also been incorporated in the NICE guideline on suspected cancer.
The NICE guideline on ovarian cancer also provides recommendations on diagnosing suspected ovarian cancer in secondary care. An ultrasound of the abdomen and pelvis is recommended as the first imaging test in secondary care for people with suspected ovarian cancer (if this has not already been done in primary care), as well as measuring serum CA125 (if not already done in primary care). The guideline recommends calculating an RMI I score, based on characteristics seen on ultrasound, CA125 serum levels and menopausal status (described in more detail in section 3). It states that people with an RMI I score of 250 or more should be referred to a specialist MDT.
For people under 40 years with suspected ovarian cancer, the NICE guideline on ovarian cancer recommends measuring the levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta‑hCG), as well as CA125, to identify non-epithelial ovarian cancer.
The NICE guideline on ovarian cancer also provides recommendations on further imaging to characterise the extent and spread of ovarian cancer, and also on getting a tissue sample to confirm a diagnosis of ovarian cancer. Histopathology is generally used as the reference standard for assessing the accuracy of tests to identify people who are likely to have ovarian cancer. As well as distinguishing between malignant and benign tumours, this testing can also determine the type of ovarian cancer present. If tissue samples are not taken, clinical follow-up may be needed to determine the presence, or absence, of ovarian cancer.
## Care pathway
The NICE guideline on ovarian cancer contains recommendations for the management of early (stage I) and advanced (stages II to IV) ovarian cancer.# The diagnostic tests
The assessment compared 5 interventions with 1 comparator.
# The interventions
## The assessment of different neoplasias in the adnexa (ADNEX) model
The ADNEX model was developed by the International Ovarian Tumor Analysis (IOTA) group to assess people with an adnexal mass who are considered to need surgery. The model uses 3 clinical predictors and 6 ultrasound-derived predictors to estimate the probability that a pelvic tumour is benign or malignant (see table 1). Also, the model estimates probabilities that a tumour is borderline, stage I cancer, stage II to IV cancer or secondary metastatic cancer. The ADNEX model formulas are available in published literature (Van Calster et al. 2014) and the model is further described on the IOTA website. The terminology used in the model is as defined in a publication by the IOTA group (Timmerman et al. 2000), and the group run courses that teach the terms, definitions and measurement techniques needed to assess pelvic masses for the ADNEX model. An online training tool for NHS practitioners is also currently in development.
## Table 1 Criteria included in the ADNEX model
Clinical predictors
Ultrasound derived predictors
Age (years)
Serum CA125 level (units per millilitre )
Type of centre (oncology centre or other hospital)1
Maximum diameter of lesion (mm)
Proportion of solid tissue (ratio of the maximum diameter of the largest solid component and the maximum diameter of the lesion)
More than 10 cyst locules (yes or no)
Number of papillary projections (0, 1, 2, 3 or more than 3)
Acoustic shadows (yes or no)
Ascites (yes or no)
Oncology centre defined as a tertiary referral centre with a specific gynaecology oncology unit (Van Calster et al. 2014).
The ultrasound variables for the ADNEX model need B mode imaging and the IOTA group states that any modern ultrasound machine with a high-frequency (more than 6 Hz) transvaginal probe can be used. The ADNEX model has not been validated for use in people who are pregnant.
## Overa (MIA2G) serum test (Vermillion)
The Overa (MIA2G) is a CE-marked qualitative serum test that combines the results of 5 immunoassays into a single numeric result (the Overa Risk Score). The 5 biomarkers included in the test are: follicle-stimulating hormone (FSH), human epididymis protein 4 (HE4), apolipoprotein A‑1 (Apo A‑1), transferrin (TRF), and cancer antigen 125 (CA125). The serum levels of these biomarkers are determined using immunoassays run on the Roche cobas 6000 system. The Overa Risk Score is generated by the company's OvaCalc software, with results ranging between 0.0 and 10.0. A risk score of less than 5.0 indicates a low probability of malignancy and a score of 5.0 or more indicates a high probability of malignancy. The assay is for use in people over 18 years with a pelvic mass for whom surgery may be considered. It is intended to be part of preoperative assessment to help decide if a person presenting with a pelvic mass has a high or low risk of ovarian malignancy.
The company states that test results must be interpreted in conjunction with an independent clinical and imaging evaluation, and that the test is not intended for use in screening or as a stand-alone assay. The Overa (MIA2G) is available to the NHS through a private laboratory which tests samples and provides Overa Risk scores.
## Risk of malignancy index 1 (RMI I) with thresholds other than 250
The RMI I tool combines 3 pre-surgical features (measured serum CA125 levels , ultrasound imaging and menopausal status ) to create an index score: RMI I score = U×M×CA125. Definitions of these terms from the NICE guideline on ovarian cancer are in table 2.
## Table 2 Definitions of RMI I terms
Terms in RMI I equation
Description
U
Ultrasound score based on 1 point scored for the presence of each of the following features: multilocular cysts, solid areas, metastases, ascites, bilateral lesions. U=0 (0 points), U=1 (1 point) or U=3 (2 to 5 points).
M
Menopausal status: M=1 (premenopausal) or M=3 (postmenopausal). The classification of 'postmenopausal' is a woman who has had no period for more than 1 year or a woman over 50 who has had a hysterectomy.
CA125
Serum CA125 concentration measured in units per millilitre (U/ml).
The NICE guideline on ovarian cancer recommends that people with an RMI I score of 250 or more should be referred to a specialist MDT (the RMI I at this threshold is the comparator for this assessment, see section 3.15). However, this guideline also includes a research recommendation stating that further research should be done to determine the optimum RMI I threshold that should be applied in secondary care to guide the management of suspected ovarian cancer. The subsequently published Scottish Intercollegiate Guidelines Network (SIGN) guideline on the management of epithelial ovarian cancer (SIGN 135) recommends referring people with an RMI I score of more than 200 to a gynaecological oncology multidisciplinary team.
## Risk of ovarian malignancy algorithm (ROMA)
The ROMA combines serum CA125 and HE4 levels with a person's menopausal status to estimate the probability that they have epithelial ovarian cancer. Different equations are used depending on whether the person is pre- or postmenopausal (Moore et al. 2009). Cut-off values for the ROMA score stratify individuals as being at a high or low risk of having epithelial ovarian cancer. Cut-off values vary depending on which manufacturers' HE4 and CA125 assays are being used. The ROMA has not been validated in people under 18 years old, people being treated with chemotherapy and people who have previously been treated for a malignancy.
Three assays that measure HE4 serum levels using automated immunoassay analysers, and that are available to the NHS, are described in the following sections.
A CE‑marked chemiluminescent microparticle immunoassay designed for use on the Abbott ARCHITECT i2000SR or ARCHITECT i1000SR immunoassay analysers. It is intended for use with the ARCHITECT CA125 II assay, with results of both assays used in the ROMA to help estimate the risk that someone presenting with an adnexal mass and who will have surgery has epithelial ovarian cancer. The following cut-off values are suggested for ROMA to determine if there is a high or low risk of epithelial ovarian cancer: 7.4% for people who are premenopausal; 25.3% for people who are postmenopausal.
A CE‑marked chemiluminescent enzyme immunoassay designed for use on the LUMIPULSE G System (either the LUMIPULSE G1200 or LUMIPULSE G600 immunoassay analysers). It is intended for use with the Lumipulse G CA125 II assay, with results of both assays used in the ROMA to help estimate the risk that someone presenting with an adnexal mass and who will have surgery has epithelial ovarian cancer. The following cut-off values are suggested for ROMA to determine if there is a high or low risk of epithelial ovarian cancer: 13.1% for people who are premenopausal; 27.7% for people who are postmenopausal.
A CE‑marked immunoassay test that uses Roche's ElectroChemiLuminescence detection technology designed for use on the following immunoassay analysers: Modular analytics E170, cobas e 411, cobas e 601/e 602 and cobas e 801. It is intended for use with the Elecsys CA 125 II assay, with results of both assays used in the ROMA to help estimate the risk that someone presenting with a pelvic mass has epithelial ovarian cancer. The following cut-off values are suggested for ROMA to determine if there is a high or low risk of epithelial ovarian cancer: 11.4% for people who are premenopausal; 29.9% for people who are postmenopausal.
## Simple Rules ultrasound classification system
Simple Rules was developed by the IOTA group to assess people with a pelvic mass who are considered to need surgery. It is a scoring system based on the presence of ultrasound features, to characterise an ovarian tumour before surgery as benign or malignant. No specific make or model of ultrasound device is needed to use the Simples Rules system. A transvaginal probe is needed and image quality must be of sufficient quality to allow the ultrasound features specified by the Simple Rules system to be seen.
Terms and definitions used in the classification system are as defined by the IOTA group. The group run courses that teach the terms, definitions and measurement techniques needed to assess pelvic masses for the Simple Rules. An online training tool for NHS practitioners is also currently under development. Simple Rules has not been validated for use in people who are pregnant.
There are 5 rules that predict a malignant tumour (M‑rules) and 5 rules that predict a benign tumour (B‑rules), as described in table 3. If any M‑rules apply (and no B‑rules) then the mass is classified as malignant. If any B‑rules apply (and no M‑rules) then the mass is classified as benign. However, if both M- and B‑rules apply, or neither, then the result is inconclusive, and is either classed as malignant or further criteria are needed to assess whether the mass is likely to be malignant; for example, further expert subjective assessment of the ultrasound images.
## Table 3 Simple Rules ultrasound classification system
M‑rules
(Rules for predicting a malignant tumour)
B‑rules
(Rules for predicting a benign tumour)
Irregular solid tumour
Ascites present
Four or more papillary structures
Irregular multilocular solid tumour with largest diameter 100 mm or more
Very strong blood flow (colour score 4)
Unilocular
Solid components present, with largest solid component having a largest diameter of less than 7 mm
Acoustic shadows present
Smooth multilocular tumour with largest diameter less than 100 mm
No blood flow (colour score 1)
# The comparator
The comparator for this assessment is the RMI I used at a threshold of 250, as currently recommended in the NICE guideline on ovarian cancer.# Evidence
The diagnostics advisory committee (section 8) considered evidence on tests used in secondary care to help identify people at high risk of ovarian cancer from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
Fifty-one diagnostic cohort studies were identified (in 65 publications) that reported data on 1 or more of the included tests or risk scores. Also, an unpublished interim report of phase 5 of the International Ovarian Tumor Analysis (IOTA) study was available to the external assessment group (EAG) and committee as academic in confidence. No randomised controlled trials or controlled clinical trials were identified; neither were studies that reported how test results affect clinical management decisions. Ten studies had inclusion criteria which allowed people under 18 years to take part; but the number of participants in this age group was not reported.
All the included studies reported the accuracy of tests and risk scores to assess people with an adnexal or pelvic mass. When summary estimates of sensitivity and specificity from multiple studies were calculated, these were separate pooled estimates produced using random-effects logistic regression. The bivariate/hierarchical summary receiver operating characteristic model was not used because data sets were either too small or too heterogeneous.
Histopathology was the reference standard used to assess test accuracy in all of the identified studies. The target condition (that is, what was considered a positive reference standard test result) varied between the included studies. Some studies classified borderline ovarian tumours as positive, but others did not (and either classified them as disease negative or excluded them from analyses). Furthermore, studies varied as to whether they included people with metastases to the ovaries and germ cell tumours in analyses.
The methodological quality of the diagnostic cohort studies was assessed using the QUADAS‑2 tool. Fifteen studies had a high risk of bias in the 'flow and timing' domain, most commonly because not all patients were included in the analyses and patients did not all have the same reference standard. Regarding applicability, 26 studies were rated as 'high' concern on at least 1 domain. The EAG commented that areas of concern for applicability included how the index test was applied and whether this could be considered to be representative of routine practice. A further issue for applicability of studies was how the target condition was defined. One study, which reported the development and validation of the ADNEX model (Van Calster et al. 2014), was also assessed using the PROBAST tool; a tool developed to assess the methodological quality of prediction modelling studies.
## Assessment of test accuracy
Ten studies reported diagnostic accuracy of the RMI I using a decision threshold of 250 (the comparator for this assessment) and at least 1 further threshold value. Two studies were done in the UK, 2 elsewhere in Europe and 6 in non-European countries. CA125 assays from various manufacturers were used in the studies.
In studies that directly compared RMI I at a threshold of 250 and 200, no statistically significant difference between the sensitivity and specificity of RMI I at these thresholds was seen in any of the target condition categories (see table 4).
## Table 4 Comparative accuracy of RMI I at thresholds of 200 and 250
Source
Subgroup
Index test
Sensitivity % (95% CI)
Specificity % (95% CI)
Target condition: All malignant tumours including borderline
Summary estimates (6 studies; n=1,079)
All
RMI I (200)
(65.6 to 75.6)
(88.9 to 93.1)
RMI I (250)
(63.7 to 73.9)
(89.3 to 93.5)
Target condition: Ovarian malignancies including borderline
Yamamoto et al. 2009 (n=253)
All
RMI I (200)
(65.2 to 89.5)
(81.8 to 89.9)
RMI I (250)
(57.2 to 83.9)
(84.4 to 92.0)
Target condition: All malignant tumours excluding borderline
Summary estimates (2 studies; n=248)
All
RMI I (200)
(64.3 to 81.3)
(83.2 to 94.2)
RMI I (250)
(56.9 to 75.0)
(87.7 to 96.9)
Abbreviations: CI, confidence interval; RMI I, risk of malignancy index 1.
## Risk of ovarian malignancy algorithm (ROMA)
Fourteen studies (in 22 publications) reported diagnostic accuracy data for the ROMA using either Abbott ARCHITECT assays (9 studies) or Roche Elecsys assays (5 studies). No studies were identified that used the Fujirebio Lumipulse G automated CLEIA system.
All of the 9 ROMA studies which used Abbott ARCHITECT assays were done outside the UK: 3 in European countries, 4 in Asia, 1 in the US and 1 in Oman. No direct comparisons (that is, when both tests were assessed in the same patient cohort) between ROMA and RMI I (threshold of 250) were identified.
Three studies made a direct comparison between ROMA using Abbott ARCHITECT assays and RMI I (threshold of 200), shown in table 5. One study (Al Musalhi et al. 2016) did not exclude participants from analysis based on their final histopathological diagnosis; but the other 2 studies did. Sensitivity was highest when people with borderline tumours and non-epithelial ovarian cancers were excluded from analysis, and lowest when all participants (regardless of final histopathological diagnosis) were included. The reverse was true for specificity. When all participants were included in the analysis (Al Musalhi et al. 2016) there was no statistically significant difference between the sensitivity and specificity estimates of ROMA and RMI I (threshold of 200). This was also true for the summary sensitivity estimate when the target condition was 'epithelial ovarian malignancies excluding borderline'; however specificity was statistically significantly lower for ROMA compared with RMI I (threshold of 200).
## Table 5 Comparative accuracy of ROMA (using Abbott ARCHITECT assays) and RMI I (threshold of 200)
Source
Subgroup
Index test
Sensitivity % (95% CI)
Specificity % (95% CI)
Target condition: All malignant tumours including borderline
Al Musalhi et al. 2016
All (n=213)
ROMA1
(60.4 to 86.4)
(81.9 to 92.4)
RMI I (200)
(62.7 to 88.0)
(75.1 to 87.4)
Premenopausal (n=162)
ROMA1
(29.8 to 74.3)
(83.9 to 94.5)
RMI I (200)
(34.0 to 78.2)
(78.1 to 90.5)
Postmenopausal (n=51)
ROMA1
(75.7 to 99.1)
(57.8 to 92.9)
RMI I (200)
(73.0 to 99.0)
(46.0 to 83.5)
Target condition: Epithelial ovarian malignancies including borderline
Winarto et al. 2014
All
(n=128)
ROMA
(81.5 to 96.6)
(30.0 to 55.9)
RMI I (200)
(69.1 to 89.2)
(52.3 to 77.3)
Target condition: Epithelial ovarian malignancies excluding borderline
Summary estimate (2 studies)
All
(n=1,172)
ROMA
(93.6 to 98.2)
(50.0 to 56.7)
RMI I (200)
(90.0 to 95.9)
(77.5 to 82.9)
Manufacturer's suggested thresholds not used.
Abbreviations: CI, confidence interval; RMI I, risk of malignancy index 1; ROMA, risk of ovarian malignancy algorithm.
Further identified studies assessed the performance of the ROMA score (using the Abbott ARCHITECT assays and at the company's suggested thresholds) without comparison with RMI I, across a range of target conditions. These included epithelial ovarian malignancies (both including and excluding borderline tumours). One study reported that the sensitivity of the ROMA was higher when the target condition was stage III or IV epithelial ovarian cancer, rather than stage I or II. Also, accuracy data at ROMA thresholds different from those suggested by the manufacturer were identified, but the EAG commented that no alternative threshold offered a clear performance advantage.
All of the 5 ROMA studies that used Roche Elecsys assays were done outside the UK: 1 in a European country, 3 in Asia and 1 in the US. No direct comparisons (that is, when both tests were assessed in the same cohort) between ROMA and RMI I (threshold of 250) were identified. One study (Yanaranop et al. 2016) made a direct comparison between ROMA using Roche Elecsys assays and RMI I (threshold of 200). In this study, people with a final histological diagnosis of borderline ovarian tumour were classified as disease negative. Differences between the ROMA and RMI I (threshold of 200) sensitivity (83.8% compared with 78.4%) and specificity (68.6% compared with 79.6%) values were not statistically significant. The data were similar when stratified by menopausal status. When people with non-epithelial ovarian cancer were excluded from analysis in this study (target condition epithelial ovarian malignancies), sensitivity for both ROMA and RMI I (threshold of 200) increased, but not statistically significantly. Sensitivity was higher for ROMA when the target condition was stage II to IV epithelial ovarian malignancies (97.2%; 95% confidence interval 85.5 to 99.9%) when compared with stage I epithelial ovarian malignancies (76.7%; 95% CI 57.7 to 90.1%). This was also the case for RMI I (threshold of 200).
Four further studies assessed the ROMA score (using Roche Elecsys assays) without comparison with RMI I. Two of these studies included all participants in analyses (Janas et al. 2015; Shulman et al. 2016; target condition all malignant tumours including borderline), shown in table 6.
## Table 6 Diagnostic accuracy of ROMA (using Roche Elecsys assays and manufacturer's suggested thresholds)
Source
Subgroup
Sensitivity %
(95% CI)
Specificity %
(95% CI)
Target condition: All malignant tumours including borderline
Summary estimate (2 studies; n=1,252)
All
(74.2 to 83.5)
(76.3 to 81.6)
Janas et al. 2015
Premenopausal (n=132)
(55.5 to 99.7)
(74.0 to 88.3)
Postmenopausal
(n=127)
(65.6 to 88.4)
(64.5 to 88.4)
Abbreviation: CI, confidence interval.
Two studies assessed the performance of the ROMA score (using the Roche Elecsys assays and at the company's suggested thresholds) without comparison with RMI I and with a target condition of ovarian malignancies excluding borderline tumours. The sensitivity estimates from these studies were very different (95.5% and 53.8%) and no summary estimate was calculated. Also, accuracy data at ROMA thresholds different from those suggested by the manufacturer were identified, but the EAG commented that no alternative threshold offered a clear performance advantage.
None of the included studies assessed the ROMA score and used the Fujirebio Lumipulse G HE4 assay. The EAG identified 2 studies that used a ROMA score calculated using a manual Fujirebio tumour marker enzyme immunometric assay (EIA) assay; however this assay was outside the scope of this assessment.
## Simple Rules
Seventeen published studies had data on the diagnostic accuracy of Simple Rules. Eleven of these studies were done in Europe, including 3 in the UK. Two studies were multinational and included UK participants, 2 studies were done in Thailand, 1 was done in Brazil and 1 study did not provide detail on location. Also, the provided interim report (academic in confidence) had diagnostic accuracy results for Simple Rules. In studies included in summary estimates of sensitivity and specificity, Simple Rules was done by a level 2 or 3 examiner as defined by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) classification system; 1 study also reported data from level 1 examiners.
Four published studies and the unpublished interim report provided direct comparison of the accuracy of Simple Rules and RMI I at a threshold of 200. The summary estimate of sensitivity was statistically significantly higher for Simple Rules (93.9%; 95% CI 92.8 to 94.9%) when compared with RMI I (threshold of 200; 66.9%; 95% CI 64.8 to 68.9%); however the summary specificity estimate was statistically significantly lower (74.2% compared with 90.1% ). All these studies included all participants in analysis, regardless of their final histopathological diagnosis (target condition all malignant tumours including borderline). The unpublished interim report also directly compared Simple Rules and RMI I (threshold of 250; academic in confidence).
A further 4 studies had data on the accuracy of Simple Rules for the same target condition but without a direct comparison with RMI I. There was no statistically significant change in sensitivity (94.2%; 95% CI 93.3 to 95.1%) or specificity (76.1%; 95% CI 74.9 to 77.3%) when data from these studies were included in the summary estimates of Simple Rules accuracy (a total of 8 published studies and the unpublished interim work).
Three studies directly compared Simple Rules and RMI I (threshold of 200) stratified by menopausal status. There was no statistically significant difference between the sensitivity and specificity estimates for Simple Rules produced for the pre- and postmenopausal subgroups. However if data from a further study (which did not report a direct comparison with RMI I) were added, the summary estimate for specificity was statistically significantly higher for people who are premenopausal (79.3%; 95% CI 77.0 to 81.5%), when compared with people who are postmenopausal (67.3%; 95% CI 63.5 to 70.9%).
In the above estimates of accuracy for Simple Rules, inconclusive results were treated as malignancy positive. Test accuracy data were also available from some studies in which inconclusive results were instead classified by expert subjective assessment of the ultrasound images. Assessment of inconclusive results from Simple Rules using expert subjective assessment (rather than assuming them to be malignant) statistically significantly increased the specificity of the test, but statistically significantly lowered sensitivity.
## The ADNEX model
Six published studies had data on the diagnostic accuracy of the ADNEX model. One was done entirely in the UK and 2 were multicentre studies that included UK participants. The remaining 3 studies were done elsewhere in Europe. A further unpublished interim report (provided as academic in confidence) also had data on the diagnostic accuracy of the ADNEX model. Four of the studies did not report details about the people doing the ultrasound scans. In 1 study, ultrasound scans were done by EFSUMB level 2 ultrasound examiners (non-consultant gynaecology specialists, gynaecology trainee doctors and gynaecology sonographers) and in another study they were done by EFSUMB level 2 or 3 practitioners with 8 to 20 years' experience in gynaecological sonography.
The EAG focused on test accuracy at the 10% threshold. One published study and the unpublished interim report made a direct comparison between the ADNEX model and RMI I (threshold of 200). Sensitivity was statistically significantly higher for ADNEX (96.0%; 95% CI 94.5 to 97.1%) than RMI I (threshold 200; 66.0%; 95% CI 62.9 to 69.0%), but specificity was statistically significantly lower (67.0% compared with 89.0% ). Also, a further 2 studies reported on the accuracy of the ADNEX model in the same target population (all malignant tumours including borderline) but without direct comparison with RMI I. Inclusion of data from these studies in summary estimates did not cause a statistically significant change to sensitivity (96.3%; 95% CI 95.3 to 97.1%) or specificity (69.1%; 95% CI 67.4 to 70.8%) of the ADNEX model. The unpublished interim report also directly compared the ADNEX model and RMI I (threshold of 250; academic in confidence).
Two further studies had data on the accuracy of the ADNEX model without comparison with RMI I. These studies excluded people with histopathological diagnoses other than primary ovarian cancer from analysis (target condition ovarian malignancies including borderline). The summary estimate of sensitivity from these studies did not differ significantly from that of studies that included all participants in analysis; however the summary estimate of specificity (77.6%; 95% CI 73.6 to 81.2%) was statistically significantly higher.
Data stratified by menopausal status was available from 1 study. No statistically significant effect on sensitivity was reported, but specificity was statistically significantly higher for people who were premenopausal than for people who were postmenopausal.
One published study and the unpublished interim analysis directly compared the ADNEX model and Simple Rules (inconclusive results assumed to be malignant). The summary estimate of sensitivity was statistically significantly higher for ADNEX (96.0%; 95% CI 94.5 to 97.1%) than Simple Rules (92.8%; 95% CI 90.9 to 94.3%). Summary estimates of specificity were similar.
## Overa (MIA2G)
Three studies (in 4 publications) had data on the diagnostic performance of Overa (MIA2G). All the studies were done in the USA and used a score of 5 units as a threshold. No studies were identified that directly compared Overa (MIA2G) with RMI I (at any threshold). However, 1 study assessed the accuracy of the Overa (MIA2G) and ROMA (using Roche Elecsys assays and manufacturer suggested thresholds for ROMA) in the same population with a target condition of all malignancies including borderline. Overa (MIA2G) had a statistically significantly higher sensitivity (91.0% compared with 79.2% ) and statistically significantly lower specificity (65.5% compared with 78.9% ) than the ROMA in this study.
Two further studies reported the diagnostic accuracy of Overa (MIA2G) without comparison with other risk scores. The summary estimate of sensitivity was 90.2% (95% CI 84.6 to 94.3%), and specificity was 65.8% (95% CI 61.9 to 69.5%). One of these studies assessed subgroups of people who were pre- and postmenopausal; there was no statistically significant difference between these groups.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG did a systematic review to identify existing studies that assessed the cost effectiveness of the included tests and risk scores to help identify people with ovarian cancer. Five studies were identified, however 2 of these related to the use of tests in screening so were not applicable to the scope of this assessment. One of the studies (Havrilesky et al. 2015) included the ROMA and the Multivariate Index Assay algorithm (MIA; from Vermillion who also produce the Overa ). Both were dominated (that is, they cost more and produced less life years) by the use of CA125 alone or by a strategy of referring all people for specialist care (without testing). Conversely, in Forde et al. (2016) MIA dominated the use of CA125 alone (that is, it was cost saving and produced more quality-adjusted life years ). No identified studies assessed the cost effectiveness of all the tests and risk scores included in this assessment.
## Modelling approach
The EAG developed a de novo economic model designed to assess the cost effectiveness of the following tests and risk scores when used in secondary care to help decide whether to refer people with suspected ovarian cancer to a specialist multidisciplinary team (MDT):
RMI I – threshold of 250
ROMA – using Abbott ARCHITECT assays
ROMA – using Roche Elecsys assays
Overa (MIA2G) – threshold of 5 units
IOTA Simple Rules – inconclusive results assumed to be malignant
IOTA ADNEX model – threshold of 10%
RMI I – threshold of 200.
The model did not include assessment of the ROMA using Fujirebio Diagnostics' Lumipulse G HE4 assay because no studies were identified that provided data on the accuracy of the ROMA using this assay. In the base-case analysis the starting cohort was assumed to be 40 years old, consistent with the modelling produced for the NICE guideline on ovarian cancer. All costs and effects included in the model were discounted by 3.5%.
The EAG developed a decision tree and Markov model for the assessment. The decision tree was used to model short-term outcomes (up to 30 days after surgery) and the Markov model for longer-term outcomes over a lifetime horizon. In the decision tree, the alternative tests and risk scores were assessed by their ability to help decision-making about referral to a specialist MDT. After the referral, people in the decision tree were classified as being in 1 of the following states: early ovarian cancer, advanced ovarian cancer, benign mass, colorectal cancer or death (to account for mortality 30 days after surgery).
Longer-term costs and QALYs (over a lifetime horizon) were estimated using a Markov cohort model. This model included separate states for people with ovarian cancer who were treated in a specialist MDT and those who were not, to allow a beneficial effect for treatment in a specialist MDT to be applied. This treatment effect was a hazard ratio of 0.90 (95% CI 0.82 to 0.99) applied to overall survival of people with ovarian cancer (for people with both early and advanced stage ovarian cancer) and to progression-free survival for people with early stage ovarian cancer. This effect size was taken from a Cochrane review (Woo et al. 2012) which reported this hazard ratio for overall survival of people with ovarian cancer who had treatment in institutions with gynaecologic oncologists on site compared with community or general hospitals. The EAG assumed that this hazard ratio would also apply for progression-free survival, based on data in Woo et al. (2012).
The accuracy of the assessed tests and risk scores used in the model were taken from the clinical-effectiveness review and are shown in table 7. The EAG used diagnostic accuracy estimates derived from studies in which the target condition was 'all malignant tumours including borderline'; that is, studies that did not exclude participants from analysis on the basis of their final histological diagnosis. This was because the EAG considered that this population would produce estimates of test performance most representative of clinical practice. The prevalence of malignancies used in the model (21.3%; comprising ovarian malignancies, including borderline, and non-ovarian malignancies) was a summary estimate calculated from diagnostic cohort studies identified in the clinical-effectiveness review.
## Table 7 Diagnostic accuracy estimates used in the model
Sensitivity (standard error)
Specificity (standard error)
Source
RMI I – threshold of 250
Summary estimate from 1 unpublished study (IOTA 2017) and 6 studies (Davies et al. 1993; Jacobs et al. 1990; Lou et al. 2010; Morgante et al. 1999; Tingulstad et al. 1996; Ulusoy et al. 2007).
ROMA Abbott ARCHITECT
Summary estimate from Al Musalhi et al. (2016).
ROMA Roche Elecsys
Summary estimate from 2 studies (Janas et al. 2015; Shulman et al. 2016).
Overa (MIA2G) – threshold of 5 units
Summary estimate from 2 studies (Coleman et al. 2016; Zhang et al. 2015).
IOTA Simple Rules – inconclusive assumed to be malignant
Summary estimate from 1 unpublished study (IOTA 2017) and 8 studies (Adballa et al. 2013; Alcazar et al. 2013; Knafel et al. 2015; Meys et al. 2016; Sayasneh et al. 2013; Silvestre et al. 2015; Testa et al. 2014; Timmerman et al. 2010).
IOTA ADNEX model – threshold of 10%
Summary estimate from 1 unpublished study (IOTA 2017) and 3 studies (Meys et al. 2016; Sayasneh et al. 2016; Van Calster et al. 2014).
RMI I – threshold of 200
Summary estimate from 1 unpublished study (IOTA 2017) and 12 studies (Abdalla et al. 2013; Al Musalhi et al. 2016; Davies et al. 1993; Jacobs et al. 1990; Lou et al. 2010; Meys et al. 2016; Morgante et al. 1999; Sayasneh et al. 2013; Testa et al. 2014; Tingulstad et al. 1996; Ulusoy et al. 2007; Van Gorp et al. 2012).
Abbreviations: RMI I, risk of malignancy index 1; ROMA, risk of ovarian malignancy algorithm.
The costs associated with the use of the different risk scores used in the model are shown in table 8. Costs were taken from companies, published literature and routine sources of NHS costs. Further costs used in modelling were taken from modelling done for the NICE guideline on ovarian cancer, relevant NHS reference costs, Personal Social Services Research Unit publications and further identified literature. No costs related to the training needed for the use of Simple Rules and ADNEX model were included in base-case analysis. However, the effect of additional costs (to reflect potential training costs) for these tests was investigated in scenario analysis.
## Table 8 Risk score costs used in modelling
Test
Ultrasound cost1 (£)
Test cost per kit (£)
Total HE4 test-related costs2 (£)
CA125 cost3 (£)
Total cost (£)
ADNEX
Overa (MIA2G)
RMI I
ROMA (Abbott ARCHITECT)
ROMA (Roche Elecsys)
Simple Rules
Calculated from the cost of transvaginal ultrasound scans used in economic modelling for the NICE guideline on ovarian cancer and inflated to 2015/16 values.
Includes capital, quality control, maintenance, shipping, calibration and personnel costs, as set out in appendix 6 of the diagnostics assessment report.
Cost of doing a CA125 assay calculated from the NICE guideline on ovarian cancer (adjusted for inflation).
Abbreviations: RMI I, risk of malignancy index 1; ROMA, risk of ovarian malignancy algorithm.
Utility estimates used in modelling are shown in table 9.
## Table 9 Utility scores used in modelling
Utility value estimate
Source
Benign mass (assumed equal to general population)
Age dependent
Ara et al. (2010)
Early ovarian cancer
Treated by specialist MDT
Havrilesky et al. (2009)
Not treated by specialist MDT treated
Equal to treated by specialist MDT
Assumption
Advanced ovarian cancer
Treated by specialist MDT
Grann et al. (1998)
Not treated by specialist MDT treated
Equal to treated by specialist MDT
Assumption
Colorectal cancer
Dukes' A
Ness et al. (1999)
Dukes' B
Dukes' C
Dukes' D
Abbreviations: MDT, multidisciplinary team.
## Base-case results
The following assumptions were applied in the base-case analysis:
All non-ovarian malignancies were assumed to be colorectal cancer.
People with a false negative diagnosis were more likely to have early-, rather than advanced-, stage ovarian cancer.
Inconclusive results from Simple Rules were assumed to be malignant.
All people with a false positive and false negative diagnosis were operated on for a benign mass.
No disutility was applied for people who were incorrectly told that they have ovarian cancer (false positives).
In the base-case model analysis, the EAG did a pairwise analysis comparing the costs and QALYs resulting from using the included tests and risk scores with RMI I (threshold of 250), and also a fully incremental analysis (table 10). Use of Simple Rules (inconclusive assumed to be malignant) was the cheapest and second most effective, and dominated RMI I (at a threshold of 200 and 250). Use of the ADNEX model was most effective (that is, produced the most QALYs) and when compared with Simple Rules produced an incremental cost-effectiveness ratio (ICER) of £15,304 per QALY gained. Use of the ROMA and Overa (MIA2G) were dominated.
## Table 10 Base-case analysis results
Compared with RMI I (threshold of 250)
Full incremental analysis
Difference in costs
Difference in QALYs
Difference in costs / difference in QALYS
Simple Rules – inconclusive assumed to be malignant
Dominant
Cheapest
RMI I – threshold of 250
N/A
Dominated
RMI I – threshold of 200
Dominated
ADNEX – threshold of 10%
ROMA – Abbott ARCHITECT
Dominated
ROMA – Roche Elecsys
Dominated
Overa (MIA2G) – threshold of 5 units
Dominated
Abbreviations: QALY, quality-adjusted life year; RMI I, risk of malignancy index 1; ROMA, risk of ovarian malignancy algorithm.
At a maximum acceptable ICER of £20,000 per QALY gained, the ADNEX model and Simple Rules had a probability of being cost effective of 60% and 39% respectively. At a maximum acceptable ICER of £30,000 per QALY gained, these probabilities were 75% (ADNEX) and 23% (Simple Rules). The probability of RMI I (threshold of 250) being cost effective at both thresholds was about 1%, and the probabilities of the other tests and risk scores was less than 1%.
Use of the ADNEX model remained cost effective at £20,000 and £30,000 per QALY gained in one-way deterministic sensitivity analysis when most parameters were altered. Simple Rules became cost effective in some analyses, typically when the costs of using the ADNEX model were increased (or Simple Rules costs were decreased) or the diagnostic accuracy of the Simple Rules was improved relative to ADNEX. Also, when the upper bound value for the overall-survival hazard ratio for people with an ovarian malignancy treated in a specialist MDT (rather than secondary care) was used, (that is, the beneficial effect of surgery done by a specialist MDT was at its lowest level in the model), Simple Rules became cost effective at both £20,000 and £30,000 per QALY gained.
## Alternative scenario analyses
The EAG did several scenario analyses to test assumptions made about parameter values used in the base-case model analysis. Use of the ADNEX model remained cost effective in most scenario analysis. However, in some scenarios Simple Rules (inconclusive results assumed to be malignant) was cost effective. These included when a disutility (the value of which was arbitrary) was applied for people with a false positive diagnosis for 1 year and when the benefit of treatment in specialist care was reduced.
In a scenario analysis in which a higher cost of surgery done by a specialist MDT was used, RMI I (threshold of 250) was cost effective at a maximum acceptable ICER of £20,000 per QALY gained and Simple Rules was cost effective at a maximum acceptable ICER of £30,000 per QALY gained. In this scenario, an additional cost of £2,500 was added to the average cost of surgery done by a specialist MDT, to reflect expert opinion that some patients referred to a specialist MDT will have extensive surgery for ovarian cancer.
## Subgroup analyses
Results from subgroup analyses were similar to the base-case analyses when the starting age of the cohort was 50 years and also when only early stage cancer was considered. However, when the analysis was run for advanced stage cancer, Simple Rules (rather than ADNEX) was cost effective at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained. No changes to sensitivity or specificity values for tests were made in these subgroup analyses (because of a lack of data on test performance in these populations).
The EAG also did subgroup analyses for populations who were pre- and postmenopausal. Sensitivity and specificity estimates for tests or risk scores in these subgroups were taken from the clinical-effectiveness review; but relatively few studies were available to inform these estimates. A different starting age of the cohort and prevalence of malignancy (compared with the base-case analysis) was also used for these subgroups. The ADNEX model was cost effective at thresholds of £20,000 and £30,000 per QALY gained for both these subgroup analyses.# Committee discussion
The committee discussed the potential benefits of correctly identifying people referred to secondary care with suspected ovarian cancer who have a benign or malignant mass. It heard from patient and clinical experts that a correct diagnosis of a malignant mass at an early stage will increase the likelihood of survival. Patient experts also suggested that even for people with stage III ovarian cancer, earlier identification of the condition could mean that there is a lower volume of tumour on which to operate if surgery is indicated.
The committee discussed the potential disadvantages of incorrectly referring people with a benign mass to a specialist multidisciplinary team (MDT). The committee heard that false positive results (that is, people with a benign mass who are incorrectly told that it is likely to be malignant) lead to unnecessary anxiety for patients and their families, and may result in an increased number of people having surgery when in fact no surgery, or less extensive surgery, could be considered. The committee noted that this is particularly an issue for people who are premenopausal and who may wish to consider fertility-conserving surgery, as well as for people who are older or frail and wanting to avoid surgery if possible.
# Clinical effectiveness
The committee discussed the diagnostic accuracy data available for the included tests. It noted that the studies in the clinical-effectiveness review varied in which target condition they used (that is, what was considered a positive reference standard test result). The committee heard from clinical experts that although epithelial cancers are the most common form of ovarian malignancy, people referred to secondary care with suspected ovarian cancer will include those with non-ovarian tumours and non-epithelial ovarian tumours. The committee noted that studies which used a target condition of ovarian cancer or epithelial ovarian cancer retrospectively excluded patients from analysis based on their reference standard diagnosis, and that these studies had been assessed as having a high risk of bias by the external assessment group (EAG). The committee concluded that studies which used a target condition of all malignant (including borderline) tumours were most representative of clinical practice.
The committee considered the generalisability of the evidence to clinical practice in the NHS. It heard from clinical experts that the prevalence of malignancy in study populations was considerably higher than would be expected for people referred to secondary care with suspected ovarian cancer in the NHS. Clinical experts commented that a prevalence of less than 10% would be expected, and suggested 5% as a realistic prevalence of malignancy in this population. The committee heard from the EAG that, in addition, most studies did not report the distribution of disease stages among patients with ovarian cancer. Therefore, it noted that the spectrum of disease in the studies may not reflect that seen in secondary care in the NHS. The committee concluded that the study populations, for all tests, may not be representative of the clinical population for this assessment. In particular, the differing levels of disease severity in the study populations and in secondary care in the NHS could mean that the sensitivity and specificity estimates obtained from these studies are not accurate estimates of how the tests would perform in secondary care in the NHS.
The committee considered the test accuracy of the Simple Rules and ADNEX. It noted that studies showed that they were statistically significantly more sensitive than RMI I. The committee then considered the expertise of practitioners doing and interpreting ultrasound scans in studies assessing the Simple Rules system and the ADNEX model. The committee heard from clinical experts that practitioners in these studies had a higher level of skill and experience than is generally available in secondary care in the NHS, and noted that there were limited data available on the accuracy of tests done by less experienced operators. The committee heard that although image acquisition would generally be straightforward for NHS practitioners, additional training would be needed in interpreting the images to use the Simple Rules or ADNEX model. The committee heard from clinical experts that the local organisation of care would be likely to affect test performance in practice; and that there is uncertainty about the effect of NHS service models on how well the Simple Rules and ADNEX model would perform in secondary care. For example, if a model of delivery in which patients are seen, scanned and their condition managed in 1 setting was used, this may lead to improved performance of the tests through a concentration of services and skills. It also heard from clinical experts that no data have been published on inter-observer variation using the IOTA tests in the NHS. The committee therefore concluded that there is considerable uncertainty about the likely performance of the Simple Rules and ADNEX tests in secondary care in the NHS, and that the accuracy reported in the studies may not be achieved in clinical practice in the NHS.
The committee considered the test accuracy data for the ROMA and Overa (MIA2G). It noted that relatively few studies were identified for these tests, particularly studies with a direct comparison with RMI I. The committee concluded that there is considerable uncertainty about the diagnostic accuracy of these tests; however it is possible that the tests may offer improved accuracy relative to RMI I.
The committee considered data on the accuracy of RMI I at thresholds other than 250. It noted that most studies with a direct comparison of RMI I at 250 and another threshold used a threshold of 200, and that there were relatively few studies with other alternative thresholds. It also noted that there was very little difference in the summary estimates of sensitivity and specificity for RMI I at thresholds of 200 and 250 obtained from studies with a direct comparison. The committee therefore concluded that RMI I used with a threshold of 200 was unlikely to offer accuracy benefits over using this test with a threshold of 250, and noted that the use of RMI I at a threshold of 250 is recommended in the NICE guideline on ovarian cancer.
The committee discussed how the stage of ovarian cancer (early or advanced) could affect test accuracy. It heard from clinical experts that about 70% of people identified with ovarian cancer have advanced stage cancer. However, the main benefit of tests such as RMI I in secondary care is in identifying early stage ovarian cancer, with advanced stage ovarian cancer being more apparent from imaging. The committee heard from the EAG that very few data were available to inform estimates of test accuracy by stage of ovarian cancer. Two studies assessing the ROMA reported that sensitivity was lower for detecting early stage ovarian cancers. However most studies did not provide details on the stage of cancer of study participants included in analysis. The committee heard from clinical experts that populations in studies were likely to include more cases of advanced than early stage ovarian cancers, and that the performance of tests to detect early and advanced stage ovarian cancer could differ substantially. The committee concluded that there is uncertainty about how accurate the tests are at correctly detecting early stage ovarian cancer, potentially the most relevant group for this assessment. The committee also concluded that data on the accuracy of tests to detect early stage ovarian cancer would be important for any future assessment (see section 6.1).
# Cost effectiveness
The committee discussed the sensitivity and specificity estimates used in the cost-effectiveness modelling. It noted that these estimates were taken from the clinical-effectiveness review and that the concerns about the applicability of data from these studies to NHS secondary care (see sections 5.4 and 5.5) also apply to the model. The committee also noted that relatively few studies were available to inform test accuracy estimates for the ROMA and Overa (MIA2G) tests (see section 5.6).
The committee noted that tests with the highest sensitivity (ADNEX and Simple Rules) that resulted in more people with ovarian cancer being referred to a specialist MDT tended to be cost effective. It considered the parameter used in the model for the beneficial effect of a referral to a specialist MDT for people with ovarian cancer; a hazard ratio for overall and progression-free survival obtained from a Cochrane review (see section 4.31). The committee heard that estimates from this review were based on studies with a mixed cohort of early and advanced stage ovarian cancer, and that because advanced stage was likely to be predominant in this cohort, the summary estimate may not be an accurate reflection of the beneficial effect of specialist MDT treatment on people with early stage ovarian cancer. It also heard that the benefits for people with early stage ovarian cancer of having their surgery done by a gynaecological oncology specialist are potentially more difficult to assess than those for people with advanced stage cancer. An improved quality of surgery is likely to lead to more accurate staging of the cancer, which will help with subsequent treatment decisions. For example, accurate staging may show that chemotherapy is not needed (for low-risk stage I disease); but inadequate staging in a non-specialist centre could lead to inappropriate use of chemotherapy or the need for further surgery to accurately stage the cancer. The committee also heard from clinical experts that people with a false negative test result will have their condition managed in secondary care, and if their ovarian malignancy is recognised at a later date they will then be referred to a specialist MDT. The effect of this delayed referral, rather than lack of referral, to a specialist MDT on patient outcomes is unclear. The committee concluded that, because of a lack of data, there is considerable uncertainty about the effect of false negative test results on people with ovarian cancer, particularly if they have early stage ovarian cancer.
The committee discussed the costs included in the model for people referred to a specialist MDT. It noted that the cost of an MDT meeting had been included, but heard from clinical experts that additional costs may be incurred when a patient is referred to a specialist MDT for discussion; such as costs for the time taken by radiologists to review images in advance of the meeting. The committee heard from the EAG that these additional costs were not captured in the model. The committee also noted that in the base case, the model used NHS reference costs for surgery, and that this may not adequately capture the cost of extensive surgery potentially needed for people with advanced stage cancer, who make up 75% of the population with an ovarian malignancy in the model. It heard from clinical experts who suggested that the costs associated with more extensive surgery should be included in the model. The committee noted that in a scenario analysis in which additional surgery costs were assumed, RMI I (threshold 250) was cost effective at a maximum acceptable incremental cost-effectiveness ratio of £20,000 per quality-adjusted life year gained. The committee concluded that the costs of a referral to, and treatment by, a specialist MDT may have been underestimated in the model, and that this could affect the model results, such as which tests seemed to be cost effective.
The committee discussed the costs of CA125 testing included in the model. It heard from the EAG that the economic model assumed that all patients have a CA125 test in secondary care, even if they previously had one in primary care. The committee heard from clinical experts that the reasons for patients having another CA125 test in secondary care are: CA125 levels may have changed since the first test was carried out; some risk scores are only compatible with a specific brand of CA125 test; and some tests include CA125 as part of an array. The committee concluded that the assumption in the economic model in relation to CA125 testing costs was valid.
The committee considered its discussions on the clinical- and cost-effectiveness evidence. It concluded that:
There is considerable uncertainty about the estimates of test accuracy used in modelling because: relatively few studies were found to inform estimates (for the ROMA and Overa ; see section 5.6); the high prevalence of malignancy in studies suggested that they were not representative of clinical populations in secondary care in the NHS (see section 5.4); and that the level of expertise of people interpreting scans for the Simple Rules and the ADNEX model in studies was higher than would be routinely available in the NHS (see section 5.5).
There is uncertainty about the accuracy of tests to detect early stage ovarian cancer (see section 5.8), and about the likely effect on outcomes for people with early stage ovarian cancer who have a delayed referral to a specialist MDT, as a result of an initial false negative test result (see section 5.10).
There is uncertainty about the costs of assessment and treatment at a specialist MDT, and that higher costs would impact model results (see section 5.11).
# Other considerations
The committee discussed the accuracy of tests, noting that tests with higher sensitivity had lower specificity. The committee heard from clinical experts that tests with high sensitivity reduce the number of missed cases of ovarian cancer, but that lower test specificity will result in more false positive referrals to specialist MDTs. The committee heard from clinical experts that there is very limited specialist MDT capacity for personnel in relation to the current case demand, and that increasing the number of false positive referrals to specialist MDTs would reduce the quality of assessment by limiting time available for discussion for each patient. Clinical experts commented that this could adversely affect, or delay, decisions made in specialist MDT meetings about patient treatment. The committee concluded that using tests with lower specificity would have a large impact on specialist MDT services, but the model has not captured the impact because of a lack of data on the effect this would have on patient care and clinical outcomes and because of its structure.
The committee considered the accuracy of the tests for people who are pre- and postmenopausal. It noted that relatively few studies provided accuracy estimates stratified by menopausal status. The committee further noted that the EAG did cost-effectiveness analyses for pre- and postmenopausal subgroups; however there were relatively few data to inform the tests' performance in pre- and postmenopausal populations in this analysis. The committee heard from clinical experts that menopausal status could considerably affect the performance of the tests, and that further data are needed to assess the performance of the tests in these subgroups (see section 6.1).
The committee discussed the likely effect of test results on decisions made about patient care. It noted that no data were available on the effect of test results on decisions about patient care or referral. The committee heard from clinical experts that in practice results from tests such as the RMI I are used alongside further information, such as imaging, when making decisions about patient care and referral. It noted therefore that increased accuracy of testing may not correspond to changes in decision-making. The committee concluded that there is uncertainty about how the results of the tests included in the assessment would be used in clinical practice in the NHS, and that further research on this would be useful (see section 6.2).
The committee heard from patient experts that access to tests in primary care for people with ovarian cancer symptoms varied, and that getting a referral to secondary care could take a long time. It heard further from clinical experts that about 60% of people referred to secondary care have a late stage of cancer, and they are often referred from colorectal and urological cancer services and emergency care. The committee agreed that differences in initial assessment may lead to variation in patient outcomes. The committee noted that tests for suspected ovarian cancer in primary care were outside of the scope of this assessment and that evidence from this setting had not been reviewed.
The committee discussed the use of tests in sequence. It heard from clinical experts that the use of a highly sensitive test followed by a highly specific test may improve accuracy of referral. The committee noted that the EAG had looked for studies that assessed the use of included tests in combination or sequence in the clinical-effectiveness review; however very few data were found (1 study with a lack of detail about how test results were combined to produce a positive result). The committee considered that the use of tests in sequence could be cost effective and further research is needed to inform accuracy estimates (see section 6.3).
# Research considerations
The committee noted that there is an ongoing National Institute for Health Research funded diagnostic test accuracy study; the ROCkeTS (Refining Ovarian Cancer Test Accuracy Scores) study, which will report in 2019 or 2020. This study will evaluate existing and new risk prediction models for people with symptoms of suspected ovarian cancer against a comparator of RMI I (threshold of 250). It will assess patients using the IOTA Simple Rules and ADNEX tests, as well as biomarker assays. Practitioners doing ultrasound scans as part of the study will have an IOTA training course; therefore the study will provide test accuracy data for NHS practitioners with a defined amount of training. The study will also report costs and resource use associated with the diagnostic tests. The recruited study population will be people referred to secondary care in the NHS; the committee noted that the results are likely to be very relevant to future updates of this guidance.# Recommendations for further research
Further diagnostic accuracy studies, or analyses of existing data sets, are recommended to assess the accuracy of the tests included in this assessment in the following subgroups:
people who are premenopausal
people who are postmenopausal
people with suspected early stage ovarian cancer, that is, disease apparently confined to the pelvis.Future studies should be done in populations that are representative of people with suspected ovarian cancer who are assessed in NHS secondary care.
Further research is recommended to assess:
inter-observer reproducibility of tests involving ultrasound scans (the ADNEX model and Simple Rules)
changes in clinical management based on test results from the ADNEX model, Overa (MIA2G), ROMA and Simple Rules.
Further research is recommended to assess the diagnostic accuracy of the tests included in this assessment when used in combination; for example sequentially.
|
{'Recommendations': 'There is currently not enough evidence to recommend the routine adoption of the IOTA ADNEX model, Overa (MIA2G), RMI\xa0I (at thresholds other than 200 or 250), ROMA or IOTA Simple Rules in secondary care in the NHS to help decide whether to refer people with suspected ovarian cancer to a specialist multidisciplinary team (MDT).\n\nThe NICE guideline on ovarian cancer recommends that people with an RMI\xa0I of 250\xa0or more are referred to a specialist MDT. Evidence suggests that there is no substantial change in accuracy if the threshold for RMI\xa0I is lowered to 200.\n\nThe IOTA ADNEX model, Overa (MIA2G), RMI\xa0I (at thresholds other than 250), ROMA and IOTA Simple Rules show promise. Further research is recommended on test accuracy and the impact of the test results on clinical decision-making (see section\xa06 for detailed research recommendations).', 'Clinical need and practice': '# The problem addressed\n\nTests and risk scores are used in secondary care to help determine if a person referred with suspected ovarian cancer is likely to have an ovarian malignancy. Results inform decisions about whether they should be referred to a specialist multidisciplinary team (MDT) for further assessment and treatment. Currently, serum biomarker CA125 and pelvic ultrasound scans are widely used in secondary care, as part of the risk of malignancy index\xa01 (RMI\xa0I) score, in deciding whether a referral to a specialist MDT is needed. However, not all ovarian malignancies show elevated CA125 levels (particularly early stage ovarian cancer). Also elevated levels of CA125 are not always indicative of ovarian cancer, because they may be raised from other causes, such as endometriosis, fibroids, pregnancy, pelvic inflammatory disease, liver disease or heart failure. Tests and risk scores included in this assessment (ADNEX, Overa [MIA2G], RMI\xa0I at thresholds other than 250, ROMA and Simple Rules) may be better able to distinguish between benign and malignant ovarian tumours, and increase the proportion of people with a correct referral from secondary care to a specialist MDT.\n\nIncreasing the proportion of people with ovarian cancer who get a correct referral to a specialist MDT is likely to improve patient outcomes. Also, improved testing could lead to more accurate recognition of people referred to secondary care with suspected ovarian cancer who do not have the condition. This could reduce inappropriate referrals to specialist care for further assessment and treatment, as well as the costs and anxiety that this can cause.\n\n# The condition\n\nOvarian cancer starts in cells in, or near, the ovaries. Primary ovarian tumours are classified based on the tissue that they develop from, with 3\xa0main types: epithelial ovarian tumours, sex cord-stromal tumours of the ovary and germ cell tumours of the ovary. Each subtype of tumour can be benign, malignant or intermediate (borderline malignant). About 90% of primary ovarian cancers are malignant epithelial tumours. Non-epithelial ovarian cancers make up a higher proportion of ovarian cancer in people who are premenopausal.\n\nData from Cancer Research UK (ovarian cancer statistics) suggests:\n\nThere were about 7,400\xa0new cases of ovarian cancer in the UK in 2014, accounting for 2% of all new cancer cases.\n\nThe incidence of ovarian cancer increases with age, with more than half of cases between 2012 and 2014 happening in people aged 65\xa0years and over.\n\nThere were about 50\xa0new cases in people under 19\xa0years in this time period, about 600\xa0new cases in people under 40\xa0years and about 1,400\xa0new cases in people under 50\xa0years.\n\n# The diagnostics and care pathways\n\n## Diagnosis\n\nThe NICE guideline on ovarian cancer includes recommendations on criteria and tests to use in primary care when deciding whether to refer someone to secondary care with suspected ovarian cancer. Recommendations from this guideline have also been incorporated in the NICE guideline on suspected cancer.\n\nThe NICE guideline on ovarian cancer also provides recommendations on diagnosing suspected ovarian cancer in secondary care. An ultrasound of the abdomen and pelvis is recommended as the first imaging test in secondary care for people with suspected ovarian cancer (if this has not already been done in primary care), as well as measuring serum CA125 (if not already done in primary care). The guideline recommends calculating an RMI\xa0I score, based on characteristics seen on ultrasound, CA125 serum levels and menopausal status (described in more detail in section\xa03). It states that people with an RMI\xa0I score of 250 or more should be referred to a specialist MDT.\n\nFor people under 40\xa0years with suspected ovarian cancer, the NICE guideline on ovarian cancer recommends measuring the levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta‑hCG), as well as CA125, to identify non-epithelial ovarian cancer.\n\nThe NICE guideline on ovarian cancer also provides recommendations on further imaging to characterise the extent and spread of ovarian cancer, and also on getting a tissue sample to confirm a diagnosis of ovarian cancer. Histopathology is generally used as the reference standard for assessing the accuracy of tests to identify people who are likely to have ovarian cancer. As well as distinguishing between malignant and benign tumours, this testing can also determine the type of ovarian cancer present. If tissue samples are not taken, clinical follow-up may be needed to determine the presence, or absence, of ovarian cancer.\n\n## Care pathway\n\nThe NICE guideline on ovarian cancer contains recommendations for the management of early (stage\xa0I) and advanced (stages\xa0II to\xa0IV) ovarian cancer.', 'The diagnostic tests': "The assessment compared 5\xa0interventions with 1\xa0comparator.\n\n# The interventions\n\n## The assessment of different neoplasias in the adnexa (ADNEX) model\n\nThe ADNEX model was developed by the International Ovarian Tumor Analysis (IOTA) group to assess people with an adnexal mass who are considered to need surgery. The model uses 3\xa0clinical predictors and 6\xa0ultrasound-derived predictors to estimate the probability that a pelvic tumour is benign or malignant (see table\xa01). Also, the model estimates probabilities that a tumour is borderline, stage\xa0I cancer, stage\xa0II to\xa0IV cancer or secondary metastatic cancer. The ADNEX model formulas are available in published literature (Van Calster et al. 2014) and the model is further described on the IOTA website. The terminology used in the model is as defined in a publication by the IOTA group (Timmerman et al. 2000), and the group run courses that teach the terms, definitions and measurement techniques needed to assess pelvic masses for the ADNEX model. An online training tool for NHS practitioners is also currently in development.\n\n## Table 1 Criteria included in the ADNEX model\n\nClinical predictors\n\nUltrasound derived predictors\n\nAge (years)\n\nSerum CA125 level (units per millilitre [U/ml])\n\nType of centre (oncology centre or other hospital)1\n\nMaximum diameter of lesion (mm)\n\nProportion of solid tissue (ratio of the maximum diameter of the largest solid component and the maximum diameter of the lesion)\n\nMore than 10\xa0cyst locules (yes or no)\n\nNumber of papillary projections (0, 1, 2, 3 or more than 3)\n\nAcoustic shadows (yes or no)\n\nAscites (yes or no)\n\nOncology centre defined as a tertiary referral centre with a specific gynaecology oncology unit (Van Calster et al. 2014).\n\nThe ultrasound variables for the ADNEX model need B\xa0mode imaging and the IOTA group states that any modern ultrasound machine with a high-frequency (more than 6\xa0Hz) transvaginal probe can be used. The ADNEX model has not been validated for use in people who are pregnant.\n\n## Overa (MIA2G) serum test (Vermillion)\n\nThe Overa (MIA2G) is a CE-marked qualitative serum test that combines the results of 5\xa0immunoassays into a single numeric result (the Overa Risk Score). The 5\xa0biomarkers included in the test are: follicle-stimulating hormone (FSH), human epididymis protein\xa04 (HE4), apolipoprotein A‑1 (Apo A‑1), transferrin (TRF), and cancer antigen\xa0125 (CA125). The serum levels of these biomarkers are determined using immunoassays run on the Roche cobas 6000 system. The Overa Risk Score is generated by the company's OvaCalc software, with results ranging between 0.0 and 10.0. A risk score of less than 5.0 indicates a low probability of malignancy and a score of 5.0 or more indicates a high probability of malignancy. The assay is for use in people over 18\xa0years with a pelvic mass for whom surgery may be considered. It is intended to be part of preoperative assessment to help decide if a person presenting with a pelvic mass has a high or low risk of ovarian malignancy.\n\nThe company states that test results must be interpreted in conjunction with an independent clinical and imaging evaluation, and that the test is not intended for use in screening or as a stand-alone assay. The Overa (MIA2G) is available to the NHS through a private laboratory which tests samples and provides Overa Risk scores.\n\n## Risk of malignancy index\xa01 (RMI\xa0I) with thresholds other than 250\n\nThe RMI\xa0I tool combines 3 pre-surgical\xa0features (measured serum CA125 levels [CA125], ultrasound imaging [U] and menopausal status [M]) to create an index score: RMI\xa0I score = U×M×CA125. Definitions of these terms from the NICE guideline on ovarian cancer are in table\xa02.\n\n## Table 2 Definitions of RMI\xa0I terms\n\nTerms in RMI\xa0I equation\n\nDescription\n\nU\n\nUltrasound score based on 1\xa0point scored for the presence of each of the following features: multilocular cysts, solid areas, metastases, ascites, bilateral lesions. U=0 (0\xa0points), U=1 (1\xa0point) or U=3 (2\xa0to 5\xa0points).\n\nM\n\nMenopausal status: M=1 (premenopausal) or M=3 (postmenopausal). The classification of 'postmenopausal' is a woman who has had no period for more than 1\xa0year or a woman over 50 who has had a hysterectomy.\n\nCA125\n\nSerum CA125 concentration measured in units per millilitre (U/ml).\n\nThe NICE guideline on ovarian cancer recommends that people with an RMI\xa0I score of 250\xa0or more should be referred to a specialist MDT (the RMI\xa0I at this threshold is the comparator for this assessment, see section\xa03.15). However, this guideline also includes a research recommendation stating that further research should be done to determine the optimum RMI\xa0I threshold that should be applied in secondary care to guide the management of suspected ovarian cancer. The subsequently published Scottish Intercollegiate Guidelines Network (SIGN) guideline on the management of epithelial ovarian cancer (SIGN\xa0135) recommends referring people with an RMI\xa0I score of more than 200\xa0to a gynaecological oncology multidisciplinary team.\n\n## Risk of ovarian malignancy algorithm (ROMA)\n\nThe ROMA combines serum CA125 and HE4\xa0levels with a person's menopausal status to estimate the probability that they have epithelial ovarian cancer. Different equations are used depending on whether the person is pre- or postmenopausal (Moore et al. 2009). Cut-off values for the ROMA score stratify individuals as being at a high or low risk of having epithelial ovarian cancer. Cut-off values vary depending on which manufacturers' HE4 and CA125 assays are being used. The ROMA has not been validated in people under 18\xa0years old, people being treated with chemotherapy and people who have previously been treated for a malignancy.\n\nThree assays that measure HE4\xa0serum levels using automated immunoassay analysers, and that are available to the NHS, are described in the following sections.\n\nA CE‑marked chemiluminescent microparticle immunoassay designed for use on the Abbott ARCHITECT i2000SR or ARCHITECT i1000SR immunoassay analysers. It is intended for use with the ARCHITECT CA125\xa0II assay, with results of both assays used in the ROMA to help estimate the risk that someone presenting with an adnexal mass and who will have surgery has epithelial ovarian cancer. The following cut-off values are suggested for ROMA to determine if there is a high or low risk of epithelial ovarian cancer: 7.4% for people who are premenopausal; 25.3% for people who are postmenopausal.\n\nA CE‑marked chemiluminescent enzyme immunoassay designed for use on the LUMIPULSE\xa0G System (either the LUMIPULSE G1200 or LUMIPULSE G600 immunoassay analysers). It is intended for use with the Lumipulse G CA125\xa0II assay, with results of both assays used in the ROMA to help estimate the risk that someone presenting with an adnexal mass and who will have surgery has epithelial ovarian cancer. The following cut-off values are suggested for ROMA to determine if there is a high or low risk of epithelial ovarian cancer: 13.1% for people who are premenopausal; 27.7% for people who are postmenopausal.\n\nA CE‑marked immunoassay test that uses Roche's ElectroChemiLuminescence detection technology designed for use on the following immunoassay analysers: Modular analytics E170, cobas\xa0e\xa0411, cobas\xa0e\xa0601/e\xa0602 and cobas\xa0e\xa0801. It is intended for use with the Elecsys CA 125\xa0II assay, with results of both assays used in the ROMA to help estimate the risk that someone presenting with a pelvic mass has epithelial ovarian cancer. The following cut-off values are suggested for ROMA to determine if there is a high or low risk of epithelial ovarian cancer: 11.4% for people who are premenopausal; 29.9% for people who are postmenopausal.\n\n## Simple Rules ultrasound classification system\n\nSimple Rules was developed by the IOTA group to assess people with a pelvic mass who are considered to need surgery. It is a scoring system based on the presence of ultrasound features, to characterise an ovarian tumour before surgery as benign or malignant. No specific make or model of ultrasound device is needed to use the Simples Rules system. A transvaginal probe is needed and image quality must be of sufficient quality to allow the ultrasound features specified by the Simple Rules system to be seen.\n\nTerms and definitions used in the classification system are as defined by the IOTA group. The group run courses that teach the terms, definitions and measurement techniques needed to assess pelvic masses for the Simple Rules. An online training tool for NHS practitioners is also currently under development. Simple Rules has not been validated for use in people who are pregnant.\n\nThere are 5\xa0rules that predict a malignant tumour (M‑rules) and 5\xa0rules that predict a benign tumour (B‑rules), as described in table\xa03. If any M‑rules apply (and no B‑rules) then the mass is classified as malignant. If any B‑rules apply (and no M‑rules) then the mass is classified as benign. However, if both M- and B‑rules apply, or neither, then the result is inconclusive, and is either classed as malignant or further criteria are needed to assess whether the mass is likely to be malignant; for example, further expert subjective assessment of the ultrasound images.\n\n## Table 3 Simple Rules ultrasound classification system\n\nM‑rules\n\n(Rules for predicting a malignant tumour)\n\nB‑rules\n\n(Rules for predicting a benign tumour)\n\nIrregular solid tumour\n\nAscites present\n\nFour or more papillary structures\n\nIrregular multilocular solid tumour with largest diameter 100\xa0mm or more\n\nVery strong blood flow (colour score\xa04)\n\nUnilocular\n\nSolid components present, with largest solid component having a largest diameter of less than 7\xa0mm\n\nAcoustic shadows present\n\nSmooth multilocular tumour with largest diameter less than 100\xa0mm\n\nNo blood flow (colour score\xa01)\n\n# The comparator\n\nThe comparator for this assessment is the RMI\xa0I used at a threshold of 250, as currently recommended in the NICE guideline on ovarian cancer.", 'Evidence': "The diagnostics advisory committee (section\xa08) considered evidence on tests used in secondary care to help identify people at high risk of ovarian cancer from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nFifty-one diagnostic cohort studies were identified (in 65\xa0publications) that reported data on 1\xa0or more of the included tests or risk scores. Also, an unpublished interim report of phase\xa05 of the International Ovarian Tumor Analysis (IOTA) study was available to the external assessment group (EAG) and committee as academic in confidence. No randomised controlled trials or controlled clinical trials were identified; neither were studies that reported how test results affect clinical management decisions. Ten studies had inclusion criteria which allowed people under 18\xa0years to take part; but the number of participants in this age group was not reported.\n\nAll the included studies reported the accuracy of tests and risk scores to assess people with an adnexal or pelvic mass. When summary estimates of sensitivity and specificity from multiple studies were calculated, these were separate pooled estimates produced using random-effects logistic regression. The bivariate/hierarchical summary receiver operating characteristic model was not used because data sets were either too small or too heterogeneous.\n\nHistopathology was the reference standard used to assess test accuracy in all of the identified studies. The target condition (that is, what was considered a positive reference standard test result) varied between the included studies. Some studies classified borderline ovarian tumours as positive, but others did not (and either classified them as disease negative or excluded them from analyses). Furthermore, studies varied as to whether they included people with metastases to the ovaries and germ cell tumours in analyses.\n\nThe methodological quality of the diagnostic cohort studies was assessed using the QUADAS‑2 tool. Fifteen studies had a high risk of bias in the 'flow and timing' domain, most commonly because not all patients were included in the analyses and patients did not all have the same reference standard. Regarding applicability, 26\xa0studies were rated as 'high' concern on at least 1\xa0domain. The EAG commented that areas of concern for applicability included how the index test was applied and whether this could be considered to be representative of routine practice. A further issue for applicability of studies was how the target condition was defined. One study, which reported the development and validation of the ADNEX model (Van Calster et al. 2014), was also assessed using the PROBAST tool; a tool developed to assess the methodological quality of prediction modelling studies.\n\n## Assessment of test accuracy\n\nTen studies reported diagnostic accuracy of the RMI\xa0I using a decision threshold of 250 (the comparator for this assessment) and at least 1\xa0further threshold value. Two studies were done in the UK, 2\xa0elsewhere in Europe and 6\xa0in non-European countries. CA125 assays from various manufacturers were used in the studies.\n\nIn studies that directly compared RMI\xa0I at a threshold of 250 and 200, no statistically significant difference between the sensitivity and specificity of RMI\xa0I at these thresholds was seen in any of the target condition categories (see table\xa04).\n\n## Table 4 Comparative accuracy of RMI\xa0I at thresholds of 200 and 250\n\nSource\n\nSubgroup\n\nIndex test\n\nSensitivity % (95% CI)\n\nSpecificity % (95% CI)\n\nTarget condition: All malignant tumours including borderline\n\nSummary estimates (6 studies; n=1,079)\n\nAll\n\nRMI\xa0I (200)\n\n(65.6 to 75.6)\n\n(88.9 to 93.1)\n\nRMI\xa0I (250)\n\n(63.7 to 73.9)\n\n(89.3 to 93.5)\n\nTarget condition: Ovarian malignancies including borderline\n\nYamamoto et al. 2009 (n=253)\n\nAll\n\nRMI\xa0I (200)\n\n(65.2 to 89.5)\n\n(81.8 to 89.9)\n\nRMI\xa0I (250)\n\n(57.2 to 83.9)\n\n(84.4 to 92.0)\n\nTarget condition: All malignant tumours excluding borderline\n\nSummary estimates (2 studies; n=248)\n\nAll\n\nRMI\xa0I (200)\n\n(64.3 to 81.3)\n\n(83.2 to 94.2)\n\nRMI\xa0I (250)\n\n(56.9 to 75.0)\n\n(87.7 to 96.9)\n\nAbbreviations: CI, confidence interval; RMI\xa0I, risk of malignancy index\xa01.\n\n## Risk of ovarian malignancy algorithm (ROMA)\n\nFourteen studies (in 22\xa0publications) reported diagnostic accuracy data for the ROMA using either Abbott ARCHITECT assays (9\xa0studies) or Roche Elecsys assays (5\xa0studies). No studies were identified that used the Fujirebio Lumipulse\xa0G automated CLEIA system.\n\nAll of the 9\xa0ROMA studies which used Abbott ARCHITECT assays were done outside the UK: 3\xa0in European countries, 4\xa0in Asia, 1\xa0in the US and 1\xa0in Oman. No direct comparisons (that is, when both tests were assessed in the same patient cohort) between ROMA and RMI\xa0I (threshold of 250) were identified.\n\nThree studies made a direct comparison between ROMA using Abbott ARCHITECT assays and RMI\xa0I (threshold of 200), shown in table\xa05. One study (Al Musalhi et al. 2016) did not exclude participants from analysis based on their final histopathological diagnosis; but the other 2\xa0studies did. Sensitivity was highest when people with borderline tumours and non-epithelial ovarian cancers were excluded from analysis, and lowest when all participants (regardless of final histopathological diagnosis) were included. The reverse was true for specificity. When all participants were included in the analysis (Al Musalhi et al. 2016) there was no statistically significant difference between the sensitivity and specificity estimates of ROMA and RMI\xa0I (threshold of 200). This was also true for the summary sensitivity estimate when the target condition was 'epithelial ovarian malignancies excluding borderline'; however specificity was statistically significantly lower for ROMA compared with RMI\xa0I (threshold of 200).\n\n## Table 5 Comparative accuracy of ROMA (using Abbott ARCHITECT assays) and RMI\xa0I (threshold of 200)\n\nSource\n\nSubgroup\n\nIndex test\n\nSensitivity % (95% CI)\n\nSpecificity % (95% CI)\n\nTarget condition: All malignant tumours including borderline\n\nAl Musalhi et al. 2016\n\nAll (n=213)\n\nROMA1\n\n(60.4 to 86.4)\n\n(81.9 to 92.4)\n\nRMI\xa0I (200)\n\n(62.7 to 88.0)\n\n(75.1 to 87.4)\n\nPremenopausal (n=162)\n\nROMA1\n\n(29.8 to 74.3)\n\n(83.9 to 94.5)\n\nRMI\xa0I (200)\n\n(34.0 to 78.2)\n\n(78.1 to 90.5)\n\nPostmenopausal (n=51)\n\nROMA1\n\n(75.7 to 99.1)\n\n(57.8 to 92.9)\n\nRMI\xa0I (200)\n\n(73.0 to 99.0)\n\n(46.0 to 83.5)\n\nTarget condition: Epithelial ovarian malignancies including borderline\n\nWinarto et al. 2014\n\nAll\n\n(n=128)\n\nROMA\n\n(81.5 to 96.6)\n\n(30.0 to 55.9)\n\nRMI\xa0I (200)\n\n(69.1 to 89.2)\n\n(52.3 to 77.3)\n\nTarget condition: Epithelial ovarian malignancies excluding borderline\n\nSummary estimate (2 studies)\n\nAll\n\n(n=1,172)\n\nROMA\n\n(93.6 to 98.2)\n\n(50.0 to 56.7)\n\nRMI\xa0I (200)\n\n(90.0 to 95.9)\n\n(77.5 to 82.9)\n\nManufacturer's suggested thresholds not used.\n\nAbbreviations: CI, confidence interval; RMI\xa0I, risk of malignancy index\xa01; ROMA, risk of ovarian malignancy algorithm.\n\nFurther identified studies assessed the performance of the ROMA score (using the Abbott ARCHITECT assays and at the company's suggested thresholds) without comparison with RMI\xa0I, across a range of target conditions. These included epithelial ovarian malignancies (both including and excluding borderline tumours). One study reported that the sensitivity of the ROMA was higher when the target condition was stage\xa0III or\xa0IV epithelial ovarian cancer, rather than stage\xa0I or\xa0II. Also, accuracy data at ROMA thresholds different from those suggested by the manufacturer were identified, but the EAG commented that no alternative threshold offered a clear performance advantage.\n\nAll of the 5\xa0ROMA studies that used Roche Elecsys assays were done outside the UK: 1\xa0in a European country, 3\xa0in Asia and 1\xa0in the US. No direct comparisons (that is, when both tests were assessed in the same cohort) between ROMA and RMI\xa0I (threshold of 250) were identified. One study (Yanaranop et al. 2016) made a direct comparison between ROMA using Roche Elecsys assays and RMI\xa0I (threshold of 200). In this study, people with a final histological diagnosis of borderline ovarian tumour were classified as disease negative. Differences between the ROMA and RMI\xa0I (threshold of 200) sensitivity (83.8% compared with 78.4%) and specificity (68.6% compared with 79.6%) values were not statistically significant. The data were similar when stratified by menopausal status. When people with non-epithelial ovarian cancer were excluded from analysis in this study (target condition epithelial ovarian malignancies), sensitivity for both ROMA and RMI\xa0I (threshold of 200) increased, but not statistically significantly. Sensitivity was higher for ROMA when the target condition was stage\xa0II\xa0to\xa0IV epithelial ovarian malignancies (97.2%; 95% confidence interval [CI] 85.5 to 99.9%) when compared with stage\xa0I epithelial ovarian malignancies (76.7%; 95% CI 57.7 to 90.1%). This was also the case for RMI\xa0I (threshold of 200).\n\nFour further studies assessed the ROMA score (using Roche Elecsys assays) without comparison with RMI\xa0I. Two of these studies included all participants in analyses (Janas et al. 2015; Shulman et al. 2016; target condition all malignant tumours including borderline), shown in table\xa06.\n\n## Table 6 Diagnostic accuracy of ROMA (using Roche Elecsys assays and manufacturer's suggested thresholds)\n\nSource\n\nSubgroup\n\nSensitivity %\n\n(95% CI)\n\nSpecificity %\n\n(95% CI)\n\nTarget condition: All malignant tumours including borderline\n\nSummary estimate (2 studies; n=1,252)\n\nAll\n\n(74.2 to 83.5)\n\n(76.3 to 81.6)\n\nJanas et al. 2015\n\nPremenopausal (n=132)\n\n(55.5 to 99.7)\n\n(74.0 to 88.3)\n\nPostmenopausal\n\n(n=127)\n\n(65.6 to 88.4)\n\n(64.5 to 88.4)\n\nAbbreviation: CI, confidence interval.\n\nTwo studies assessed the performance of the ROMA score (using the Roche Elecsys assays and at the company's suggested thresholds) without comparison with RMI\xa0I and with a target condition of ovarian malignancies excluding borderline tumours. The sensitivity estimates from these studies were very different (95.5% and 53.8%) and no summary estimate was calculated. Also, accuracy data at ROMA thresholds different from those suggested by the manufacturer were identified, but the EAG commented that no alternative threshold offered a clear performance advantage.\n\nNone of the included studies assessed the ROMA score and used the Fujirebio Lumipulse\xa0G HE4 assay. The EAG identified 2\xa0studies that used a ROMA score calculated using a manual Fujirebio tumour marker enzyme immunometric assay (EIA) assay; however this assay was outside the scope of this assessment.\n\n## Simple Rules\n\nSeventeen published studies had data on the diagnostic accuracy of Simple Rules. Eleven of these studies were done in Europe, including 3 in the UK. Two studies were multinational and included UK participants, 2\xa0studies were done in Thailand, 1 was done in Brazil and 1 study did not provide detail on location. Also, the provided interim report (academic in confidence) had diagnostic accuracy results for Simple Rules. In studies included in summary estimates of sensitivity and specificity, Simple Rules was done by a level\xa02 or\xa03 examiner as defined by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) classification system; 1 study also reported data from level\xa01 examiners.\n\nFour published studies and the unpublished interim report provided direct comparison of the accuracy of Simple Rules and RMI\xa0I at a threshold of 200. The summary estimate of sensitivity was statistically significantly higher for Simple Rules (93.9%; 95% CI 92.8 to 94.9%) when compared with RMI\xa0I (threshold of 200; 66.9%; 95% CI 64.8 to 68.9%); however the summary specificity estimate was statistically significantly lower (74.2% [95% CI 72.6 to 75.8%] compared with 90.1% [95% CI 88.9 to 91.2%]). All these studies included all participants in analysis, regardless of their final histopathological diagnosis (target condition all malignant tumours including borderline). The unpublished interim report also directly compared Simple Rules and RMI\xa0I (threshold of 250; academic in confidence).\n\nA further 4\xa0studies had data on the accuracy of Simple Rules for the same target condition but without a direct comparison with RMI\xa0I. There was no statistically significant change in sensitivity (94.2%; 95% CI 93.3 to 95.1%) or specificity (76.1%; 95% CI 74.9 to 77.3%) when data from these studies were included in the summary estimates of Simple Rules accuracy (a total of 8\xa0published studies and the unpublished interim work).\n\nThree studies directly compared Simple Rules and RMI\xa0I (threshold of 200) stratified by menopausal status. There was no statistically significant difference between the sensitivity and specificity estimates for Simple Rules produced for the pre- and postmenopausal subgroups. However if data from a further study (which did not report a direct comparison with RMI\xa0I) were added, the summary estimate for specificity was statistically significantly higher for people who are premenopausal (79.3%; 95% CI 77.0 to 81.5%), when compared with people who are postmenopausal (67.3%; 95% CI 63.5 to 70.9%).\n\nIn the above estimates of accuracy for Simple Rules, inconclusive results were treated as malignancy positive. Test accuracy data were also available from some studies in which inconclusive results were instead classified by expert subjective assessment of the ultrasound images. Assessment of inconclusive results from Simple Rules using expert subjective assessment (rather than assuming them to be malignant) statistically significantly increased the specificity of the test, but statistically significantly lowered sensitivity.\n\n## The ADNEX model\n\nSix published studies had data on the diagnostic accuracy of the ADNEX model. One was done entirely in the UK and 2\xa0were multicentre studies that included UK participants. The remaining 3\xa0studies were done elsewhere in Europe. A further unpublished interim report (provided as academic in confidence) also had data on the diagnostic accuracy of the ADNEX model. Four of the studies did not report details about the people doing the ultrasound scans. In 1\xa0study, ultrasound scans were done by EFSUMB level\xa02 ultrasound examiners (non-consultant gynaecology specialists, gynaecology trainee doctors and gynaecology sonographers) and in another study they were done by EFSUMB level\xa02 or 3\xa0practitioners with 8\xa0to 20\xa0years' experience in gynaecological sonography.\n\nThe EAG focused on test accuracy at the 10% threshold. One published study and the unpublished interim report made a direct comparison between the ADNEX model and RMI\xa0I (threshold of 200). Sensitivity was statistically significantly higher for ADNEX (96.0%; 95% CI 94.5 to 97.1%) than RMI\xa0I (threshold 200; 66.0%; 95% CI 62.9 to 69.0%), but specificity was statistically significantly lower (67.0% [95% CI 64.2 to 69.6%] compared with 89.0% [95% CI 87.0 to 90.7%]). Also, a further 2\xa0studies reported on the accuracy of the ADNEX model in the same target population (all malignant tumours including borderline) but without direct comparison with RMI\xa0I. Inclusion of data from these studies in summary estimates did not cause a statistically significant change to sensitivity (96.3%; 95% CI 95.3 to 97.1%) or specificity (69.1%; 95% CI 67.4 to 70.8%) of the ADNEX model. The unpublished interim report also directly compared the ADNEX model and RMI\xa0I (threshold of 250; academic in confidence).\n\nTwo further studies had data on the accuracy of the ADNEX model without comparison with RMI\xa0I. These studies excluded people with histopathological diagnoses other than primary ovarian cancer from analysis (target condition ovarian malignancies including borderline). The summary estimate of sensitivity from these studies did not differ significantly from that of studies that included all participants in analysis; however the summary estimate of specificity (77.6%; 95% CI 73.6 to 81.2%) was statistically significantly higher.\n\nData stratified by menopausal status was available from 1\xa0study. No statistically significant effect on sensitivity was reported, but specificity was statistically significantly higher for people who were premenopausal than for people who were postmenopausal.\n\nOne published study and the unpublished interim analysis directly compared the ADNEX model and Simple Rules (inconclusive results assumed to be malignant). The summary estimate of sensitivity was statistically significantly higher for ADNEX (96.0%; 95% CI 94.5 to 97.1%) than Simple Rules (92.8%; 95% CI 90.9 to 94.3%). Summary estimates of specificity were similar.\n\n## Overa (MIA2G)\n\nThree studies (in 4\xa0publications) had data on the diagnostic performance of Overa (MIA2G). All the studies were done in the USA and used a score of 5\xa0units as a threshold. No studies were identified that directly compared Overa (MIA2G) with RMI\xa0I (at any threshold). However, 1\xa0study assessed the accuracy of the Overa (MIA2G) and ROMA (using Roche Elecsys assays and manufacturer suggested thresholds for ROMA) in the same population with a target condition of all malignancies including borderline. Overa (MIA2G) had a statistically significantly higher sensitivity (91.0% [95% CI 86.8 to 94.0%] compared with 79.2% [73.7 to 83.8%]) and statistically significantly lower specificity (65.5% [95% CI 62.0 to 68.8%] compared with 78.9% [75.8 to 81.7%]) than the ROMA in this study.\n\nTwo further studies reported the diagnostic accuracy of Overa (MIA2G) without comparison with other risk scores. The summary estimate of sensitivity was 90.2% (95% CI 84.6 to 94.3%), and specificity was 65.8% (95% CI 61.9 to 69.5%). One of these studies assessed subgroups of people who were pre- and postmenopausal; there was no statistically significant difference between these groups.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG did a systematic review to identify existing studies that assessed the cost effectiveness of the included tests and risk scores to help identify people with ovarian cancer. Five studies were identified, however 2 of these related to the use of tests in screening so were not applicable to the scope of this assessment. One of the studies (Havrilesky et al. 2015) included the ROMA and the Multivariate Index Assay algorithm (MIA; from Vermillion who also produce the Overa [MIA2G; multivariate index assay 2nd generation]). Both were dominated (that is, they cost more and produced less life years) by the use of CA125 alone or by a strategy of referring all people for specialist care (without testing). Conversely, in Forde et al. (2016) MIA dominated the use of CA125 alone (that is, it was cost saving and produced more quality-adjusted life years [QALYs]). No identified studies assessed the cost effectiveness of all the tests and risk scores included in this assessment.\n\n## Modelling approach\n\nThe EAG developed a de novo economic model designed to assess the cost effectiveness of the following tests and risk scores when used in secondary care to help decide whether to refer people with suspected ovarian cancer to a specialist multidisciplinary team (MDT):\n\nRMI\xa0I – threshold of 250\n\nROMA – using Abbott ARCHITECT assays\n\nROMA – using Roche Elecsys assays\n\nOvera (MIA2G) – threshold of 5\xa0units\n\nIOTA Simple Rules – inconclusive results assumed to be malignant\n\nIOTA ADNEX model – threshold of 10%\n\nRMI\xa0I – threshold of 200.\n\nThe model did not include assessment of the ROMA using Fujirebio Diagnostics' Lumipulse\xa0G HE4 assay because no studies were identified that provided data on the accuracy of the ROMA using this assay. In the base-case analysis the starting cohort was assumed to be 40\xa0years old, consistent with the modelling produced for the NICE guideline on ovarian cancer. All costs and effects included in the model were discounted by 3.5%.\n\nThe EAG developed a decision tree and Markov model for the assessment. The decision tree was used to model short-term outcomes (up to 30\xa0days after surgery) and the Markov model for longer-term outcomes over a lifetime horizon. In the decision tree, the alternative tests and risk scores were assessed by their ability to help decision-making about referral to a specialist MDT. After the referral, people in the decision tree were classified as being in 1\xa0of the following states: early ovarian cancer, advanced ovarian cancer, benign mass, colorectal cancer or death (to account for mortality 30\xa0days after surgery).\n\nLonger-term costs and QALYs (over a lifetime horizon) were estimated using a Markov cohort model. This model included separate states for people with ovarian cancer who were treated in a specialist MDT and those who were not, to allow a beneficial effect for treatment in a specialist MDT to be applied. This treatment effect was a hazard ratio of 0.90 (95% CI 0.82 to 0.99) applied to overall survival of people with ovarian cancer (for people with both early and advanced stage ovarian cancer) and to progression-free survival for people with early stage ovarian cancer. This effect size was taken from a Cochrane review (Woo et al. 2012) which reported this hazard ratio for overall survival of people with ovarian cancer who had treatment in institutions with gynaecologic oncologists on site compared with community or general hospitals. The EAG assumed that this hazard ratio would also apply for progression-free survival, based on data in Woo et al. (2012).\n\nThe accuracy of the assessed tests and risk scores used in the model were taken from the clinical-effectiveness review and are shown in table\xa07. The EAG used diagnostic accuracy estimates derived from studies in which the target condition was 'all malignant tumours including borderline'; that is, studies that did not exclude participants from analysis on the basis of their final histological diagnosis. This was because the EAG considered that this population would produce estimates of test performance most representative of clinical practice. The prevalence of malignancies used in the model (21.3%; comprising ovarian malignancies, including borderline, and non-ovarian malignancies) was a summary estimate calculated from diagnostic cohort studies identified in the clinical-effectiveness review.\n\n## Table 7 Diagnostic accuracy estimates used in the model\n\n\n\nSensitivity (standard error)\n\nSpecificity (standard error)\n\nSource\n\nRMI\xa0I – threshold of 250\n\n% (1.4%)\n\n% (0.7%)\n\nSummary estimate from 1\xa0unpublished study (IOTA 2017) and 6\xa0studies (Davies et al. 1993; Jacobs et al. 1990; Lou et al. 2010; Morgante et al. 1999; Tingulstad et al. 1996; Ulusoy et al. 2007).\n\nROMA Abbott ARCHITECT\n\n% (6.6%)\n\n% (2.7%)\n\nSummary estimate from Al Musalhi et al. (2016).\n\nROMA Roche Elecsys\n\n% (2.4%)\n\n% (1.4%)\n\nSummary estimate from 2\xa0studies (Janas et al. 2015; Shulman et al. 2016).\n\nOvera (MIA2G) – threshold of 5 units\n\n% (2.5%)\n\n% (1.9%)\n\nSummary estimate from 2\xa0studies (Coleman et al. 2016; Zhang et al. 2015).\n\nIOTA Simple Rules – inconclusive assumed to be malignant\n\n% (0.5%)\n\n% (0.6%)\n\nSummary estimate from 1\xa0unpublished study (IOTA 2017) and 8\xa0studies (Adballa et al. 2013; Alcazar et al. 2013; Knafel et al. 2015; Meys et al. 2016; Sayasneh et al. 2013; Silvestre et al. 2015; Testa et al. 2014; Timmerman et al. 2010).\n\nIOTA ADNEX model – threshold of 10%\n\n% (0.5%)\n\n% (0.9%)\n\nSummary estimate from 1\xa0unpublished study (IOTA 2017) and 3\xa0studies (Meys et al. 2016; Sayasneh et al. 2016; Van Calster et al. 2014).\n\nRMI\xa0I – threshold of 200\n\n% (0.9%)\n\n% (0.5%)\n\nSummary estimate from 1\xa0unpublished study (IOTA 2017) and 12\xa0studies (Abdalla et al. 2013; Al Musalhi et al. 2016; Davies et al. 1993; Jacobs et al. 1990; Lou et al. 2010; Meys et al. 2016; Morgante et al. 1999; Sayasneh et al. 2013; Testa et al. 2014; Tingulstad et al. 1996; Ulusoy et al. 2007; Van Gorp et al. 2012).\n\nAbbreviations: RMI\xa0I, risk of malignancy index\xa01; ROMA, risk of ovarian malignancy algorithm.\n\nThe costs associated with the use of the different risk scores used in the model are shown in table\xa08. Costs were taken from companies, published literature and routine sources of NHS costs. Further costs used in modelling were taken from modelling done for the NICE guideline on ovarian cancer, relevant NHS reference costs, Personal Social Services Research Unit publications and further identified literature. No costs related to the training needed for the use of Simple Rules and ADNEX model were included in base-case analysis. However, the effect of additional costs (to reflect potential training costs) for these tests was investigated in scenario analysis.\n\n## Table 8 Risk score costs used in modelling\n\nTest\n\nUltrasound cost1 (£)\n\nTest cost per kit (£)\n\nTotal HE4 test-related costs2 (£)\n\nCA125 cost3 (£)\n\nTotal cost (£)\n\nADNEX\n\n\n\n–\n\n–\n\n\n\n\n\nOvera (MIA2G)\n\n\n\n\n\n–\n\n–\n\n\n\nRMI\xa0I\n\n\n\n–\n\n–\n\n\n\n\n\nROMA (Abbott ARCHITECT)\n\n\n\n\n\n\n\n\n\n\n\nROMA (Roche Elecsys)\n\n\n\n\n\n\n\n\n\n\n\nSimple Rules\n\n\n\n–\n\n–\n\n–\n\n\n\nCalculated from the cost of transvaginal ultrasound scans used in economic modelling for the NICE guideline on ovarian cancer and inflated to 2015/16 values.\n\nIncludes capital, quality control, maintenance, shipping, calibration and personnel costs, as set out in appendix\xa06 of the diagnostics assessment report.\n\nCost of doing a CA125 assay calculated from the NICE guideline on ovarian cancer (adjusted for inflation).\n\nAbbreviations: RMI\xa0I, risk of malignancy index\xa01; ROMA, risk of ovarian malignancy algorithm.\n\nUtility estimates used in modelling are shown in table\xa09.\n\n## Table 9 Utility scores used in modelling\n\n\n\nUtility value estimate\n\nSource\n\nBenign mass (assumed equal to general population)\n\nAge dependent\n\nAra et al. (2010)\n\nEarly ovarian cancer\n\nTreated by specialist MDT\n\n\n\nHavrilesky et al. (2009)\n\nNot treated by specialist MDT treated\n\nEqual to treated by specialist MDT\n\nAssumption\n\nAdvanced ovarian cancer\n\nTreated by specialist MDT\n\n\n\nGrann et al. (1998)\n\nNot treated by specialist MDT treated\n\nEqual to treated by specialist MDT\n\nAssumption\n\nColorectal cancer\n\nDukes' A\n\n\n\nNess et al. (1999)\n\nDukes' B\n\n\n\nDukes' C\n\n\n\nDukes' D\n\n\n\nAbbreviations: MDT, multidisciplinary team.\n\n## Base-case results\n\nThe following assumptions were applied in the base-case analysis:\n\nAll non-ovarian malignancies were assumed to be colorectal cancer.\n\nPeople with a false negative diagnosis were more likely to have early-, rather than advanced-, stage ovarian cancer.\n\nInconclusive results from Simple Rules were assumed to be malignant.\n\nAll people with a false positive and false negative diagnosis were operated on for a benign mass.\n\nNo disutility was applied for people who were incorrectly told that they have ovarian cancer (false positives).\n\nIn the base-case model analysis, the EAG did a pairwise analysis comparing the costs and QALYs resulting from using the included tests and risk scores with RMI\xa0I (threshold of 250), and also a fully incremental analysis (table\xa010). Use of Simple Rules (inconclusive assumed to be malignant) was the cheapest and second most effective, and dominated RMI\xa0I (at a threshold of 200 and 250). Use of the ADNEX model was most effective (that is, produced the most QALYs) and when compared with Simple Rules produced an incremental cost-effectiveness ratio (ICER) of £15,304 per QALY gained. Use of the ROMA and Overa (MIA2G) were dominated.\n\n## Table 10 Base-case analysis results\n\n\n\nCompared with RMI\xa0I (threshold of 250)\n\nFull incremental analysis\n\nDifference in costs\n\nDifference in QALYs\n\nDifference in costs / difference in QALYS\n\nSimple Rules – inconclusive assumed to be malignant\n\n−£2\n\n\n\nDominant\n\nCheapest\n\nRMI\xa0I – threshold of 250\n\n£0\n\n\n\nN/A\n\nDominated\n\nRMI\xa0I – threshold of 200\n\n£4\n\n\n\n£2,483\n\nDominated\n\nADNEX – threshold of 10%\n\n£30\n\n\n\n£1,274\n\n£15,304\n\nROMA – Abbott ARCHITECT\n\n£38\n\n\n\n£7,506\n\nDominated\n\nROMA – Roche Elecsys\n\n£44\n\n\n\n£6,409\n\nDominated\n\nOvera (MIA2G) – threshold of 5 units\n\n£105\n\n\n\n£6,038\n\nDominated\n\nAbbreviations: QALY, quality-adjusted life year; RMI\xa0I, risk of malignancy index\xa01; ROMA, risk of ovarian malignancy algorithm.\n\nAt a maximum acceptable ICER of £20,000 per QALY gained, the ADNEX model and Simple Rules had a probability of being cost effective of 60% and 39% respectively. At a maximum acceptable ICER of £30,000 per QALY gained, these probabilities were 75% (ADNEX) and 23% (Simple Rules). The probability of RMI\xa0I (threshold of 250) being cost effective at both thresholds was about 1%, and the probabilities of the other tests and risk scores was less than 1%.\n\nUse of the ADNEX model remained cost effective at £20,000 and £30,000 per QALY gained in one-way deterministic sensitivity analysis when most parameters were altered. Simple Rules became cost effective in some analyses, typically when the costs of using the ADNEX model were increased (or Simple Rules costs were decreased) or the diagnostic accuracy of the Simple Rules was improved relative to ADNEX. Also, when the upper bound value for the overall-survival hazard ratio for people with an ovarian malignancy treated in a specialist MDT (rather than secondary care) was used, (that is, the beneficial effect of surgery done by a specialist MDT was at its lowest level in the model), Simple Rules became cost effective at both £20,000 and £30,000 per QALY gained.\n\n## Alternative scenario analyses\n\nThe EAG did several scenario analyses to test assumptions made about parameter values used in the base-case model analysis. Use of the ADNEX model remained cost effective in most scenario analysis. However, in some scenarios Simple Rules (inconclusive results assumed to be malignant) was cost effective. These included when a disutility (the value of which was arbitrary) was applied for people with a false positive diagnosis for 1\xa0year and when the benefit of treatment in specialist care was reduced.\n\nIn a scenario analysis in which a higher cost of surgery done by a specialist MDT was used, RMI\xa0I (threshold of 250) was cost effective at a maximum acceptable ICER of £20,000 per QALY gained and Simple Rules was cost effective at a maximum acceptable ICER of £30,000 per QALY gained. In this scenario, an additional cost of £2,500 was added to the average cost of surgery done by a specialist MDT, to reflect expert opinion that some patients referred to a specialist MDT will have extensive surgery for ovarian cancer.\n\n## Subgroup analyses\n\nResults from subgroup analyses were similar to the base-case analyses when the starting age of the cohort was 50\xa0years and also when only early stage cancer was considered. However, when the analysis was run for advanced stage cancer, Simple Rules (rather than ADNEX) was cost effective at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained. No changes to sensitivity or specificity values for tests were made in these subgroup analyses (because of a lack of data on test performance in these populations).\n\nThe EAG also did subgroup analyses for populations who were pre- and postmenopausal. Sensitivity and specificity estimates for tests or risk scores in these subgroups were taken from the clinical-effectiveness review; but relatively few studies were available to inform these estimates. A different starting age of the cohort and prevalence of malignancy (compared with the base-case analysis) was also used for these subgroups. The ADNEX model was cost effective at thresholds of £20,000 and £30,000 per QALY gained for both these subgroup analyses.", 'Committee discussion': "The committee discussed the potential benefits of correctly identifying people referred to secondary care with suspected ovarian cancer who have a benign or malignant mass. It heard from patient and clinical experts that a correct diagnosis of a malignant mass at an early stage will increase the likelihood of survival. Patient experts also suggested that even for people with stage\xa0III ovarian cancer, earlier identification of the condition could mean that there is a lower volume of tumour on which to operate if surgery is indicated.\n\nThe committee discussed the potential disadvantages of incorrectly referring people with a benign mass to a specialist multidisciplinary team (MDT). The committee heard that false positive results (that is, people with a benign mass who are incorrectly told that it is likely to be malignant) lead to unnecessary anxiety for patients and their families, and may result in an increased number of people having surgery when in fact no surgery, or less extensive surgery, could be considered. The committee noted that this is particularly an issue for people who are premenopausal and who may wish to consider fertility-conserving surgery, as well as for people who are older or frail and wanting to avoid surgery if possible.\n\n# Clinical effectiveness\n\nThe committee discussed the diagnostic accuracy data available for the included tests. It noted that the studies in the clinical-effectiveness review varied in which target condition they used (that is, what was considered a positive reference standard test result). The committee heard from clinical experts that although epithelial cancers are the most common form of ovarian malignancy, people referred to secondary care with suspected ovarian cancer will include those with non-ovarian tumours and non-epithelial ovarian tumours. The committee noted that studies which used a target condition of ovarian cancer or epithelial ovarian cancer retrospectively excluded patients from analysis based on their reference standard diagnosis, and that these studies had been assessed as having a high risk of bias by the external assessment group (EAG). The committee concluded that studies which used a target condition of all malignant (including borderline) tumours were most representative of clinical practice.\n\nThe committee considered the generalisability of the evidence to clinical practice in the NHS. It heard from clinical experts that the prevalence of malignancy in study populations was considerably higher than would be expected for people referred to secondary care with suspected ovarian cancer in the NHS. Clinical experts commented that a prevalence of less than 10% would be expected, and suggested 5% as a realistic prevalence of malignancy in this population. The committee heard from the EAG that, in addition, most studies did not report the distribution of disease stages among patients with ovarian cancer. Therefore, it noted that the spectrum of disease in the studies may not reflect that seen in secondary care in the NHS. The committee concluded that the study populations, for all tests, may not be representative of the clinical population for this assessment. In particular, the differing levels of disease severity in the study populations and in secondary care in the NHS could mean that the sensitivity and specificity estimates obtained from these studies are not accurate estimates of how the tests would perform in secondary care in the NHS.\n\nThe committee considered the test accuracy of the Simple Rules and ADNEX. It noted that studies showed that they were statistically significantly more sensitive than RMI\xa0I. The committee then considered the expertise of practitioners doing and interpreting ultrasound scans in studies assessing the Simple Rules system and the ADNEX model. The committee heard from clinical experts that practitioners in these studies had a higher level of skill and experience than is generally available in secondary care in the NHS, and noted that there were limited data available on the accuracy of tests done by less experienced operators. The committee heard that although image acquisition would generally be straightforward for NHS practitioners, additional training would be needed in interpreting the images to use the Simple Rules or ADNEX model. The committee heard from clinical experts that the local organisation of care would be likely to affect test performance in practice; and that there is uncertainty about the effect of NHS service models on how well the Simple Rules and ADNEX model would perform in secondary care. For example, if a model of delivery in which patients are seen, scanned and their condition managed in 1\xa0setting was used, this may lead to improved performance of the tests through a concentration of services and skills. It also heard from clinical experts that no data have been published on inter-observer variation using the IOTA tests in the NHS. The committee therefore concluded that there is considerable uncertainty about the likely performance of the Simple Rules and ADNEX tests in secondary care in the NHS, and that the accuracy reported in the studies may not be achieved in clinical practice in the NHS.\n\nThe committee considered the test accuracy data for the ROMA and Overa (MIA2G). It noted that relatively few studies were identified for these tests, particularly studies with a direct comparison with RMI\xa0I. The committee concluded that there is considerable uncertainty about the diagnostic accuracy of these tests; however it is possible that the tests may offer improved accuracy relative to RMI\xa0I.\n\nThe committee considered data on the accuracy of RMI\xa0I at thresholds other than 250. It noted that most studies with a direct comparison of RMI\xa0I at 250 and another threshold used a threshold of 200, and that there were relatively few studies with other alternative thresholds. It also noted that there was very little difference in the summary estimates of sensitivity and specificity for RMI\xa0I at thresholds of 200 and 250 obtained from studies with a direct comparison. The committee therefore concluded that RMI\xa0I used with a threshold of 200 was unlikely to offer accuracy benefits over using this test with a threshold of 250, and noted that the use of RMI\xa0I at a threshold of 250 is recommended in the NICE guideline on ovarian cancer.\n\nThe committee discussed how the stage of ovarian cancer (early or advanced) could affect test accuracy. It heard from clinical experts that about 70% of people identified with ovarian cancer have advanced stage cancer. However, the main benefit of tests such as RMI\xa0I in secondary care is in identifying early stage ovarian cancer, with advanced stage ovarian cancer being more apparent from imaging. The committee heard from the EAG that very few data were available to inform estimates of test accuracy by stage of ovarian cancer. Two studies assessing the ROMA reported that sensitivity was lower for detecting early stage ovarian cancers. However most studies did not provide details on the stage of cancer of study participants included in analysis. The committee heard from clinical experts that populations in studies were likely to include more cases of advanced than early stage ovarian cancers, and that the performance of tests to detect early and advanced stage ovarian cancer could differ substantially. The committee concluded that there is uncertainty about how accurate the tests are at correctly detecting early stage ovarian cancer, potentially the most relevant group for this assessment. The committee also concluded that data on the accuracy of tests to detect early stage ovarian cancer would be important for any future assessment (see section\xa06.1).\n\n# Cost effectiveness\n\nThe committee discussed the sensitivity and specificity estimates used in the cost-effectiveness modelling. It noted that these estimates were taken from the clinical-effectiveness review and that the concerns about the applicability of data from these studies to NHS secondary care (see sections\xa05.4 and\xa05.5) also apply to the model. The committee also noted that relatively few studies were available to inform test accuracy estimates for the ROMA and Overa (MIA2G) tests (see section\xa05.6).\n\nThe committee noted that tests with the highest sensitivity (ADNEX and Simple Rules) that resulted in more people with ovarian cancer being referred to a specialist MDT tended to be cost effective. It considered the parameter used in the model for the beneficial effect of a referral to a specialist MDT for people with ovarian cancer; a hazard ratio for overall and progression-free survival obtained from a Cochrane review (see section\xa04.31). The committee heard that estimates from this review were based on studies with a mixed cohort of early and advanced stage ovarian cancer, and that because advanced stage was likely to be predominant in this cohort, the summary estimate may not be an accurate reflection of the beneficial effect of specialist MDT treatment on people with early stage ovarian cancer. It also heard that the benefits for people with early stage ovarian cancer of having their surgery done by a gynaecological oncology specialist are potentially more difficult to assess than those for people with advanced stage cancer. An improved quality of surgery is likely to lead to more accurate staging of the cancer, which will help with subsequent treatment decisions. For example, accurate staging may show that chemotherapy is not needed (for low-risk stage\xa0I disease); but inadequate staging in a non-specialist centre could lead to inappropriate use of chemotherapy or the need for further surgery to accurately stage the cancer. The committee also heard from clinical experts that people with a false negative test result will have their condition managed in secondary care, and if their ovarian malignancy is recognised at a later date they will then be referred to a specialist MDT. The effect of this delayed referral, rather than lack of referral, to a specialist MDT on patient outcomes is unclear. The committee concluded that, because of a lack of data, there is considerable uncertainty about the effect of false negative test results on people with ovarian cancer, particularly if they have early stage ovarian cancer.\n\nThe committee discussed the costs included in the model for people referred to a specialist MDT. It noted that the cost of an MDT meeting had been included, but heard from clinical experts that additional costs may be incurred when a patient is referred to a specialist MDT for discussion; such as costs for the time taken by radiologists to review images in advance of the meeting. The committee heard from the EAG that these additional costs were not captured in the model. The committee also noted that in the base case, the model used NHS reference costs for surgery, and that this may not adequately capture the cost of extensive surgery potentially needed for people with advanced stage cancer, who make up 75% of the population with an ovarian malignancy in the model. It heard from clinical experts who suggested that the costs associated with more extensive surgery should be included in the model. The committee noted that in a scenario analysis in which additional surgery costs were assumed, RMI\xa0I (threshold 250) was cost effective at a maximum acceptable incremental cost-effectiveness ratio of £20,000 per quality-adjusted life year gained. The committee concluded that the costs of a referral to, and treatment by, a specialist MDT may have been underestimated in the model, and that this could affect the model results, such as which tests seemed to be cost effective.\n\nThe committee discussed the costs of CA125 testing included in the model. It heard from the EAG that the economic model assumed that all patients have a CA125 test in secondary care, even if they previously had one in primary care. The committee heard from clinical experts that the reasons for patients having another CA125 test in secondary care are: CA125 levels may have changed since the first test was carried out; some risk scores are only compatible with a specific brand of CA125 test; and some tests include CA125 as part of an array. The committee concluded that the assumption in the economic model in relation to CA125 testing costs was valid.\n\nThe committee considered its discussions on the clinical- and cost-effectiveness evidence. It concluded that:\n\nThere is considerable uncertainty about the estimates of test accuracy used in modelling because: relatively few studies were found to inform estimates (for the ROMA and Overa [MIA2G]; see section\xa05.6); the high prevalence of malignancy in studies suggested that they were not representative of clinical populations in secondary care in the NHS (see section\xa05.4); and that the level of expertise of people interpreting scans for the Simple Rules and the ADNEX model in studies was higher than would be routinely available in the NHS (see section\xa05.5).\n\nThere is uncertainty about the accuracy of tests to detect early stage ovarian cancer (see section\xa05.8), and about the likely effect on outcomes for people with early stage ovarian cancer who have a delayed referral to a specialist MDT, as a result of an initial false negative test result (see section\xa05.10).\n\nThere is uncertainty about the costs of assessment and treatment at a specialist MDT, and that higher costs would impact model results (see section\xa05.11).\n\n# Other considerations\n\nThe committee discussed the accuracy of tests, noting that tests with higher sensitivity had lower specificity. The committee heard from clinical experts that tests with high sensitivity reduce the number of missed cases of ovarian cancer, but that lower test specificity will result in more false positive referrals to specialist MDTs. The committee heard from clinical experts that there is very limited specialist MDT capacity for personnel in relation to the current case demand, and that increasing the number of false positive referrals to specialist MDTs would reduce the quality of assessment by limiting time available for discussion for each patient. Clinical experts commented that this could adversely affect, or delay, decisions made in specialist MDT meetings about patient treatment. The committee concluded that using tests with lower specificity would have a large impact on specialist MDT services, but the model has not captured the impact because of a lack of data on the effect this would have on patient care and clinical outcomes and because of its structure.\n\nThe committee considered the accuracy of the tests for people who are pre- and postmenopausal. It noted that relatively few studies provided accuracy estimates stratified by menopausal status. The committee further noted that the EAG did cost-effectiveness analyses for pre- and postmenopausal subgroups; however there were relatively few data to inform the tests' performance in pre- and postmenopausal populations in this analysis. The committee heard from clinical experts that menopausal status could considerably affect the performance of the tests, and that further data are needed to assess the performance of the tests in these subgroups (see section\xa06.1).\n\nThe committee discussed the likely effect of test results on decisions made about patient care. It noted that no data were available on the effect of test results on decisions about patient care or referral. The committee heard from clinical experts that in practice results from tests such as the RMI\xa0I are used alongside further information, such as imaging, when making decisions about patient care and referral. It noted therefore that increased accuracy of testing may not correspond to changes in decision-making. The committee concluded that there is uncertainty about how the results of the tests included in the assessment would be used in clinical practice in the NHS, and that further research on this would be useful (see section\xa06.2).\n\nThe committee heard from patient experts that access to tests in primary care for people with ovarian cancer symptoms varied, and that getting a referral to secondary care could take a long time. It heard further from clinical experts that about 60% of people referred to secondary care have a late stage of cancer, and they are often referred from colorectal and urological cancer services and emergency care. The committee agreed that differences in initial assessment may lead to variation in patient outcomes. The committee noted that tests for suspected ovarian cancer in primary care were outside of the scope of this assessment and that evidence from this setting had not been reviewed.\n\nThe committee discussed the use of tests in sequence. It heard from clinical experts that the use of a highly sensitive test followed by a highly specific test may improve accuracy of referral. The committee noted that the EAG had looked for studies that assessed the use of included tests in combination or sequence in the clinical-effectiveness review; however very few data were found (1\xa0study with a lack of detail about how test results were combined to produce a positive result). The committee considered that the use of tests in sequence could be cost effective and further research is needed to inform accuracy estimates (see section\xa06.3).\n\n# Research considerations\n\nThe committee noted that there is an ongoing National Institute for Health Research funded diagnostic test accuracy study; the ROCkeTS (Refining Ovarian Cancer Test Accuracy Scores) study, which will report in 2019 or 2020. This study will evaluate existing and new risk prediction models for people with symptoms of suspected ovarian cancer against a comparator of RMI\xa0I (threshold of 250). It will assess patients using the IOTA Simple Rules and ADNEX tests, as well as biomarker assays. Practitioners doing ultrasound scans as part of the study will have an IOTA training course; therefore the study will provide test accuracy data for NHS practitioners with a defined amount of training. The study will also report costs and resource use associated with the diagnostic tests. The recruited study population will be people referred to secondary care in the NHS; the committee noted that the results are likely to be very relevant to future updates of this guidance.", 'Recommendations for further research': 'Further diagnostic accuracy studies, or analyses of existing data sets, are recommended to assess the accuracy of the tests included in this assessment in the following subgroups:\n\npeople who are premenopausal\n\npeople who are postmenopausal\n\npeople with suspected early stage ovarian cancer, that is, disease apparently confined to the pelvis.Future studies should be done in populations that are representative of people with suspected ovarian cancer who are assessed in NHS secondary care.\n\nFurther research is recommended to assess:\n\ninter-observer reproducibility of tests involving ultrasound scans (the ADNEX model and Simple Rules)\n\nchanges in clinical management based on test results from the ADNEX model, Overa (MIA2G), ROMA and Simple Rules.\n\nFurther research is recommended to assess the diagnostic accuracy of the tests included in this assessment when used in combination; for example sequentially.'}
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https://www.nice.org.uk/guidance/dg31
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Evidence-based recommendations on tests in secondary care to identify people at high risk of ovarian cancer. The tests are the IOTA ADNEX model, Overa (MIA2G), RMI I (at thresholds other than 250), ROMA and IOTA Simple Rules.
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0efe89161c74478dd39e8b312b81a914f630ba00
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nice
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Regorafenib for previously treated unresectable or metastatic gastrointestinal stromal tumours
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Regorafenib for previously treated unresectable or metastatic gastrointestinal stromal tumours
Evidence-based recommendations on on regorafenib (Stivarga) for previously treated gastrointestinal stromal tumours in adults.
# Recommendations
Regorafenib is recommended as an option for treating unresectable or metastatic gastrointestinal stromal tumours in adults whose disease has progressed on, or who are intolerant to, prior treatment with imatinib and sunitinib, only if:
their Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 1 and
the company provides regorafenib with the discount agreed in the patient access scheme.
When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with regorafenib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for unresectable or metastatic gastrointestinal stromal tumours after disease progression on, or intolerance to, prior treatment with imatinib and sunitinib is best supportive care.
The evidence shows that people having regorafenib have longer before their disease progresses compared with those having best supportive care. However there is some uncertainty around how long regorafenib increases the overall length of time people live compared with those on best supportive care.
Regorafenib meets NICE's criteria to be considered a life-extending end-of-life treatment, and the most plausible cost-effectiveness estimate is around £44,000 per quality-adjusted life year gained. Therefore it can be recommended for use in the NHS.
Regorafenib is only recommended for people who have an ECOG performance status of 0 to 1 because in clinical practice, regorafenib is only expected to be used in people who have an ECOG performance status of 0 to 1; there is limited evidence for its use in people with a performance status of 2 or more.# The technology
Regorafenib (Stivarga, Bayer)
Marketing authorisation
Regorafenib is indicated 'for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib'.
Recommended dose and schedule
The recommended dose of regorafenib is 160 mg (4 tablets of 40 mg) taken once daily for 3 weeks followed by 1 week off therapy. This 4‑week period is considered a treatment cycle.
Price
£3,744.00 for 84 tablets of 40 mg (excluding VAT; British national formulary edition 72).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of regorafenib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Clinical management
## Best supportive care is the most appropriate comparator
The patient and clinical experts explained that gastrointestinal stromal tumours (GIST) are a rare disease that often takes years to diagnose because people have non-specific symptoms. The clinical expert advised that first-line treatment for metastatic GIST is imatinib, which is generally well tolerated. Once disease has progressed, patients are switched to sunitinib, which on average gives 6 to 12 months benefit before the disease progresses again but has more side effects than imatinib and requires careful monitoring. The patient and clinical experts explained that there are no alternative third-line treatment options after disease progression or if patients are intolerant to imatinib and sunitinib other than best supportive care. Regorafenib is currently available on the Cancer Drugs Fund for metastatic GIST after disease progression or intolerance to imatinib and disease progression after sunitinib, only if the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The clinical expert explained that the only alternative to best supportive care and regorafenib (through the Cancer Drugs Fund) was to participate in a clinical trial but noted that these were rare. The committee concluded that best supportive care is the most appropriate comparator for this appraisal.
# Treatment options
## People with unresectable or metastatic GIST would greatly value another treatment option
The patient experts advised that regorafenib is well tolerated, with side effects (such as sore feet and hands, constipation and diarrhoea) that can be managed. The clinical experts described how dose adjustments and scheduling were important in treating GIST and that these are managed on an individual basis to achieve a balance between the minimal effective dose and side effects that can be tolerated. The patient experts explained that regorafenib allows people to remain actively engaged in work and family life, while reducing anxiety and increasing quality of life. Regorafenib also provides an important further treatment option to people who cannot tolerate sunitinib. One patient expert described how extending life was a priority to enable patients to spend more time with their families and it was important to be able to lead a near-normal life while having treatment. The committee recognised the importance of a potentially life-extending treatment with manageable side effects. The committee concluded that a treatment option for people with metastatic or unresectable GIST after imatinib and sunitinib would be greatly valued, particularly if it extended life and had manageable side effects.
# Clinical evidence
## Treatment with regorafenib in the GRID trial is in line with clinical practice
The evidence for regorafenib submitted by the company came from GRID, a multicentre double-blind randomised controlled trial with 199 patients who had previously had treatment with imatinib and sunitinib. It compared regorafenib plus best supportive care (133 patients) with placebo plus best supportive care (66 patients). Best supportive care included various treatments such as analgesics, radiation therapy for pain control and palliative surgery. After disease progression, patients receiving placebo were given the option to cross over to regorafenib, and patients already receiving regorafenib were offered open-label regorafenib if it was considered clinically beneficial. In the trial, treatment could be delayed or reduced according to a pre-specified schedule. The clinical experts confirmed that dose reductions were common in clinical practice, because of the side effects associated with regorafenib, and managed on an individual basis. The clinical experts explained that treatment would only be stopped in clinical practice if there was clear disease progression and worsening clinical symptoms. Clinical guidelines recommend continued treatment with tyrosine kinase inhibitors as long as there is continued benefit. The clinical experts also advised that there was uncertainty around whether patients in the GRID trial could have other off-label treatments after disease progression that are not standard practice in the NHS. The committee concluded that using regorafenib after disease progression was in line with the marketing authorisation and current clinical practice.
## Performance status should be taken into account in the final recommendations
Patients in the GRID trial had an ECOG performance status of 0 to 1 and the summary of product characteristics for regorafenib states that there are limited data in patients with a performance status of 2 or above. Regorafenib is currently provided by the Cancer Drugs Fund to people who have a performance status of 0 to 1, in line with trial evidence. The clinical experts explained that very few people for whom regorafenib would be considered present with a performance status of 2 in clinical practice; this is because treatment is actively managed in specialist centres to prevent performance status from deteriorating, particularly given the tolerability issues associated with sunitinib. The committee concluded that in line with the clinical evidence and the use of regorafenib in clinical practice, it would take performance status into account when making its final recommendations.
## Correcting for crossover in the GRID trial is appropriate for estimating overall survival
In the GRID trial there was a high level of crossover (88%) from the placebo arm to open-label regorafenib after disease progression. The company and the ERG agreed that a statistical correction for crossover was needed to produce unbiased estimates of overall survival in the placebo arm. The company carried out 2 crossover corrections using the iterative parameter estimation (IPE) and rank preserving structural failure time (RPSFT) methods. Both methods aimed to reconstruct individual patient data for overall survival in the placebo arm as if there had been no crossover. The ERG advised that both the IPE and RPSFT methods were appropriate for correcting crossover. The committee concluded that given the high level of crossover from placebo to regorafenib, an intention-to-treat analysis was not appropriate and a statistical correction for overall survival was needed.
# Survival results from the GRID trial
## Regorafenib is clinically effective in improving progression-free survival compared with best supportive care
Data from 2015 from the GRID trial showed that regorafenib improved progression-free survival (hazard ratio 0.27, 95% confidence interval 0.19 to 0.39). Data from 2017 showed that after crossover correction, median overall survival in the placebo arm was around 8 months compared with 17.4 months for regorafenib. The 2017 data showed a larger overall survival benefit after correcting for crossover (unadjusted HR 0.90; 95% CI 0.68 to 1.19, RPSFT HR 0.48; 95% CI 0.07 to 3.33, IPE HR 0.45; 95% CI 0.06 to 3.69). The committee understood that although not statistically significant, the point estimates did show improved overall survival with regorafenib. The committee concluded that there was evidence that regorafenib is clinically effective in improving progression-free survival compared with best supportive care but that there was uncertainty about the magnitude of overall survival benefit.
# The company's economic model
## The company's survival model is appropriate for decision-making
The company submitted a partitioned survival model with 3 health states (progression free, progressed and death) that used survival data from the GRID trial. The company's base case modelled treatment duration by using the treatment discontinuation curve from GRID. Therefore the company's base case included the additional cost of regorafenib in the treatment arm after disease progression in line with the GRID trial (open-label regorafenib was offered to patients randomised to regorafenib after progression if it was considered clinically beneficial). Use of regorafenib after disease progression is in line with clinical practice (see section 3.3). The company's base case also incorporated dose intensity by including the mean observed dose of regorafenib from GRID (including doses of 0 mg). The ERG agreed that the company's approach to modelling treatment duration and dose intensity was appropriate. The committee concluded that the company's model, using trial data to model treatment duration and dose intensity and including the additional cost of regorafenib after disease progression, was appropriate for decision-making.
# Overall survival data from the GRID trial
## There is uncertainty in the adjustment for overall survival but analyses using 2017 data are acceptable
The company's base case included overall survival estimates based on the most recent data from GRID (2017 data). The ERG initially had several concerns with using the 2017 data related to:
methodological assumptions in the treatment switching adjustment
the impact of recensoring on adjusted overall survival and the cost effectiveness of regorafenib
reasons for a large decrease in overall survival in the placebo arm after adjusting for treatment switching when using the 2017 data compared with the 2015 data.Using different data cut-offs for estimating overall survival had a large impact on the cost-effectiveness results. Regorafenib appeared to be more cost effective when using the 2017 data for overall survival than when the 2015 data were used. The company responded to the ERG's concerns with additional explanations, and the ERG accepted the company's rationale and justifications of the methods used. The ERG confirmed that there was no conclusive evidence that the company had performed the treatment switching adjustment incorrectly, and accepted it was appropriate to use the most recent (2017) data. The committee concluded that while there was some remaining uncertainty, the analysis using 2017 data for estimating overall survival was acceptable.
# Crossover correction
## Both RPSFT and IPE adjustments of overall survival should be considered
The company's base case included an estimated treatment effect for overall survival with an IPE crossover correction. The ERG advised that the IPE method is an extension to the RPSFT method using parametric methods and the assumption of a common treatment effect (that is, people receive the same treatment benefit regardless of when they receive treatment). This assumption may not hold if people in the trial were able to receive a variety of off-label treatments after disease progression (see section 3.3). The ERG noted that both the IPE and RPSFT methods were appropriate and gave similar estimates of overall survival for the placebo arm (median overall survival IPE 8.0 months and RPSFT 8.4 months). In its revised explorations, the ERG considered both IPE- and RPSFT-corrected overall survival estimates as acceptable. The committee recognised that using the RPSFT rather than the IPE method did not have a large impact on the cost-effectiveness estimate of regorafenib. The committee concluded that cost-effectiveness results using either IPE or RPSFT adjustments should be considered in its decision-making.
# Recensoring to avoid bias
## Analyses with and without recensoring should be considered
The company's base case included an IPE adjustment with recensoring (in line with guidance from the Decision Support Unit). Recensoring is used to reduce the risk of bias associated with a treatment-switching adjustment, and recensoring data at an earlier time point aims to avoid informative censoring (because treatment switching is not random). The ERG advised that recensoring may lead to biased estimates of the average treatment effect when the proportional treatment effect assumptions do not hold, and there is some academic debate on whether to use recensoring because the estimated treatment effect is generally larger when it is used. The company provided further analyses that explored the impact of recensoring. The ERG advised that it was appropriate to consider analyses with and without recensoring. The committee noted that recensoring had a large impact on the cost-effectiveness estimate and that regorafenib appeared to be more cost effective if recensoring was used. The committee concluded that the arguments for and against recensoring were evenly balanced and that results both with and without recensoring should be considered when assessing the cost effectiveness of regorafenib.
# Extrapolation of overall survival
## A shorter-tailed Weibull distribution is appropriate for estimating overall survival and is clinically plausible
The company's base case included a log-logistic extrapolation of overall survival because it provided the best fit to the trial data from GRID. The company highlighted that log-logistic, Weibull and Gompertz models were considered clinically plausible by the clinical experts. The ERG advised that clinical plausibility of extrapolations was critical and the evidence for longer-tailed and shorter-tailed distributions appeared to be evenly balanced. The clinical experts explained that very few people with unresectable or metastatic GIST whose disease has progressed on, or who are intolerant to, treatment with imatinib and sunitinib will survive for 10 years. The choice of extrapolation method for estimating overall survival had a large impact on the cost-effectiveness results for regorafenib. A log-logistic extrapolation resulted in a larger proportion of people surviving after 10 years compared with the Weibull extrapolation and the clinical experts and committee considered this to be optimistic. The committee agreed that a Weibull extrapolation would be more appropriate because it had a shorter tail length and more plausibly reflected the survival of people at this stage of the disease. It noted that in the company's base case, regorafenib became less cost effective when the Weibull and Gompertz models were used. The committee concluded that an overall survival extrapolation that used a shorter-tailed Weibull model was most appropriate because it best reflected the survival outcomes of the population.
## Including additional background mortality is appropriate
The ERG explained that causes of mortality in the GRID trial would largely be related to GIST but it was likely that additional general mortality would have occurred after the trial ended. The ERG's base case incorporated this additional background mortality but the company's did not. The committee understood that the impact of background mortality was likely to be lower when a shorter-tailed Weibull extrapolation was used. The committee concluded that including an adjustment for general mortality was appropriate.
# Utility values
## Including age-related utility decrements is appropriate
Utility estimates for health-related quality of life were taken from the GRID trial, which reported the EQ-5D and European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). Both the company and ERG base cases used EQ-5D data from paired samples that were not split by treatment arm. The company stated that a repeated measures analysis would have been biased because more measurements were taken when patients did not have disease progression and there were no clinically meaningful differences in EQ-5D between the treatment arms. The ERG's base case also applied age-related utility decrements because utility often declines with age; this was not included in the company's base case. The committee understood that the addition of age-related utility decrements did not have a large impact on the cost-effectiveness results. The committee concluded that including age-related utility decrements was appropriate.
# End of life
## Regorafenib meets the end-of-life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. In the GRID trial the adjusted median overall survival in the placebo plus best supportive care arm was less than 12 months (RPSFT-corrected median overall survival 8.4 months and IPE-corrected median overall survival 8.0 months). The company's economic model predicted mean undiscounted life years of 0.97 for the IPE-adjusted placebo arm and 1.01 for the RPSFT-adjusted placebo arm when recensoring was applied. The committee concluded that regorafenib was indicated for people with a short life expectancy. The median overall survival improvement in the GRID trial was at least 9 months for patients treated with regorafenib compared with those having best supportive care, depending on which crossover correction method was used. The crossover-corrected mean overall survival benefit for regorafenib was around 1.2 years longer compared with best supportive care in the ERG's revised base case, but less than 1.2 years when recensoring was used (estimates taken from the company's economic model). The committee concluded that regorafenib offered an extension to life of at least 3 months compared with best supportive care.
# Cost-effectiveness results
## Regorafenib is a cost-effective use of NHS resources
The committee considered the cost effectiveness of regorafenib as estimated using its preferred analyses, which included:
data for overall survival (see section 3.8)
crossover adjustment using either RPSFT or IPE (see section 3.9)
analyses with and without recensoring (see section 3.10)
-verall survival extrapolation using a Weibull distribution (see section 3.11)
background mortality (see section 3.12)
age-related utility decrements (see section 3.13).The committee discussed that, using its preferred analyses, the incremental cost-effectiveness ratio (ICER) was likely to lie between £40,000 and £48,000 per quality-adjusted life year (QALY) gained. It concluded that the most plausible ICER was the midpoint of that range: around £44,000 per QALY gained. The committee concluded that, given that regorafenib met the criteria for being a life-extending, end-of-life treatment, it could be recommended as a cost-effective use of NHS resources.
# Other factors
## The committee did not identify any other factors that affected its recommendations
The committee considered whether its recommendations were associated with any potential issues related to equality. The committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of technology.
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{'Recommendations': "Regorafenib is recommended as an option for treating unresectable or metastatic gastrointestinal stromal tumours in adults whose disease has progressed on, or who are intolerant to, prior treatment with imatinib and sunitinib, only if:\n\ntheir Eastern Cooperative Oncology Group (ECOG) performance status is 0\xa0to\xa01 and\n\nthe company provides regorafenib with the discount agreed in the patient access scheme.\n\nWhen using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with regorafenib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for unresectable or metastatic gastrointestinal stromal tumours after disease progression on, or intolerance to, prior treatment with imatinib and sunitinib is best supportive care.\n\nThe evidence shows that people having regorafenib have longer before their disease progresses compared with those having best supportive care. However there is some uncertainty around how long regorafenib increases the overall length of time people live compared with those on best supportive care.\n\nRegorafenib meets NICE's criteria to be considered a life-extending end-of-life treatment, and the most plausible cost-effectiveness estimate is around £44,000 per quality-adjusted life year gained. Therefore it can be recommended for use in the NHS.\n\nRegorafenib is only recommended for people who have an ECOG performance status of 0\xa0to\xa01 because in clinical practice, regorafenib is only expected to be used in people who have an ECOG performance status of 0\xa0to\xa01; there is limited evidence for its use in people with a performance status of 2\xa0or more.", 'The technology ': "Regorafenib (Stivarga, Bayer)\n\nMarketing authorisation\n\nRegorafenib is indicated 'for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib'.\n\nRecommended dose and schedule\n\nThe recommended dose of regorafenib is 160\xa0mg (4\xa0tablets of 40\xa0mg) taken once daily for 3\xa0weeks followed by 1\xa0week off therapy. This 4‑week period is considered a treatment cycle.\n\nPrice\n\n£3,744.00 for 84\xa0tablets of 40\xa0mg (excluding VAT; British national formulary [BNF] edition\xa072).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of regorafenib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Clinical management\n\n## Best supportive care is the most appropriate comparator\n\nThe patient and clinical experts explained that gastrointestinal stromal tumours (GIST) are a rare disease that often takes years to diagnose because people have non-specific symptoms. The clinical expert advised that first-line treatment for metastatic GIST is imatinib, which is generally well tolerated. Once disease has progressed, patients are switched to sunitinib, which on average gives 6\xa0to 12\xa0months benefit before the disease progresses again but has more side effects than imatinib and requires careful monitoring. The patient and clinical experts explained that there are no alternative third-line treatment options after disease progression or if patients are intolerant to imatinib and sunitinib other than best supportive care. Regorafenib is currently available on the Cancer Drugs Fund for metastatic GIST after disease progression or intolerance to imatinib and disease progression after sunitinib, only if the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0\xa0to\xa01. The clinical expert explained that the only alternative to best supportive care and regorafenib (through the Cancer Drugs Fund) was to participate in a clinical trial but noted that these were rare. The committee concluded that best supportive care is the most appropriate comparator for this appraisal.\n\n# Treatment options\n\n## People with unresectable or metastatic GIST would greatly value another treatment option\n\nThe patient experts advised that regorafenib is well tolerated, with side effects (such as sore feet and hands, constipation and diarrhoea) that can be managed. The clinical experts described how dose adjustments and scheduling were important in treating GIST and that these are managed on an individual basis to achieve a balance between the minimal effective dose and side effects that can be tolerated. The patient experts explained that regorafenib allows people to remain actively engaged in work and family life, while reducing anxiety and increasing quality of life. Regorafenib also provides an important further treatment option to people who cannot tolerate sunitinib. One patient expert described how extending life was a priority to enable patients to spend more time with their families and it was important to be able to lead a near-normal life while having treatment. The committee recognised the importance of a potentially life-extending treatment with manageable side effects. The committee concluded that a treatment option for people with metastatic or unresectable GIST after imatinib and sunitinib would be greatly valued, particularly if it extended life and had manageable side effects.\n\n# Clinical evidence\n\n## Treatment with regorafenib in the GRID trial is in line with clinical practice\n\nThe evidence for regorafenib submitted by the company came from GRID, a multicentre double-blind randomised controlled trial with 199\xa0patients who had previously had treatment with imatinib and sunitinib. It compared regorafenib plus best supportive care (133\xa0patients) with placebo plus best supportive care (66\xa0patients). Best supportive care included various treatments such as analgesics, radiation therapy for pain control and palliative surgery. After disease progression, patients receiving placebo were given the option to cross over to regorafenib, and patients already receiving regorafenib were offered open-label regorafenib if it was considered clinically beneficial. In the trial, treatment could be delayed or reduced according to a pre-specified schedule. The clinical experts confirmed that dose reductions were common in clinical practice, because of the side effects associated with regorafenib, and managed on an individual basis. The clinical experts explained that treatment would only be stopped in clinical practice if there was clear disease progression and worsening clinical symptoms. Clinical guidelines recommend continued treatment with tyrosine kinase inhibitors as long as there is continued benefit. The clinical experts also advised that there was uncertainty around whether patients in the GRID trial could have other off-label treatments after disease progression that are not standard practice in the NHS. The committee concluded that using regorafenib after disease progression was in line with the marketing authorisation and current clinical practice.\n\n## Performance status should be taken into account in the final recommendations\n\nPatients in the GRID trial had an ECOG performance status of 0\xa0to\xa01 and the summary of product characteristics for regorafenib states that there are limited data in patients with a performance status of 2\xa0or above. Regorafenib is currently provided by the Cancer Drugs Fund to people who have a performance status of 0\xa0to\xa01, in line with trial evidence. The clinical experts explained that very few people for whom regorafenib would be considered present with a performance status of\xa02 in clinical practice; this is because treatment is actively managed in specialist centres to prevent performance status from deteriorating, particularly given the tolerability issues associated with sunitinib. The committee concluded that in line with the clinical evidence and the use of regorafenib in clinical practice, it would take performance status into account when making its final recommendations.\n\n## Correcting for crossover in the GRID trial is appropriate for estimating overall survival\n\nIn the GRID trial there was a high level of crossover (88%) from the placebo arm to open-label regorafenib after disease progression. The company and the ERG agreed that a statistical correction for crossover was needed to produce unbiased estimates of overall survival in the placebo arm. The company carried out 2\xa0crossover corrections using the iterative parameter estimation (IPE) and rank preserving structural failure time (RPSFT) methods. Both methods aimed to reconstruct individual patient data for overall survival in the placebo arm as if there had been no crossover. The ERG advised that both the IPE and RPSFT methods were appropriate for correcting crossover. The committee concluded that given the high level of crossover from placebo to regorafenib, an intention-to-treat analysis was not appropriate and a statistical correction for overall survival was needed.\n\n# Survival results from the GRID trial\n\n## Regorafenib is clinically effective in improving progression-free survival compared with best supportive care\n\nData from 2015 from the GRID trial showed that regorafenib improved progression-free survival (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.19 to 0.39). Data from 2017 showed that after crossover correction, median overall survival in the placebo arm was around 8\xa0months compared with 17.4\xa0months for regorafenib. The 2017 data showed a larger overall survival benefit after correcting for crossover (unadjusted HR\xa00.90; 95% CI\xa00.68 to\xa01.19, RPSFT HR\xa00.48; 95% CI\xa00.07 to\xa03.33, IPE HR\xa00.45; 95% CI\xa00.06 to 3.69). The committee understood that although not statistically significant, the point estimates did show improved overall survival with regorafenib. The committee concluded that there was evidence that regorafenib is clinically effective in improving progression-free survival compared with best supportive care but that there was uncertainty about the magnitude of overall survival benefit.\n\n# The company's economic model\n\n## The company's survival model is appropriate for decision-making\n\nThe company submitted a partitioned survival model with 3\xa0health states (progression free, progressed and death) that used survival data from the GRID trial. The company's base case modelled treatment duration by using the treatment discontinuation curve from GRID. Therefore the company's base case included the additional cost of regorafenib in the treatment arm after disease progression in line with the GRID trial (open-label regorafenib was offered to patients randomised to regorafenib after progression if it was considered clinically beneficial). Use of regorafenib after disease progression is in line with clinical practice (see section\xa03.3). The company's base case also incorporated dose intensity by including the mean observed dose of regorafenib from GRID (including doses of 0\xa0mg). The ERG agreed that the company's approach to modelling treatment duration and dose intensity was appropriate. The committee concluded that the company's model, using trial data to model treatment duration and dose intensity and including the additional cost of regorafenib after disease progression, was appropriate for decision-making.\n\n# Overall survival data from the GRID trial\n\n## There is uncertainty in the adjustment for overall survival but analyses using 2017 data are acceptable\n\nThe company's base case included overall survival estimates based on the most recent data from GRID (2017 data). The ERG initially had several concerns with using the 2017 data related to:\n\nmethodological assumptions in the treatment switching adjustment\n\nthe impact of recensoring on adjusted overall survival and the cost effectiveness of regorafenib\n\nreasons for a large decrease in overall survival in the placebo arm after adjusting for treatment switching when using the 2017 data compared with the 2015 data.Using different data cut-offs for estimating overall survival had a large impact on the cost-effectiveness results. Regorafenib appeared to be more cost effective when using the 2017 data for overall survival than when the 2015 data were used. The company responded to the ERG's concerns with additional explanations, and the ERG accepted the company's rationale and justifications of the methods used. The ERG confirmed that there was no conclusive evidence that the company had performed the treatment switching adjustment incorrectly, and accepted it was appropriate to use the most recent (2017) data. The committee concluded that while there was some remaining uncertainty, the analysis using 2017 data for estimating overall survival was acceptable.\n\n# Crossover correction\n\n## Both RPSFT and IPE adjustments of overall survival should be considered\n\nThe company's base case included an estimated treatment effect for overall survival with an IPE crossover correction. The ERG advised that the IPE method is an extension to the RPSFT method using parametric methods and the assumption of a common treatment effect (that is, people receive the same treatment benefit regardless of when they receive treatment). This assumption may not hold if people in the trial were able to receive a variety of off-label treatments after disease progression (see section\xa03.3). The ERG noted that both the IPE and RPSFT methods were appropriate and gave similar estimates of overall survival for the placebo arm (median overall survival IPE 8.0\xa0months and RPSFT 8.4\xa0months). In its revised explorations, the ERG considered both IPE- and RPSFT-corrected overall survival estimates as acceptable. The committee recognised that using the RPSFT rather than the IPE method did not have a large impact on the cost-effectiveness estimate of regorafenib. The committee concluded that cost-effectiveness results using either IPE or RPSFT adjustments should be considered in its decision-making.\n\n# Recensoring to avoid bias\n\n## Analyses with and without recensoring should be considered\n\nThe company's base case included an IPE adjustment with recensoring (in line with guidance from the Decision Support Unit). Recensoring is used to reduce the risk of bias associated with a treatment-switching adjustment, and recensoring data at an earlier time point aims to avoid informative censoring (because treatment switching is not random). The ERG advised that recensoring may lead to biased estimates of the average treatment effect when the proportional treatment effect assumptions do not hold, and there is some academic debate on whether to use recensoring because the estimated treatment effect is generally larger when it is used. The company provided further analyses that explored the impact of recensoring. The ERG advised that it was appropriate to consider analyses with and without recensoring. The committee noted that recensoring had a large impact on the cost-effectiveness estimate and that regorafenib appeared to be more cost effective if recensoring was used. The committee concluded that the arguments for and against recensoring were evenly balanced and that results both with and without recensoring should be considered when assessing the cost effectiveness of regorafenib.\n\n# Extrapolation of overall survival\n\n## A shorter-tailed Weibull distribution is appropriate for estimating overall survival and is clinically plausible\n\nThe company's base case included a log-logistic extrapolation of overall survival because it provided the best fit to the trial data from GRID. The company highlighted that log-logistic, Weibull and Gompertz models were considered clinically plausible by the clinical experts. The ERG advised that clinical plausibility of extrapolations was critical and the evidence for longer-tailed and shorter-tailed distributions appeared to be evenly balanced. The clinical experts explained that very few people with unresectable or metastatic GIST whose disease has progressed on, or who are intolerant to, treatment with imatinib and sunitinib will survive for 10\xa0years. The choice of extrapolation method for estimating overall survival had a large impact on the cost-effectiveness results for regorafenib. A log-logistic extrapolation resulted in a larger proportion of people surviving after 10\xa0years compared with the Weibull extrapolation and the clinical experts and committee considered this to be optimistic. The committee agreed that a Weibull extrapolation would be more appropriate because it had a shorter tail length and more plausibly reflected the survival of people at this stage of the disease. It noted that in the company's base case, regorafenib became less cost effective when the Weibull and Gompertz models were used. The committee concluded that an overall survival extrapolation that used a shorter-tailed Weibull model was most appropriate because it best reflected the survival outcomes of the population.\n\n## Including additional background mortality is appropriate\n\nThe ERG explained that causes of mortality in the GRID trial would largely be related to GIST but it was likely that additional general mortality would have occurred after the trial ended. The ERG's base case incorporated this additional background mortality but the company's did not. The committee understood that the impact of background mortality was likely to be lower when a shorter-tailed Weibull extrapolation was used. The committee concluded that including an adjustment for general mortality was appropriate.\n\n# Utility values\n\n## Including age-related utility decrements is appropriate\n\nUtility estimates for health-related quality of life were taken from the GRID trial, which reported the EQ-5D and European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). Both the company and ERG base cases used EQ-5D data from paired samples that were not split by treatment arm. The company stated that a repeated measures analysis would have been biased because more measurements were taken when patients did not have disease progression and there were no clinically meaningful differences in EQ-5D between the treatment arms. The ERG's base case also applied age-related utility decrements because utility often declines with age; this was not included in the company's base case. The committee understood that the addition of age-related utility decrements did not have a large impact on the cost-effectiveness results. The committee concluded that including age-related utility decrements was appropriate.\n\n# End of life\n\n## Regorafenib meets the end-of-life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. In the GRID trial the adjusted median overall survival in the placebo plus best supportive care arm was less than 12\xa0months (RPSFT-corrected median overall survival 8.4\xa0months and IPE-corrected median overall survival 8.0\xa0months). The company's economic model predicted mean undiscounted life years of 0.97\xa0for the IPE-adjusted placebo arm and 1.01\xa0for the RPSFT-adjusted placebo arm when recensoring was applied. The committee concluded that regorafenib was indicated for people with a short life expectancy. The median overall survival improvement in the GRID trial was at least 9\xa0months for patients treated with regorafenib compared with those having best supportive care, depending on which crossover correction method was used. The crossover-corrected mean overall survival benefit for regorafenib was around 1.2\xa0years longer compared with best supportive care in the ERG's revised base case, but less than 1.2\xa0years when recensoring was used (estimates taken from the company's economic model). The committee concluded that regorafenib offered an extension to life of at least 3\xa0months compared with best supportive care.\n\n# Cost-effectiveness results\n\n## Regorafenib is a cost-effective use of NHS resources\n\nThe committee considered the cost effectiveness of regorafenib as estimated using its preferred analyses, which included:\n\ndata for overall survival (see section\xa03.8)\n\ncrossover adjustment using either RPSFT or IPE (see section\xa03.9)\n\nanalyses with and without recensoring (see section\xa03.10)\n\noverall survival extrapolation using a Weibull distribution (see section\xa03.11)\n\nbackground mortality (see section\xa03.12)\n\nage-related utility decrements (see section\xa03.13).The committee discussed that, using its preferred analyses, the incremental cost-effectiveness ratio (ICER) was likely to lie between £40,000 and £48,000 per quality-adjusted life year (QALY) gained. It concluded that the most plausible ICER was the midpoint of that range: around £44,000 per QALY gained. The committee concluded that, given that regorafenib met the criteria for being a life-extending, end-of-life treatment, it could be recommended as a cost-effective use of NHS resources.\n\n# Other factors\n\n## The committee did not identify any other factors that affected its recommendations\n\nThe committee considered whether its recommendations were associated with any potential issues related to equality. The committee concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\nThe Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of technology."}
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https://www.nice.org.uk/guidance/ta488
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Evidence-based recommendations on on regorafenib (Stivarga) for previously treated gastrointestinal stromal tumours in adults.
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ba26c071ed80be2ae4b0ded4c860ef08e5811cba
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nice
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Total distal radioulnar joint replacement for symptomatic joint instability or arthritis
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Total distal radioulnar joint replacement for symptomatic joint instability or arthritis
Evidence-based recommendations on total distal radioulnar joint replacement for symptomatic joint instability or arthritis in adults. This involves removing the wrist end of the ulna (one of the forearm bones) and replacing it with a metal prosthesis that also attaches to the wrist end of the radius (the other forearm bone).
# Recommendations
Current evidence on the safety and efficacy of total distal radioulnar joint replacement for symptomatic joint instability or arthritis is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to do total distal radioulnar joint replacement for symptomatic joint instability or arthritis should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having total distal radioulnar joint replacement for symptomatic joint instability or arthritis (see section 7.2).
Patient selection and the procedure should only be done by clinicians with special expertise in hand and wrist surgery.
Further research should provide information on patient selection, and continue to collect long-term outcomes. NICE may update the guidance on publication of further evidence.# Indications and current treatments
Distal radioulnar joint instability can be caused by injury, arthritis or failure of previous surgery. The wrist can become swollen and painful, which often limits hand movement and grip strength.
Initial treatment includes rest, analgesia and corticosteroid injections. If symptoms do not respond to conservative measures, surgical options include excision of the ulnar head or ulnar head replacement. Another option is to fuse the ulnar head to the radius and excise a small segment of bone proximal to the joint, to allow the hand to turn over.# The procedure
Total distal radioulnar replacement differs from conventional treatment because it involves replacing all 3 components of the distal radioulnar joint. The aim of the procedure is to increase stability of the joint and improve pain-free movement.
The procedure is done with the patient under general or regional anaesthesia, and with a tourniquet applied to the upper arm. Radiological screening is used during the procedure to check the position of the joint. An incision is made along the ulnar border and the ulnar head is removed, taking care to avoid damage to the ulnar nerve, tendons and artery. A plate bearing a socket is fixed to the radius, and the ulna component of the prosthesis is then inserted and attached to the radial component, using a ball to allow pronation and supination. The range of motion of the joint is checked and the wound is closed. Patients are usually encouraged to start full range-of-motion exercises about 2 weeks after the procedure.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a case series of 41 patients, there was a statistically significant decrease in the mean pain score (measured on a visual analogue scale from 0 to 10) from 8 before the procedure to 2 at follow-up (mean 61 months, range 24 months to 99 months; p<0.001). In a case series of 19 patients, there was a statistically significant decrease in the mean pain score (measured on a VAS from 0 to 10) from 5.3 before the procedure to 3.5 at follow-up (mean 4 years and 1 month, range 1 year to 7 years; p=0.02). In a case series of 17 patients, there was a statistically significant decrease in the mean pain score (measured on a VAS from 0 to 10) from 7.4 before the procedure to 2.2 at follow-up (mean 39 months, range 12 months to 79 months; p=0.001).
In the case series of 41 patients, there was a statistically significant decrease in the disabilities of the arm, shoulder and hand (DASH) score (range 0 to 100; lower scores better) from 56 before the procedure to 27 at follow-up (p=0.008). There was also a statistically significant decrease in the patient-rated wrist evaluation (PRWE) score (range 0 to 100; lower scores better) from 64 before the procedure to 30 at follow-up (p=0.002). In the case series of 19 patients, there was a decrease in the DASH score from 39 before the procedure to 31 at follow-up (p=0.07). In a case series of 35 patients who had a second-generation prosthesis, the mean PRWE score at 5‑year follow-up was 14 (n=19) and the mean DASH score was 22 (n=18).
In the case series of 41 patients, mean pronation increased from 69° to 77° (p=0.48), supination from 62° to 73° (p=0.021), extension from 55° to 56° (p=0.28) and flexion from 53° to 56° (p=0.065) at follow-up. In the case series of 19 patients, mean pronation increased from 79° to 88° (p=0.01), supination from 70° to 72° (p=0.7), extension from 48° to 59° (p=0.01) and flexion from 39° to 46° (p=0.29) at follow-up. In the case series of 35 patients who had a second-generation prosthesis, the mean pronation increased from 62° to 83° and the mean supination increased from 51° to 75° at 5‑year follow-up (p values not reported). In the case series of 17 patients, mean pronation increased from 56° to 78° (p=0.30) and mean supination increased from 56° to 72° (p=0.04) at follow-up.
In the case series of 41 patients, there was a statistically significant increase in mean grip strength after the procedure from 31 kg to 49 kg (p<0.001) at follow-up. In the case series of 19 patients, there was a statistically significant increase in mean grip strength after the procedure from 10 kg to 16 kg (p=0.01) at follow-up. In the case series of 35 patients who had a second-generation prosthesis, the mean grip strength increased from 44% of the contralateral side to 94% of the contralateral side at 5‑year follow-up (p value not reported).
In a systematic review of 315 patients, for those papers using 1 particular type of implant, there were 7 revisions of 246 implants, giving an implant survival rate of 97% at a mean follow-up of 56 months (range 24 months to 75 months).
In the case series of 41 patients, 5% (2/41) of patients were not satisfied with the procedure and would not advise patients with the same pathology to have the procedure. In the case series of 35 patients who had a second-generation prosthesis, the mean satisfaction score after the procedure was 9.6 out of 10.0. In a case series of 13 patients with a median follow-up of 60 months, all patients were satisfied with their wrist motion and ability to perform activities of daily living. In a case series of 10 patients, all 7 patients who responded to a follow-up questionnaire were either satisfied or very satisfied with the outcome of their surgery.
The specialist advisers listed the following key efficacy outcomes: pain reduction, reduction in feeling of instability, improved function, grip and lifting strength, restoration of forearm range of motion, and return to work and pre-existing activity.
Four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Extensor carpi ulnaris (ECU) tendonitis was reported in 17% (6/35) and 20% (9/46) of wrists in 2 case series of 35 and 41 patients respectively. Additional surgery was needed by 1 patient who developed pain along the ECU tendon in a case series of 17 patients.
Infection was reported in 1 patient in the case series of 41 patients; the implant was removed and replaced after the infection had resolved. Minor soft tissue infection was reported in 6% (2/35) of patients in the case series of 35 patients.
Ectopic bone formation around the ulnar stem was reported in 7% (3/46) of patients in the case series of 41 patients. Ectopic bone formation was reported in 14% (5/35) of patients in the case series of 35 patients.
Osteophytes were reported in 9% (4/46) of joints in the case series of 41 patients; they developed within 2 years of the procedure and were removed from the distal ulnar stem.
Screw or cap loosening was reported in 1 patient in the case series of 35 patients. Loosening of the implant and pain was reported in 1 patient who had a first-generation implant in the case series of 17 patients; a revision was done with a second-generation implant. Aseptic ulnar component loosening, which needed revision surgery, was reported in 1 patient in a case series of 10 patients.
Debridement of prominent screw tips on the radial styloid was reported in 14% (2/14) of joints in a case series of 13 patients. A small surgical procedure to burr down the prominent ends of the screw tips was reported in 30% (3/10) of patients in the case series of 10 patients.
De Quervain's disease was reported in 1 patient in a case series of 9 patients; the patient needed further surgery 1 year after the distal radioulnar joint replacement. Transient carpal tunnel syndrome was reported in 1 patient in the same study. Median neuropathy was reported in 1 patient in the case series of 10 patients. Radial plate malposition, implant failure, and lunate-implant impingement were each reported in 1 patient in the case series of 41 patients.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers described the following anecdotal adverse event: the ulna stem breaking after high energy trauma. They considered that the following was a theoretical adverse event: the polyethylene ball component wearing out over time.
Four commentaries from patients who had experience of this procedure were received, which were discussed by the committee.# Further information
For related NICE guidance, see the NICE website.
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2721-0
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{'Recommendations': "Current evidence on the safety and efficacy of total distal radioulnar joint replacement for symptomatic joint instability or arthritis is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do total distal radioulnar joint replacement for symptomatic joint instability or arthritis should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having total distal radioulnar joint replacement for symptomatic joint instability or arthritis (see section\xa07.2).\n\nPatient selection and the procedure should only be done by clinicians with special expertise in hand and wrist surgery.\n\nFurther research should provide information on patient selection, and continue to collect long-term outcomes. NICE may update the guidance on publication of further evidence.", 'Indications and current treatments': 'Distal radioulnar joint instability can be caused by injury, arthritis or failure of previous surgery. The wrist can become swollen and painful, which often limits hand movement and grip strength.\n\nInitial treatment includes rest, analgesia and corticosteroid injections. If symptoms do not respond to conservative measures, surgical options include excision of the ulnar head or ulnar head replacement. Another option is to fuse the ulnar head to the radius and excise a small segment of bone proximal to the joint, to allow the hand to turn over.', 'The procedure': 'Total distal radioulnar replacement differs from conventional treatment because it involves replacing all 3\xa0components of the distal radioulnar joint. The aim of the procedure is to increase stability of the joint and improve pain-free movement.\n\nThe procedure is done with the patient under general or regional anaesthesia, and with a tourniquet applied to the upper arm. Radiological screening is used during the procedure to check the position of the joint. An incision is made along the ulnar border and the ulnar head is removed, taking care to avoid damage to the ulnar nerve, tendons and artery. A plate bearing a socket is fixed to the radius, and the ulna component of the prosthesis is then inserted and attached to the radial component, using a ball to allow pronation and supination. The range of motion of the joint is checked and the wound is closed. Patients are usually encouraged to start full range-of-motion exercises about 2\xa0weeks after the procedure.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a case series of 41\xa0patients, there was a statistically significant decrease in the mean pain score (measured on a visual analogue scale [VAS] from 0\xa0to\xa010) from\xa08 before the procedure to\xa02 at follow-up (mean 61\xa0months, range 24\xa0months to 99\xa0months; p<0.001). In a case series of 19\xa0patients, there was a statistically significant decrease in the mean pain score (measured on a VAS from 0\xa0to\xa010) from\xa05.3 before the procedure to\xa03.5 at follow-up (mean 4\xa0years and 1\xa0month, range 1\xa0year to 7\xa0years; p=0.02). In a case series of 17\xa0patients, there was a statistically significant decrease in the mean pain score (measured on a VAS from 0\xa0to\xa010) from\xa07.4 before the procedure to\xa02.2 at follow-up (mean 39\xa0months, range 12\xa0months to 79\xa0months; p=0.001).\n\nIn the case series of 41\xa0patients, there was a statistically significant decrease in the disabilities of the arm, shoulder and hand (DASH) score (range 0\xa0to\xa0100; lower scores better) from\xa056 before the procedure to\xa027 at follow-up (p=0.008). There was also a statistically significant decrease in the patient-rated wrist evaluation (PRWE) score (range 0\xa0to\xa0100; lower scores better) from\xa064 before the procedure to\xa030 at follow-up (p=0.002). In the case series of 19\xa0patients, there was a decrease in the DASH score from\xa039 before the procedure to\xa031 at follow-up (p=0.07). In a case series of 35\xa0patients who had a second-generation prosthesis, the mean PRWE score at 5‑year follow-up was\xa014 (n=19) and the mean DASH score was\xa022 (n=18).\n\nIn the case series of 41\xa0patients, mean pronation increased from 69°\xa0to\xa077° (p=0.48), supination from 62°\xa0to\xa073° (p=0.021), extension from 55°\xa0to\xa056° (p=0.28) and flexion from 53°\xa0to\xa056° (p=0.065) at follow-up. In the case series of 19\xa0patients, mean pronation increased from 79°\xa0to\xa088° (p=0.01), supination from 70°\xa0to\xa072° (p=0.7), extension from 48°\xa0to\xa059° (p=0.01) and flexion from 39°\xa0to\xa046° (p=0.29) at follow-up. In the case series of 35\xa0patients who had a second-generation prosthesis, the mean pronation increased from 62°\xa0to\xa083° and the mean supination increased from 51°\xa0to\xa075° at 5‑year follow-up (p\xa0values not reported). In the case series of 17\xa0patients, mean pronation increased from 56°\xa0to\xa078° (p=0.30) and mean supination increased from 56°\xa0to\xa072° (p=0.04) at follow-up.\n\nIn the case series of 41\xa0patients, there was a statistically significant increase in mean grip strength after the procedure from 31\xa0kg to 49\xa0kg (p<0.001) at follow-up. In the case series of 19\xa0patients, there was a statistically significant increase in mean grip strength after the procedure from 10\xa0kg to 16\xa0kg (p=0.01) at follow-up. In the case series of 35\xa0patients who had a second-generation prosthesis, the mean grip strength increased from 44% of the contralateral side to 94% of the contralateral side at 5‑year follow-up (p\xa0value not reported).\n\nIn a systematic review of 315\xa0patients, for those papers using 1\xa0particular type of implant, there were 7\xa0revisions of 246\xa0implants, giving an implant survival rate of 97% at a mean follow-up of 56\xa0months (range 24\xa0months to 75\xa0months).\n\nIn the case series of 41\xa0patients, 5% (2/41) of patients were not satisfied with the procedure and would not advise patients with the same pathology to have the procedure. In the case series of 35\xa0patients who had a second-generation prosthesis, the mean satisfaction score after the procedure was 9.6 out of 10.0. In a case series of 13\xa0patients with a median follow-up of 60\xa0months, all patients were satisfied with their wrist motion and ability to perform activities of daily living. In a case series of 10\xa0patients, all 7\xa0patients who responded to a follow-up questionnaire were either satisfied or very satisfied with the outcome of their surgery.\n\nThe specialist advisers listed the following key efficacy outcomes: pain reduction, reduction in feeling of instability, improved function, grip and lifting strength, restoration of forearm range of motion, and return to work and pre-existing activity.\n\nFour commentaries from patients who had experience of this procedure were received, which were discussed by the committee.', 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nExtensor carpi ulnaris (ECU) tendonitis was reported in 17% (6/35) and 20% (9/46) of wrists in 2\xa0case series of 35\xa0and 41\xa0patients respectively. Additional surgery was needed by 1\xa0patient who developed pain along the ECU tendon in a case series of 17\xa0patients.\n\nInfection was reported in 1\xa0patient in the case series of 41\xa0patients; the implant was removed and replaced after the infection had resolved. Minor soft tissue infection was reported in 6% (2/35) of patients in the case series of 35\xa0patients.\n\nEctopic bone formation around the ulnar stem was reported in 7% (3/46) of patients in the case series of 41\xa0patients. Ectopic bone formation was reported in 14% (5/35) of patients in the case series of 35\xa0patients.\n\nOsteophytes were reported in 9% (4/46) of joints in the case series of 41\xa0patients; they developed within 2\xa0years of the procedure and were removed from the distal ulnar stem.\n\nScrew or cap loosening was reported in 1\xa0patient in the case series of 35\xa0patients. Loosening of the implant and pain was reported in 1\xa0patient who had a first-generation implant in the case series of 17\xa0patients; a revision was done with a second-generation implant. Aseptic ulnar component loosening, which needed revision surgery, was reported in 1\xa0patient in a case series of 10\xa0patients.\n\nDebridement of prominent screw tips on the radial styloid was reported in 14% (2/14) of joints in a case series of 13\xa0patients. A small surgical procedure to burr down the prominent ends of the screw tips was reported in 30% (3/10) of patients in the case series of 10\xa0patients.\n\nDe Quervain's disease was reported in 1\xa0patient in a case series of 9\xa0patients; the patient needed further surgery 1\xa0year after the distal radioulnar joint replacement. Transient carpal tunnel syndrome was reported in 1\xa0patient in the same study. Median neuropathy was reported in 1\xa0patient in the case series of 10\xa0patients. Radial plate malposition, implant failure, and lunate-implant impingement were each reported in 1\xa0patient in the case series of 41\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers described the following anecdotal adverse event: the ulna stem breaking after high energy trauma. They considered that the following was a theoretical adverse event: the polyethylene ball component wearing out over time.\n\nFour commentaries from patients who had experience of this procedure were received, which were discussed by the committee.", 'Further information': 'For related NICE guidance, see the NICE website.\n\nThis guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2721-0'}
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https://www.nice.org.uk/guidance/ipg595
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Evidence-based recommendations on total distal radioulnar joint replacement for symptomatic joint instability or arthritis in adults. This involves removing the wrist end of the ulna (one of the forearm bones) and replacing it with a metal prosthesis that also attaches to the wrist end of the radius (the other forearm bone).
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64c70f17b3907f50bca23ba274937bb6544493f6
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nice
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Extracranial to intracranial bypass for intracranial atherosclerosis
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Extracranial to intracranial bypass for intracranial atherosclerosis
Evidence-based recommendations on extracranial to intracranial bypass for intracranial atherosclerosis. This involves joining a blood vessel from outside the skull to one inside the skull to bypass a narrowed or partially blocked vessel.
# Recommendations
This document replaces previous guidance on extracranial to intracranial bypass for intracranial atherosclerosis (interventional procedures guidance 348).
Current evidence on the safety and efficacy of extracranial to intracranial bypass for intracranial atherosclerosis shows that there is no benefit to the patient from the intervention. There are major concerns around its safety, therefore this procedure should not be used to treat this condition.# Indications and current treatments
Intracranial atherosclerosis is usually a progressive condition which narrows and hardens the blood vessels supplying the brain, limiting its blood supply. This can cause transient ischaemic attacks or permanent neurological damage (stroke).
Conservative management of atherosclerosis includes smoking cessation, and antiplatelet, lipid-lowering and antihypertensive medication. Endovascular techniques (angioplasty or stenting) may be used to dilate an arterial narrowing.# The procedure
The aim of extracranial to intracranial bypass for intracranial atherosclerosis is to increase blood flow in intracranial arteries to relieve symptoms of cerebral hypoperfusion or reduce the risk of stroke. Under general anaesthesia, the extracranial donor artery (usually the superficial temporal artery) is anastomosed to a superficial cerebral artery (usually a subpial middle cerebral artery branch) through a mini-craniotomy. Typically, an end-to-side anastomosis is used. A graft (for example a radial artery or a saphenous vein graft) may be needed to allow higher flow.
Careful pre-operative planning involving ultrasound, angiography, computed tomography (CT), single-photon emission CT scanning or brain reserve testing is needed.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
A systematic review of 2,591 patients (2 randomised controlled trials with follow-up intervals of 56 and 25 months, and 19 non-randomised studies with follow-up not stated) reported no difference in stroke rates (any type) between patients having extracranial to intracranial (EC‑IC) bypass (plus best medical treatment) and those having medical treatment only (in the RCTs n=1,691; odds ratio 0.99, 95% confidence interval 0.79 to 1.23, p=0.91 and in the non-randomised studies , n=881; OR 0.80, 95% CI 0.54 to1.18, p=0.25). In the same systematic review, ischaemic stroke rate was not statistically significantly different between patients having EC‑IC bypass and those having medical treatment only (in the RCTs n=1,573; OR 0.69, 95% CI 0.44 to 1.08, p=0.11 and in the non-randomised studies , n=640; OR 0.72, 95% CI 0.44 to 1.18, p=0.19). Two RCTs reported a statistically significantly smaller probability of stroke, vascular event or vascular death among the patients having EC‑IC bypass when compared with patients having medical treatment only (n=1,573; OR 0.68, 95% CI 0.51 to 0.91, p=0.009). No statistically significant difference in ischaemic stroke rate was seen in the systematic review of 2,591 patients (13 non-randomised studies; n=673; OR 0.69, 95% CI 0.45 to 1.04, p=0.079). Two non-randomised studies (n=361) reported no statistically significant difference in intracranial haemorrhage rates between patients having EC‑IC bypass when compared with patients having medical treatment only (OR 1.14, 95% CI 0.44 to 2.93, p=0.79) in the same systematic review. A systematic review of 506 patients reported a statistically significantly lower rate of stroke 12 months after surgery in patients with severe stage I failure (loss of autoregulatory vasodilation) who had EC‑IC bypass (1%) than in patients having medical treatment only (19%, 95% CI 1.17 to 4.08, p=0.015). In the same systematic review, stroke rate was not statistically significantly different in patients with stage II failure (autoregulatory failure characterised by decreases of cerebral blood flow and increases of oxygen extraction fraction) who had EC‑IC bypass (0%) when compared with patients having medical treatment only (13%, 95% CI 0.89 to 3.63, p=0.10). In an RCT of 1,377 patients, EC‑IC bypass surgery was associated with a 14% (90% CI 3 to 34) increased relative risk of fatal and non-fatal stroke (Mantel-Haenszel chi-squared =1.72) at a mean follow-up of 56 months (p value not reported). In an RCT (n=195) comparing 97 patients having EC‑IC bypass with 98 patients who had medical treatment only, ipsilateral ischaemic stroke rate was not statistically significantly different between groups (rate difference 2%, 95% CI −10 to 14, p=0.81) at 2‑year follow-up. A case series of 204 patients who had EC‑IC bypass reported the rate of patients free of stroke or fatal stroke to be 92% (138/150) at 1‑year follow-up and 87% (86/99) at 5‑year follow-up.
In the systematic review of 2,591 patients, 11 non-randomised studies reported a statistically significantly smaller risk of transient ischaemic attack or amaurosis in patients who had EC‑IC bypass when compared with patients who had medical treatment only (n=524; OR, 0.34, 95% CI 0.16 to 0.69, p=0.003). Three non-randomised studies from the same systematic review reported no statistically significant difference in normalisation of cerebral haemodynamics between patients who had EC-IC bypass and those having medical treatment only (n=56; OR 6.63, 95% CI 1.85 to 23.78).
The RCT of 1,377 patients reported a graft patency rate, assessed by angiography, of 96% (576/600) in patients who had EC‑IC bypass, at a median of 32 days post-procedure. In the RCT of 195 patients, graft failure rate at 2‑year follow-up was 2% (2/97) in patients who had EC‑IC bypass.
In an RCT of 43 patients there was no statistically significant difference in neurocognitive function (measured by 14 standardised neuropsychological tests and the Centre for Epidemiological Studies depression scale), at 2‑year follow-up, between patients who had EC‑IC bypass and patients who had medical treatment only (point estimate 0.02, 95% CI, 20.50 to 0.54, p=0.93).
The specialist advisers listed reduction in stroke rate compared with medical treatment only as the key efficacy outcome.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a randomised controlled trial (RCT; n=1,377) comparing 663 patients who had extracranial to intracranial (EC‑IC) bypass with 714 patients who had medical treatment only, the rate of cerebral and retinal ischaemic events was higher in the EC‑IC-bypass group (12% ) than in the medical group (3% ) within 30 days of surgery (or 39 days of randomisation for the medical group), no p value reported. The same RCT reported a higher rate of major stroke, defined as an 'inability to function without assistance', in the group who had EC‑IC bypass (3% ) compared with the medical-treatment-only group (1% ), within 30 days of surgery or 39 days of randomisation, p value not reported. A case series of 876 patients with occlusive cerebrovascular disease reported no statistically significant difference in the rate of post-procedure stroke in asymptomatic patients who had EC‑IC bypass (2% ) when compared with asymptomatic patients who had intracranial stenting (4% , p=0.341). The same case series reported a statistically significantly higher rate of post-procedure stroke in symptomatic patients who had EC-IC bypass (25% ) than in symptomatic patients who had intracranial stenting (10% , p<0.001).
In the case series of 876 patients with occlusive cerebrovascular disease, asymptomatic patients were no more likely to be transferred to another care facility, rather than home, if they had EC‑IC bypass (16% ) when compared with patients who had intracranial stenting (9% , p=0.08). Symptomatic patients were statistically significantly more likely to be transferred to another care facility, rather than home, if they had EC‑IC bypass (66% ) when compared with patients who had intracranial stenting (53% , p=0.08). In a case series of 415 patients who had EC‑IC bypass, destination at discharge for patients with post-procedure stroke was home (59% ), short-term facility (25% ) and long-term facility (9% ).
The following adverse events were reported in the RCT of 195 patients who had EC‑IC bypass: epidural or subdural haematoma (2% ), seizures (2% ), respiratory disorder (1% ), hypotension (1% ), and wound infection (1% ). The following adverse events happened to the same patient (1% ): deep vein thrombosis, atrial flutter, cardiac tamponade and pulmonary embolus. Haemorrhage, haematoma complicating the procedure, hydrocephalus, ventriculostomy, mechanical ventilation, deep vein thrombosis, pulmonary embolism and placement of an inferior vena cava filter were reported in the case series of 415 patients who had EC‑IC bypass (no frequencies were reported).
Reperfusion injury with cerebral oedema was reported in 1 patient in a case series of 85 patients who had EC‑IC bypass.
Temporary dysesthesia on the graft harvest site (1/13) and haematoma at the graft harvest site (1/13) was reported in a case series of 13 patients who had EC‑IC bypass.
As well as safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly happen, even if they have never done so). For this procedure, specialist advisers listed no anecdotal adverse events. They did not identify any theoretical adverse events that had not previously been reported.# Further information
For related NICE guidance, see the NICE website.
Patient commentaries were sought but none was received.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2719-7
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{'Recommendations': 'This document replaces previous guidance on extracranial to intracranial bypass for intracranial atherosclerosis (interventional procedures guidance 348).\n\nCurrent evidence on the safety and efficacy of extracranial to intracranial bypass for intracranial atherosclerosis shows that there is no benefit to the patient from the intervention. There are major concerns around its safety, therefore this procedure should not be used to treat this condition.', 'Indications and current treatments': 'Intracranial atherosclerosis is usually a progressive condition which narrows and hardens the blood vessels supplying the brain, limiting its blood supply. This can cause transient ischaemic attacks or permanent neurological damage (stroke).\n\nConservative management of atherosclerosis includes smoking cessation, and antiplatelet, lipid-lowering and antihypertensive medication. Endovascular techniques (angioplasty or stenting) may be used to dilate an arterial narrowing.', 'The procedure': 'The aim of extracranial to intracranial bypass for intracranial atherosclerosis is to increase blood flow in intracranial arteries to relieve symptoms of cerebral hypoperfusion or reduce the risk of stroke. Under general anaesthesia, the extracranial donor artery (usually the superficial temporal artery) is anastomosed to a superficial cerebral artery (usually a subpial middle cerebral artery branch) through a mini-craniotomy. Typically, an end-to-side anastomosis is used. A graft (for example a radial artery or a saphenous vein graft) may be needed to allow higher flow.\n\nCareful pre-operative planning involving ultrasound, angiography, computed tomography (CT), single-photon emission CT scanning or brain reserve testing is needed.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nA systematic review of 2,591\xa0patients (2\xa0randomised controlled trials [RCTs] with follow-up intervals of 56\xa0and 25\xa0months, and 19\xa0non-randomised studies with follow-up not stated) reported no difference in stroke rates (any type) between patients having extracranial to intracranial (EC‑IC) bypass (plus best medical treatment) and those having medical treatment only (in the RCTs n=1,691; odds ratio [OR] 0.99, 95% confidence interval [CI] 0.79 to 1.23, p=0.91 and in the non-randomised studies [18 studies], n=881; OR 0.80, 95% CI 0.54 to1.18, p=0.25). In the same systematic review, ischaemic stroke rate was not statistically significantly different between patients having EC‑IC bypass and those having medical treatment only (in the RCTs n=1,573; OR 0.69, 95% CI 0.44 to 1.08, p=0.11 and in the non-randomised studies [13 studies], n=640; OR 0.72, 95% CI 0.44 to 1.18, p=0.19). Two RCTs reported a statistically significantly smaller probability of stroke, vascular event or vascular death among the patients having EC‑IC bypass when compared with patients having medical treatment only (n=1,573; OR 0.68, 95% CI 0.51 to 0.91, p=0.009). No statistically significant difference in ischaemic stroke rate was seen in the systematic review of 2,591 patients (13\xa0non-randomised studies; n=673; OR 0.69, 95% CI 0.45 to 1.04, p=0.079). Two non-randomised studies (n=361) reported no statistically significant difference in intracranial haemorrhage rates between patients having EC‑IC bypass when compared with patients having medical treatment only (OR 1.14, 95% CI 0.44 to 2.93, p=0.79) in the same systematic review. A systematic review of 506\xa0patients reported a statistically significantly lower rate of stroke 12\xa0months after surgery in patients with severe stage\xa0I failure (loss of autoregulatory vasodilation) who had EC‑IC bypass (1%) than in patients having medical treatment only (19%, 95% CI 1.17 to 4.08, p=0.015). In the same systematic review, stroke rate was not statistically significantly different in patients with stage\xa0II failure (autoregulatory failure characterised by decreases of cerebral blood flow and increases of oxygen extraction fraction) who had EC‑IC bypass (0%) when compared with patients having medical treatment only (13%, 95% CI 0.89 to 3.63, p=0.10). In an RCT of 1,377\xa0patients, EC‑IC bypass surgery was associated with a 14% (90% CI\xa03\xa0to 34) increased relative risk of fatal and non-fatal stroke (Mantel-Haenszel chi-squared =1.72) at a mean follow-up of 56\xa0months (p\xa0value not reported). In an RCT (n=195) comparing 97\xa0patients having EC‑IC bypass with 98\xa0patients who had medical treatment only, ipsilateral ischaemic stroke rate was not statistically significantly different between groups (rate difference 2%, 95% CI −10 to 14, p=0.81) at 2‑year follow-up. A case series of 204\xa0patients who had EC‑IC bypass reported the rate of patients free of stroke or fatal stroke to be 92% (138/150) at 1‑year follow-up and 87% (86/99) at 5‑year follow-up.\n\nIn the systematic review of 2,591\xa0patients, 11\xa0non-randomised studies reported a statistically significantly smaller risk of transient ischaemic attack or amaurosis in patients who had EC‑IC bypass when compared with patients who had medical treatment only (n=524; OR, 0.34, 95% CI 0.16 to 0.69, p=0.003). Three non-randomised studies from the same systematic review reported no\xa0statistically significant difference in normalisation of cerebral haemodynamics between patients who had EC-IC bypass and those having medical treatment only (n=56; OR 6.63, 95% CI 1.85 to 23.78).\n\nThe RCT of 1,377\xa0patients reported a graft patency rate, assessed by angiography, of 96% (576/600) in patients who had EC‑IC bypass, at a median of 32\xa0days post-procedure. In the RCT of 195\xa0patients, graft failure rate at 2‑year follow-up was 2% (2/97) in patients who had EC‑IC bypass.\n\nIn an RCT of 43\xa0patients there was no statistically significant difference in neurocognitive function (measured by 14\xa0standardised neuropsychological tests and the Centre for Epidemiological Studies depression scale), at 2‑year follow-up, between patients who had EC‑IC bypass and patients who had medical treatment only (point estimate 0.02, 95% CI, 20.50 to 0.54, p=0.93).\n\nThe specialist advisers listed reduction in stroke rate compared with medical treatment only as the key efficacy outcome.', 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT; n=1,377) comparing 663\xa0patients who had extracranial to intracranial (EC‑IC) bypass with 714\xa0patients who had medical treatment only, the rate of cerebral and retinal ischaemic events was higher in the EC‑IC-bypass group (12% [81/663]) than in the medical group (3% [24/714]) within 30\xa0days of surgery (or 39\xa0days of randomisation for the medical group), no p\xa0value reported. The same RCT reported a higher rate of major stroke, defined as an 'inability to function without assistance', in the group who had EC‑IC bypass (3% [20/663]) compared with the medical-treatment-only group (1% [9/714]), within 30\xa0days of surgery or 39\xa0days of randomisation, p value not reported. A case series of 876\xa0patients with occlusive cerebrovascular disease reported no statistically significant difference in the rate of post-procedure stroke in asymptomatic patients who had EC‑IC bypass (2% [2/123]) when compared with asymptomatic patients who had intracranial stenting (4% [10/243], p=0.341). The same case series reported a statistically significantly higher rate of post-procedure stroke in symptomatic patients who had EC-IC bypass (25% [32/126]) than in symptomatic patients who had intracranial stenting (10% [40/384], p<0.001).\n\nIn the case series of 876\xa0patients with occlusive cerebrovascular disease, asymptomatic patients were no more likely to be transferred to another care facility, rather than home, if they had EC‑IC bypass (16% [19/121]) when compared with patients who had intracranial stenting (9% [21/237], p=0.08). Symptomatic patients were statistically significantly more likely to be transferred to another care facility, rather than home, if they had EC‑IC bypass (66% [80/121]) when compared with patients who had intracranial stenting (53% [180/338], p=0.08). In a case series of 415\xa0patients who had EC‑IC bypass, destination at discharge for patients with post-procedure stroke was home (59% [41/69]), short-term facility (25% [17/69]) and long-term facility (9% [6/69]).\n\nThe following adverse events were reported in the RCT of 195\xa0patients who had EC‑IC bypass: epidural or subdural haematoma (2% [2/97]), seizures (2% [2/97]), respiratory disorder (1% [1/97]), hypotension (1% [1/97]), and wound infection (1% [1/97]). The following adverse events happened to the same patient (1% [1/97]): deep vein thrombosis, atrial flutter, cardiac tamponade and pulmonary embolus. Haemorrhage, haematoma complicating the procedure, hydrocephalus, ventriculostomy, mechanical ventilation, deep vein thrombosis, pulmonary embolism and placement of an inferior vena cava filter were reported in the case series of 415\xa0patients who had EC‑IC bypass (no frequencies were reported).\n\nReperfusion injury with cerebral oedema was reported in 1\xa0patient in a case series of 85\xa0patients who had EC‑IC bypass.\n\nTemporary dysesthesia on the graft harvest site (1/13) and haematoma at the graft harvest site (1/13) was reported in a case series of 13\xa0patients who had EC‑IC bypass.\n\nAs well as safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly happen, even if they have never done so). For this procedure, specialist advisers listed no anecdotal adverse events. They did not identify any theoretical adverse events that had not previously been reported.", 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentaries were sought but none was received.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2719-7'}
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https://www.nice.org.uk/guidance/ipg596
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Evidence-based recommendations on extracranial to intracranial bypass for intracranial atherosclerosis. This involves joining a blood vessel from outside the skull to one inside the skull to bypass a narrowed or partially blocked vessel.
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12c9c4e154b37c4cb7b79da2d17256e801d9d33f
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nice
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Sarilumab for moderate to severe rheumatoid arthritis
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Sarilumab for moderate to severe rheumatoid arthritis
Evidence-based recommendations on sarilumab (Kevzara) for treating moderate to severe rheumatoid arthritis in adults.
# Recommendations
Sarilumab, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying antirheumatic drugs (DMARDs), only if:
disease is severe (a disease activity score of more than 5.1) and
the company provides sarilumab with the discount agreed in the patient access scheme.
Sarilumab, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
they cannot have rituximab and
the company provides sarilumab with the discount agreed in the patient access scheme.
Sarilumab, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to rituximab and at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
the company provides sarilumab with the discount agreed in the patient access scheme.
Sarilumab can be used as monotherapy for people who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections 1.1 or 1.2 are met.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. After an initial response within 6 months, withdraw treatment if at least a moderate EULAR response is not maintained.
When using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with sarilumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trials showed sarilumab plus methotrexate or conventional DMARDs to be more effective than methotrexate or conventional DMARDs for treating moderate to severe active rheumatoid arthritis that has not responded adequately to conventional DMARDs. The trials also showed that for treating severe active rheumatoid arthritis that has not responded adequately to conventional DMARDs, sarilumab alone is more effective than adalimumab alone.
Because there are no trials comparing sarilumab with other biological DMARDs, the company did an indirect comparison. This showed that sarilumab with conventional DMARDs (including methotrexate) or alone works as well as most of the biological DMARDs that NICE has already recommended.
Based on the health-related benefits and costs compared with conventional and biological DMARDs, sarilumab plus methotrexate or sarilumab alone is recommended as a cost-effective treatment for severe active rheumatoid arthritis, in line with previous recommendations in:
NICE technology appraisal guidance on baricitinib
certolizumab pegol (after a TNF-alpha inhibitor)
adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (after conventional DMARDs)
tocilizumab
tofacitinib
golimumab (after DMARDs)
adalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha inhibitor).# The technology
Marketing authorisation
Sarilumab (Kevzara, Sanofi) has a marketing authorisation in the UK for the 'treatment of moderately to severely active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs.' Sarilumab can be given as monotherapy or in combination with methotrexate.
Recommended dose and schedule
The recommended dose of sarilumab is 200 mg administered once every 2 weeks. A reduction in dose from 200 mg once every 2 weeks to 150 mg once every 2 weeks is recommended for management of neutropenia, thrombocytopenia and liver enzyme elevations. Sarilumab is administered subcutaneously using a pre-filled pen or syringe. See the summary of product characteristics for details.
Price
The list price per pre-filled pen or syringe of 150 mg or 200 mg of sarilumab is £456.13.
The average cost per patient per year is estimated at £11,900 based on the list price.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of sarilumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Sanofi and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatment pathway
## Sarilumab can be used at 5 different points in the pathway
Sarilumab's marketing authorisation and the company submission covers its use at 5 points in the treatment pathway, specifically in adults with:
moderate, active rheumatoid arthritis that has not responded adequately to conventional disease-modifying antirheumatic drugs (DMARDs)
severe, active rheumatoid arthritis that has not responded adequately to conventional DMARDs
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, when rituximab is contraindicated or withdrawn because of adverse events
severe, active rheumatoid arthritis that has not responded adequately to rituximab and biological DMARDs.The committee also noted that the marketing authorisation includes the use of sarilumab alone or with methotrexate.
## NICE technology appraisal guidance exists for these points in the rheumatoid arthritis treatment pathway
NICE currently recommends the use of the biological DMARDs in its technology appraisal guidance on baricitinib, and adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are tumour necrosis factor (TNF)-alpha inhibitors) and tofacitinib, in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, less than 3.2 but more than 2.6 indicates mild disease and 2.6 or less indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that adalimumab, baricitinib, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy. The guidance recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose) and should only be continued according to EULAR response at 6 months.
For people with severe rheumatoid arthritis who have already had at least 1 TNF‑alpha inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommend the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol, baricitinib or tofacitinib in combination with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance recommends adalimumab, etanercept, certolizumab pegol, baricitinib or tofacitinib as monotherapy. NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha inhibitors nor rituximab have worked. See the NICE Pathway on rheumatoid arthritis for more details.
## Sarilumab offers an additional treatment option
The patient experts explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical expert stated that choosing an appropriate treatment depends on disease severity and response to treatment. The clinical expert noted that the disease sometimes does not respond adequately to the first biological DMARD prescribed. When there is not an adequate response the treatment is stopped and the next available treatment in the pathway is prescribed. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological DMARDs after failure of conventional DMARDs. The clinical and patient experts highlighted that sarilumab is administered by injection at home, which has major benefits for both patients and the health system. Sarilumab has a longer shelf-life when kept out of the fridge and the clinical expert emphasised that having a treatment that lasts 14 days rather than a number of hours is an important practical factor for people, especially those who travel. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological DMARDs.
# Subgroups
## The company's subgroups and comparators are appropriate
The company analysed 5 distinct subgroups in which sarilumab could be used. These were people with:
moderate, active rheumatoid arthritis that has not responded adequately to conventional DMARDs
severe, active rheumatoid arthritis that has not responded adequately to conventional DMARDs
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1 TNF-alpha inhibitor
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, when rituximab is contraindicated or withdrawn because of adverse events
severe, active rheumatoid arthritis that has not responded adequately to rituximab and biological DMARDs.The relevant comparators varied by subgroup. The committee concluded that it was appropriate to consider the 5 groups separately and that the company had included the appropriate comparators.
# Clinical effectiveness
## The trials are adequate and suitable for decision-making
The company's clinical evidence came from 5 randomised controlled trials and 1 long-term safety study. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.2. The trials were:
MOBILITY-A, a phase II trial which included people whose disease responded inadequately to methotrexate. Five sarilumab doses (100 mg or 150 mg once weekly and 100 mg, 150 mg or 200 mg once every 2 weeks) were given in combination with methotrexate and the comparator was methotrexate plus placebo. The primary outcome was the proportion of people who had a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 12.
MOBILITY-B, a phase III trial which included people whose disease responded inadequately to methotrexate. Sarilumab 150 mg or 200 mg was given once every 2 weeks in combination with methotrexate and the comparator was methotrexate plus placebo. The primary outcomes were: the proportion of people reaching ACR20 at week 24; change in physical function using the Health Assessment Questionnaire Disability Index (HAQ-DI) at week 16; and the change in Modified Total Sharp Score (mTSS) at week 52.
MONARCH, a phase III trial which included people whose disease responded inadequately or who were intolerant to methotrexate. Sarilumab 200 mg plus placebo was given once every 2 weeks and the comparator was adalimumab plus placebo. The primary outcome was the change from baseline in disease activity score 28 – erythrocyte sedimentation rate (DAS28-ESR) at week 24.
TARGET, a phase III trial which included people whose disease responded inadequately or who were intolerant to TNF-alpha inhibitors. Sarilumab 150 mg or 200 mg was given once every 2 weeks in combination with conventional DMARDs. The comparator was placebo plus conventional DMARDs. The primary outcomes were the proportion of people reaching ACR20 at week 24 and the change in physical function using HAQ-DI at week 12.
ASCERTAIN, a phase III trial which included people whose disease responded inadequately or who were intolerant to TNF-alpha inhibitors. Sarilumab 150 mg or 200 mg was given once every 2 weeks in combination with conventional DMARDs. The comparator was tocilizumab 4 to 8 mg plus conventional DMARDs. The primary outcome was description and number of adverse events.
EXTEND, a phase III open-label extension study which included people whose disease responded inadequately to methotrexate and TNF-alpha inhibitors. The trial assessed sarilumab plus conventional DMARDs and sarilumab monotherapy. The primary endpoint was safety.The committee concluded that the trials were relevant and adequate for its decision-making.
## Sarilumab plus methotrexate is more clinically effective than placebo plus methotrexate, and sarilumab alone is more clinically effective than adalimumab alone for moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs
In MOBILITY-A, sarilumab plus methotrexate showed a statistically significant improvement in ACR20 at 12 weeks compared with placebo plus methotrexate (sarilumab 200 mg 65%, placebo 46%; p=0.0426). In MOBILITY-B, sarilumab plus methotrexate showed a statistically significant improvement in ACR20 at 24 weeks compared with placebo plus methotrexate (sarilumab 200 mg 66%, placebo 33%; p<0.0001). In MONARCH, sarilumab plus placebo showed a statistically significant improvement in ACR20 at 24 weeks compared with adalimumab 40 mg plus placebo (sarilumab 200 mg 72%, adalimumab 40 mg 58%; p=0.0074). The committee concluded that sarilumab plus methotrexate is more clinically effective than placebo plus methotrexate, and that sarilumab alone is more clinically effective than adalimumab alone for moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs.
## Sarilumab is more clinically effective than conventional DMARDs for moderate to severe rheumatoid arthritis which has responded inadequately to TNF-alpha inhibitors
The TARGET trial showed that sarilumab plus methotrexate led to a statistically significant improvement in ACR20 compared with methotrexate at 24 weeks (sarilumab 200 mg 61%, placebo 34%; p<0.001). The company did not report comparative statistics for ASCERTAIN because the trial was powered for safety rather clinical effectiveness. The committee concluded that sarilumab is more clinically effective than conventional DMARDs for moderate to severe rheumatoid arthritis which has responded inadequately to TNF-alpha inhibitors.
## Sarilumab has an increased rate of adverse events compared with methotrexate
In the MOBILITY trials the rate of adverse events was higher in the sarilumab 200 mg group (ranging from 65% to 78%) compared with the methotrexate group (ranging from 47% to 62%). In the MONARCH trial, adalimumab and sarilumab had similar adverse event rates (63.6% and 64.1% respectively). The committee concluded that sarilumab plus methotrexate has a slightly higher rate of adverse events compared with methotrexate.
# Indirect comparison
## Network meta-analyses show that sarilumab with conventional DMARDs or alone works as well as biological DMARDs
Because the only direct evidence available on the comparative effectiveness of sarilumab and the biological DMARDs was with adalimumab, the company did a network meta-analyses. The company did separate analyses for patients whose disease responded inadequately to either conventional or biological DMARDs, using ACR20/50/70 score, HAQ-DI, European League Against Rheumatism (EULAR) responses, DAS28 remission, mTSS, serious infections and serious adverse events. In the conventional DMARD group the analyses were further split into combination therapy and monotherapy. EULAR responses were not identified for all the relevant comparators in the NICE scope because of a lack of reporting in the trials. The company transformed ACR responses into EULAR responses to inform treatment effectiveness in the economic model (section 3.13). At 24 weeks' follow-up, for patients whose disease responded inadequately to conventional DMARDs, the network meta-analysis showed:
sarilumab 200 mg plus conventional DMARDs gave better ACR20/50/70 response rates than conventional DMARDs
sarilumab 200 mg plus conventional DMARDs gave similar ACR20/50/70 response rates to the biological DMARDs
sarilumab 200 mg alone gave better ACR20/50/70 response rates than conventional DMARDs alone
sarilumab 200 mg alone gave similar ACR20/50/70 response rates to biological DMARDs alone.At 24 weeks' follow-up, for patients whose disease inadequately responded to biological DMARDs, the network meta-analysis showed:
sarilumab 200 mg plus conventional DMARDs gave better ACR20/50/70 response rates than conventional DMARDs
sarilumab 200 mg plus conventional DMARDs gave similar ACR20/50/70 response rates to the biological DMARDs plus conventional DMARDs.The committee concluded that sarilumab works as well as biological DMARDs in moderate to severe rheumatoid arthritis that has responded inadequately to conventional or biological DMARDs.
## Sarilumab monotherapy may have similar clinical effectiveness to sarilumab plus conventional DMARDs
The company was not able to identify any evidence on sarilumab monotherapy in patients whose disease responded inadequately to biological DMARDs. The company assumed that the efficacy of sarilumab monotherapy would be equal to that of sarilumab in combination with conventional DMARDs. The ERG noted that this assumption was reasonable but recognised the considerable uncertainty caused by the absence of direct data. The committee agreed that, in the absence of direct evidence, it is reasonable to assume sarilumab monotherapy has similar effectiveness to sarilumab plus conventional DMARDs in people whose disease has responded inadequately to biological DMARDs.
## The company's network meta-analysis is suitable for decision-making
The ERG stated that there was some uncertainty in the methods used by the company in the network meta-analysis. Following a request by the ERG at the clarification stage, the company provided updated results using the ERG's preferred assumptions which had been used by the assessment group in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis for patients whose disease responded inadequately to conventional DMARDs. The company noted that the results of the new network meta-analysis were comparable to those of its original analyses and that the conclusion that sarilumab is comparable to other biological DMARDs was unchanged. The ERG noted that the statistically significant result for sarilumab compared with other biological DMARD treatments (both as combination therapy and monotherapy) should be treated with caution as it may be a consequence of underestimating the uncertainty in treatment effects resulting from the use of a fixed-effects model. The committee reviewed both analyses and concluded that the methods used by the company in the network meta-analysis were in line with previous NICE technology appraisal guidance, and that the network meta-analysis was therefore suitable for decision-making.
# Cost effectiveness
## The company's model structure is appropriate for decision-making
The company used a patient-level Markov model for its economic evaluation. The model categorised patients based on their EULAR response (good, moderate or no response) at 6 months. Response rates were based on the company's network meta-analysis which transformed ACR 20/50/70 response to EULAR response. The company analysed cost effectiveness for each of the subgroups described in section 3.5. The ERG stated that the model was not an individual patient-based discrete event simulation as used by the assessment group in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The committee noted the difference between the company's model structure and the structure accepted in the previous guidance but accepted that the company's model was appropriate for its decision-making.
## The company's method for calculating utility is appropriate
The company stated that that EQ-5D utility data were not available for all comparators across all patient populations. Following a request by the ERG at the clarification stage, the company used Hernandez et al. (2013) to estimate EQ-5D data based on patient characteristics (HAQ score, pain on a visual analogue scale, age and sex). The ERG stated that Hernandez et al. was used in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The committee concluded it was appropriate for decision-making.
## The company's methods for calculating costs are appropriate
The company's model included costs associated with drug acquisition, drug administration and monitoring, and hospitalisation. The model treatment sequences included a TNF-alpha inhibitor bundle in the base case. The TNF-alpha inhibitor bundle used the pooled efficacy of etanercept, an etanercept biosimilar, adalimumab, infliximab, an infliximab biosimilar, golimumab and certolizumab pegol with the price weighted according to the estimated market share of each. The company did not include the cost of biosimilars for rituximab or adalimumab, but stated that at the time of submission the rituximab biosimilar was not available and the adalimumab biosimilar had not received its marketing authorisation. The ERG stated that in the company's original base case the incremental cost-effectiveness ratio (ICER) for sarilumab compared with rituximab was more than £100,000 per quality-adjusted life year (QALY) gained, and so reducing the price of rituximab would not change the conclusion for this population. Sarilumab and several of the other biological DMARDs have patient access schemes. The company had incorporated the patient access scheme prices for sarilumab, certolizumab pegol and golimumab in the model, but not the confidential patient access schemes for abatacept and tocilizumab. The committee concluded that the costs used in the company's model were appropriate.
## The company's updated treatment sequences are acceptable
During the clarification stage the ERG requested that the company update the sequences in which treatments are given for each subgroup to match those agreed in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The company provided updated sequences, but the ERG noted that in the group of patients whose disease has responded inadequately to biological DMARDs, a second line of biological treatment had been added in error. This error was corrected in the ERG's additional analyses and the committee accepted this.
## The ERG's changes to how patients progress from treatment for moderate disease to treatment for severe disease are appropriate
Following a request by the ERG at the clarification stage, the company updated the model to allow patients treated for moderate disease to progress to treatment for severe disease. The ERG explained that this progression, although not used in previous NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis, was requested because it provided a more accurate representation of clinical practice. The company updated its analyses but the ERG identified 2 issues with the company's methods:
In the company's model patients went through a moderate treatment sequence first and then transitioned to the severe sequences only if their HAQ-DI score was above a certain threshold. The HAQ-DI score was calculated through a regression which was related to a DAS28 score of 5.1. The ERG noted that changes in HAQ-DI and DAS28 values should have been calculated instead of using absolute values because the relationship between them is not linear.
Patients should have progressed to the severe sequences when their DAS28 score increased above 5.1, without waiting until they reached the end of the moderate sequence.The ERG corrected these points in its additional analyses. The committee considered the changes made by the ERG and concluded that they were appropriate.
## There were some concerns with how response to treatment was implemented
In the company's model patients were assessed for response to treatment at 6 months. Patients who had a moderate or good EULAR response were assumed to have an associated reduction in HAQ-DI score, which was assumed to be independent of treatment, and the treatment was stopped if the patient did not have at least moderate EULAR response at 6 months. The ERG stated that the company had used a linear approach to HAQ-DI score progression, which would have had a favourable effect for sarilumab when compared with conventional DMARDs. It explained that a non-linear method was more appropriate and had been accepted in previous NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The ERG had used this method in its additional analyses. The committee concluded that the non-linear approach to HAQ-DI progression was appropriate and therefore accepted the ERG's additional analyses.
# Cost-effectiveness results
## Sarilumab with methotrexate is not cost effective for moderate disease after conventional DMARDs
In the ERG's additional analysis for the population with moderate active rheumatoid arthritis that has responded inadequately to conventional DMARDs, the ICER for sarilumab compared with conventional DMARDs was £63,438 per QALY gained. The ERG also calculated new ICERs using the confidential patient access scheme prices for abatacept and intravenous tocilizumab; this comparison produced similar estimates of cost effectiveness. The committee considered that sarilumab plus conventional DMARDs was not cost effective in people with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.
## Sarilumab with methotrexate is cost effective for severe active rheumatoid arthritis after conventional DMARDs
In the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to conventional DMARDs, tocilizumab (intravenous and subcutaneous) was dominated by sarilumab plus conventional DMARDs (that is, sarilumab was both less costly and more effective). The ICERs for the TNF-alpha inhibitor bundle plus methotrexate and abatacept plus methotrexate compared with sarilumab plus methotrexate were both over £100,000 per QALY gained. The ERG also calculated ICERs using the confidential patient access scheme prices for abatacept and intravenous tocilizumab, which produced very similar estimates of cost effectiveness. The committee therefore recommended sarilumab plus conventional DMARDs for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.
## Sarilumab with methotrexate is not cost effective for severe disease after biological DMARDs if rituximab is a treatment option
In the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to biological DMARDs for whom rituximab is a treatment option, the ICER for a sequence where sarilumab plus conventional DMARDs replaced rituximab plus conventional DMARDs was over £100,000 per QALY gained. The committee concluded that sarilumab plus conventional DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs if rituximab is a treatment option.
## Sarilumab with methotrexate is cost effective for severe disease after biological DMARDs if rituximab is not a treatment option
In the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to biological DMARDs for whom rituximab is contraindicated, the incremental analysis for sarilumab compared with the TNF-alpha inhibitor bundle resulted in an ICER of £34,979 per QALY gained. Subcutaneous abatacept plus methotrexate was dominated by sarilumab plus methotrexate (that is, sarilumab was both less costly and more effective) and the ICERs for tocilizumab (intravenous and subcutaneous) plus methotrexate compared with sarilumab plus methotrexate were over £100,000 per QALY gained. The ERG updated its additional analysis using the confidential patient access scheme prices, which produced similar estimates of cost effectiveness. The committee therefore recommended sarilumab plus conventional DMARDs for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is not a treatment option.
## Sarilumab with methotrexate is cost effective for severe disease after rituximab and other biological DMARDs
In the ERG's additional analysis for the population with severe rheumatoid arthritis population that has not responded adequately to rituximab and other biological DMARDs, the ICER for intravenous or subcutaneous tocilizumab plus methotrexate compared with sarilumab plus methotrexate was over £100,000 per QALY gained. The ERG also updated its additional analysis using the confidential patient access scheme prices, which produced similar estimates of cost effectiveness. The committee therefore recommended sarilumab plus conventional DMARDs for people with severe rheumatoid arthritis whose disease has not responded adequately to rituximab and other biological DMARDs.
## Sarilumab monotherapy is cost effective for severe active rheumatoid arthritis after conventional DMARDs if methotrexate is not suitable
In the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to conventional DMARDs for whom methotrexate is contraindicated, sarilumab alone compared with a TNF-alpha inhibitor bundle alone in the incremental analysis had an ICER of £34,422 per QALY gained. In the incremental analysis subcutaneous tocilizumab was extendedly dominated by sarilumab alone (that is, the ICER for subcutaneous tocilizumab was higher than the next more effective alternative, which was intravenous tocilizumab). The ICER for intravenous tocilizumab compared with sarilumab was over £100,000 per QALY gained. The ERG updated this additional analysis using the confidential comparator patient access scheme prices, which produced similar estimates of cost effectiveness. The committee concluded that sarilumab monotherapy is cost effective for severe active rheumatoid arthritis after conventional DMARDs if methotrexate is not suitable.
## The recommendation for people whose condition has responded inadequately to biological DMARDs also applies to sarilumab monotherapy
In the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to biological DMARDs for whom methotrexate is contraindicated, the ICER for sarilumab compared with the TNF-alpha inhibitor bundle was £31,433 per QALY gained. The ERG stated that this analysis was subject to considerable uncertainty because the clinical effectiveness of sarilumab monotherapy was assumed to be equal to sarilumab in combination with conventional DMARDs. The committee acknowledged its decision that in the absence of direct evidence sarilumab monotherapy may have a similar clinical effectiveness to sarilumab plus conventional DMARDs in people whose disease has responded inadequately to biological DMARDs. The committee concluded that its recommendations for sarilumab plus conventional DMARDs in people whose disease has responded inadequately to biological DMARDs should also apply to sarilumab alone.
|
{'Recommendations': 'Sarilumab, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying antirheumatic drugs (DMARDs), only if:\n\ndisease is severe (a disease activity score [DAS28] of more than 5.1) and\n\nthe company provides sarilumab with the discount agreed in the patient access scheme.\n\nSarilumab, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other\xa0DMARDs, including at least 1\xa0biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthey cannot have rituximab and\n\nthe company provides sarilumab with the discount agreed in the patient access scheme.\n\nSarilumab, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to rituximab and at least 1 biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthe company provides sarilumab with the discount agreed in the patient access scheme.\n\nSarilumab can be used as monotherapy for people who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections 1.1 or 1.2 are met.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. After an initial response within 6\xa0months, withdraw treatment if at least a moderate EULAR response is not maintained.\n\nWhen using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with sarilumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trials showed sarilumab plus methotrexate or conventional\xa0DMARDs to be more effective than methotrexate or conventional\xa0DMARDs for treating moderate to severe active rheumatoid arthritis that has not responded adequately to conventional\xa0DMARDs. The trials also showed that for treating severe active rheumatoid arthritis that has not responded adequately to conventional\xa0DMARDs, sarilumab alone is more effective than adalimumab alone.\n\nBecause there are no trials comparing sarilumab with other biological\xa0DMARDs, the company did an indirect comparison. This showed that sarilumab with conventional\xa0DMARDs (including methotrexate) or alone works as well as most of the biological\xa0DMARDs that NICE has already recommended.\n\nBased on the health-related benefits and costs compared with conventional and biological\xa0DMARDs, sarilumab plus methotrexate or sarilumab alone is recommended as a cost-effective treatment for severe active rheumatoid arthritis, in line with previous recommendations in:\n\nNICE technology appraisal guidance on baricitinib\n\ncertolizumab pegol (after a TNF-alpha inhibitor)\n\nadalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (after conventional\xa0DMARDs)\n\ntocilizumab\n\ntofacitinib\n\ngolimumab (after\xa0DMARDs)\n\nadalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha inhibitor).', 'The technology': "Marketing authorisation\n\nSarilumab (Kevzara, Sanofi) has a marketing authorisation in the UK for the 'treatment of moderately to severely active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs.' Sarilumab can be given as monotherapy or in combination with methotrexate.\n\nRecommended dose and schedule\n\nThe recommended dose of sarilumab is 200\xa0mg administered once every 2\xa0weeks. A reduction in dose from 200\xa0mg once every 2\xa0weeks to 150\xa0mg once every 2\xa0weeks is recommended for management of neutropenia, thrombocytopenia and liver enzyme elevations. Sarilumab is administered subcutaneously using a pre-filled pen or syringe. See the summary of product characteristics for details.\n\nPrice\n\nThe list price\xa0per\xa0pre-filled pen or syringe of 150\xa0mg or 200\xa0mg of sarilumab is £456.13.\n\nThe average cost\xa0per\xa0patient\xa0per\xa0year is estimated at £11,900 based on the list price.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of sarilumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Sanofi and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Sarilumab can be used at 5 different points in the pathway\n\nSarilumab's marketing authorisation and the company submission covers its use at 5\xa0points in the treatment pathway, specifically in adults with:\n\nmoderate, active rheumatoid arthritis that has not responded adequately to conventional disease-modifying antirheumatic drugs (DMARDs)\n\nsevere, active rheumatoid arthritis that has not responded adequately to conventional\xa0DMARDs\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological\xa0DMARDs\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological\xa0DMARDs, when rituximab is contraindicated or withdrawn because of adverse events\n\nsevere, active rheumatoid arthritis that has not responded adequately to rituximab and biological\xa0DMARDs.The committee also noted that the marketing authorisation includes the use of sarilumab alone or with methotrexate.\n\n## NICE technology appraisal guidance exists for these points in the rheumatoid arthritis treatment pathway\n\nNICE currently recommends the use of the biological\xa0DMARDs in its technology appraisal guidance on baricitinib, and adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are tumour necrosis factor (TNF)-alpha inhibitors) and tofacitinib, in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional\xa0DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, less than 3.2 but more than 2.6 indicates mild disease and 2.6 or less indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that adalimumab, baricitinib, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy. The guidance recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price\xa0per\xa0dose) and should only be continued according to EULAR response at 6\xa0months.\n\nFor people with severe rheumatoid arthritis who have already had at least 1\xa0TNF‑alpha inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommend the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol, baricitinib or tofacitinib in combination with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance recommends adalimumab, etanercept, certolizumab pegol, baricitinib or tofacitinib as monotherapy. NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha inhibitors nor rituximab have worked. See the NICE Pathway on rheumatoid arthritis for more details.\n\n## Sarilumab offers an additional treatment option\n\nThe patient experts explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical expert stated that choosing an appropriate treatment depends on disease severity and response to treatment. The clinical expert noted that the disease sometimes does not respond adequately to the first biological DMARD prescribed. When there is not an adequate response the treatment is stopped and the next available treatment in the pathway is prescribed. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological\xa0DMARDs after failure of conventional\xa0DMARDs. The clinical and patient experts highlighted that sarilumab is administered by injection at home, which has major benefits for both patients and the health system. Sarilumab has a longer shelf-life when kept out of the fridge and the clinical expert emphasised that having a treatment that lasts 14 days rather than a number of hours is an important practical factor for people, especially those who travel. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological\xa0DMARDs.\n\n# Subgroups\n\n## The company's subgroups and comparators are appropriate\n\nThe company analysed 5\xa0distinct subgroups in which sarilumab could be used. These were people with:\n\nmoderate, active rheumatoid arthritis that has not responded adequately to conventional\xa0DMARDs\n\nsevere, active rheumatoid arthritis that has not responded adequately to conventional\xa0DMARDs\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological\xa0DMARDs, including at least 1 TNF-alpha inhibitor\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological\xa0DMARDs, when rituximab is contraindicated or withdrawn because of adverse events\n\nsevere, active rheumatoid arthritis that has not responded adequately to rituximab and biological\xa0DMARDs.The relevant comparators varied by subgroup. The committee concluded that it was appropriate to consider the 5\xa0groups separately and that the company had included the appropriate comparators.\n\n# Clinical effectiveness\n\n## The trials are adequate and suitable for decision-making\n\nThe company's clinical evidence came from 5\xa0randomised controlled trials and 1\xa0long-term safety study. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.2. The trials were:\n\nMOBILITY-A, a phase II trial which included people whose disease responded inadequately to methotrexate. Five sarilumab doses (100\xa0mg or 150\xa0mg once weekly and 100\xa0mg, 150\xa0mg or 200\xa0mg once every 2\xa0weeks) were given in combination with methotrexate and the comparator was methotrexate plus placebo. The primary outcome was the proportion of people who had a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week\xa012.\n\nMOBILITY-B, a phase III trial which included people whose disease responded inadequately to methotrexate. Sarilumab 150\xa0mg or 200\xa0mg was given once every 2\xa0weeks in combination with methotrexate and the comparator was methotrexate plus placebo. The primary outcomes were: the proportion of people reaching ACR20 at week\xa024; change in physical function using the Health Assessment Questionnaire Disability Index (HAQ-DI) at week\xa016; and the change in Modified Total Sharp Score (mTSS) at week\xa052.\n\nMONARCH, a phase III trial which included people whose disease responded inadequately or who were intolerant to methotrexate. Sarilumab 200\xa0mg plus placebo was given once every 2\xa0weeks and the comparator was adalimumab plus placebo. The primary outcome was the change from baseline in disease activity score 28 – erythrocyte sedimentation rate (DAS28-ESR) at week\xa024.\n\nTARGET, a phase III trial which included people whose disease responded inadequately or who were intolerant to TNF-alpha inhibitors. Sarilumab 150\xa0mg or 200\xa0mg was given once every 2\xa0weeks in combination with conventional\xa0DMARDs. The comparator was placebo plus conventional\xa0DMARDs. The primary outcomes were the proportion of people reaching ACR20 at week\xa024 and the change in physical function using HAQ-DI at week\xa012.\n\nASCERTAIN, a phase III trial which included people whose disease responded inadequately or who were intolerant to TNF-alpha inhibitors. Sarilumab 150\xa0mg or 200\xa0mg was given once every 2\xa0weeks in combination with conventional\xa0DMARDs. The comparator was tocilizumab 4 to 8\xa0mg plus conventional\xa0DMARDs. The primary outcome was description and number of adverse events.\n\nEXTEND, a phase III open-label extension study which included people whose disease responded inadequately to methotrexate and TNF-alpha inhibitors. The trial assessed sarilumab plus conventional\xa0DMARDs and sarilumab monotherapy. The primary endpoint was safety.The committee concluded that the trials were relevant and adequate for its decision-making.\n\n## Sarilumab plus methotrexate is more clinically effective than placebo plus methotrexate, and sarilumab alone is more clinically effective than adalimumab alone for moderate to severe rheumatoid arthritis which has responded inadequately to conventional\xa0DMARDs\n\nIn MOBILITY-A, sarilumab plus methotrexate showed a statistically significant improvement in ACR20 at 12\xa0weeks compared with placebo plus methotrexate (sarilumab 200\xa0mg 65%, placebo 46%; p=0.0426). In MOBILITY-B, sarilumab plus methotrexate showed a statistically significant improvement in ACR20 at 24\xa0weeks compared with placebo plus methotrexate (sarilumab 200\xa0mg 66%, placebo 33%; p<0.0001). In MONARCH, sarilumab plus placebo showed a statistically significant improvement in ACR20 at 24\xa0weeks compared with adalimumab 40\xa0mg plus placebo (sarilumab 200\xa0mg 72%, adalimumab 40\xa0mg 58%; p=0.0074). The committee concluded that sarilumab plus methotrexate is more clinically effective than placebo plus methotrexate, and that sarilumab alone is more clinically effective than adalimumab alone for moderate to severe rheumatoid arthritis which has responded inadequately to conventional\xa0DMARDs.\n\n## Sarilumab is more clinically effective than conventional\xa0DMARDs for moderate to severe rheumatoid arthritis which has responded inadequately to TNF-alpha inhibitors\n\nThe TARGET trial showed that sarilumab plus methotrexate led to a statistically significant improvement in ACR20 compared with methotrexate at 24\xa0weeks (sarilumab 200\xa0mg 61%, placebo 34%; p<0.001). The company did not report comparative statistics for ASCERTAIN because the trial was powered for safety rather clinical effectiveness. The committee concluded that sarilumab is more clinically effective than conventional\xa0DMARDs for moderate to severe rheumatoid arthritis which has responded inadequately to TNF-alpha inhibitors.\n\n## Sarilumab has an increased rate of adverse events compared with methotrexate\n\nIn the MOBILITY trials the rate of adverse events was higher in the sarilumab 200\xa0mg group (ranging from 65% to 78%) compared with the methotrexate group (ranging from 47% to 62%). In the MONARCH trial, adalimumab and sarilumab had similar adverse event rates (63.6% and 64.1% respectively). The committee concluded that sarilumab plus methotrexate has a slightly higher rate of adverse events compared with methotrexate.\n\n# Indirect comparison\n\n## Network meta-analyses show that sarilumab with conventional\xa0DMARDs or alone works as well as biological\xa0DMARDs\n\nBecause the only direct evidence available on the comparative effectiveness of sarilumab and the biological\xa0DMARDs was with adalimumab, the company did a network meta-analyses. The company did separate analyses for patients whose disease responded inadequately to either conventional or biological\xa0DMARDs, using ACR20/50/70 score, HAQ-DI, European League Against Rheumatism (EULAR) responses, DAS28 remission, mTSS, serious infections and serious adverse events. In the conventional DMARD group the analyses were further split into combination therapy and monotherapy. EULAR responses were not identified for all the relevant comparators in the NICE scope because of a lack of reporting in the trials. The company transformed ACR responses into EULAR responses to inform treatment effectiveness in the economic model (section 3.13). At 24\xa0weeks' follow-up, for patients whose disease responded inadequately to conventional\xa0DMARDs, the network meta-analysis showed:\n\nsarilumab 200\xa0mg plus conventional\xa0DMARDs gave better ACR20/50/70 response rates than conventional\xa0DMARDs\n\nsarilumab 200\xa0mg plus conventional\xa0DMARDs gave similar ACR20/50/70 response rates to the biological\xa0DMARDs\n\nsarilumab 200\xa0mg alone gave better ACR20/50/70 response rates than conventional\xa0DMARDs alone\n\nsarilumab 200\xa0mg alone gave similar ACR20/50/70 response rates to biological\xa0DMARDs alone.At 24\xa0weeks' follow-up, for patients whose disease inadequately responded to biological\xa0DMARDs, the network meta-analysis showed:\n\nsarilumab 200\xa0mg plus conventional\xa0DMARDs gave better ACR20/50/70 response rates than conventional\xa0DMARDs\n\nsarilumab 200\xa0mg plus conventional\xa0DMARDs gave similar ACR20/50/70 response rates to the biological\xa0DMARDs plus conventional\xa0DMARDs.The committee concluded that sarilumab works as well as biological\xa0DMARDs in moderate to severe rheumatoid arthritis that has responded inadequately to conventional or biological\xa0DMARDs.\n\n## Sarilumab monotherapy may have similar clinical effectiveness to sarilumab plus conventional\xa0DMARDs\n\nThe company was not able to identify any evidence on sarilumab monotherapy in patients whose disease responded inadequately to biological\xa0DMARDs. The company assumed that the efficacy of sarilumab monotherapy would be equal to that of sarilumab in combination with conventional\xa0DMARDs. The ERG noted that this assumption was reasonable but recognised the considerable uncertainty caused by the absence of direct data. The committee agreed that, in the absence of direct evidence, it is reasonable to assume sarilumab monotherapy has similar effectiveness to sarilumab plus conventional\xa0DMARDs in people whose disease has responded inadequately to biological\xa0DMARDs.\n\n## The company's network meta-analysis is suitable for decision-making\n\nThe ERG stated that there was some uncertainty in the methods used by the company in the network meta-analysis. Following a request by the ERG at the clarification stage, the company provided updated results using the ERG's preferred assumptions which had been used by the assessment group in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis for patients whose disease responded inadequately to conventional\xa0DMARDs. The company noted that the results of the new network meta-analysis were comparable to those of its original analyses and that the conclusion that sarilumab is comparable to other biological\xa0DMARDs was unchanged. The ERG noted that the statistically significant result for sarilumab compared with other biological DMARD treatments (both as combination therapy and monotherapy) should be treated with caution as it may be a consequence of underestimating the uncertainty in treatment effects resulting from the use of a fixed-effects model. The committee reviewed both analyses and concluded that the methods used by the company in the network meta-analysis were in line with previous NICE technology appraisal guidance, and that the network meta-analysis was therefore suitable for decision-making.\n\n# Cost effectiveness\n\n## The company's model structure is appropriate for decision-making\n\nThe company used a patient-level Markov model for its economic evaluation. The model categorised patients based on their EULAR response (good, moderate or no response) at 6\xa0months. Response rates were based on the company's network meta-analysis which transformed ACR 20/50/70 response to EULAR response. The company analysed cost effectiveness for each of the subgroups described in section 3.5. The ERG stated that the model was not an individual patient-based discrete event simulation as used by the assessment group in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The committee noted the difference between the company's model structure and the structure accepted in the previous guidance but accepted that the company's model was appropriate for its decision-making.\n\n## The company's method for calculating utility is appropriate\n\nThe company stated that that EQ-5D utility data were not available for all comparators across all patient populations. Following a request by the ERG at the clarification stage, the company used Hernandez et al. (2013) to estimate EQ-5D data based on patient characteristics (HAQ score, pain on a visual analogue scale, age and sex). The ERG stated that Hernandez et al. was used in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The committee concluded it was appropriate for decision-making.\n\n## The company's methods for calculating costs are appropriate\n\nThe company's model included costs associated with drug acquisition, drug administration and monitoring, and hospitalisation. The model treatment sequences included a TNF-alpha inhibitor bundle in the base case. The TNF-alpha inhibitor bundle used the pooled efficacy of etanercept, an etanercept biosimilar, adalimumab, infliximab, an infliximab biosimilar, golimumab and certolizumab pegol with the price weighted according to the estimated market share of each. The company did not include the cost of biosimilars for rituximab or adalimumab, but stated that at the time of submission the rituximab biosimilar was not available and the adalimumab biosimilar had not received its marketing authorisation. The ERG stated that in the company's original base case the incremental cost-effectiveness ratio (ICER) for sarilumab compared with rituximab was more than £100,000\xa0per\xa0quality-adjusted life year (QALY) gained, and so reducing the price of rituximab would not change the conclusion for this population. Sarilumab and several of the other biological\xa0DMARDs have patient access schemes. The company had incorporated the patient access scheme prices for sarilumab, certolizumab pegol and golimumab in the model, but not the confidential patient access schemes for abatacept and tocilizumab. The committee concluded that the costs used in the company's model were appropriate.\n\n## The company's updated treatment sequences are acceptable\n\nDuring the clarification stage the ERG requested that the company update the sequences in which treatments are given for each subgroup to match those agreed in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The company provided updated sequences, but the ERG noted that in the group of patients whose disease has responded inadequately to biological\xa0DMARDs, a second line of biological treatment had been added in error. This error was corrected in the ERG's additional analyses and the committee accepted this.\n\n## The ERG's changes to how patients progress from treatment for moderate disease to treatment for severe disease are appropriate\n\nFollowing a request by the ERG at the clarification stage, the company updated the model to allow patients treated for moderate disease to progress to treatment for severe disease. The ERG explained that this progression, although not used in previous NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis, was requested because it provided a more accurate representation of clinical practice. The company updated its analyses but the ERG identified 2 issues with the company's methods:\n\nIn the company's model patients went through a moderate treatment sequence first and then transitioned to the severe sequences only if their HAQ-DI score was above a certain threshold. The HAQ-DI score was calculated through a regression which was related to a DAS28 score of 5.1. The ERG noted that changes in HAQ-DI and DAS28 values should have been calculated instead of using absolute values because the relationship between them is not linear.\n\nPatients should have progressed to the severe sequences when their DAS28 score increased above 5.1, without waiting until they reached the end of the moderate sequence.The ERG corrected these points in its additional analyses. The committee considered the changes made by the ERG and concluded that they were appropriate.\n\n## There were some concerns with how response to treatment was implemented\n\nIn the company's model patients were assessed for response to treatment at 6\xa0months. Patients who had a moderate or good EULAR response were assumed to have an associated reduction in HAQ-DI score, which was assumed to be independent of treatment, and the treatment was stopped if the patient did not have at least moderate EULAR response at 6\xa0months. The ERG stated that the company had used a linear approach to HAQ-DI score progression, which would have had a favourable effect for sarilumab when compared with conventional\xa0DMARDs. It explained that a non-linear method was more appropriate and had been accepted in previous NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The ERG had used this method in its additional analyses. The committee concluded that the non-linear approach to HAQ-DI progression was appropriate and therefore accepted the ERG's additional analyses.\n\n# Cost-effectiveness results\n\n## Sarilumab with methotrexate is not cost effective for moderate disease after conventional\xa0DMARDs\n\nIn the ERG's additional analysis for the population with moderate active rheumatoid arthritis that has responded inadequately to conventional\xa0DMARDs, the ICER for sarilumab compared with conventional\xa0DMARDs was £63,438\xa0per\xa0QALY gained. The ERG also calculated new ICERs using the confidential patient access scheme prices for abatacept and intravenous tocilizumab; this comparison produced similar estimates of cost effectiveness. The committee considered that sarilumab plus conventional\xa0DMARDs was not cost effective in people with moderate rheumatoid arthritis whose disease has responded inadequately to conventional\xa0DMARDs.\n\n## Sarilumab with methotrexate is cost effective for severe active rheumatoid arthritis after conventional\xa0DMARDs\n\nIn the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to conventional\xa0DMARDs, tocilizumab (intravenous and subcutaneous) was dominated by sarilumab plus conventional\xa0DMARDs (that is, sarilumab was both less costly and more effective). The ICERs for the TNF-alpha inhibitor bundle plus methotrexate and abatacept plus methotrexate compared with sarilumab plus methotrexate were both over £100,000\xa0per\xa0QALY gained. The ERG also calculated ICERs using the confidential patient access scheme prices for abatacept and intravenous tocilizumab, which produced very similar estimates of cost effectiveness. The committee therefore recommended sarilumab plus conventional\xa0DMARDs for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional\xa0DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.\n\n## Sarilumab with methotrexate is not cost effective for severe disease after biological\xa0DMARDs if rituximab is a treatment option\n\nIn the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to biological\xa0DMARDs for whom rituximab is a treatment option, the ICER for a sequence where sarilumab plus conventional\xa0DMARDs replaced rituximab plus conventional\xa0DMARDs was over £100,000\xa0per\xa0QALY gained. The committee concluded that sarilumab plus conventional\xa0DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological\xa0DMARDs if rituximab is a treatment option.\n\n## Sarilumab with methotrexate is cost effective for severe disease after biological\xa0DMARDs if rituximab is not a treatment option\n\nIn the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to biological\xa0DMARDs for whom rituximab is contraindicated, the incremental analysis for sarilumab compared with the TNF-alpha inhibitor bundle resulted in an ICER of £34,979\xa0per\xa0QALY gained. Subcutaneous abatacept plus methotrexate was dominated by sarilumab plus methotrexate (that is, sarilumab was both less costly and more effective) and the ICERs for tocilizumab (intravenous and subcutaneous) plus methotrexate compared with sarilumab plus methotrexate were over £100,000\xa0per\xa0QALY gained. The ERG updated its additional analysis using the confidential patient access scheme prices, which produced similar estimates of cost effectiveness. The committee therefore recommended sarilumab plus conventional\xa0DMARDs for people with severe rheumatoid arthritis whose disease has responded inadequately to biological\xa0DMARDs and for whom rituximab is not a treatment option.\n\n## Sarilumab with methotrexate is cost effective for severe disease after rituximab and other biological\xa0DMARDs\n\nIn the ERG's additional analysis for the population with severe rheumatoid arthritis population that has not responded adequately to rituximab and other biological\xa0DMARDs, the ICER for intravenous or subcutaneous tocilizumab plus methotrexate compared with sarilumab plus methotrexate was over £100,000\xa0per\xa0QALY gained. The ERG also updated its additional analysis using the confidential patient access scheme prices, which produced similar estimates of cost effectiveness. The committee therefore recommended sarilumab plus conventional\xa0DMARDs for people with severe rheumatoid arthritis whose disease has not responded adequately to rituximab and other biological\xa0DMARDs.\n\n## Sarilumab monotherapy is cost effective for severe active rheumatoid arthritis after conventional\xa0DMARDs if methotrexate is not suitable\n\nIn the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to conventional\xa0DMARDs for whom methotrexate is contraindicated, sarilumab alone compared with a TNF-alpha inhibitor bundle alone in the incremental analysis had an ICER of £34,422\xa0per\xa0QALY gained. In the incremental analysis subcutaneous tocilizumab was extendedly dominated by sarilumab alone (that is, the ICER for subcutaneous tocilizumab was higher than the next more effective alternative, which was intravenous tocilizumab). The ICER for intravenous tocilizumab compared with sarilumab was over £100,000\xa0per\xa0QALY gained. The ERG updated this additional analysis using the confidential comparator patient access scheme prices, which produced similar estimates of cost effectiveness. The committee concluded that sarilumab monotherapy is cost effective for severe active rheumatoid arthritis after conventional\xa0DMARDs if methotrexate is not suitable.\n\n## The recommendation for people whose condition has responded inadequately to biological\xa0DMARDs also applies to sarilumab monotherapy\n\nIn the ERG's additional analysis for the population with severe rheumatoid arthritis that has responded inadequately to biological\xa0DMARDs for whom methotrexate is contraindicated, the ICER for sarilumab compared with the TNF-alpha inhibitor bundle was £31,433\xa0per\xa0QALY gained. The ERG stated that this analysis was subject to considerable uncertainty because the clinical effectiveness of sarilumab monotherapy was assumed to be equal to sarilumab in combination with conventional\xa0DMARDs. The committee acknowledged its decision that in the absence of direct evidence sarilumab monotherapy may have a similar clinical effectiveness to sarilumab plus conventional\xa0DMARDs in people whose disease has responded inadequately to biological\xa0DMARDs. The committee concluded that its recommendations for sarilumab plus conventional\xa0DMARDs in people whose disease has responded inadequately to biological\xa0DMARDs should also apply to sarilumab alone."}
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https://www.nice.org.uk/guidance/ta485
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Evidence-based recommendations on sarilumab (Kevzara) for treating moderate to severe rheumatoid arthritis in adults.
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c002c2e10d36bf798293c6383ae55196f9d3caf4
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nice
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Aflibercept for treating choroidal neovascularisation
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Aflibercept for treating choroidal neovascularisation
Evidence-based recommendations on aflibercept (Eylea) for treating choroidal neovascularisation in adults.
# Recommendations
Aflibercept is recommended, within its marketing authorisation, as an option for treating visual impairment because of myopic choroidal neovascularisation in adults, only if the company provides aflibercept with the discount agreed in the patient access scheme.
If patients and their clinicians consider both aflibercept and ranibizumab to be suitable treatments, the least costly should be used, taking into account anticipated administration costs, dosage and price per dose.
Why the committee made these recommendations
Ranibizumab is already recommended by NICE for treating choroidal neovascularisation. An indirect comparison of aflibercept and ranibizumab shows that both drugs provide similar overall health benefits. The total costs of aflibercept are the same as or less than those of ranibizumab.
Because it is has similar costs and overall health benefits to ranibizumab, aflibercept is also recommended as a cost-effective option for treating choroidal neovascularisation.# The technology
Aflibercept (Eylea, Bayer)
Marketing authorisation
Aflibercept has a UK marketing authorisation for 'treating visual impairment due to myopic choroidal neovascularisation in adults'.
Recommended dose and schedule
The recommended dose is a single intravitreal injection of 2 mg aflibercept (equivalent to 50 microlitres).
Extra doses may be used if visual or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease. For full details, see the summary of product characteristics.
Price
The list price of aflibercept 40 mg/mL is £816 per 0.1‑mL vial (excluding VAT; British national formulary online ).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of aflibercept, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Aflibercept compared with ranibizumab
## The comparison of aflibercept and ranibizumab is appropriate
NICE has already produced technology appraisal guidance on ranibizumab in this indication. The company presented a cost comparison case, in which it proposed that:
the overall health benefits associated with aflibercept are similar to or greater than those associated with ranibizumab
the total costs associated with aflibercept are similar to or lower than those associated with ranibizumab.The committee understood that treatment with ranibizumab is the standard of care for choroidal neovascularisation in the NHS. The committee concluded that it was appropriate for the company to compare aflibercept with ranibizumab.
# Clinical effectiveness
## Aflibercept and ranibizumab are similarly effective in treating choroidal neovascularisation
The company presented an indirect treatment comparison comparing mean change in best corrected visual acuity with aflibercept and ranibizumab at 3 months. This used data from 3 trials: the MYRROR and RADIANCE randomised controlled trials of aflibercept and ranibizumab respectively, which were linked by the VIP trial of verteporfin photodynamic therapy and placebo. The committee was concerned that VIP was relatively old and included neither aflibercept nor ranibizumab. It was also concerned that the indirect comparison was based on a small number of patients, because there were only 31 patients in the placebo arm of MYRROR. The committee noted that the difference in retreatment criteria between the trials made it difficult to compare them. Retreatment in MYRROR was guided by a combination of both disease activity and visual acuity, whereas in RADIANCE there were 2 separate ranibizumab retreatment arms, 1 based on visual acuity and the other based on disease activity. Mean change in best corrected visual acuity for aflibercept compared with ranibizumab was 1.34 letters using the visual acuity retreatment arm (95% confidence interval –5.35 to 8.00) and 0.94 using the disease activity retreatment arm (95% CI –5.67 to 7.56). The committee understood from the clinical expert and patient and professional organisations that in clinical practice, aflibercept is considered to be slightly more effective than ranibizumab. It concluded that despite uncertainties in the indirect treatment comparison, aflibercept is as effective as ranibizumab in treating choroidal neovascularisation.
# Adverse events
## Adverse events with aflibercept are likely to be similar to those with ranibizumab
The committee understood that the only direct evidence comparing the rates of adverse events with aflibercept and ranibizumab was from a clinical trial in wet age-related macular degeneration, which showed that they were similar. The ERG confirmed that the types and rates of adverse events in MYRROR and RADIANCE also seem to be similar, although it is not possible to link the trials together for an indirect comparison. The committee concluded that the adverse events associated with aflibercept were likely to be similar to those associated with ranibizumab when treating choroidal neovascularisation.
# Overall health benefits
## Aflibercept provides similar overall health benefits to ranibizumab
The committee concluded that because both the gain in best corrected visual acuity and adverse events with aflibercept and ranibizumab were similar, the treatments were also likely to provide similar overall health benefits.
# Resource use
## It is appropriate to assume the same number of aflibercept and ranibizumab injections
The company assumed the same number of aflibercept and ranibizumab injections in the first year, based on the mean number in the MYRROR trial. Its rationale was that the confidence intervals for the mean number of injections in MYRROR and the 2 arms of RADIANCE overlapped, and that market research suggested that the retreatment criteria in MYRROR best reflected clinical practice in England. The ERG explained that the retreatment criteria in MYRROR were more similar to the disease activity retreatment arm of RADIANCE than the visual acuity retreatment arm. The committee was concerned that because the mean number of injections in the disease activity retreatment arm of RADIANCE was lower than the mean number of injections in MYRROR (3.5 compared with 4.2), assuming equal injection frequency may underestimate the costs associated with aflibercept. However, it noted comments from the clinical expert and patient and professional organisations that it takes the same number of injections with both aflibercept and ranibizumab to stabilise the disease. Some comments suggested that fewer injections are needed with aflibercept compared with ranibizumab. Having considered the evidence, the committee agreed that it was appropriate to assume the same number of injections with both aflibercept and ranibizumab.
# Cost comparison results
## Aflibercept meets the criteria for a successful cost comparison
The committee considered the company's cost comparison, which assumed equal injection frequency and included all patient access schemes. The results showed that the total costs associated with aflibercept are similar to or lower than those associated with ranibizumab (the exact results cannot be reported here because the discounts are confidential). The committee concluded that the criteria for a positive cost comparison were met, because:
the overall health benefits associated with aflibercept were similar to or greater than the overall health benefits associated with ranibizumab
the total costs associated with aflibercept were similar to or lower than the total costs associated with ranibizumab.The committee therefore recommended aflibercept as a cost-effective use of NHS resources for treating visual impairment because of myopic choroidal neovascularisation in adults.
|
{'Recommendations': 'Aflibercept is recommended, within its marketing authorisation, as an option for treating visual impairment because of myopic choroidal neovascularisation in adults, only if the company provides aflibercept with the discount agreed in the patient access scheme.\n\nIf patients and their clinicians consider both aflibercept and ranibizumab to be suitable treatments, the least costly should be used, taking into account anticipated administration costs, dosage and price per dose.\n\nWhy the committee made these recommendations\n\nRanibizumab is already recommended by NICE for treating choroidal neovascularisation. An indirect comparison of aflibercept and ranibizumab shows that both drugs provide similar overall health benefits. The total costs of aflibercept are the same as or less than those of ranibizumab.\n\nBecause it is has similar costs and overall health benefits to ranibizumab, aflibercept is also recommended as a cost-effective option for treating choroidal neovascularisation.', 'The technology': "Aflibercept (Eylea, Bayer)\n\nMarketing authorisation\n\nAflibercept has a UK marketing authorisation for 'treating visual impairment due to myopic choroidal neovascularisation in adults'.\n\nRecommended dose and schedule\n\nThe recommended dose is a single intravitreal injection of 2\xa0mg aflibercept (equivalent to 50 microlitres).\n\nExtra doses may be used if visual or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease. For full details, see the summary of product characteristics.\n\nPrice\n\nThe list price of aflibercept 40\xa0mg/mL is £816 per 0.1‑mL vial (excluding VAT; British national formulary [BNF] online [accessed July 2017]).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of aflibercept, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Bayer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Aflibercept compared with ranibizumab\n\n## The comparison of aflibercept and ranibizumab is appropriate\n\nNICE has already produced technology appraisal guidance on ranibizumab in this indication. The company presented a cost comparison case, in which it proposed that:\n\nthe overall health benefits associated with aflibercept are similar to or greater than those associated with ranibizumab\n\nthe total costs associated with aflibercept are similar to or lower than those associated with ranibizumab.The committee understood that treatment with ranibizumab is the standard of care for choroidal neovascularisation in the NHS. The committee concluded that it was appropriate for the company to compare aflibercept with ranibizumab.\n\n# Clinical effectiveness\n\n## Aflibercept and ranibizumab are similarly effective in treating choroidal neovascularisation\n\nThe company presented an indirect treatment comparison comparing mean change in best corrected visual acuity with aflibercept and ranibizumab at 3 months. This used data from 3 trials: the MYRROR and RADIANCE randomised controlled trials of aflibercept and ranibizumab respectively, which were linked by the VIP trial of verteporfin photodynamic therapy and placebo. The committee was concerned that VIP was relatively old and included neither aflibercept nor ranibizumab. It was also concerned that the indirect comparison was based on a small number of patients, because there were only 31 patients in the placebo arm of MYRROR. The committee noted that the difference in retreatment criteria between the trials made it difficult to compare them. Retreatment in MYRROR was guided by a combination of both disease activity and visual acuity, whereas in RADIANCE there were 2 separate ranibizumab retreatment arms, 1 based on visual acuity and the other based on disease activity. Mean change in best corrected visual acuity for aflibercept compared with ranibizumab was 1.34 letters using the visual acuity retreatment arm (95% confidence interval [CI] –5.35\xa0to\xa08.00) and 0.94 using the disease activity retreatment arm (95% CI –5.67\xa0to\xa07.56). The committee understood from the clinical expert and patient and professional organisations that in clinical practice, aflibercept is considered to be slightly more effective than ranibizumab. It concluded that despite uncertainties in the indirect treatment comparison, aflibercept is as effective as ranibizumab in treating choroidal neovascularisation.\n\n# Adverse events\n\n## Adverse events with aflibercept are likely to be similar to those with ranibizumab\n\nThe committee understood that the only direct evidence comparing the rates of adverse events with aflibercept and ranibizumab was from a clinical trial in wet age-related macular degeneration, which showed that they were similar. The ERG confirmed that the types and rates of adverse events in MYRROR and RADIANCE also seem to be similar, although it is not possible to link the trials together for an indirect comparison. The committee concluded that the adverse events associated with aflibercept were likely to be similar to those associated with ranibizumab when treating choroidal neovascularisation.\n\n# Overall health benefits\n\n## Aflibercept provides similar overall health benefits to ranibizumab\n\nThe committee concluded that because both the gain in best corrected visual acuity and adverse events with aflibercept and ranibizumab were similar, the treatments were also likely to provide similar overall health benefits.\n\n# Resource use\n\n## It is appropriate to assume the same number of aflibercept and ranibizumab injections\n\nThe company assumed the same number of aflibercept and ranibizumab injections in the first year, based on the mean number in the MYRROR trial. Its rationale was that the confidence intervals for the mean number of injections in MYRROR and the 2 arms of RADIANCE overlapped, and that market research suggested that the retreatment criteria in MYRROR best reflected clinical practice in England. The ERG explained that the retreatment criteria in MYRROR were more similar to the disease activity retreatment arm of RADIANCE than the visual acuity retreatment arm. The committee was concerned that because the mean number of injections in the disease activity retreatment arm of RADIANCE was lower than the mean number of injections in MYRROR (3.5 compared with 4.2), assuming equal injection frequency may underestimate the costs associated with aflibercept. However, it noted comments from the clinical expert and patient and professional organisations that it takes the same number of injections with both aflibercept and ranibizumab to stabilise the disease. Some comments suggested that fewer injections are needed with aflibercept compared with ranibizumab. Having considered the evidence, the committee agreed that it was appropriate to assume the same number of injections with both aflibercept and ranibizumab.\n\n# Cost comparison results\n\n## Aflibercept meets the criteria for a successful cost comparison\n\nThe committee considered the company's cost comparison, which assumed equal injection frequency and included all patient access schemes. The results showed that the total costs associated with aflibercept are similar to or lower than those associated with ranibizumab (the exact results cannot be reported here because the discounts are confidential). The committee concluded that the criteria for a positive cost comparison were met, because:\n\nthe overall health benefits associated with aflibercept were similar to or greater than the overall health benefits associated with ranibizumab\n\nthe total costs associated with aflibercept were similar to or lower than the total costs associated with ranibizumab.The committee therefore recommended aflibercept as a cost-effective use of NHS resources for treating visual impairment because of myopic choroidal neovascularisation in adults."}
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https://www.nice.org.uk/guidance/ta486
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Evidence-based recommendations on aflibercept (Eylea) for treating choroidal neovascularisation in adults.
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0a1876b4e55b41fd288ad8784e1ab2b4646288e7
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nice
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Sinusitis (acute): antimicrobial prescribing
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Sinusitis (acute): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute sinusitis. It aims to limit antibiotic use and reduce antimicrobial resistance. Acute sinusitis is usually caused by a virus, lasts for about 2 to 3 weeks, and most people get better without antibiotics. Withholding antibiotics rarely leads to complications.
# Background
Acute sinusitis (also known as rhinosinusitis) is self-limiting and usually triggered by a viral infection of the upper respiratory tract (for example, a common cold).
Only about 2% of cases are complicated by bacterial infection, but it is very difficult to distinguish these.
Symptoms can last for 2 to 3 weeks – most people will get better within this time without treatment, regardless of cause (bacteria or virus).
Antibiotics are not needed for most people. The number of people improving with antibiotics is similar to the number getting adverse effects, such as diarrhoea.
Complications of acute sinusitis are rare (about 2.5 to 4.3 per million people per year). Withholding antibiotics is unlikely to lead to complications.
Previous antibiotic use may lead to resistant organisms if the same antibiotic is used again.# Recommendations
# Managing acute sinusitis
## People presenting with symptoms for around 10 days or less
Do not offer an antibiotic prescription.
Give advice about:
the usual course of acute sinusitis (2 to 3 weeks)
an antibiotic not being needed
managing symptoms, including fever, with self-care (see the recommendations on self-care)
seeking medical help if symptoms worsen rapidly or significantly, do not improve after 3 weeks, or they become systemically very unwell.
Reassess if symptoms worsen rapidly or significantly, taking account of:
alternative diagnoses such as a dental infection
any symptoms or signs suggesting a more serious illness or condition.
See symptoms and signs of acute sinusitis and the evidence and committee discussion on no antibiotic.
## People presenting with symptoms for around 10 days or more with no improvement
Consider prescribing a high-dose nasal corticosteroid for 14 days for adults and children aged 12 years and over, being aware that nasal corticosteroids:
may improve symptoms but are not likely to affect how long they last
could cause systemic effects, particularly in people already taking another corticosteroid
may be difficult for people to use correctly.High-dose nasal corticosteroids used in the studies were mometasone 200 micrograms twice a day and fluticasone 110 micrograms twice a day. This is an off-label use of nasal corticosteroids See NICE's information on prescribing medicines.See the evidence and committee discussion on nasal corticosteroids.
Consider no antibiotic prescription or a back-up antibiotic prescription (see the recommendations on choice of antibiotic), taking account of:
evidence that antibiotics make little difference to how long symptoms last, or the proportion of people with improved symptoms
withholding antibiotics is unlikely to lead to complications
possible adverse effects, particularly diarrhoea and nausea
factors that might make a bacterial cause more likely (see symptoms and signs).
When a back-up antibiotic prescription is given, give verbal and written advice about:
managing symptoms, including fever, with self-care (see the recommendations on self-care)
an antibiotic not being needed immediately
using the back-up prescription if symptoms do not improve within 7 days or if they worsen rapidly or significantly at any time
seeking medical help if symptoms worsen rapidly or significantly despite taking the antibiotic, or the antibiotic has been stopped because it was not tolerated.
Reassess if symptoms worsen rapidly or significantly despite taking treatment, taking account of:
alternative diagnoses such as a dental infection
any signs or symptoms suggesting a more serious illness or condition
previous antibiotic use, which may lead to resistant organisms.
See the evidence and committee discussion on back-up antibiotics.
## People presenting at any time who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high risk of complications
Offer an immediate antibiotic prescription (see the recommendations on choice of antibiotic).
Refer people to hospital if they have symptoms and signs of acute sinusitis associated with any of the following:
a severe systemic infection (see the NICE guideline on sepsis)
intraorbital or periorbital complications, including periorbital oedema or cellulitis, a displaced eyeball, double vision, ophthalmoplegia, or newly reduced visual acuity
intracranial complications, including swelling over the frontal bone, symptoms or signs of meningitis, severe frontal headache, or focal neurological signs.
See the evidence and committee discussion on choice of antibiotic.
# Choice of antibiotic
When prescribing antibiotics for acute sinusitis:
follow the recommendations in table 1 for adults aged 18 years and over
follow the recommendations in table 2 for children and young people under 18 years.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic
Phenoxymethylpenicillin:
mg four times a day for 5 days
First choice if systemically very unwell, symptoms and signs of a more serious illness or condition, or at high risk of complications
Co‑amoxiclav:
/125 mg three times a day for 5 days
Alternative first choices for penicillin allergy or intolerance (for people who are not pregnant)
Doxycycline:
mg on first day, then 100 mg once a day for 4 days (5-day course in total)
Clarithromycin:
mg twice a day for 5 days
Alternative first choice for penicillin allergy in pregnancy
Erythromycin:
mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
Second-choice oral antibiotic (worsening symptoms on first choice taken for at least 2 to 3 days)
Co‑amoxiclav:
/125 mg three times a day for 5 days
Alternative second choice for penicillin allergy or intolerance, or worsening symptoms on second choice taken for at least 2 to 3 days
Consult a local microbiologist
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breast-feeding.
If co‑amoxiclav has been used first choice, consult a local microbiologist for advice on second choice.
Treatment
Antibiotic, dosage and course length
First-choice oral antibiotic
Phenoxymethylpenicillin:
months to 11 months, 62.5 mg four times a day for 5 days
year to 5 years, 125 mg four times a day for 5 days
years to 11 years, 250 mg four times a day for 5 days
years to 17 years, 500 mg four times a day for 5 days
First choice if systemically very unwell, symptoms and signs of a more serious illness or condition, or at high risk of complications
Co‑amoxiclav:
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day for 5 days
year to 5 years, 5 ml of 125/31 suspension three times a day or 0.25 ml/kg of 125/31 suspension three times a day for 5 days
years to 11 years, 5 ml of 250/62 suspension three times a day or 0.15 ml/kg of 250/62 suspension three times a day for 5 days
years to 17 years, 250/125 mg three times a day or 500/125 mg three times a day for 5 days
Alternative first choices for penicillin allergy or intolerance (for people who are not pregnant)
Clarithromycin:
Under 8 kg, 7.5 mg/kg twice a day for 5 days
kg to 11 kg, 62.5 mg twice a day for 5 days
kg to 19 kg, 125 mg twice a day for 5 days
kg to 29 kg, 187.5 mg twice a day for 5 days
kg to 40 kg, 250 mg twice a day for 5 days
years to 17 years, 250 mg twice a day or 500 mg twice a day for 5 days
Doxycycline:
years to 17 years, 200 mg on first day, then 100 mg once a day for 4 days (5-day course in total)
Doxycycline is contraindicated in children under 12 years
Alternative first choice for penicillin allergy in pregnancy
Erythromycin:
years to 17 years, 250 mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
Second-choice oral antibiotic (worsening symptoms on first choice taken for at least 2 to 3 days)
Co-amoxiclav:
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day for 5 days
year to 5 years, 5 ml of 125/31 suspension three times a day or 0.25 ml/kg of 125/31 suspension three times a day for 5 days
years to 11 years, 5 ml of 250/62 suspension three times a day or 0.15 ml/kg of 250/62 suspension three times a day for 5 days
years to 17 years, 250/125 mg three times a day or 500/125 mg three times a day for 5 days
Alternative second choice for penicillin allergy or intolerance, or worsening symptoms on second choice taken for at least 2 to 3 days
Consult a local microbiologist
See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment.
The age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.
If co‑amoxiclav used as first choice, consult a local microbiologist for advice on second choice.
See the evidence and committee discussion on choice of antibiotic and antibiotic course length.
# Self-care
Consider paracetamol or ibuprofen for pain or fever (assess and manage children aged under 5 who present with fever as outlined in the NICE guideline on fever in under 5s).
Explain that some people may wish to try nasal saline or nasal decongestants, although there is not enough evidence to show that they help to relieve nasal congestion.
Explain that no evidence was found for using oral decongestants, antihistamines, mucolytics, steam inhalation, or warm face packs.
See the evidence and committee discussion on self-care.# Symptoms and signs
# Common symptoms and signs
Adults with acute sinusitis usually present with:
nasal blockage or congestion
nasal discharge
dental or facial pain or pressure
reduction or loss of the sense of smell.
Children (particularly young children) often present with non‑specific symptoms in the upper respiratory tract. Symptoms of acute sinusitis in children may include the following, but these can be present for many upper respiratory tract infections:
nasal blockage or congestion
discoloured nasal discharge
cough during the day or at night.
# Factors that might make a bacterial cause more likely
It is difficult to distinguish viral and bacterial acute sinusitis. A bacterial cause may be more likely if several of the following are present:
symptoms for more than 10 days
discoloured or purulent nasal discharge
severe localised unilateral pain (particularly pain over teeth and jaw)
fever
marked deterioration after an initial milder phase.# Summary of the evidence
# Self-care
## Nasal saline
Nasal saline for up to 28 days did not reduce the time to resolution of symptoms in adults. This was based on very low quality evidence from a systematic review of randomised controlled trials (RCTs) (King et al. 2015). In the largest trial, in children aged 6 to 10 years, there were statistically significant reductions in nasal symptom scores, but these may not be clinically important (low quality evidence).
Nasal saline irrigation is safe but may cause minor adverse effects, such as irritation (low to moderate quality evidence).
## Nasal decongestants
Nasal decongestants offered no benefit in children compared with either placebo or mineral salts. This was based on a systematic review of RCTs (Smith et al. 2013; low quality evidence). No systematic reviews or RCTs of nasal decongestants in adults were identified.
Nasal decongestants containing sympathomimetics can cause rebound congestion and should not be used for longer than 7 days (BNF information on the nose).
## Other interventions
No systematic reviews or RCTs of steam inhalation or applying warm face packs were identified.
No systematic reviews or RCTs of paracetamol or ibuprofen were identified. However, these medicines have a well-established efficacy and safety profile for managing pain and fever.
No systematic reviews or RCTs of oral decongestants, antihistamines or mucolytics were identified.
Based on experience, the committee agreed that it was reasonable to consider paracetamol or ibuprofen for acute sinusitis despite no evidence for their use in this condition. This is because these medicines have well-established efficacy and safety profiles for managing pain and fever generally.
Based on experience, the committee agreed that people with acute sinusitis may wish to try self-care with nasal saline or nasal decongestants to relieve nasal congestion, but it should be explained that there is not enough evidence to recommend these. It should be explained to people that no evidence was found for using oral decongestants, antihistamines, mucolytics, steam inhalation or warm face packs in acute sinusitis.
# Nasal corticosteroids
High-dose nasal corticosteroids (equivalent to mometasone 400 micrograms a day) for 14 to 21 days (with or without an antibiotic) produced a statistically significant improvement in symptoms in adults and children aged 12 years and over compared with placebo. This was based on high quality evidence from a systematic review of RCTs (Zalmanovici Trestioreanu et al. 2013) and moderate quality evidence from 1 additional RCT (Keith at al. 2012). However, it is not clear whether this statistically significant reduction in symptom score is clinically important. The number needed to treat (NNT) was 17 for 1 additional person with acute sinusitis to have improved or resolved symptoms with a high‑dose nasal corticosteroid compared with placebo. Lower doses (equivalent to mometasone 200 micrograms a day) were not significantly better than placebo.
Mometasone 200 micrograms twice a day produced a statistically significant reduction in symptoms compared with mometasone 200 micrograms once a day and compared with amoxicillin 500 mg three times a day for 10 days. This was based on 1 RCT (Meltzer at al. 2005), which excluded people with suspected acute bacterial sinusitis and compared nasal corticosteroids alone with antibiotics (moderate quality evidence).
Systemic effects (mineralocorticoid and glucocorticoid) may occur with nasal corticosteroids, including a range of psychological or behavioural effects (particularly in children) (Drug Safety Update, September 2010).
Adverse events for nasal corticosteroids in the studies were not significantly different from placebo (low to moderate quality evidence).
The steroid burden of nasal corticosteroids needs to be considered in people already taking oral or inhaled corticosteroids (Ekins-Daukes et al. 2002), particularly in children due to systemic effects.
## Committee discussion on nasal corticosteroids
The committee agreed, based on the evidence, that a high-dose nasal corticosteroid could be considered for adults and children aged 12 years and over presenting with prolonged symptoms of acute sinusitis (symptoms for more than 10 days with no improvement).
However, the committee discussed that prescribers need to weigh up the small improvement in symptoms, which may not be clinically important, against possible systemic effects. The committee also recognised that it may be difficult for some people to use a nasal spray correctly.
The committee acknowledged that some of the evidence did not include people with a suspected bacterial cause of acute sinusitis.
# No antibiotic
Acute sinusitis is a self-limiting infection usually triggered by a viral infection, so most people will not benefit from an antibiotic.
Only 0.5% to 2.2% of acute viral sinusitis becomes complicated by a bacterial infection (International Consensus Statement on Allergy and Rhinology: rhinosinusitis). The most common bacterial causes are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus (EPOS 2012 position paper).
Complications of acute sinusitis are rare, with an incidence in large epidemiological studies of 2.5 to 4.3 per million people per year (International Consensus Statement on Allergy and Rhinology: rhinosinusitis). The most common complications are orbital, then intracranial, with osseous complications being least common (International Consensus Statement on Allergy and Rhinology: rhinosinusitis). In a Dutch study (Hansen et al. 2012), severe complications were estimated to occur in 1:12,000 children and 1:32,000 adults with acute sinusitis who were otherwise healthy.
## Efficacy of antibiotics
Antibiotics did not significantly increase the proportion of adults with cure or improvement at 3 to 5 days follow-up compared with placebo (very low quality evidence). At longer durations of follow-up (approximately 7 to 15 days), there was a statistically significant difference in effectiveness for antibiotics compared with placebo, although the clinical difference in cure, improvement or clinical failure is small (moderate quality evidence). This benefit was not maintained in the longer term (approximately 16 to 60 days follow‑up) (low to moderate quality evidence). Where statistically significant benefits were seen for antibiotics compared with placebo, the NNT ranged between 7 and 21 depending on the outcomes considered, with little effect on the duration of illness. This was based on evidence from 3 systematic reviews and meta-analyses of RCTs (Ahovuo-Saloranta et al. 2014, Falagas et al. 2008 and Rosenfeld et al. 2007).
The NNT was 15 for 1 additional person with acute sinusitis to be cured with antibiotics, based on a meta-analysis of individual patient data (Young et al. 2008). Common clinical symptoms and signs could not confidently identify subgroups of people who may benefit from antibiotics, although people with purulent nasal discharge in the pharynx (observed by the doctor) had some prognostic value in identifying people who were more likely to benefit (NNT 8).
Antibiotics produced variable results in children, based on evidence from 2 systematic reviews (Cronin et al. 2013 and Falagas et al. 2008). In 1 systematic review, more children had symptom improvement at 10 to 14 days follow-up with antibiotics compared with placebo (NNT 8; low quality evidence). However, in the other systematic review, antibiotics did not significantly increase cure or improvement compared with placebo (moderate quality evidence).
## Safety of antibiotics
Allergic reactions to penicillins occur in 1 to 10% of people and anaphylactic reactions occur in less than 0.05%. People with a history of atopic allergy (for example, asthma, eczema, and hay fever) are at a higher risk of anaphylactic reactions to penicillins. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin).
Antibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE Clinical Knowledge Summary : diarrhoea – antibiotic associated).
Antibiotics were associated with significantly more adverse events than placebo. The number need to harm (NNH) ranged between 8 and 11 for all adverse effects, and was about 18 for diarrhoea. This was based on low to high quality evidence from 3 systematic reviews (Falagas et al. 2008, Lemiengre et al. 2012 and Rosenfeld et al. 2007).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Acute sinusitis usually follows a common cold, and symptoms for around 10 days or less are more likely to be associated with a cold rather than viral or bacterial acute sinusitis. Therefore, the committee agreed that an antibiotic prescription should not be offered to people presenting with acute sinusitis symptoms for around 10 days or less.
Prolonged symptoms (for around 10 days or more with no improvement) could be due to either viral or bacterial acute sinusitis. Viral acute sinusitis is more likely, but even bacterial sinusitis is usually self-limiting and does not routinely need antibiotics.
The committee recognised that people with symptoms that worsen rapidly or significantly should be reassessed to rule out alternative diagnoses and to identify any signs or symptoms suggesting a more serious illness or condition.
The committee acknowledged the recommendation in the previous NICE guideline on upper respiratory tract infections for a 'no' or back-up (delayed) antimicrobial prescribing strategy in acute sinusitis.
# Back-up antibiotics
A back-up antibiotic prescription (either patient-led collection or delayed collection) or no antibiotic prescription was as effective as an immediate antibiotic prescription for managing upper respiratory tract infections (including acute sinusitis). This was based on low to moderate quality evidence from 1 RCT in adults (de la Poza Abad et al. 2015). No systematic reviews or RCTs of back-up antibiotic prescribing in children were identified.
There were no significant differences in adverse events between back-up antibiotic prescription and no prescription strategies, compared with an immediate antibiotic prescription. This was based on low quality evidence from 1 RCT in adults (de la Poza Abad et al. 2015).
## Committee discussion on back-up antibiotics
Based on evidence, the committee agreed that no antibiotic prescription or a back-up antibiotic prescription could be considered for people presenting with prolonged acute sinusitis symptoms (symptoms for around 10 days or more with no improvement).
The committee discussed that prescribers need to weigh up the small clinical benefits from antibiotics against their potential to cause adverse effects.
A back-up antibiotic prescription could be used if symptoms worsen rapidly or significantly, or do not improve within the next 7 days (by which time most self-limiting acute sinusitis infections would be starting to resolve).
The committee recognised that people with symptoms that worsen rapidly or significantly despite taking an antibiotic should be reassessed to rule out alternative diagnoses and to identify any signs or symptoms suggesting a more serious illness or condition. They were aware that previous antibiotic use may lead to resistant organisms if the same antibiotic is used again (see the committee discussion on choice of antibiotic).
The committee discussed that prolonged acute sinusitis symptoms could have a viral or a bacterial cause, and distinguishing between these is difficult. Viral acute sinusitis is more likely, but a bacterial cause may be more likely if several of the following are present: symptoms for more than 10 days, discoloured or purulent nasal discharge, severe localised unilateral pain (particularly pain over teeth and jaw), fever, or marked deterioration after an initial milder phase. The committee discussed that a back-up antibiotic may be preferred when multiple factors suggest a bacterial cause is more likely.
The committee acknowledged the recommendations in the previous NICE guideline on upper respiratory tract infections for a 'no' or a back-up antimicrobial prescribing strategy in acute sinusitis. An immediate antibiotic prescription is not recommended unless people are systemically very unwell, have symptoms and signs of a more serious illness, or are at high risk of serious complications because of pre-existing comorbidity.
# Choice of antibiotic
There were no major differences in clinical effectiveness between classes of antibiotics, including penicillins, cephalosporins, macrolides, tetracyclines, folate inhibitors and quinolones. This was based on very low to moderate quality evidence from 2 systematic reviews and meta-analyses of RCTs in adults (Ahovuo-Saloranta et al. 2014 and Karageorgopoulos et al. 2008). Some differences that were statistically significant were seen for some comparisons, for some end points at some time points only.
Phenoxymethylpenicillin and amoxicillin were similar in terms of cure and improvement at 10 days (2 RCTs from the systematic reviews; moderate to high quality evidence) and 14 to 16 days (1 RCT from the systematic reviews; moderate quality evidence). There was no significant difference in duration of illness in 2 RCTs, and in 1 RCT the duration of illness was significantly lower with either amoxicillin or phenoxymethylpenicillin, compared with placebo (moderate quality evidence).
There were no significant differences between the antibiotics used in the studies in 1 systematic review in children (Smith 2013; low to very low quality evidence).
There were significantly fewer drop-outs because of adverse effects in studies of cephalosporins (1.3%) or macrolides (2.1%), compared with co-amoxiclav (4.4% or 4.8%). This was based on high quality evidence from 1 systematic review in adults (Ahovuo-Saloranta et al. 2014). In a further systematic review (Karageorgopoulos et al. 2008), results varied for different safety outcomes, but overall there did not appear to be differences between quinolones and beta‑lactam antibiotics (very low quality evidence).
There were no significant differences in adverse events between phenoxymethylpenicillin and amoxicillin reported in the 3 RCTs included in the systematic reviews (low to moderate quality evidence).
There were no significant differences in adverse events between classes of antibiotics in 1 systematic review in children ((Smith et al. 2013; very low quality evidence).
## Committee discussion on choice of antibiotic
Based on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.
The committee recognised the need to balance a person's need for antibiotics against their risk of developing a resistant organism following antibiotic treatment. The committee was aware of evidence that the risk of resistance to amoxicillin is increased following a course of amoxicillin. The effect is greatest in the month immediately after treatment but may persist for up to 12 months.
The committee discussed that, if an antibiotic is needed to treat an infection that is not life-threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as C. difficile. For infections that are not life threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective.
Based on evidence, their experience and resistance data, the committee agreed to recommend the narrow-spectrum antibiotic phenoxymethylpenicillin as the first choice. Phenoxymethylpenicillin has a narrower spectrum of activity than amoxicillin and its use will have the lowest risk of resistance, while having equivalent microbiological activity to amoxicillin. The committee agreed that organisms causing acute sinusitis that are resistant to phenoxymethylpenicillin are also likely to be resistant to amoxicillin.
The dosage of phenoxymethylpenicillin 500 mg four times a day agreed for adults (with corresponding usual doses in children), is lower than that used in studies in the evidence review, but dose formulations to give these higher doses are not available in the UK.
Based on evidence, their experience and resistance data, the committee agreed to recommend co-amoxiclav as the first-choice antibiotic for people presenting at any time who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high risk of complications. These people are more likely to have an infection that is resistant to phenoxymethylpenicillin. Co-amoxiclav is a broad-spectrum antimicrobial that combines a penicillin (amoxicillin) with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone. The dosage of 500/125 mg three times a day for adults (with corresponding usual doses in children) was used in studies in the evidence review.
Based on evidence, their experience and resistance data, the committee agreed to recommend the following alternative first-choice antibiotics for use in penicillin allergy or phenoxymethylpenicillin intolerance:
doxycycline (a tetracycline; adults and young people over 12 years only). The dosage of doxycycline 200 mg on the first day, then 100 mg once a day for a further 4 days was used in studies in the evidence review.
clarithromycin (a macrolide). The dosage of clarithromycin 500 mg twice a day for adults (with corresponding usual doses in children) was used in studies in the evidence review.
In pregnancy, erythromycin was recommended if there is true penicillin allergy. No studies of erythromycin were included in the evidence review, so the committee discussed and agreed a dosage of 250 mg to 500 mg four times a day or 500 mg to 1000 mg twice a day.
The committee also discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
Based on evidence, their experience and resistance data, the committee agreed to recommend co-amoxiclav as the second-choice antibiotic for use only if symptoms get worse on a first-choice antibiotic taken for at least 2 to 3 days. People with suspected bacterial infection who do not respond to a first-choice antibiotic may be more likely to have an infection that is resistant to phenoxymethylpenicillin or a viral infection, and if their condition is worsening they should be reviewed. The dosage of 500/125 mg three times a day for adults (with corresponding usual doses in children) was used in studies in the evidence review and is appropriate for people in whom first-line treatment has failed.
# Antibiotic course length
There was no significant difference in cure or improvement between a short course of antibiotic (3 to 7 days) and a long course (6 to 10 days). This was based on high quality evidence from 1 systematic review (Falagas et al. 2009). There was also no difference in cure or improvement in a subgroup analysis for treatment duration of 5 days compared with 10 days (high quality evidence) and in a subgroup of short course (3 to 7 days) compared with long course (6 to 10 days) of beta-lactam antibiotics (high quality evidence).
There was no significant difference in adverse events between a short course of antibiotic (3 to 7 days) and a long course (6 to 10 days), based on high quality evidence from 1 systematic review in adults (Falagas et al. 2009). However, in sensitivity analyses, there were significantly fewer adverse events with a 5-day course compared with a 10-day course of antibiotics (moderate quality evidence).
## Committee discussions on antibiotic course length
The committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed.
Based on evidence, their experience and resistance data, the committee agreed that a 5-day course for all the recommended antibiotics was sufficient to treat acute sinusitis in adults and children. This takes into account the overall efficacy and safety evidence for antibiotics, and minimises the risk of resistance. Studies in the evidence review for specific antibiotics in acute sinusitis sometimes had longer course lengths than 5 days.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (for example, nasal corticosteroids) (see the NICE guideline on medicines adherence ).
# Resource implications
Respiratory tract infections, including acute sinusitis, are a common reason for consultations in primary care, and therefore are a common reason for potential antibiotic prescribing. In a 2011 survey of UK primary care (Gulliford et al. 2014), consultations for sinusitis accounted for 9% of all consultations for respiratory tract infections, but the median practice issued an antibiotic prescription for 91% of these.
There is potential for resource savings if a no antibiotic or a back-up antibiotic prescription is used. One open-label RCT (de la Poza Abad et al. 2015) found there were significantly lower rates of antibiotic collection with back-up (delayed) antibiotic prescriptions (either prescription collection or patient-led ) compared with the immediate prescription group (89.1%, p<0.001; low quality evidence).
Recommended high-dose nasal corticosteroids are available as generic and proprietary products and costs per unit (excluding VAT) range between £1.71 and £12.99 (Drug Tariff, October 2017).
Recommended antibiotics are all available as generic formulations, see Drug Tariff for costs
See the full evidence review for more information.
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{'Background': 'Acute sinusitis (also known as rhinosinusitis) is self-limiting and usually triggered by a viral infection of the upper respiratory tract (for example, a common cold).\n\nOnly about 2% of cases are complicated by bacterial infection, but it is very difficult to distinguish these.\n\nSymptoms can last for 2 to 3 weeks – most people will get better within this time without treatment, regardless of cause (bacteria or virus).\n\nAntibiotics are not needed for most people. The number of people improving with antibiotics is similar to the number getting adverse effects, such as diarrhoea.\n\nComplications of acute sinusitis are rare (about 2.5 to 4.3 per million people per year). Withholding antibiotics is unlikely to lead to complications.\n\nPrevious antibiotic use may lead to resistant organisms if the same antibiotic is used again.', 'Recommendations': "# Managing acute sinusitis\n\n## People presenting with symptoms for around 10\xa0days or less\n\nDo not offer an antibiotic prescription.\n\nGive advice about:\n\nthe usual course of acute sinusitis (2 to 3\xa0weeks)\n\nan antibiotic not being needed\n\nmanaging symptoms, including fever, with self-care (see the recommendations on self-care)\n\nseeking medical help if symptoms worsen rapidly or significantly, do not improve after 3\xa0weeks, or they become systemically very unwell.\n\nReassess if symptoms worsen rapidly or significantly, taking account of:\n\nalternative diagnoses such as a dental infection\n\nany symptoms or signs suggesting a more serious illness or condition.\n\nSee symptoms and signs of acute sinusitis and the evidence and committee discussion on no antibiotic.\n\n## People presenting with symptoms for around 10\xa0days or more with no improvement\n\nConsider prescribing a high-dose nasal corticosteroid for 14\xa0days for adults and children aged 12\xa0years and over, being aware that nasal corticosteroids:\n\nmay improve symptoms but are not likely to affect how long they last\n\ncould cause systemic effects, particularly in people already taking another corticosteroid\n\nmay be difficult for people to use correctly.High-dose nasal corticosteroids used in the studies were mometasone 200\xa0micrograms twice a day and fluticasone 110\xa0micrograms twice a day. This is an off-label use of nasal corticosteroids See NICE's information on prescribing medicines.See the evidence and committee discussion on nasal corticosteroids.\n\nConsider no antibiotic prescription or a back-up antibiotic prescription (see the recommendations on choice of antibiotic), taking account of:\n\nevidence that antibiotics make little difference to how long symptoms last, or the proportion of people with improved symptoms\n\nwithholding antibiotics is unlikely to lead to complications\n\npossible adverse effects, particularly diarrhoea and nausea\n\nfactors that might make a bacterial cause more likely (see symptoms and signs).\n\nWhen a back-up antibiotic prescription is given, give verbal and written advice about:\n\nmanaging symptoms, including fever, with self-care (see the recommendations on self-care)\n\nan antibiotic not being needed immediately\n\nusing the back-up prescription if symptoms do not improve within 7\xa0days or if they worsen rapidly or significantly at any time\n\nseeking medical help if symptoms worsen rapidly or significantly despite taking the antibiotic, or the antibiotic has been stopped because it was not tolerated.\n\nReassess if symptoms worsen rapidly or significantly despite taking treatment, taking account of:\n\nalternative diagnoses such as a dental infection\n\nany signs or symptoms suggesting a more serious illness or condition\n\nprevious antibiotic use, which may lead to resistant organisms.\n\nSee the evidence and committee discussion on back-up antibiotics.\n\n## People presenting at any time who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high risk of complications\n\nOffer an immediate antibiotic prescription (see the recommendations on choice of antibiotic).\n\nRefer people to hospital if they have symptoms and signs of acute sinusitis associated with any of the following:\n\na severe systemic infection (see the NICE guideline on sepsis)\n\nintraorbital or periorbital complications, including periorbital oedema or cellulitis, a displaced eyeball, double vision, ophthalmoplegia, or newly reduced visual acuity\n\nintracranial complications, including swelling over the frontal bone, symptoms or signs of meningitis, severe frontal headache, or focal neurological signs.\n\nSee the evidence and committee discussion on choice of antibiotic.\n\n# Choice of antibiotic\n\nWhen prescribing antibiotics for acute sinusitis:\n\nfollow the recommendations in table\xa01 for adults aged 18\xa0years and over\n\nfollow the recommendations in table\xa02 for children and young people under 18\xa0years.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic\n\nPhenoxymethylpenicillin:\n\nmg four times a day for 5\xa0days\n\nFirst choice if systemically very unwell, symptoms and signs of a more serious illness or condition, or at high risk of complications\n\nCo‑amoxiclav:\n\n/125\xa0mg three times a day for 5\xa0days\n\nAlternative first choices for penicillin allergy or intolerance (for people who are not pregnant)\n\nDoxycycline:\n\nmg on first day, then 100\xa0mg once a day for 4\xa0days (5-day course in total)\n\n\n\nClarithromycin:\n\nmg twice a day for 5\xa0days\n\nAlternative first choice for penicillin allergy in pregnancy\n\nErythromycin:\n\nmg to 500\xa0mg four times a day or 500\xa0mg to 1,000\xa0mg twice a day for 5\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSecond-choice oral antibiotic (worsening symptoms on first choice taken for at least 2\xa0to 3\xa0days)\n\nCo‑amoxiclav:\n\n/125\xa0mg three times a day for 5\xa0days\n\nAlternative second choice for penicillin allergy or intolerance, or worsening symptoms on second choice taken for at least 2\xa0to 3\xa0days\n\nConsult a local microbiologist\n\nSee the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breast-feeding.\n\nIf co‑amoxiclav has been used first choice, consult a local microbiologist for advice on second choice.\n\nTreatment\n\nAntibiotic, dosage and course length\n\nFirst-choice oral antibiotic\n\nPhenoxymethylpenicillin:\n\nmonths to 11\xa0months, 62.5\xa0mg four times a day for 5\xa0days\n\nyear to 5\xa0years, 125\xa0mg four times a day for 5\xa0days\n\nyears to 11\xa0years, 250\xa0mg four times a day for 5\xa0days\n\nyears to 17 years, 500\xa0mg four times a day for 5\xa0days\n\nFirst choice if systemically very unwell, symptoms and signs of a more serious illness or condition, or at high risk of complications\n\nCo‑amoxiclav:\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days\n\nyear to 5\xa0years, 5\xa0ml of 125/31 suspension three times a day or 0.25\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days\n\nyears to 11\xa0years, 5\xa0ml of 250/62 suspension three times a day or 0.15\xa0ml/kg of 250/62 suspension three times a day for 5\xa0days\n\nyears to 17\xa0years, 250/125\xa0mg three times a day or 500/125\xa0mg three times a day for 5\xa0days\n\nAlternative first choices for penicillin allergy or intolerance (for people who are not pregnant)\n\nClarithromycin:\n\nUnder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0days\n\nyears to 17\xa0years, 250\xa0mg twice a day or 500\xa0mg twice a day for 5\xa0days\n\n\n\nDoxycycline:\n\nyears to 17\xa0years, 200\xa0mg on first day, then 100\xa0mg once a day for 4\xa0days (5-day course in total)\n\nDoxycycline is contraindicated in children under 12\xa0years\n\nAlternative first choice for penicillin allergy in pregnancy\n\nErythromycin:\n\nyears to 17 years, 250 mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSecond-choice oral antibiotic (worsening symptoms on first choice taken for at least 2\xa0to 3\xa0days)\n\nCo-amoxiclav:\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days\n\nyear to 5\xa0years, 5\xa0ml of 125/31 suspension three times a day or 0.25\xa0ml/kg of 125/31 suspension three times a day for 5\xa0days\n\nyears to 11\xa0years, 5\xa0ml of 250/62 suspension three times a day or 0.15\xa0ml/kg of 250/62 suspension three times a day for 5\xa0days\n\nyears to 17\xa0years, 250/125\xa0mg three times a day or 500/125\xa0mg three times a day for 5\xa0days\n\nAlternative second choice for penicillin allergy or intolerance, or worsening symptoms on second choice taken for at least 2\xa0to 3\xa0days\n\nConsult a local microbiologist\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment.\n\nThe age bands apply to children of average size and, in practice, the prescriber will use the age bands in conjunction with other factors such as the severity of the condition being treated and the child's size in relation to the average size of children of the same age.\n\nIf co‑amoxiclav used as first choice, consult a local microbiologist for advice on second choice.\n\nSee the evidence and committee discussion on choice of antibiotic and antibiotic course length.\n\n# Self-care\n\nConsider paracetamol or ibuprofen for pain or fever (assess and manage children aged under 5 who present with fever as outlined in the NICE guideline on fever in under 5s).\n\nExplain that some people may wish to try nasal saline or nasal decongestants, although there is not enough evidence to show that they help to relieve nasal congestion.\n\nExplain that no evidence was found for using oral decongestants, antihistamines, mucolytics, steam inhalation, or warm face packs.\n\nSee the evidence and committee discussion on self-care.", 'Symptoms and signs': '# Common symptoms and signs\n\nAdults with acute sinusitis usually present with:\n\n\n\nnasal blockage or congestion\n\nnasal discharge\n\ndental or facial pain or pressure\n\nreduction or loss of the sense of smell.\n\n\n\nChildren (particularly young children) often present with non‑specific symptoms in the upper respiratory tract. Symptoms of acute sinusitis in children may include the following, but these can be present for many upper respiratory tract infections:\n\n\n\nnasal blockage or congestion\n\ndiscoloured nasal discharge\n\ncough during the day or at night.\n\n\n\n# Factors that might make a bacterial cause more likely\n\nIt is difficult to distinguish viral and bacterial acute sinusitis. A bacterial cause may be more likely if several of the following are present:\n\nsymptoms for more than 10\xa0days\n\ndiscoloured or purulent nasal discharge\n\nsevere localised unilateral pain (particularly pain over teeth and jaw)\n\nfever\n\nmarked deterioration after an initial milder phase.', 'Summary of the evidence': "# Self-care\n\n## Nasal saline\n\nNasal saline for up to 28\xa0days did not reduce the time to resolution of symptoms in adults. This was based on very low quality evidence from a systematic review of randomised controlled trials (RCTs) (King et al. 2015). In the largest trial, in children aged 6 to 10\xa0years, there were statistically significant reductions in nasal symptom scores, but these may not be clinically important (low quality evidence).\n\nNasal saline irrigation is safe but may cause minor adverse effects, such as irritation (low to moderate quality evidence).\n\n## Nasal decongestants\n\nNasal decongestants offered no benefit in children compared with either placebo or mineral salts. This was based on a systematic review of RCTs (Smith et al. 2013; low quality evidence). No systematic reviews or RCTs of nasal decongestants in adults were identified.\n\nNasal decongestants containing sympathomimetics can cause rebound congestion and should not be used for longer than 7\xa0days (BNF information on the nose).\n\n## Other interventions\n\nNo systematic reviews or RCTs of steam inhalation or applying warm face packs were identified.\n\nNo systematic reviews or RCTs of paracetamol or ibuprofen were identified. However, these medicines have a well-established efficacy and safety profile for managing pain and fever.\n\nNo systematic reviews or RCTs of oral decongestants, antihistamines or mucolytics were identified.\n\nBased on experience, the committee agreed that it was reasonable to consider paracetamol or ibuprofen for acute sinusitis despite no evidence for their use in this condition. This is because these medicines have well-established efficacy and safety profiles for managing pain and fever generally.\n\nBased on experience, the committee agreed that people with acute sinusitis may wish to try self-care with nasal saline or nasal decongestants to relieve nasal congestion, but it should be explained that there is not enough evidence to recommend these. It should be explained to people that no evidence was found for using oral decongestants, antihistamines, mucolytics, steam inhalation or warm face packs in acute sinusitis.\n\n# Nasal corticosteroids\n\nHigh-dose nasal corticosteroids (equivalent to mometasone 400\xa0micrograms a day) for 14 to 21\xa0days (with or without an antibiotic) produced a statistically significant improvement in symptoms in adults and children aged 12\xa0years and over compared with placebo. This was based on high quality evidence from a systematic review of RCTs (Zalmanovici Trestioreanu et al. 2013) and moderate quality evidence from 1 additional RCT (Keith at al. 2012). However, it is not clear whether this statistically significant reduction in symptom score is clinically important. The number needed to treat (NNT) was 17 for 1 additional person with acute sinusitis to have improved or resolved symptoms with a high‑dose nasal corticosteroid compared with placebo. Lower doses (equivalent to mometasone 200\xa0micrograms a day) were not significantly better than placebo.\n\nMometasone 200\xa0micrograms twice a day produced a statistically significant reduction in symptoms compared with mometasone 200\xa0micrograms once a day and compared with amoxicillin 500\xa0mg three times a day for 10\xa0days. This was based on 1 RCT (Meltzer at al. 2005), which excluded people with suspected acute bacterial sinusitis and compared nasal corticosteroids alone with antibiotics (moderate quality evidence).\n\nSystemic effects (mineralocorticoid and glucocorticoid) may occur with nasal corticosteroids, including a range of psychological or behavioural effects (particularly in children) (Drug Safety Update, September 2010).\n\nAdverse events for nasal corticosteroids in the studies were not significantly different from placebo (low to moderate quality evidence).\n\nThe steroid burden of nasal corticosteroids needs to be considered in people already taking oral or inhaled corticosteroids (Ekins-Daukes et al. 2002), particularly in children due to systemic effects.\n\n## Committee discussion on nasal corticosteroids\n\nThe committee agreed, based on the evidence, that a high-dose nasal corticosteroid could be considered for adults and children aged 12\xa0years and over presenting with prolonged symptoms of acute sinusitis (symptoms for more than 10\xa0days with no improvement).\n\nHowever, the committee discussed that prescribers need to weigh up the small improvement in symptoms, which may not be clinically important, against possible systemic effects. The committee also recognised that it may be difficult for some people to use a nasal spray correctly.\n\nThe committee acknowledged that some of the evidence did not include people with a suspected bacterial cause of acute sinusitis.\n\n# No antibiotic\n\nAcute sinusitis is a self-limiting infection usually triggered by a viral infection, so most people will not benefit from an antibiotic.\n\nOnly 0.5% to 2.2% of acute viral sinusitis becomes complicated by a bacterial infection (International Consensus Statement on Allergy and Rhinology: rhinosinusitis). The most common bacterial causes are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus (EPOS 2012 position paper).\n\nComplications of acute sinusitis are rare, with an incidence in large epidemiological studies of 2.5 to 4.3 per million people per year (International Consensus Statement on Allergy and Rhinology: rhinosinusitis). The most common complications are orbital, then intracranial, with osseous complications being least common (International Consensus Statement on Allergy and Rhinology: rhinosinusitis). In a Dutch study (Hansen et al. 2012), severe complications were estimated to occur in 1:12,000 children and 1:32,000 adults with acute sinusitis who were otherwise healthy.\n\n## Efficacy of antibiotics\n\nAntibiotics did not significantly increase the proportion of adults with cure or improvement at 3 to 5\xa0days follow-up compared with placebo (very low quality evidence). At longer durations of follow-up (approximately 7 to 15\xa0days), there was a statistically significant difference in effectiveness for antibiotics compared with placebo, although the clinical difference in cure, improvement or clinical failure is small (moderate quality evidence). This benefit was not maintained in the longer term (approximately 16 to 60\xa0days follow‑up) (low to moderate quality evidence). Where statistically significant benefits were seen for antibiotics compared with placebo, the NNT ranged between 7 and 21 depending on the outcomes considered, with little effect on the duration of illness. This was based on evidence from 3 systematic reviews and meta-analyses of RCTs (Ahovuo-Saloranta et al. 2014, Falagas et al. 2008 and Rosenfeld et al. 2007).\n\nThe NNT was 15 for 1 additional person with acute sinusitis to be cured with antibiotics, based on a meta-analysis of individual patient data (Young et al. 2008). Common clinical symptoms and signs could not confidently identify subgroups of people who may benefit from antibiotics, although people with purulent nasal discharge in the pharynx (observed by the doctor) had some prognostic value in identifying people who were more likely to benefit (NNT 8).\n\nAntibiotics produced variable results in children, based on evidence from 2 systematic reviews (Cronin et al. 2013 and Falagas et al. 2008). In 1 systematic review, more children had symptom improvement at 10 to 14\xa0days follow-up with antibiotics compared with placebo (NNT 8; low quality evidence). However, in the other systematic review, antibiotics did not significantly increase cure or improvement compared with placebo (moderate quality evidence).\n\n## Safety of antibiotics\n\nAllergic reactions to penicillins occur in 1 to 10% of people and anaphylactic reactions occur in less than 0.05%. People with a history of atopic allergy (for example, asthma, eczema, and hay fever) are at a higher risk of anaphylactic reactions to penicillins. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin).\n\nAntibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE Clinical Knowledge Summary [CKS]: diarrhoea – antibiotic associated).\n\nAntibiotics were associated with significantly more adverse events than placebo. The number need to harm (NNH) ranged between 8 and 11 for all adverse effects, and was about 18 for diarrhoea. This was based on low to high quality evidence from 3 systematic reviews (Falagas et al. 2008, Lemiengre et al. 2012 and Rosenfeld et al. 2007).\n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.\n\nAcute sinusitis usually follows a common cold, and symptoms for around 10\xa0days or less are more likely to be associated with a cold rather than viral or bacterial acute sinusitis. Therefore, the committee agreed that an antibiotic prescription should not be offered to people presenting with acute sinusitis symptoms for around 10\xa0days or less.\n\nProlonged symptoms (for around 10\xa0days or more with no improvement) could be due to either viral or bacterial acute sinusitis. Viral acute sinusitis is more likely, but even bacterial sinusitis is usually self-limiting and does not routinely need antibiotics.\n\nThe committee recognised that people with symptoms that worsen rapidly or significantly should be reassessed to rule out alternative diagnoses and to identify any signs or symptoms suggesting a more serious illness or condition.\n\nThe committee acknowledged the recommendation in the previous NICE guideline on upper respiratory tract infections for a 'no' or back-up (delayed) antimicrobial prescribing strategy in acute sinusitis.\n\n# Back-up antibiotics\n\nA back-up antibiotic prescription (either patient-led collection or delayed collection) or no antibiotic prescription was as effective as an immediate antibiotic prescription for managing upper respiratory tract infections (including acute sinusitis). This was based on low to moderate quality evidence from 1 RCT in adults (de la Poza Abad et al. 2015). No systematic reviews or RCTs of back-up antibiotic prescribing in children were identified.\n\nThere were no significant differences in adverse events between back-up antibiotic prescription and no prescription strategies, compared with an immediate antibiotic prescription. This was based on low quality evidence from 1 RCT in adults (de la Poza Abad et al. 2015).\n\n## Committee discussion on back-up antibiotics\n\nBased on evidence, the committee agreed that no antibiotic prescription or a back-up antibiotic prescription could be considered for people presenting with prolonged acute sinusitis symptoms (symptoms for around 10\xa0days or more with no improvement).\n\nThe committee discussed that prescribers need to weigh up the small clinical benefits from antibiotics against their potential to cause adverse effects.\n\nA back-up antibiotic prescription could be used if symptoms worsen rapidly or significantly, or do not improve within the next 7\xa0days (by which time most self-limiting acute sinusitis infections would be starting to resolve).\n\nThe committee recognised that people with symptoms that worsen rapidly or significantly despite taking an antibiotic should be reassessed to rule out alternative diagnoses and to identify any signs or symptoms suggesting a more serious illness or condition. They were aware that previous antibiotic use may lead to resistant organisms if the same antibiotic is used again (see the committee discussion on choice of antibiotic).\n\nThe committee discussed that prolonged acute sinusitis symptoms could have a viral or a bacterial cause, and distinguishing between these is difficult. Viral acute sinusitis is more likely, but a bacterial cause may be more likely if several of the following are present: symptoms for more than 10\xa0days, discoloured or purulent nasal discharge, severe localised unilateral pain (particularly pain over teeth and jaw), fever, or marked deterioration after an initial milder phase. The committee discussed that a back-up antibiotic may be preferred when multiple factors suggest a bacterial cause is more likely.\n\nThe committee acknowledged the recommendations in the previous NICE guideline on upper respiratory tract infections for a 'no' or a back-up antimicrobial prescribing strategy in acute sinusitis. An immediate antibiotic prescription is not recommended unless people are systemically very unwell, have symptoms and signs of a more serious illness, or are at high risk of serious complications because of pre-existing comorbidity.\n\n# Choice of antibiotic\n\nThere were no major differences in clinical effectiveness between classes of antibiotics, including penicillins, cephalosporins, macrolides, tetracyclines, folate inhibitors and quinolones. This was based on very low to moderate quality evidence from 2 systematic reviews and meta-analyses of RCTs in adults (Ahovuo-Saloranta et al. 2014 and Karageorgopoulos et al. 2008). Some differences that were statistically significant were seen for some comparisons, for some end points at some time points only.\n\nPhenoxymethylpenicillin and amoxicillin were similar in terms of cure and improvement at 10\xa0days (2 RCTs from the systematic reviews; moderate to high quality evidence) and 14 to 16\xa0days (1 RCT from the systematic reviews; moderate quality evidence). There was no significant difference in duration of illness in 2 RCTs, and in 1 RCT the duration of illness was significantly lower with either amoxicillin or phenoxymethylpenicillin, compared with placebo (moderate quality evidence).\n\nThere were no significant differences between the antibiotics used in the studies in 1\xa0systematic review in children (Smith 2013; low to very low quality evidence).\n\nThere were significantly fewer drop-outs because of adverse effects in studies of cephalosporins (1.3%) or macrolides (2.1%), compared with co-amoxiclav (4.4% or 4.8%). This was based on high quality evidence from 1 systematic review in adults (Ahovuo-Saloranta et al. 2014). In a further systematic review (Karageorgopoulos et al. 2008), results varied for different safety outcomes, but overall there did not appear to be differences between quinolones and beta‑lactam antibiotics (very low quality evidence).\n\nThere were no significant differences in adverse events between phenoxymethylpenicillin and amoxicillin reported in the 3 RCTs included in the systematic reviews (low to moderate quality evidence).\n\nThere were no significant differences in adverse events between classes of antibiotics in 1 systematic review in children ((Smith et al. 2013; very low quality evidence).\n\n## Committee discussion on choice of antibiotic\n\nBased on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.\n\nThe committee recognised the need to balance a person's need for antibiotics against their risk of developing a resistant organism following antibiotic treatment. The committee was aware of evidence that the risk of resistance to amoxicillin is increased following a course of amoxicillin. The effect is greatest in the month immediately after treatment but may persist for up to 12 months.\n\nThe committee discussed that, if an antibiotic is needed to treat an infection that is not life-threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as C. difficile. For infections that are not life threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend the narrow-spectrum antibiotic phenoxymethylpenicillin as the first choice. Phenoxymethylpenicillin has a narrower spectrum of activity than amoxicillin and its use will have the lowest risk of resistance, while having equivalent microbiological activity to amoxicillin. The committee agreed that organisms causing acute sinusitis that are resistant to phenoxymethylpenicillin are also likely to be resistant to amoxicillin.\n\nThe dosage of phenoxymethylpenicillin 500\xa0mg four times a day agreed for adults (with corresponding usual doses in children), is lower than that used in studies in the evidence review, but dose formulations to give these higher doses are not available in the UK.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend co-amoxiclav as the first-choice antibiotic for people presenting at any time who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high risk of complications. These people are more likely to have an infection that is resistant to phenoxymethylpenicillin. Co-amoxiclav is a broad-spectrum antimicrobial that combines a penicillin (amoxicillin) with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone. The dosage of 500/125\xa0mg three times a day for adults (with corresponding usual doses in children) was used in studies in the evidence review.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend the following alternative first-choice antibiotics for use in penicillin allergy or phenoxymethylpenicillin intolerance:\n\n\n\ndoxycycline (a tetracycline; adults and young people over 12\xa0years only). The dosage of doxycycline 200\xa0mg on the first day, then 100\xa0mg once a day for a further 4 days was used in studies in the evidence review.\n\nclarithromycin (a macrolide). The dosage of clarithromycin 500\xa0mg twice a day for adults (with corresponding usual doses in children) was used in studies in the evidence review.\n\n\n\nIn pregnancy, erythromycin was recommended if there is true penicillin allergy. No studies of erythromycin were included in the evidence review, so the committee discussed and agreed a dosage of 250\xa0mg to 500\xa0mg four times a day or 500\xa0mg to 1000\xa0mg twice a day.\n\nThe committee also discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend co-amoxiclav as the second-choice antibiotic for use only if symptoms get worse on a first-choice antibiotic taken for at least 2 to 3\xa0days. People with suspected bacterial infection who do not respond to a first-choice antibiotic may be more likely to have an infection that is resistant to phenoxymethylpenicillin or a viral infection, and if their condition is worsening they should be reviewed. The dosage of 500/125\xa0mg three times a day for adults (with corresponding usual doses in children) was used in studies in the evidence review and is appropriate for people in whom first-line treatment has failed.\n\n# Antibiotic course length\n\nThere was no significant difference in cure or improvement between a short course of antibiotic (3 to 7\xa0days) and a long course (6 to 10\xa0days). This was based on high quality evidence from 1 systematic review (Falagas et al. 2009). There was also no difference in cure or improvement in a subgroup analysis for treatment duration of 5\xa0days compared with 10\xa0days (high quality evidence) and in a subgroup of short course (3 to 7\xa0days) compared with long course (6 to 10\xa0days) of beta-lactam antibiotics (high quality evidence).\n\nThere was no significant difference in adverse events between a short course of antibiotic (3 to 7\xa0days) and a long course (6 to 10\xa0days), based on high quality evidence from 1 systematic review in adults (Falagas et al. 2009). However, in sensitivity analyses, there were significantly fewer adverse events with a 5-day course compared with a 10-day course of antibiotics (moderate quality evidence).\n\n## Committee discussions on antibiotic course length\n\nThe committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed.\n\nBased on evidence, their experience and resistance data, the committee agreed that a 5-day course for all the recommended antibiotics was sufficient to treat acute sinusitis in adults and children. This takes into account the overall efficacy and safety evidence for antibiotics, and minimises the risk of resistance. Studies in the evidence review for specific antibiotics in acute sinusitis sometimes had longer course lengths than 5\xa0days.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (for example, nasal corticosteroids) (see the NICE guideline on medicines adherence ).\n\n# Resource implications\n\nRespiratory tract infections, including acute sinusitis, are a common reason for consultations in primary care, and therefore are a common reason for potential antibiotic prescribing. In a 2011 survey of UK primary care (Gulliford et al. 2014), consultations for sinusitis accounted for 9% of all consultations for respiratory tract infections, but the median practice issued an antibiotic prescription for 91% of these.\n\nThere is potential for resource savings if a no antibiotic or a back-up antibiotic prescription is used. One open-label RCT (de la Poza Abad et al. 2015) found there were significantly lower rates of antibiotic collection with back-up (delayed) antibiotic prescriptions (either prescription collection [26%] or patient-led [34.7%]) compared with the immediate prescription group (89.1%, p<0.001; low quality evidence).\n\nRecommended high-dose nasal corticosteroids are available as generic and proprietary products and costs per unit (excluding VAT) range between £1.71 and £12.99 (Drug Tariff, October 2017).\n\nRecommended antibiotics are all available as generic formulations, see Drug Tariff for costs\n\nSee the full evidence review for more information.'}
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https://www.nice.org.uk/guidance/ng79
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This guideline sets out an antimicrobial prescribing strategy for acute sinusitis. It aims to limit antibiotic use and reduce antimicrobial resistance. Acute sinusitis is usually caused by a virus, lasts for about 2 to 3 weeks, and most people get better without antibiotics. Withholding antibiotics rarely leads to complications.
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7a44752c6eebbb557cf90fa4ae0f81cf36448bb8
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nice
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Cataracts in adults: management
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Cataracts in adults: management
This guideline covers managing cataracts in adults aged 18 and over. It aims to improve care before, during and after cataract surgery by optimising service organisation, referral and surgical management, and reducing complications. It further aims to improve the availability of information for people with cataracts before, during and after cataract surgery.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Patient information
Give people with cataracts, and their family members or carers (as appropriate), both oral and written information. Information should be tailored to the person's needs, for example, in an accessible format. For more guidance on giving information to people and discussing their preferences, see the NICE guideline on patient experience in adult NHS services, particularly recommendations 1.2.12 and 1.2.13 on capacity and consent. For guidance on eye tests for people living with dementia, see the section on sensory impairment in the NICE guideline on dementia.
## At referral for cataract surgery
At referral for cataract surgery, give people information about:
cataracts:
what cataracts are
how they can affect vision
how they can affect quality of life
cataract surgery:
what it involves and how long it takes
possible risks and benefits
what support might be needed after surgery
likely recovery time
likely long-term outcomes, including the possibility that people might need spectacles for some tasks
how vision and quality of life may be affected without surgery.
## Before cataract surgery
At the preoperative outpatient appointment, review and expand on the topics in recommendation 1.1.2, and give people information about:
the refractive implications of different intraocular lenses (see recommendation 1.5.3)
types of anaesthesia
the person's individual risk of complications during or after surgery (for example, the risk of postoperative retinal detachment in people with high myopia; also see recommendations 1.3.10 and 1.3.11)
what to do and what to expect on the day of cataract surgery
what to do and what to expect after cataract surgery
what support might be needed after surgery
medicines after surgery (for example, eye drops) and medicines that people may be already taking (for example, anticoagulants)
the refractive implications after previous corneal refractive surgery, if appropriate (see recommendation 1.3.6)
bilateral simultaneous cataract surgery, if appropriate (also see recommendations 1.6.3 and 1.6.4).
## On the day of cataract surgery
On the day of surgery, before the operation, give people information about:
their position on the list
what to expect during and after surgery.
On the day of surgery, after the operation, give people information about:
what visual changes to expect
signs and symptoms of potential complications to look out for
any restrictions on activities, for example, driving
possible problems and who to contact
emergency situations and who to contact
eye drops
pain management
their next appointment and who they will see.
## After cataract surgery
At the first appointment after cataract surgery, give people information about:
eye drops
what to do if their vision changes
who to contact if they have concerns or queries
when it is appropriate to get new spectacles and how to do so
second-eye cataract surgery if there is a cataract in the non-operated eye
arrangements for managing ocular comorbidities.
# Referral for cataract surgery
Base the decision to refer a person with a cataract for surgery on a discussion with them (and their family members or carers, as appropriate) that includes:
how the cataract affects the person's vision and quality of life
whether 1 or both eyes are affected
what cataract surgery involves, including possible risks and benefits
how the person's quality of life may be affected if they choose not to have cataract surgery
whether the person wants to have cataract surgery.
Do not restrict access to cataract surgery on the basis of visual acuity.
# Preoperative assessment and biometry
## Biometry techniques
Use optical biometry to measure the axial length of the eye for people having cataract surgery.
Use ultrasound biometry if optical biometry:
is not possible or
does not give accurate measurements.
Use keratometry to measure the curvature of the cornea for people having cataract surgery.
Consider corneal topography for people having cataract surgery:
who have abnormally flat or steep corneas
who have irregular corneas
who have significant astigmatism
who have had previous corneal refractive surgery or
if it is not possible to get an accurate keratometry measurement.
## Biometry formulas
For people who have not had previous corneal refractive surgery, use 1 of the following to calculate the intraocular lens power before cataract surgery:
If the axial length is less than 22.00 mm, use Haigis or Hoffer Q.
If the axial length is between 22.00 and 26.00 mm, use Barrett Universal II if it is installed on the biometry device and does not need the results to be transcribed by hand. Use SRK/T if not.
If the axial length is more than 26.00 mm, use Haigis or SRK/T.
Advise people who have had previous corneal refractive surgery that refractive outcomes after cataract surgery are difficult to predict, and that they may need further surgery if they do not want to wear spectacles for distance vision.
If people have had previous corneal refractive surgery, adjust for the altered relationship between the anterior and posterior corneal curvature. Do not use standard biometry techniques or historical data alone.
Surgeons should think about modifying a manufacturer's recommended intraocular lens constant, guided by learning gained from their previous deviations from predicted refractive outcomes.
## Second-eye prediction
Consider using 50% of the first-eye prediction error in observed refractive outcome to guide calculations for the intraocular lens power for second-eye cataract surgery.
## Risk stratification
Consider using a validated risk stratification algorithm for people who have been referred for cataract surgery, to identify people at increased risk of complications during and after surgery.
Explain the results of the risk stratification to the person, and discuss how it may affect their decisions.
To minimise the risk of complications during and after surgery, ensure that surgeons in training are closely supervised when they perform cataract surgery in:
people who are at high risk of complications or
people for whom the impact of complications would be especially severe (for example, people with only 1 functional eye).
Explain to people who are at risk of developing a dense cataract that there is an increased risk of complications if surgery is delayed and the cataract becomes more dense.
# Intraocular lens selection
Please note: the recommendations around lens design and material have been removed to allow for further consideration.
Do not offer multifocal intraocular lenses for people having cataract surgery.
Offer monovision for use after cataract surgery to people who have either anisometropia or monovision preoperatively and would like to remain with it.
Please note: the recommendations around lens design and material have been removed to allow for further consideration.
## Addressing pre-existing astigmatism
Consider on‑axis surgery or limbal-relaxing incisions to reduce postoperative astigmatism.
# Preventing wrong lens implant errors
## Before cataract surgery
Before the preoperative biometry assessment, ensure that the person's correct medical notes are used by confirming the person's:
name
address and
date of birth.
Immediately after the preoperative biometry assessment:
check that the biometry results include the person's name, address, date of birth and hospital number
either
use electronic data transfer to upload the biometry results to an electronic health record or
securely fix the printed biometry results to the person's medical notes
do not transcribe the results by hand.
At the preoperative assessment:
discuss the refractive implications of different intraocular lenses with the person
base the choice of intraocular lens on the person's chosen refractive outcome
record the discussion and the person's choices in their medical notes.
## On the day of cataract surgery
The person's medical notes, including biometry results, must be available in theatre on the day of the cataract surgery.
Use a checklist based on the World Health Organization (WHO) surgical safety checklist, modified to include the following cataract surgery checks, to ensure that:
the person's identity has been confirmed and matches information in:
the consent form
the biometry results and
the person's medical notes
the eye to be operated on has been checked and clearly marked
there is only 1 intraocular lens in the theatre, that matches the person's selected lens type and prescription
at least 1 additional identical intraocular lens is in stock
alternative intraocular lenses are in stock in case the selected lens needs to be changed if there are complications during surgery
at least 2 members of the team, including the surgeon, have previously checked the appropriateness, accuracy and consistency of all:
formulas
calculations and
intraocular lens constants.
Before giving the person anaesthetic, ensure that:
there is only 1 intraocular lens in the theatre, that matches the person's selected lens type and prescription
at least 1 additional identical intraocular lens is in stock
alternative intraocular lenses are in stock in case the selected lens needs to be changed if there are complications during surgery.
Immediately before the operation, the surgeon should:
confirm the person's identity and ensure that the correct medical notes are being used, especially if using electronic patient records
refer to the printed biometry results, not to transcribed information in the person's medical notes
refer to the person's medical notes to check which refractive outcome they preferred
verify that the correct intraocular lens has been selected and is available in theatre.
## Occurrence of wrong lens implant errors
If a wrong lens is implanted, refer to NHS England's Never Events policy, and together with the whole multidisciplinary team:
undertake a root-cause analysis to determine the reasons for the incident
establish strategies and implementation tools to stop it from happening again.
# Surgical timing and technique
## Laser-assisted cataract surgery
Only use femtosecond laser-assisted cataract surgery as part of a randomised controlled trial that includes collection of resource-use data, comparing femtosecond laser-assisted cataract surgery with ultrasound phacoemulsification.
## Bilateral surgery
Offer second-eye cataract surgery using the same criteria as for the first-eye surgery (see referral for cataract surgery).
Consider bilateral simultaneous cataract surgery for:
people who are at low risk of ocular complications during and after surgery or
people who need to have general anaesthesia for cataract surgery but for whom general anaesthesia carries an increased risk of complications or distress.
Discuss the potential risks and benefits of bilateral simultaneous cataract surgery with people, which should include:
the potential immediate visual improvement in both eyes
how it will not be possible to choose a different intraocular lens based on the outcome in the first eye
the risk of complications in both eyes during and after surgery that could cause long-term visual impairment
the likely need for additional support after the operation.
# Anaesthesia
Offer sub‑Tenon's or topical (with or without intracameral) anaesthesia for people having cataract surgery.
If both sub‑Tenon's and topical (with or without intracameral) anaesthesia are contraindicated, consider peribulbar anaesthesia.
Do not offer retrobulbar anaesthesia for people having cataract surgery.
Consider sedation, administered by an experienced ophthalmic anaesthetist, as an adjunct to anaesthesia for people if, for example:
they have high levels of anxiety
they have postural or musculoskeletal problems
surgery is expected to take longer than usual.
Consider hyaluronidase as an adjunct to sub‑Tenon's anaesthesia, particularly if trying to stop the eye moving during surgery.
# Preventing and managing complications
## Floppy iris syndrome
Consider intracameral phenylephrine to increase pupil size in people at risk of floppy iris syndrome.
## Capsular tension rings
Do not use capsular tension rings in routine, uncomplicated cataract surgery.
Consider using capsular tension rings for people with pseudoexfoliation.
## Endophthalmitis
Use preoperative antiseptics in line with standard surgical practice.
Use intracameral cefuroxime during cataract surgery to prevent endophthalmitis.
Use commercially prepared or pharmacy-prepared intracameral antibiotic solutions to prevent dilution errors.
## Cystoid macular oedema
Consider topical steroids in combination with non-steroidal anti-inflammatory drugs (NSAIDs):
after cataract surgery for people at increased risk of cystoid macular oedema, for example, people with diabetes or uveitis
to manage cystoid macular oedema.
Offer topical steroids and/or NSAIDs after cataract surgery to prevent inflammation and cystoid macular oedema.
## Posterior capsule rupture
When dealing with posterior capsule rupture, follow a protocol that covers:
removing vitreous from the wound and anterior chamber
minimising traction on the retina
removing lens fragments in the posterior chamber or vitreous cavity
removing soft lens matter
implications for any lens insertion.
## Postoperative eye protection
Offer eye protection for people whose eye shows residual effects of anaesthesia at the time of discharge after cataract surgery.
# Postoperative assessment
Commissioners and service providers should ensure that the following are in place:
Processes that identify complications after surgery and ensure that there is prompt access to specialist ophthalmology services.
Processes to ensure that the UK Minimum Cataract Dataset for National Audit is completed.
Arrangements so that healthcare professionals discuss second-eye cataract surgery with people who have a cataract in their non-operated eye.
Consider collecting patient visual function and quality-of-life data for entry into an electronic dataset.
Do not offer in‑person, first-day review to people after uncomplicated cataract surgery.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
A cataract is defined as any opacity in the crystalline lens of the eye. It can affect one or both eyes. The changes to the transparency and refractive index of the lens result in various levels of visual impairment. This impairment is associated with decreased quality of life because it may restrict the person's ability to carry out daily activities and function independently, while increasing the risk of accidents and falls.
Cataracts most commonly affect adults as a result of biological ageing (age-related cataracts) and may be classified according to the area of the lens that is affected (nuclear sclerotic, cortical or posterior subcapsular cataracts). Cataracts can also occur in children, and may be classified according to the age of onset (congenital or infantile/juvenile cataracts). This guideline only covers cataracts in people who are 18 years or older.
Cataracts may occur secondary to hereditary factors, trauma, inflammation, metabolic or nutritional disorders, and exposure to radiation. In addition, lifestyle factors such as tobacco smoking and high alcohol intake are associated with an increased risk of developing age-related cataracts. Most cataracts are progressive, although the decline in visual function may be variable and unpredictable. The natural history of cataracts depends on the type and severity of the cataract and the presence of comorbid ocular conditions. In severe, untreated cases, cataracts can lead to significant reduction in vision, which is reversible with cataract surgery, although some level of visual impairment may persist.
Cataract surgery has a high success rate in improving visual function, with low morbidity and mortality. It is the most common operation performed in the NHS, with an ever growing need as the population ages.
Cataract management usually involves a multidisciplinary team that includes ophthalmologists, optometrists, nurses and technicians. Diagnosis is usually based on self-reported symptoms and a series of tests performed by an optometrist, normally based in the community. Symptoms may include blurred vision, difficulty seeing at night, sensitivity to light or glare, seeing 'halos' around lights and double vision in a single eye. Diagnostic tests include a visual acuity test, and slit-lamp and retinal examinations.
In adults with early age-related cataracts, non-surgical management may include prescription of spectacles. Alternatively, adults with age-related cataracts may be referred for surgery by an optometrist or a GP. The clinical threshold used to access cataract surgery varies across NHS trusts in England. This has resulted in differences in access to cataract surgery, because policies vary in scope and content and are not necessarily consistent with research evidence or guidance provided by the Department of Health in Action on cataracts and the Royal College of Ophthalmologists' Cataract surgery guidelines.
Guidance on appropriate referral criteria for cataract surgery is needed to address patient need and to optimise the allocation of NHS resources. In addition, an understanding of the most clinically and cost-effective methods for undertaking cataract surgery, and recommendations to minimise complications and surgical errors such as wrong intraocular lens implants, are needed to further improve patient care.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Toric lenses for astigmatism
What is the cost effectiveness of toric lenses compared with on‑axis or limbal-relaxing incision surgery, or non‑toric lenses with no further intervention, in an NHS context, taking account of the whole care pathway cost implications from pre- to postoperative phases, stratified by the preoperative level of astigmatism?
## Why this is important
There is clear evidence that toric lenses are effective at reducing levels of postoperative astigmatism, but evidence on their cost effectiveness is much less conclusive. Although a cost–utility analysis of toric lenses was evidenced from the USA, it was not possible to relate the costs to a UK NHS perspective. Acquisition costs of toric lenses are unlikely to exceed those of standard monofocal lenses, but their use has possible associated costs, including additional preoperative tests, biometry measurements, surgical time and equipment (toric markers), postoperative assessments and further surgery, which could be significant. A comparison with on‑axis or limbal-relaxing incisions would be advantageous because there are currently no resource constraints for using these techniques. Further cost-effectiveness research using UK NHS costings would be of benefit in helping to formulate future recommendations about their use.
# Quality of life in cataract surgery
What vision-specific, quality-of-life measures best capture visual changes in a population with cataracts?
## Why this is important
Although visual acuity is still commonly used to decide whether cataract surgery is needed, it is a crude measure that will often fail to detect other vision problems that may justify surgery (for example, glare and loss of colour vision). The best possible decision-making aids would be measures of preoperative and postoperative vision-related quality of life, which could then be used to identity groups of people who do not have an improvement in quality of life after surgery. However, most prioritisation criteria are based primarily on visual acuity and visual function (usually measured using the VF‑14), which capture only part of the impact of a cataract on quality of life. The development and validation of suitable vision-specific, quality-of-life measures would aid the decision-making process for cataract surgery, and help to accurately quantify the quality of life gains that may be expected from surgery. Particular consideration should be given to people with learning disabilities/cognitive impairment, or any other groups who may find it more difficult to self-report their own symptoms or quality of life.
# Indicators and thresholds for referral for cataract surgery
What is the association between preoperative vision- and health-related quality of life, and postoperative vision-related quality of life, health-related quality of life, and self-reported postoperative improvement?
## Why this is important
In contrast to the data linking preoperative visual acuity and visual function with postoperative visual acuity and visual function, there is a lack of evidence on the association between preoperative vision- and health-related quality on postoperative outcomes and levels of satisfaction for people having cataract surgery. This makes it difficult either to identify those groups of individuals who may achieve the largest gains from surgery, or to provide people with accurate information about what their potential gains may be. Robust information around the link between preoperative patient characteristics and outcomes would be useful both for prioritisation of surgery, and to help better inform individuals about the levels of gain they may individually expect to get from surgery.
# Interventions to manage cystoid macular oedema
What is the most effective postoperative medical management for cystoid macular oedema?
## Why this is important
Although there is evidence for using steroids and non-steroidal anti-inflammatory drugs (NSAIDs) in treating cystoid macular oedema, no evidence has been identified for interventions such as acetazolamide, steroid-based anti-inflammatory drugs or intraocular anti-vascular endothelial growth factors (anti-VEGFs). Further randomised controlled trials with increased numbers of participants would be of benefit to the evidence base, which would help lead to the formulation of future recommendations for the postoperative treatment cystoid macular oedema.
# Interventions to prevent endophthalmitis
What is the effectiveness of postoperative antibiotic drops to reduce rates of endophthalmitis after cataract surgery?
## Why this is important
There is a lack of evidence on postoperative antibiotics to reduce rates of endophthalmitis, which may be because they are provided as part of standard good clinical practice in the UK. In addition, it is recognised that patients are invariably receiving other drops (for example, steroids), which are likely to be offered in combination with postoperative antibiotic drops, and often in a single-drop product. Well-conducted randomised controlled trials of postoperative antibiotics in people having cataract surgery would help add to the evidence base and so inform future recommendations on their use.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Patient information\n\nGive people with cataracts, and their family members or carers (as appropriate), both oral and written information. Information should be tailored to the person's needs, for example, in an accessible format. For more guidance on giving information to people and discussing their preferences, see the NICE guideline on patient experience in adult NHS services, particularly recommendations\xa01.2.12 and\xa01.2.13 on capacity and consent. For guidance on eye tests for people living with dementia, see the section on sensory impairment in the NICE guideline on dementia.\n\n## At referral for cataract surgery\n\nAt referral for cataract surgery, give people information about:\n\ncataracts:\n\n\n\nwhat cataracts are\n\nhow they can affect vision\n\nhow they can affect quality of life\n\n\n\ncataract surgery:\n\n\n\nwhat it involves and how long it takes\n\npossible risks and benefits\n\nwhat support might be needed after surgery\n\nlikely recovery time\n\nlikely long-term outcomes, including the possibility that people might need spectacles for some tasks\n\nhow vision and quality of life may be affected without surgery.\n\n\n\n## Before cataract surgery\n\nAt the preoperative outpatient appointment, review and expand on the topics in recommendation\xa01.1.2, and give people information about:\n\nthe refractive implications of different intraocular lenses (see recommendation\xa01.5.3)\n\ntypes of anaesthesia\n\nthe person's individual risk of complications during or after surgery (for example, the risk of postoperative retinal detachment in people with high myopia; also see recommendations\xa01.3.10 and\xa01.3.11)\n\nwhat to do and what to expect on the day of cataract surgery\n\nwhat to do and what to expect after cataract surgery\n\nwhat support might be needed after surgery\n\nmedicines after surgery (for example, eye drops) and medicines that people may be already taking (for example, anticoagulants)\n\nthe refractive implications after previous corneal refractive surgery, if appropriate (see recommendation\xa01.3.6)\n\nbilateral simultaneous cataract surgery, if appropriate (also see recommendations\xa01.6.3 and\xa01.6.4).\n\n## On the day of cataract surgery\n\nOn the day of surgery, before the operation, give people information about:\n\ntheir position on the list\n\nwhat to expect during and after surgery.\n\nOn the day of surgery, after the operation, give people information about:\n\nwhat visual changes to expect\n\nsigns and symptoms of potential complications to look out for\n\nany restrictions on activities, for example, driving\n\npossible problems and who to contact\n\nemergency situations and who to contact\n\neye drops\n\npain management\n\ntheir next appointment and who they will see.\n\n## After cataract surgery\n\nAt the first appointment after cataract surgery, give people information about:\n\neye drops\n\nwhat to do if their vision changes\n\nwho to contact if they have concerns or queries\n\nwhen it is appropriate to get new spectacles and how to do so\n\nsecond-eye cataract surgery if there is a cataract in the non-operated eye\n\narrangements for managing ocular comorbidities.\n\n# Referral for cataract surgery\n\nBase the decision to refer a person with a cataract for surgery on a discussion with them (and their family members or carers, as appropriate) that includes:\n\nhow the cataract affects the person's vision and quality of life\n\nwhether 1\xa0or both eyes are affected\n\nwhat cataract surgery involves, including possible risks and benefits\n\nhow the person's quality of life may be affected if they choose not to have cataract surgery\n\nwhether the person wants to have cataract surgery.\n\nDo not restrict access to cataract surgery on the basis of visual acuity.\n\n# Preoperative assessment and biometry\n\n## Biometry techniques\n\nUse optical biometry to measure the axial length of the eye for people having cataract surgery.\n\nUse ultrasound biometry if optical biometry:\n\nis not possible or\n\ndoes not give accurate measurements.\n\nUse keratometry to measure the curvature of the cornea for people having cataract surgery.\n\nConsider corneal topography for people having cataract surgery:\n\nwho have abnormally flat or steep corneas\n\nwho have irregular corneas\n\nwho have significant astigmatism\n\nwho have had previous corneal refractive surgery or\n\nif it is not possible to get an accurate keratometry measurement.\n\n## Biometry formulas\n\nFor people who have not had previous corneal refractive surgery, use 1\xa0of the following to calculate the intraocular lens power before cataract surgery:\n\nIf the axial length is less than 22.00\xa0mm, use Haigis or Hoffer\xa0Q.\n\nIf the axial length is between 22.00\xa0and 26.00\xa0mm, use Barrett Universal\xa0II if it is installed on the biometry device and does not need the results to be transcribed by hand. Use SRK/T if not.\n\nIf the axial length is more than 26.00\xa0mm, use Haigis or SRK/T.\n\nAdvise people who have had previous corneal refractive surgery that refractive outcomes after cataract surgery are difficult to predict, and that they may need further surgery if they do not want to wear spectacles for distance vision.\n\nIf people have had previous corneal refractive surgery, adjust for the altered relationship between the anterior and posterior corneal curvature. Do not use standard biometry techniques or historical data alone.\n\nSurgeons should think about modifying a manufacturer's recommended intraocular lens constant, guided by learning gained from their previous deviations from predicted refractive outcomes.\n\n## Second-eye prediction\n\nConsider using 50% of the first-eye prediction error in observed refractive outcome to guide calculations for the intraocular lens power for second-eye cataract surgery.\n\n## Risk stratification\n\nConsider using a validated risk stratification algorithm for people who have been referred for cataract surgery, to identify people at increased risk of complications during and after surgery.\n\nExplain the results of the risk stratification to the person, and discuss how it may affect their decisions.\n\nTo minimise the risk of complications during and after surgery, ensure that surgeons in training are closely supervised when they perform cataract surgery in:\n\npeople who are at high risk of complications or\n\npeople for whom the impact of complications would be especially severe (for example, people with only 1\xa0functional eye).\n\nExplain to people who are at risk of developing a dense cataract that there is an increased risk of complications if surgery is delayed and the cataract becomes more dense.\n\n# Intraocular lens selection\n\nPlease note: the recommendations around lens design and material have been removed to allow for further consideration.\n\nDo not offer multifocal intraocular lenses for people having cataract surgery.\n\nOffer monovision for use after cataract surgery to people who have either anisometropia or monovision preoperatively and would like to remain with it.\n\nPlease note: the recommendations around lens design and material have been removed to allow for further consideration.\n\n## Addressing pre-existing astigmatism\n\nConsider on‑axis surgery or limbal-relaxing incisions to reduce postoperative astigmatism.\n\n# Preventing wrong lens implant errors\n\n## Before cataract surgery\n\nBefore the preoperative biometry assessment, ensure that the person's correct medical notes are used by confirming the person's:\n\nname\n\naddress and\n\ndate of birth.\n\nImmediately after the preoperative biometry assessment:\n\ncheck that the biometry results include the person's name, address, date of birth and hospital number\n\neither\n\n\n\nuse electronic data transfer to upload the biometry results to an electronic health record or\n\nsecurely fix the printed biometry results to the person's medical notes\n\n\n\ndo not transcribe the results by hand.\n\nAt the preoperative assessment:\n\ndiscuss the refractive implications of different intraocular lenses with the person\n\nbase the choice of intraocular lens on the person's chosen refractive outcome\n\nrecord the discussion and the person's choices in their medical notes.\n\n## On the day of cataract surgery\n\nThe person's medical notes, including biometry results, must be available in theatre on the day of the cataract surgery.\n\nUse a checklist based on the World Health Organization (WHO) surgical safety checklist, modified to include the following cataract surgery checks, to ensure that:\n\nthe person's identity has been confirmed and matches information in:\n\n\n\nthe consent form\n\nthe biometry results and\n\nthe person's medical notes\n\n\n\nthe eye to be operated on has been checked and clearly marked\n\nthere is only 1\xa0intraocular lens in the theatre, that matches the person's selected lens type and prescription\n\nat least 1\xa0additional identical intraocular lens is in stock\n\nalternative intraocular lenses are in stock in case the selected lens needs to be changed if there are complications during surgery\n\nat least 2\xa0members of the team, including the surgeon, have previously checked the appropriateness, accuracy and consistency of all:\n\n\n\nformulas\n\ncalculations and\n\nintraocular lens constants.\n\n\n\nBefore giving the person anaesthetic, ensure that:\n\nthere is only 1\xa0intraocular lens in the theatre, that matches the person's selected lens type and prescription\n\nat least 1\xa0additional identical intraocular lens is in stock\n\nalternative intraocular lenses are in stock in case the selected lens needs to be changed if there are complications during surgery.\n\nImmediately before the operation, the surgeon should:\n\nconfirm the person's identity and ensure that the correct medical notes are being used, especially if using electronic patient records\n\nrefer to the printed biometry results, not to transcribed information in the person's medical notes\n\nrefer to the person's medical notes to check which refractive outcome they preferred\n\nverify that the correct intraocular lens has been selected and is available in theatre.\n\n## Occurrence of wrong lens implant errors\n\nIf a wrong lens is implanted, refer to NHS England's Never Events policy, and together with the whole multidisciplinary team:\n\nundertake a root-cause analysis to determine the reasons for the incident\n\nestablish strategies and implementation tools to stop it from happening again.\n\n# Surgical timing and technique\n\n## Laser-assisted cataract surgery\n\nOnly use femtosecond laser-assisted cataract surgery as part of a randomised controlled trial that includes collection of resource-use data, comparing femtosecond laser-assisted cataract surgery with ultrasound phacoemulsification.\n\n## Bilateral surgery\n\nOffer second-eye cataract surgery using the same criteria as for the first-eye surgery (see referral for cataract surgery).\n\nConsider bilateral simultaneous cataract surgery for:\n\npeople who are at low risk of ocular complications during and after surgery or\n\npeople who need to have general anaesthesia for cataract surgery but for whom general anaesthesia carries an increased risk of complications or distress.\n\nDiscuss the potential risks and benefits of bilateral simultaneous cataract surgery with people, which should include:\n\nthe potential immediate visual improvement in both eyes\n\nhow it will not be possible to choose a different intraocular lens based on the outcome in the first eye\n\nthe risk of complications in both eyes during and after surgery that could cause long-term visual impairment\n\nthe likely need for additional support after the operation.\n\n# Anaesthesia\n\nOffer sub‑Tenon's or topical (with or without intracameral) anaesthesia for people having cataract surgery.\n\nIf both sub‑Tenon's and topical (with or without intracameral) anaesthesia are contraindicated, consider peribulbar anaesthesia.\n\nDo not offer retrobulbar anaesthesia for people having cataract surgery.\n\nConsider sedation, administered by an experienced ophthalmic anaesthetist, as an adjunct to anaesthesia for people if, for example:\n\nthey have high levels of anxiety\n\nthey have postural or musculoskeletal problems\n\nsurgery is expected to take longer than usual.\n\nConsider hyaluronidase as an adjunct to sub‑Tenon's anaesthesia, particularly if trying to stop the eye moving during surgery.\n\n# Preventing and managing complications\n\n## Floppy iris syndrome\n\nConsider intracameral phenylephrine to increase pupil size in people at risk of floppy iris syndrome.\n\n## Capsular tension rings\n\nDo not use capsular tension rings in routine, uncomplicated cataract surgery.\n\nConsider using capsular tension rings for people with pseudoexfoliation.\n\n## Endophthalmitis\n\nUse preoperative antiseptics in line with standard surgical practice.\n\nUse intracameral cefuroxime during cataract surgery to prevent endophthalmitis.\n\nUse commercially prepared or pharmacy-prepared intracameral antibiotic solutions to prevent dilution errors.\n\n## Cystoid macular oedema\n\nConsider topical steroids in combination with non-steroidal anti-inflammatory drugs (NSAIDs):\n\nafter cataract surgery for people at increased risk of cystoid macular oedema, for example, people with diabetes or uveitis\n\nto manage cystoid macular oedema.\n\nOffer topical steroids and/or NSAIDs after cataract surgery to prevent inflammation and cystoid macular oedema.\n\n## Posterior capsule rupture\n\nWhen dealing with posterior capsule rupture, follow a protocol that covers:\n\nremoving vitreous from the wound and anterior chamber\n\nminimising traction on the retina\n\nremoving lens fragments in the posterior chamber or vitreous cavity\n\nremoving soft lens matter\n\nimplications for any lens insertion.\n\n## Postoperative eye protection\n\nOffer eye protection for people whose eye shows residual effects of anaesthesia at the time of discharge after cataract surgery.\n\n# Postoperative assessment\n\nCommissioners and service providers should ensure that the following are in place:\n\nProcesses that identify complications after surgery and ensure that there is prompt access to specialist ophthalmology services.\n\nProcesses to ensure that the UK Minimum Cataract Dataset for National Audit is completed.\n\nArrangements so that healthcare professionals discuss second-eye cataract surgery with people who have a cataract in their non-operated eye.\n\nConsider collecting patient visual function and quality-of-life data for entry into an electronic dataset.\n\nDo not offer in‑person, first-day review to people after uncomplicated cataract surgery.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "A cataract is defined as any opacity in the crystalline lens of the eye. It can affect one or both eyes. The changes to the transparency and refractive index of the lens result in various levels of visual impairment. This impairment is associated with decreased quality of life because it may restrict the person's ability to carry out daily activities and function independently, while increasing the risk of accidents and falls.\n\nCataracts most commonly affect adults as a result of biological ageing (age-related cataracts) and may be classified according to the area of the lens that is affected (nuclear sclerotic, cortical or posterior subcapsular cataracts). Cataracts can also occur in children, and may be classified according to the age of onset (congenital or infantile/juvenile cataracts). This guideline only covers cataracts in people who are 18\xa0years or older.\n\nCataracts may occur secondary to hereditary factors, trauma, inflammation, metabolic or nutritional disorders, and exposure to radiation. In addition, lifestyle factors such as tobacco smoking and high alcohol intake are associated with an increased risk of developing age-related cataracts. Most cataracts are progressive, although the decline in visual function may be variable and unpredictable. The natural history of cataracts depends on the type and severity of the cataract and the presence of comorbid ocular conditions. In severe, untreated cases, cataracts can lead to significant reduction in vision, which is reversible with cataract surgery, although some level of visual impairment may persist.\n\nCataract surgery has a high success rate in improving visual function, with low morbidity and mortality. It is the most common operation performed in the NHS, with an ever growing need as the population ages.\n\nCataract management usually involves a multidisciplinary team that includes ophthalmologists, optometrists, nurses and technicians. Diagnosis is usually based on self-reported symptoms and a series of tests performed by an optometrist, normally based in the community. Symptoms may include blurred vision, difficulty seeing at night, sensitivity to light or glare, seeing 'halos' around lights and double vision in a single eye. Diagnostic tests include a visual acuity test, and slit-lamp and retinal examinations.\n\nIn adults with early age-related cataracts, non-surgical management may include prescription of spectacles. Alternatively, adults with age-related cataracts may be referred for surgery by an optometrist or a GP. The clinical threshold used to access cataract surgery varies across NHS trusts in England. This has resulted in differences in access to cataract surgery, because policies vary in scope and content and are not necessarily consistent with research evidence or guidance provided by the Department of Health in Action on cataracts and the Royal College of Ophthalmologists' Cataract surgery guidelines.\n\nGuidance on appropriate referral criteria for cataract surgery is needed to address patient need and to optimise the allocation of NHS resources. In addition, an understanding of the most clinically and cost-effective methods for undertaking cataract surgery, and recommendations to minimise complications and surgical errors such as wrong intraocular lens implants, are needed to further improve patient care.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Toric lenses for astigmatism\n\nWhat is the cost effectiveness of toric lenses compared with on‑axis or limbal-relaxing incision surgery, or non‑toric lenses with no further intervention, in an NHS context, taking account of the whole care pathway cost implications from pre- to postoperative phases, stratified by the preoperative level of astigmatism?\n\n## Why this is important\n\nThere is clear evidence that toric lenses are effective at reducing levels of postoperative astigmatism, but evidence on their cost effectiveness is much less conclusive. Although a cost–utility analysis of toric lenses was evidenced from the USA, it was not possible to relate the costs to a UK NHS perspective. Acquisition costs of toric lenses are unlikely to exceed those of standard monofocal lenses, but their use has possible associated costs, including additional preoperative tests, biometry measurements, surgical time and equipment (toric markers), postoperative assessments and further surgery, which could be significant. A comparison with on‑axis or limbal-relaxing incisions would be advantageous because there are currently no resource constraints for using these techniques. Further cost-effectiveness research using UK NHS costings would be of benefit in helping to formulate future recommendations about their use.\n\n# Quality of life in cataract surgery\n\nWhat vision-specific, quality-of-life measures best capture visual changes in a population with cataracts?\n\n## Why this is important\n\nAlthough visual acuity is still commonly used to decide whether cataract surgery is needed, it is a crude measure that will often fail to detect other vision problems that may justify surgery (for example, glare and loss of colour vision). The best possible decision-making aids would be measures of preoperative and postoperative vision-related quality of life, which could then be used to identity groups of people who do not have an improvement in quality of life after surgery. However, most prioritisation criteria are based primarily on visual acuity and visual function (usually measured using the VF‑14), which capture only part of the impact of a cataract on quality of life. The development and validation of suitable vision-specific, quality-of-life measures would aid the decision-making process for cataract surgery, and help to accurately quantify the quality of life gains that may be expected from surgery. Particular consideration should be given to people with learning disabilities/cognitive impairment, or any other groups who may find it more difficult to self-report their own symptoms or quality of life.\n\n# Indicators and thresholds for referral for cataract surgery\n\nWhat is the association between preoperative vision- and health-related quality of life, and postoperative vision-related quality of life, health-related quality of life, and self-reported postoperative improvement?\n\n## Why this is important\n\nIn contrast to the data linking preoperative visual acuity and visual function with postoperative visual acuity and visual function, there is a lack of evidence on the association between preoperative vision- and health-related quality on postoperative outcomes and levels of satisfaction for people having cataract surgery. This makes it difficult either to identify those groups of individuals who may achieve the largest gains from surgery, or to provide people with accurate information about what their potential gains may be. Robust information around the link between preoperative patient characteristics and outcomes would be useful both for prioritisation of surgery, and to help better inform individuals about the levels of gain they may individually expect to get from surgery.\n\n# Interventions to manage cystoid macular oedema\n\nWhat is the most effective postoperative medical management for cystoid macular oedema?\n\n## Why this is important\n\nAlthough there is evidence for using steroids and non-steroidal anti-inflammatory drugs (NSAIDs) in treating cystoid macular oedema, no evidence has been identified for interventions such as acetazolamide, steroid-based anti-inflammatory drugs or intraocular anti-vascular endothelial growth factors (anti-VEGFs). Further randomised controlled trials with increased numbers of participants would be of benefit to the evidence base, which would help lead to the formulation of future recommendations for the postoperative treatment cystoid macular oedema.\n\n# Interventions to prevent endophthalmitis\n\nWhat is the effectiveness of postoperative antibiotic drops to reduce rates of endophthalmitis after cataract surgery?\n\n## Why this is important\n\nThere is a lack of evidence on postoperative antibiotics to reduce rates of endophthalmitis, which may be because they are provided as part of standard good clinical practice in the UK. In addition, it is recognised that patients are invariably receiving other drops (for example, steroids), which are likely to be offered in combination with postoperative antibiotic drops, and often in a single-drop product. Well-conducted randomised controlled trials of postoperative antibiotics in people having cataract surgery would help add to the evidence base and so inform future recommendations on their use."}
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https://www.nice.org.uk/guidance/ng77
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This guideline covers managing cataracts in adults aged 18 and over. It aims to improve care before, during and after cataract surgery by optimising service organisation, referral and surgical management, and reducing complications. It further aims to improve the availability of information for people with cataracts before, during and after cataract surgery.
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4c4541e90bf0270e0d707cf79ed20c60b8e95e62
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nice
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Cystic fibrosis: diagnosis and management
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Cystic fibrosis: diagnosis and management
This guideline covers diagnosing and managing cystic fibrosis. It specifies how to monitor the condition and manage the symptoms to improve quality of life. There are also detailed recommendations on treating the most common infections in people with cystic fibrosis.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
This guideline incorporates recommendations from 2 NICE technology appraisals:
Mannitol dry powder for inhalation for treating cystic fibrosis (NICE technology appraisal guidance 266)
Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis (NICE technology appraisal guidance 276).
These technology appraisals still apply, and have not been replaced by the guideline.
# Diagnosis of cystic fibrosis
Be aware that cystic fibrosis can be diagnosed based on:
positive test results in people with no symptoms, for example infant screening (blood spot immunoreactive trypsin test) followed by sweat and gene tests for confirmation or
clinical manifestations, supported by sweat or gene test results for confirmation or
clinical manifestations alone, in the rare case of people with symptoms who have normal sweat or gene test results.
Assess for cystic fibrosis and, when clinically appropriate, perform a sweat test (for children and young people) or a cystic fibrosis gene test (for adults) in people with any of the following:
family history
congenital intestinal atresia
meconium ileus
symptoms and signs that suggest distal intestinal obstruction syndrome
faltering growth (in infants and young children)
undernutrition
recurrent and chronic pulmonary disease, such as:
recurrent lower respiratory tract infections
clinical or radiological evidence of lung disease (in particular bronchiectasis)
persistent chest X-ray changes
chronic wet or productive cough
chronic sinus disease
-bstructive azoospermia (in young people and adults)
acute or chronic pancreatitis
malabsorption
rectal prolapse (in children)
pseudo-Bartter syndrome.
Refer people with suspected cystic fibrosis to a specialist cystic fibrosis centre if:
they have a positive or equivocal sweat test result
their assessment suggests they have cystic fibrosis but their test results are normal
gene testing reveals 1 or more cystic fibrosis mutations.
# Information and support
Provide people who are newly diagnosed with cystic fibrosis and their family members or carers (as appropriate) with opportunities to discuss their concerns.
Information and support should be provided by healthcare professionals with expertise in cystic fibrosis.
Provide people with suspected or diagnosed cystic fibrosis and their family members or carers (as appropriate) with relevant information that they can understand, and opportunities for discussion on topics such as:
their diagnosis
monitoring of their condition
management choices for their condition
possible or existing complications or comorbidities
implications for living independently.
Provide people with cystic fibrosis and their family members or carers (as appropriate) with information about their care pathway.
Give information to people with cystic fibrosis and to family members or carers in ways that are individually appropriate. Avoid jargon and use formats that they prefer, for example:
face-to-face discussions
copies of correspondence
written information (such as leaflets)
any digital media and reliable internet sources that are available.
When appropriate, provide people with cystic fibrosis and their family members or carers with opportunities for discussion with relevant expert professionals on:
available resources and support, such as local support and advocacy services
managing the risks of cross-infection
implications of the condition for school and education
career planning
transition to adult care
foreign travel
fertility and contraception
pregnancy and parenting
-rgan transplantation
end of life care.
Provide people with cystic fibrosis with information about how to contact other people with cystic fibrosis without risking cross-infection (see preventing cross-infection), for example by directing them to online support groups.
For more information on communication, providing information and shared decision making in adult NHS services, see NICE guidelines on patient experience in adult NHS services and shared decision making.
Be aware that people with cystic fibrosis and their family members or carers will need emotional support and some may need specialist psychological support (see psychological assessment), in particular:
at diagnosis
at times of transition (for example, when starting or changing school, moving from education to work, or changing to living independently for the first time)
in relation to fertility, including family planning, pregnancy and infertility
to cope with complications of cystic fibrosis
when waiting for or having organ transplantation
when approaching the end of life.
# Service delivery
## Service configuration
Care for people with cystic fibrosis should be provided by a specialist cystic fibrosis multidisciplinary team based at a specialist cystic fibrosis centre (see multidisciplinary team).
Specialist cystic fibrosis centres should:
plan patient care (including outpatient and inpatient care), taking into account the risk of cross-infection (see preventing cross-infection)
maintain local and national registers of patients that include information about their clinical condition, treatment and outcomes
audit practice and outcomes.
When a shared-care model is used for children and young people, it should include:
formal arrangements between the local paediatric team at the shared-care centre and the multidisciplinary team at the specialist cystic fibrosis centre
direct involvement of specialist cystic fibrosis multidisciplinary team members
an annual assessment and at least one other review per year by the specialist cystic fibrosis multidisciplinary team, in addition to reviews by the local paediatric team (see annual and routine reviews).
If available and when clinically appropriate, outreach care for adults with cystic fibrosis may be provided by the specialist cystic fibrosis multidisciplinary team at a local hospital.
The specialist cystic fibrosis centre should have a point of contact available at all times (day or night) for urgent enquiries from people with cystic fibrosis and their family members or carers (as appropriate).
Consider telemedicine or home visits for routine monitoring when they are more appropriate than outpatient visits and if the person with cystic fibrosis prefers it.
Make arrangements (including providing equipment and expert support) for people to have intravenous antibiotic therapy at home, when this is appropriate.
## Multidisciplinary team
The specialist cystic fibrosis multidisciplinary team should include at least one of each (depending on the size of the clinic) of the following professionals, who should have specialist expertise in the condition:
specialist paediatricians or adult physicians
specialist nurses
specialist physiotherapists
specialist dietitians
specialist pharmacists
specialist clinical psychologists.
The specialist cystic fibrosis multidisciplinary team should be led by a specialist paediatrician or adult physician.
The specialist cystic fibrosis multidisciplinary team should either include or have access to social workers.
Social workers should provide advice and support to people with cystic fibrosis and their family members or carers (as appropriate), for example on:
help with adjusting to long-term treatment (such as taking regular medicines)
education
employment
government benefits
respite care.
Specialist nurses (working with specialist paediatricians or physicians) should coordinate care and facilitate communication between other members of the cystic fibrosis team, and act as advocates for people with cystic fibrosis and their family members or carers (as appropriate). Key clinical roles could include:
support during and after diagnosis and when starting treatment
triage
advanced clinical assessment
coordinating home intravenous antibiotic services, including intravenous access.
Specialist physiotherapists should assess and advise people with cystic fibrosis at clinic, at inpatient admissions, during pulmonary exacerbations and at their annual review. Assessment and advice could cover airway clearance, nebuliser use, musculoskeletal disorders, exercise, physical activity and urinary incontinence.
Specialist dietitians should assess and advise people with cystic fibrosis about all aspects of nutrition at outpatient clinic visits, during inpatient admissions and at their annual review (see nutritional interventions).
Specialist pharmacists should advise people with cystic fibrosis on medicines optimisation at outpatient clinic visits, during inpatient admissions, on discharge from hospital and at annual review. They should advise healthcare professionals on all aspects of medicines use and prescribing, and support GPs, community pharmacists and homecare providers to ensure that people with cystic fibrosis get the medicines they need without interruption.
Specialist clinical psychologists should assess and advise people with cystic fibrosis and their family members or carers (as appropriate) at outpatient clinic visits and (if needed) at other outpatient appointments, during inpatient admissions, and at their annual review (see psychological assessment).
The specialist cystic fibrosis multidisciplinary team should either include or have access to specialist expertise relevant to cystic fibrosis in the following areas:
microbiology
pulmonary physiology
diabetes
gastroenterology
hepatology
rheumatology
psychiatry
interventional radiology
surgery (gastrointestinal, thoracic, and ear, nose and throat)
-bstetrics
palliative care.
The specialist cystic fibrosis multidisciplinary team should work with GPs, and provide timely information so that GPs can support people with cystic fibrosis by:
prescribing cystic fibrosis medicines:
in batches of at least 1 month at a time for routine medicines
for longer periods if advised by the specialist team
following guidance on arrangements for prescriptions of unlicensed medicines
providing routine annual immunisation, including any alterations for people with cystic fibrosis and flu vaccinations for family members and carers
managing health problems not related to cystic fibrosis
certification of illnesses
working in partnership with cystic fibrosis homecare teams, particularly for end of life care
providing care for the person's family members or carers.
## Transition to adult services
Begin discussing the transition process to adult services with young people with cystic fibrosis when they are 12 years old, and with their family members or carers (as appropriate).
All cystic fibrosis services should have a coordinated and documented pathway for transition from children's to adults' services that includes plans for managing all cystic-fibrosis-related aspects of care.
Ask people with cystic fibrosis and their family members or carers (as appropriate) for feedback on the quality of the transition service, taking account of the section on planning and developing transition services in the NICE guideline on transition for young people using health or social care services.
For more guidance on managing transition from children's to adults' services, see the NICE guideline on transition for young people using health or social care services. In particular, see the sections on:
transition planning, for guidance on when transition should happen
named workers
-verarching principles, for guidance on joint responsibility and working together with other organisations.
# Complications of cystic fibrosis
Be aware that people with cystic fibrosis are at risk of the following common complications:
being underweight
meconium ileus (affects 1 in 7 newborn babies)
fat-soluble vitamin deficiencies (including vitamins A, D, E and K)
distal intestinal obstruction syndrome
muscle pains and arthralgia
male infertility caused by obstructive azoospermia (almost all males with cystic fibrosis are infertile)
reduced female fertility
upper airway complications, including nasal polyps and sinusitis (prevalence increases with age)
chronic liver disease (the prevalence increases with age until early adulthood)
urinary stress incontinence
cystic-fibrosis-related diabetes (uncommon in children under 10 years, but the prevalence increases with age and it affects up to 1 in 2 adults)
reduced bone mineral density (including osteoporosis).
Be aware that people with cystic fibrosis are at risk of the following less common complications:
cystic-fibrosis-related arthritis
delayed puberty (associated with severe cystic fibrosis)
renal calculi (incidence increases with age and 1 in 20 adults are affected).
# Annual and routine reviews
Be aware that:
the aim of cystic fibrosis care is to prevent or limit symptoms and complications of the condition
routine monitoring and annual assessments are crucial in providing effective care.
Offer people with cystic fibrosis a comprehensive annual review that includes the following:
a pulmonary assessment (see pulmonary monitoring)
an assessment of nutrition and intestinal absorption (see nutritional interventions and exocrine pancreatic insufficiency)
an assessment for liver disease (see liver disease)
testing for cystic-fibrosis-related diabetes, from 10 years of age (see cystic-fibrosis-related diabetes)
an assessment for other potential or existing cystic fibrosis complications (see complications of cystic fibrosis)
a psychological assessment (see psychological assessment)
assessments by a specialist nurse, physiotherapist, pharmacist and social worker (see service delivery)
a review of their exercise programme (see exercise).
Provide regular routine reviews for people with cystic fibrosis, and do these more frequently immediately after diagnosis and in early life. For example:
weekly in their first month of life
every 4 weeks when they are between 1 and 12 months old
every 6 to 8 weeks when they are between 1 and 5 years old
every 8 to 12 weeks when they are over 5 years old
every 3 to 6 months as adults.
# Pulmonary monitoring, assessment and management
## Pulmonary monitoring
For people with cystic fibrosis who have clinical evidence of lung disease, base the frequency of routine reviews on their clinical condition but review children and young people at least every 8 weeks and adults at least every 3 months. If appropriate, think about using the review schedules in recommendation 1.5.3.
Include the following at each routine review, in relation to pulmonary assessment, for people with cystic fibrosis:
a clinical assessment, including a review of clinical history and medicines adherence, and a physical examination with measurement of weight and length or height
measurement of oxygen saturation
taking respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or nasal pharyngeal aspirate (NPA)
lung function testing with spirometry (including forced expiratory volume in 1 second , forced vital capacity , and forced expiratory flow 25–75%) in adults, and in children and young people who can do this.
If spirometry is normal at a routine review, consider measuring lung clearance index.
Include the following at each annual review in relation to pulmonary assessment for people with cystic fibrosis:
a clinical assessment, including a review of the clinical history and medicines adherence, and a physical examination, with measurement of weight and length or height
a physiotherapy assessment
measurement of oxygen saturation
a chest X-ray
blood tests, including white cell count, aspergillus serology and serum IgE
taking respiratory secretion samples for microbiological investigations (including non-tuberculous mycobacteria)
lung function testing (for example with spirometry, including FEV1, FVC, and FEF 25–75%) in adults, and in children and young people who can do this.
Consider measuring lung clearance index at each annual review if spirometry is normal.
For people with cystic fibrosis with lung disease who have symptoms that are concerning them or their family members or carers (as appropriate), consider which of the following may be useful:
review of clinical history
physical examination, including measurement of weight and length or height
measurement of oxygen saturation
taking respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or NPA if not
for adults, blood tests to measure white cell count and inflammatory markers such as C‑reactive protein
lung function testing, for example with spirometry (including FEV1, FVC, and FEF 25–75%) in adults, and in children and young people who can do this
lung clearance index for people with normal spirometry results.Depending on the assessments that are needed, decide whether to provide a remote telemedicine or face-to-face assessment.
Think about doing a low-dose chest CT scan for children with cystic fibrosis who have not had a chest CT scan before, to detect features that other tests (such as a plain chest X-ray) would miss (for example early bronchiectasis).
Think about doing a chest X-ray for people with cystic fibrosis during or after treatment for an exacerbation of lung disease (taking account of severity), if:
the exacerbation does not respond to treatment or
a chest X-ray before treatment showed new radiological abnormalities.
Monitor the treatment response during and after an exacerbation of lung disease by assessing whether the symptoms and signs have resolved, and as appropriate:
take respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or NPA if not
test lung function, for example with spirometry (including FEV1, FVC and FEF 25–75%) in adults, and in children and young people who can do this
measure oxygen saturation.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Think about using broncho-alveolar lavage to obtain airway samples for microbiological investigation in people with cystic fibrosis if:
they have lung disease that has not responded adequately to treatment and
the cause of the disease cannot be found with non-invasive upper airway respiratory secretion sampling (including sputum induction if appropriate).
## Airway clearance techniques
Discuss the use of airway clearance techniques with people with cystic fibrosis who do not have clinical evidence of lung disease and their parents or carers (as appropriate). Provide them with training in airway clearance techniques and explain when to use them.
Offer training in airway clearance techniques to people with cystic fibrosis who have clinical evidence of lung disease and their parents or carers (as appropriate).
When choosing an airway clearance technique for people with cystic fibrosis:
assess their ability to clear mucus from their lungs, and offer an individualised plan to optimise this
take account of their preferences and (if appropriate) those of their parents and carers
take account of any factors that may influence adherence.
Regularly assess the effectiveness of airway clearance techniques, and modify the technique or use a different one if needed.
Do not offer high-frequency chest wall oscillation as an airway clearance technique for people with cystic fibrosis except in exceptional clinical circumstances. The specialist cystic fibrosis team will decide whether these circumstances apply, and their decision would then be subject to the NHS England policy on Individual Funding Requests. Be aware that the evidence shows high-frequency chest wall oscillation is not as effective as other airway clearance techniques.
Consider using non-invasive ventilation in people with cystic fibrosis who have moderate or severe lung disease and cannot clear their lungs using standard airway clearance techniques.
## Mucoactive agents
Offer a mucoactive agent to people with cystic fibrosis who have clinical evidence of lung disease.
Offer rhDNase (dornase alfa; recombinant human deoxyribonuclease) as the first choice of mucoactive agent. October 2017: note that this was an off-label use for children under 5. See NICE's information on prescribing medicines.
If clinical evaluation or lung function testing indicates an inadequate response to rhDNase, consider both rhDNase and hypertonic sodium chloride or hypertonic sodium chloride alone. October 2017: note that this was an off-label use for children under 5. See NICE's information on prescribing medicines.
Consider mannitol dry powder for inhalation for children and young people who cannot use rhDNase and hypertonic sodium chloride because of ineligibility, intolerance or inadequate response. October 2017: note that this was an off-label use of mannitol dry powder for children. See NICE's information on prescribing medicines.
Mannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:
who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and
whose lung function is rapidly declining (forced expiratory volume in 1 second decline greater than 2% annually) and
for whom other osmotic agents are not considered appropriate.
People currently receiving mannitol whose cystic fibrosis does not meet the criteria in 1.6.21 should be able to continue treatment until they and their clinician consider it appropriate to stop.
For recommendations on using lumacaftor–ivacaftor, see the NICE technology appraisal guidance on lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation.
## Pulmonary infection
Offer flucloxacillin as antibiotic prophylaxis against respiratory Staphylococcus aureus infection for children with cystic fibrosis from the point of diagnosis up to age 3, and consider continuing up to 6 years of age. Before starting flucloxacillin, discuss the uncertainties and possible adverse effects with their parents or carers (as appropriate). For children who are allergic to penicillins, consider an alternative oral anti-Staphylococcus aureus agent. October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.
For children who are taking antibiotic prophylaxis and have a respiratory sample culture that is positive for Staphylococcus aureus:
review prophylaxis adherence and help the child's parents or carers (as appropriate) with any difficulties they are having
start treatment-dose anti-Staphylococcus aureus antibiotics
restart prophylaxis after treatment, even if treatment has not been successful.
For people who are not taking prophylaxis and have a new Staphylococcus aureus infection (that is, previous respiratory sample cultures did not show Staphylococcus aureus infection):
if they are clinically well, consider an oral anti-Staphylococcus aureus agent
if they are clinically unwell and have pulmonary disease, consider oral or intravenous (depending on infection severity) broad-spectrum antibiotics that include an anti-Staphylococcus aureus agent.
Consider a long-term antibiotic to suppress chronic methicillin-sensitive Staphylococcus aureus (MSSA) respiratory infection in people whose pulmonary disease is stable.
For people with chronic MSSA respiratory infection who become clinically unwell with pulmonary disease, consider oral or intravenous broad-spectrum antibiotics (depending on infection severity) that include an anti-Staphylococcus aureus agent.
For people with new evidence of methicillin-resistant Staphylococcus aureus (MRSA) respiratory infection (with or without pulmonary exacerbation), seek specialist microbiological advice on treatment.
Do not routinely use antibiotics to suppress chronic MRSA in people with stable pulmonary disease.
If a person with cystic fibrosis and chronic MRSA respiratory infection becomes unwell with a pulmonary exacerbation or shows a decline in pulmonary function, seek specialist microbiological advice.
For guidance on preventing the spread of infection, refer to the NICE guideline on healthcare-associated infections.
If a person with cystic fibrosis develops a new Pseudomonas aeruginosa infection (that is, recent respiratory secretion sample cultures showed no infection):
if they are clinically well:
commence eradication therapy with a course of oral or intravenous antibiotics, together with an inhaled antibiotic
follow this with an extended course of oral and inhaled antibiotics
if they are clinically unwell:
commence eradication therapy with a course of intravenous antibiotics together with an inhaled antibiotic
follow this with an extended course of oral and inhaled antibiotics.
If eradication treatment is not successful despite treatment as recommended in 1.6.33, offer sustained treatment with an inhaled antibiotic. Consider nebulised colistimethate sodium as first-line treatment. (See recommendation 1.6.37 on using colistimethate dry powder for inhalation).
Depending on infection severity, use either an oral antibiotic or a combination of 2 intravenous antibiotics of different classes for people:
who have chronic Pseudomonas aeruginosa infection (when treatment has not eradicated the infection) and
who become clinically unwell with a pulmonary disease exacerbation.
If a person with chronic Pseudomonas aeruginosa infection repeatedly becomes clinically unwell with pulmonary disease exacerbations, consider changing the antibiotic regimens used to treat exacerbations.
Colistimethate sodium dry powder for inhalation (DPI) is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:
they would clinically benefit from continued colistimethate sodium but do not tolerate it in its nebulised form and thus tobramycin therapy would otherwise be considered and
the manufacturer provides colistimethate sodium DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.
For people with chronic Pseudomonas aeruginosa infection who are clinically deteriorating despite regular inhaled colistimethate sodium, consider nebulised aztreonam, nebulised tobramycin, or tobramycin DPI (see recommendation 1.6.39 on using tobramycin DPI).October 2017: note that this was an off-label use of all the drugs listed for children under 6. See NICE's information on prescribing medicines.
Tobramycin DPI is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:
nebulised tobramycin is considered an appropriate treatment, that is, when colistimethate sodium is contraindicated, is not tolerated or has not produced an adequate clinical response and
the manufacturer provides tobramycin DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.
People currently using tobramycin DPI or colistimethate sodium DPI that is not recommended according to recommendations 1.6.37 or 1.6.39 should be able to continue treatment until they and their clinician consider it appropriate to stop. For children and young people this decision should be made jointly by the clinician, the child or young person and their parents or carers.
For people with cystic fibrosis who develop a new Burkholderia cepacia complex infection (that is, recent respiratory sample cultures showed no Burkholderia cepacia infection):
whether they are clinically well or not, give antibiotic eradication therapy using a combination of intravenous antibiotics
seek specialist microbiological advice on the choice of antibiotics to use.
Be aware that there is no evidence to support using antibiotics to suppress chronic Burkholderia cepacia complex infection in people with cystic fibrosis who have stable pulmonary status. Discuss the possible risks (for example drug toxicity) of treating the infection with the person and their family members or carers (as appropriate).
For people with cystic fibrosis who have chronic Burkholderia cepacia complex infection (when treatment has not eradicated the infection) and who become clinically unwell with a pulmonary disease exacerbation:
give a combination of oral or intravenous antibiotics
seek specialist microbiological advice on which antibiotics to use.
For people with cystic fibrosis who have chronic Burkholderia cepacia complex infection and declining pulmonary status:
consider sustained treatment with an inhaled antibiotic to suppress the infection
seek specialist microbiological advice on which antibiotic to use
stop this treatment if there is no observed benefit.
For people with cystic fibrosis who develop a Haemophilus influenzae infection (diagnosed by a positive respiratory sample culture) but do not have clinical evidence of pulmonary infection, treat with an appropriate oral antibiotic.
For people with cystic fibrosis who develop a Haemophilus influenzae infection (diagnosed by a positive respiratory sample culture) and are unwell with clinical evidence of pulmonary infection, treat with an appropriate antibiotic, given orally or intravenously depending on the severity of the illness.
For people with cystic fibrosis who are clinically well but whose airway secretions are persistently positive for non-tuberculous mycobacteria, discuss with them and their family members or carers (as appropriate):
the clinical uncertainties about non-tuberculous mycobacterial infection and
the possible benefits and risks (for example, drug toxicity) of treating it.
If a person with cystic fibrosis has a respiratory sample test positive for new non-tuberculous mycobacteria infection, repeat the test for confirmation.
If repeat testing confirms persistent non-tuberculous mycobacteria, do a chest CT scan to look for changes consistent with non-tuberculous mycobacteria disease.
Consider non-tuberculous mycobacterial therapy aimed at eradication for people with cystic fibrosis:
whose airway secretions persistently test positive for non-tuberculous mycobacteria and
who are clinically unwell with pulmonary disease, or who have a chest CT scan showing changes consistent with non-tuberculous mycobacteria disease and
whose pulmonary disease has not responded to other recommended treatments.Seek specialist microbiological advice on which antibiotics to use and on the duration of treatment.
Do not routinely use antifungal agents to suppress chronic Aspergillus fumigatus complex respiratory infection (diagnosed by persistently positive respiratory secretion sample cultures) in people with cystic fibrosis and stable pulmonary status.
For people with cystic fibrosis with chronic Aspergillus fumigatus complex respiratory infection and declining pulmonary status:
consider sustained treatment with an antifungal agent to suppress the infection
seek specialist microbiological advice on which antifungal agent to use
stop treatment or change to a different agent if there is no benefit.
For people with cystic fibrosis with elevated aspergillus serology (aspergillus-specific IgG and/or IgE) and declining pulmonary function despite optimised pulmonary treatment, think about treating for allergic bronchopulmonary aspergillosis or other aspergillus airway disease, especially if there are consistent chest X-ray or CT scan changes.
For people with cystic fibrosis who have a pulmonary disease exacerbation and no clear cause (based on recent respiratory secretion sample cultures):
use an oral or intravenous (depending on the exacerbation severity) broad-spectrum antibiotic
continue collecting respiratory secretion samples, and change treatments if a pathogen is identified and a more appropriate treatment is available.
## Immunomodulatory agents
For people with cystic fibrosis and deteriorating lung function or repeated pulmonary exacerbations, offer long-term treatment with azithromycin at an immunomodulatory dose. October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.
For people who have continued deterioration in lung function, or continuing pulmonary exacerbations while receiving long-term treatment with azithromycin, stop azithromycin and consider oral corticosteroids.
Do not offer inhaled corticosteroids as an immunomodulatory treatment for cystic fibrosis.
# Other monitoring, assessment and management
## Nutritional interventions and exocrine pancreatic insufficiency
The cystic fibrosis specialist dietitian should offer advice on the benefits of optimal nutrition, and at the annual assessment review the person's:
total nutritional intake, including energy intake (calories)
estimated nutritional needs
pancreatic enzyme replacement therapy, if appropriate.
Encourage people to increase calorie intake by increasing portion size and eating high-energy foods if there is concern about their nutrition (including weight loss and inadequate weight gain).
If increased portion size and high-energy foods are not effective, consider a trial of oral nutritional supplements.
If attempts to increase calorie intake are not effective, consider:
supplementation with enteral tube feeding or
for adults, a short-term trial of an appetite stimulant (for example up to 3 months).October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.
Test for exocrine pancreatic insufficiency in people with cystic fibrosis, using a non-invasive technique such as stool elastase estimation. If the test result is normal, repeat it if symptoms or signs suggesting malabsorption occur.
Offer oral pancreatic enzyme replacement therapy to people with exocrine pancreatic insufficiency. Adjust the dose as needed to minimise any symptoms or signs of malabsorption.
Consider an acid suppression agent (for example an H2 receptor antagonist or a proton pump inhibitor) for people who have persistent symptoms or signs of malabsorption despite optimal pancreatic enzyme replacement therapy. October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.
## Distal intestinal obstruction syndrome
Be aware that a variety of conditions can cause acute abdominal pain and resemble distal intestinal obstruction syndrome in people with cystic fibrosis, for example:
constipation
appendicitis
intussusception
cholecystitis.
Suspect distal intestinal obstruction syndrome in people with cystic fibrosis who have an acute onset of peri-umbilical or right lower quadrant abdominal pain and any of the following:
a palpable mass in the right lower quadrant
faecal loading in the right lower quadrant on a plain abdominal X-ray, especially if associated with small intestine air-fluid levels
clinical features of partial or complete intestinal obstruction, such as vomiting (especially bilious) and abdominal distension.
For people who have an acute onset of peri-umbilical abdominal pain but no other clinical or radiological features of distal intestinal obstruction syndrome, consider further imaging, for example with an:
abdominal ultrasound scan or
abdominal CT scan.
Manage suspected distal intestinal obstruction syndrome in a specialist cystic fibrosis centre, with supervision from specialists who have expertise in recognising and treating the condition and its complications.
Offer oral or intravenous fluids to ensure adequate hydration (and rehydration if needed) for people with distal intestinal obstruction syndrome.
Consider diatrizoate meglumine and diatrizoate sodium solution (Gastrografin) (orally or via an enteral tube) as first-line treatment for distal intestinal obstruction syndrome.
If diatrizoate meglumine and diatrizoate sodium solution (Gastrografin) is not effective, consider an iso-osmotic polyethylene glycol and electrolyte (PEG) solution (macrogols) (orally or via an enteral tube) as a second-line treatment.
Consider surgery as a last resort, if prolonged treatment with a PEG solution is not effective.
To reduce the risk of distal intestinal obstruction syndrome recurring:
encourage people to drink plenty of fluids
-ptimise pancreatic enzyme replacement therapy (see nutritional interventions and exocrine pancreatic insufficiency)
consider advising regular treatment with a stool-softening agent such as lactulose or a PEG solution.
## Liver disease
Perform a clinical assessment and liver function blood tests at the annual review for people with cystic fibrosis.
If liver function blood tests are abnormal, perform a liver ultrasound scan and consider ursodeoxycholic acid treatment. October 2017: note that this was an off-label use for adults. See NICE's information on prescribing medicines.
Think about stopping ursodeoxycholic acid if liver function blood tests return to normal and clinical assessment and liver ultrasound scan show no liver disease.
If ursodeoxycholic acid is stopped, monitor for re-emergence of liver disease using clinical assessment and liver function blood tests.
Think about referring people with cystic fibrosis to a liver specialist if the liver function blood test results are persistently abnormal despite treatment with ursodeoxycholic acid.
Refer people with cystic fibrosis to a liver specialist if they have any of the following:
chronic progressive liver disease, based on clinical assessment, liver function blood tests or the findings on a liver ultrasound scan
liver failure, based on clinical assessment and liver function tests
portal hypertension, haematemesis, splenomegaly or findings on a liver ultrasound scan.
## Cystic-fibrosis-related diabetes
Diagnose cystic-fibrosis-related diabetes using one of the following:
continuous glucose monitoring (CGM)
serial glucose testing over several days
-ral glucose tolerance testing (OGTT) – if OGTT is abnormal perform CGM or serial glucose testing over several days to confirm the diagnosis.
Test for cystic-fibrosis-related diabetes (as detailed in recommendation 1.7.23) in people with cystic fibrosis annually from 10 years of age.
Test for cystic-fibrosis-related diabetes at the end of the first and second trimesters of pregnancy, using CGM or OGTT.
Test for cystic-fibrosis-related diabetes in people with cystic fibrosis who are taking long-term systemic corticosteroids or receiving enteral tube feeding, using CGM or serial glucose monitoring.
Think about testing for cystic-fibrosis-related diabetes in people who still have any of the following despite optimised cystic fibrosis treatment:
unexplained weight loss
a deterioration in lung function as measured by spirometry
increased frequency of pulmonary exacerbations
excessive tiredness.
## Bone mineral density
Consider dual energy X-ray absorptiometry (DXA) bone density scans for people with cystic fibrosis who have factors that put them at high risk of low bone mineral density, such as:
frequent or long-term oral corticosteroid use
frequent intravenous antibiotic use
severe lung disease
undernutrition
previous low-impact fractures
previous transplants
post menopause.
Seek specialist advice for people with a bone mineral density standard deviation below -2.0 (Z score) or -2.5 (T score).
## Exercise
Advise people with cystic fibrosis and their family members or carers (as appropriate) that regular exercise improves both lung function and overall fitness.
Offer people with cystic fibrosis an individualised exercise programme, taking into account their capability and preferences.
Regularly review exercise programmes to monitor the person's progress and ensure that the programme continues to be appropriate for their needs.
Provide people with cystic fibrosis who are having inpatient care with:
an assessment of their exercise capacity
the facilities and support to continue their exercise programme (as appropriate), taking into account the need to prevent cross-infection (see preventing cross-infection) and local infection control guidelines.
## Psychological assessment
At the annual review, the specialist clinical psychologist should include assessments of:
general mental health and wellbeing
quality of life
any factors that are making treatment adherence difficult
indicators of emerging psychosocial problems
behaviours that affect health outcomes.
If a severe mental health condition is identified at any assessment performed by the cystic fibrosis clinical psychologist, refer the person with cystic fibrosis to a mental health practitioner. For guidance on treating mental health conditions, refer to the relevant NICE guideline.
For family members or carers of people with cystic fibrosis, the specialist clinical psychologist should:
assess any cystic-fibrosis-related needs they have
support their psychological wellbeing
refer them to mental health practitioners as needed.
# Preventing cross-infection
For recommendations on preventing and controlling infection, see the NICE guidelines on infection control in primary and community care and healthcare-associated infections, and the NICE quality standard on infection prevention and control.
To prevent cross-infection among people with cystic fibrosis in outpatient and inpatient care, use microbiological surveillance and a local infection control strategy that includes cohorting.
Inform people with cystic fibrosis, their family members or carers (as appropriate) and staff involved in their care about the risk of cross-infection and how to avoid it.
Each specialist cystic fibrosis clinic should be organised to prevent cross-infection. Separate people individually during the clinic, including by organising:
the use of communal areas
attendance at diagnostic, treatment and pharmacy facilities.
Keep people with transmissible or chronic Pseudomonas aeruginosa or Burkholderia cepacia complex infection separate from people who do not have these infections, for example by using separate outpatient clinics.
Consider keeping people with cystic fibrosis who have intermittent isolation of Pseudomonas aeruginosa separate from people who do not have this infection, for example by using separate outpatient clinics. Help people with cystic fibrosis plan their inpatient attendance to avoid contact with each other, for example when they use:
hospital restaurants, schools and recreation areas
diagnostic, treatment and pharmacy facilities (see information and support).
During inpatient care, give people with cystic fibrosis individual rooms with en-suite facilities.
# Terms used in this guideline
## Immunomodulatory dose
A dose of a drug that is less than the minimum inhibitory dose.
## Outreach care
A model of care in which the specialist multidisciplinary cystic fibrosis team provide outpatient clinics in local hospitals.
## Pulmonary exacerbation
The sudden or recent worsening of clinical symptoms or signs. This is frequently caused by an acute pulmonary infection.
## Pulmonary infection
In people with cystic fibrosis, this can be diagnosed based on symptoms or signs, or by identifying pathogens in respiratory secretion samples.
## Shared-care model (network cystic fibrosis clinic)
When a local hospital cares for people with cystic fibrosis, with oversight, support and direct involvement from members of a specialist cystic fibrosis multidisciplinary team.
## Telemedicine
Providing clinical services remotely, using phone and video messaging to communicate with the patient.
## Young people
Aged 12 to 17 years.# Context
Cystic fibrosis is a multi-system genetic disorder affecting the lungs, pancreas, liver and intestine. It can have a significant impact on life expectancy and quality of life. The current median age of those who have died is 28 years and the median predicted survival is 45.1 years.
Diagnosis is primarily made during newborn screening. The median age at diagnosis is 2 months, and 1 in every 2500 babies born in the UK has cystic fibrosis. Approximately 60% of people on the UK cystic fibrosis registry are aged over 16 years.
Many different mutations are responsible for cystic fibrosis. The UK registry shows that 90.8% of people with cystic fibrosis have one known genotype; however 8.9% of people have at least one unknown genotype.
Lung function is often reduced in cystic fibrosis. The typical measure of lung function is forced expiratory volume in 1 second (FEV1). FEV1 is a key predictor of life expectancy in people with cystic fibrosis, and optimising lung function is a major goal of care.
Lung infections are a cause of significant morbidity in cystic fibrosis. Chronic infection (for example with Staphylococcus aureus and Pseudomonas aeruginosa) may need long-term use of antibiotics.
There is variation across the country in the multidisciplinary team structures used, the arrangements services make for providing care, and in the resources available to support services. Particular problems may arise with smaller shared-care clinic arrangements. In some centres, both inpatient and outpatient facilities are limited. For example, there may be problems in arranging admission to single rooms with en‑suite facilities. If adequate protocols are not in place, then there is a risk of cross-infection.
By making robust recommendations based on the available evidence and best practice in cystic fibrosis care, this guideline will help improve care for this highly complex condition.# Recommendations for research
The committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Liver disease
Should all children with meconium ileus receive ursodeoxycholic acid from diagnosis?
## Why this is important
Liver disease is the third most common cause of mortality in people with cystic fibrosis, and around 10 to 30% of people with cystic fibrosis will develop cystic-fibrosis-related liver disease. Children with meconium ileus are at an increased risk of liver disease, and starting treatment with ursodeoxycholic acid from diagnosis may reduce this risk. Ursodeoxycholic acid appears safe, is well tolerated and cheap. Routine use could increase people's overall quality of life and reduce the need for subsequent treatment for liver disease, but more research is needed into the effectiveness and safety of this treatment.
# Airway clearance techniques
How effective are daily airway clearance techniques in maintaining lung function in infants and children with cystic fibrosis?
## Why this is important
There has been debate about the level of physiotherapy needed to preserve lung health since healthcare systems started diagnosing cystic fibrosis through newborn screening. Some clinical teams teach parents airway clearance techniques and recommend using them daily, but others use alternatives such as parental respiratory assessment tools with structured exercise. Routine airway clearance from diagnosis takes up a lot of time and places considerable responsibility on the parents and carers. These techniques are also difficult to perform, particularly with an infant or young child who does not understand what is happening. It is important to find out whether daily airway clearance techniques are helping to maintain lung health or are creating an unnecessary burden on parents and carers. Future research should look at the impact on the lives of parents, family members and carers, as well as long-term clinical outcomes for infants and children with cystic fibrosis.
# Monitoring pulmonary disease
Is lung clearance index a useful and cost-effective tool for the routine assessment and monitoring of changes in pulmonary status in people with cystic fibrosis?
## Why this is important
Assessing the severity of lung disease is difficult in younger children. Not all children under 5 years can do spirometry tests and they are not sufficiently sensitive in people with good lung function, where CT scans can show pulmonary status changes before spirometry changes. A simple, sensitive and reproducible measurement such as lung clearance index allows assessment of respiratory status in people with cystic fibrosis, and could improve clinical decision-making.
# Psychological assessment
What is the most effective measure of psychological functioning to use as a test for thresholds of concern in people with cystic fibrosis?
## Why this is important
There are no validated tools to assess psychological and behavioural problems in people with cystic fibrosis, and these would be useful to validate generic measures (for example for depression and anxiety). People with a long-term physical health condition are more likely to present with mental health problems. NHS England highlights that prevention of mental health problems is the most cost-effective service that can be provided. To prevent mental health problems, all people with cystic fibrosis would need to have their mental health status routinely and regularly assessed. People with cystic fibrosis would benefit, therefore, from having a routine test that would show who needs psychological intervention. This would allow early intervention to maintain or improve quality of life, prevent mental health problems from developing, and improve health outcomes through an improvement in wellbeing.
# Monitoring for cystic-fibrosis-related diabetes
What is the most effective strategy to detect diabetes in people with cystic fibrosis?
## Why this is important
Diabetes develops and presents very differently in people with cystic fibrosis. Although annual testing for cystic-fibrosis-related diabetes is recommended in this guideline for people over 10 with cystic fibrosis, there is a lack of evidence on how to diagnose the condition. There is currently variation in practice, with cystic fibrosis centres using different combinations of the oral glucose tolerance test, HbA1c, serial glucose testing, and continuous glucose monitoring systems. Identifying which strategy is most effective for early identification of cystic-fibrosis-related diabetes would help teams start prompt treatment and prevent the clinical decline associated with the condition.
# Mucoactive agents
What is the most clinically and cost-effective dose of rhDNase (dornase alfa; recombinant human deoxyribonuclease) for people with cystic fibrosis?
## Why this is important
People with cystic fibrosis often have complex treatment schedules, which can include multiple nebulised treatments. Taking daily rhDNase increases the burden on them. Because of this, it is essential to find out whether rhDNase needs to be taken this often to provide clinical benefit. There is some evidence that alternate-day rhDNase is just as effective, and if this is confirmed then overall treatment adherence may improve and cost savings would be made. The current evidence base is mostly small, underpowered, short-term trials, in people who have had this treatment before. Consequently, it is not clear what the long-term impact of different doses of rhDNase are for people with cystic fibrosis. It may be cost effective to switch to alternate-day rhDNase if it is shown to be as effective as daily rhDNase.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline incorporates recommendations from 2 NICE technology appraisals:\n\nMannitol dry powder for inhalation for treating cystic fibrosis (NICE technology appraisal guidance 266)\n\nColistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis (NICE technology appraisal guidance 276).\n\nThese technology appraisals still apply, and have not been replaced by the guideline.\n\n# Diagnosis of cystic fibrosis\n\nBe aware that cystic fibrosis can be diagnosed based on:\n\npositive test results in people with no symptoms, for example infant screening (blood spot immunoreactive trypsin test) followed by sweat and gene tests for confirmation or\n\nclinical manifestations, supported by sweat or gene test results for confirmation or\n\nclinical manifestations alone, in the rare case of people with symptoms who have normal sweat or gene test results.\n\nAssess for cystic fibrosis and, when clinically appropriate, perform a sweat test (for children and young people) or a cystic fibrosis gene test (for adults) in people with any of the following:\n\nfamily history\n\ncongenital intestinal atresia\n\nmeconium ileus\n\nsymptoms and signs that suggest distal intestinal obstruction syndrome\n\nfaltering growth (in infants and young children)\n\nundernutrition\n\nrecurrent and chronic pulmonary disease, such as:\n\n\n\nrecurrent lower respiratory tract infections\n\nclinical or radiological evidence of lung disease (in particular bronchiectasis)\n\npersistent chest X-ray changes\n\nchronic wet or productive cough\n\n\n\nchronic sinus disease\n\nobstructive azoospermia (in young people and adults)\n\nacute or chronic pancreatitis\n\nmalabsorption\n\nrectal prolapse (in children)\n\npseudo-Bartter syndrome.\n\nRefer people with suspected cystic fibrosis to a specialist cystic fibrosis centre if:\n\nthey have a positive or equivocal sweat test result\n\ntheir assessment suggests they have cystic fibrosis but their test results are normal\n\ngene testing reveals 1 or more cystic fibrosis mutations.\n\n# Information and support\n\nProvide people who are newly diagnosed with cystic fibrosis and their family members or carers (as appropriate) with opportunities to discuss their concerns.\n\nInformation and support should be provided by healthcare professionals with expertise in cystic fibrosis.\n\nProvide people with suspected or diagnosed cystic fibrosis and their family members or carers (as appropriate) with relevant information that they can understand, and opportunities for discussion on topics such as:\n\ntheir diagnosis\n\nmonitoring of their condition\n\nmanagement choices for their condition\n\npossible or existing complications or comorbidities\n\nimplications for living independently.\n\nProvide people with cystic fibrosis and their family members or carers (as appropriate) with information about their care pathway.\n\nGive information to people with cystic fibrosis and to family members or carers in ways that are individually appropriate. Avoid jargon and use formats that they prefer, for example:\n\nface-to-face discussions\n\ncopies of correspondence\n\nwritten information (such as leaflets)\n\nany digital media and reliable internet sources that are available.\n\nWhen appropriate, provide people with cystic fibrosis and their family members or carers with opportunities for discussion with relevant expert professionals on:\n\navailable resources and support, such as local support and advocacy services\n\nmanaging the risks of cross-infection\n\nimplications of the condition for school and education\n\ncareer planning\n\ntransition to adult care\n\nforeign travel\n\nfertility and contraception\n\npregnancy and parenting\n\norgan transplantation\n\nend of life care.\n\nProvide people with cystic fibrosis with information about how to contact other people with cystic fibrosis without risking cross-infection (see preventing cross-infection), for example by directing them to online support groups.\n\nFor more information on communication, providing information and shared decision making in adult NHS services, see NICE guidelines on patient experience in adult NHS services and shared decision making.\n\nBe aware that people with cystic fibrosis and their family members or carers will need emotional support and some may need specialist psychological support (see psychological assessment), in particular:\n\nat diagnosis\n\nat times of transition (for example, when starting or changing school, moving from education to work, or changing to living independently for the first time)\n\nin relation to fertility, including family planning, pregnancy and infertility\n\nto cope with complications of cystic fibrosis\n\nwhen waiting for or having organ transplantation\n\nwhen approaching the end of life.\n\n# Service delivery\n\n## Service configuration\n\nCare for people with cystic fibrosis should be provided by a specialist cystic fibrosis multidisciplinary team based at a specialist cystic fibrosis centre (see multidisciplinary team).\n\nSpecialist cystic fibrosis centres should:\n\nplan patient care (including outpatient and inpatient care), taking into account the risk of cross-infection (see preventing cross-infection)\n\nmaintain local and national registers of patients that include information about their clinical condition, treatment and outcomes\n\naudit practice and outcomes.\n\nWhen a shared-care model is used for children and young people, it should include:\n\nformal arrangements between the local paediatric team at the shared-care centre and the multidisciplinary team at the specialist cystic fibrosis centre\n\ndirect involvement of specialist cystic fibrosis multidisciplinary team members\n\nan annual assessment and at least one other review per year by the specialist cystic fibrosis multidisciplinary team, in addition to reviews by the local paediatric team (see annual and routine reviews).\n\nIf available and when clinically appropriate, outreach care for adults with cystic fibrosis may be provided by the specialist cystic fibrosis multidisciplinary team at a local hospital.\n\nThe specialist cystic fibrosis centre should have a point of contact available at all times (day or night) for urgent enquiries from people with cystic fibrosis and their family members or carers (as appropriate).\n\nConsider telemedicine or home visits for routine monitoring when they are more appropriate than outpatient visits and if the person with cystic fibrosis prefers it.\n\nMake arrangements (including providing equipment and expert support) for people to have intravenous antibiotic therapy at home, when this is appropriate.\n\n## Multidisciplinary team\n\nThe specialist cystic fibrosis multidisciplinary team should include at least one of each (depending on the size of the clinic) of the following professionals, who should have specialist expertise in the condition:\n\nspecialist paediatricians or adult physicians\n\nspecialist nurses\n\nspecialist physiotherapists\n\nspecialist dietitians\n\nspecialist pharmacists\n\nspecialist clinical psychologists.\n\nThe specialist cystic fibrosis multidisciplinary team should be led by a specialist paediatrician or adult physician.\n\nThe specialist cystic fibrosis multidisciplinary team should either include or have access to social workers.\n\nSocial workers should provide advice and support to people with cystic fibrosis and their family members or carers (as appropriate), for example on:\n\nhelp with adjusting to long-term treatment (such as taking regular medicines)\n\neducation\n\nemployment\n\ngovernment benefits\n\nrespite care.\n\nSpecialist nurses (working with specialist paediatricians or physicians) should coordinate care and facilitate communication between other members of the cystic fibrosis team, and act as advocates for people with cystic fibrosis and their family members or carers (as appropriate). Key clinical roles could include:\n\nsupport during and after diagnosis and when starting treatment\n\ntriage\n\nadvanced clinical assessment\n\ncoordinating home intravenous antibiotic services, including intravenous access.\n\nSpecialist physiotherapists should assess and advise people with cystic fibrosis at clinic, at inpatient admissions, during pulmonary exacerbations and at their annual review. Assessment and advice could cover airway clearance, nebuliser use, musculoskeletal disorders, exercise, physical activity and urinary incontinence.\n\nSpecialist dietitians should assess and advise people with cystic fibrosis about all aspects of nutrition at outpatient clinic visits, during inpatient admissions and at their annual review (see nutritional interventions).\n\nSpecialist pharmacists should advise people with cystic fibrosis on medicines optimisation at outpatient clinic visits, during inpatient admissions, on discharge from hospital and at annual review. They should advise healthcare professionals on all aspects of medicines use and prescribing, and support GPs, community pharmacists and homecare providers to ensure that people with cystic fibrosis get the medicines they need without interruption.\n\nSpecialist clinical psychologists should assess and advise people with cystic fibrosis and their family members or carers (as appropriate) at outpatient clinic visits and (if needed) at other outpatient appointments, during inpatient admissions, and at their annual review (see psychological assessment).\n\nThe specialist cystic fibrosis multidisciplinary team should either include or have access to specialist expertise relevant to cystic fibrosis in the following areas:\n\nmicrobiology\n\npulmonary physiology\n\ndiabetes\n\ngastroenterology\n\nhepatology\n\nrheumatology\n\npsychiatry\n\ninterventional radiology\n\nsurgery (gastrointestinal, thoracic, and ear, nose and throat)\n\nobstetrics\n\npalliative care.\n\nThe specialist cystic fibrosis multidisciplinary team should work with GPs, and provide timely information so that GPs can support people with cystic fibrosis by:\n\nprescribing cystic fibrosis medicines:\n\n\n\nin batches of at least 1 month at a time for routine medicines\n\nfor longer periods if advised by the specialist team\n\nfollowing guidance on arrangements for prescriptions of unlicensed medicines\n\n\n\nproviding routine annual immunisation, including any alterations for people with cystic fibrosis and flu vaccinations for family members and carers\n\nmanaging health problems not related to cystic fibrosis\n\ncertification of illnesses\n\nworking in partnership with cystic fibrosis homecare teams, particularly for end of life care\n\nproviding care for the person's family members or carers.\n\n## Transition to adult services\n\nBegin discussing the transition process to adult services with young people with cystic fibrosis when they are 12 years old, and with their family members or carers (as appropriate).\n\nAll cystic fibrosis services should have a coordinated and documented pathway for transition from children's to adults' services that includes plans for managing all cystic-fibrosis-related aspects of care.\n\nAsk people with cystic fibrosis and their family members or carers (as appropriate) for feedback on the quality of the transition service, taking account of the section on planning and developing transition services in the NICE guideline on transition for young people using health or social care services.\n\nFor more guidance on managing transition from children's to adults' services, see the NICE guideline on transition for young people using health or social care services. In particular, see the sections on:\n\ntransition planning, for guidance on when transition should happen\n\nnamed workers\n\noverarching principles, for guidance on joint responsibility and working together with other organisations.\n\n# Complications of cystic fibrosis\n\nBe aware that people with cystic fibrosis are at risk of the following common complications:\n\nbeing underweight\n\nmeconium ileus (affects 1 in 7 newborn babies)\n\nfat-soluble vitamin deficiencies (including vitamins A, D, E and K)\n\ndistal intestinal obstruction syndrome\n\nmuscle pains and arthralgia\n\nmale infertility caused by obstructive azoospermia (almost all males with cystic fibrosis are infertile)\n\nreduced female fertility\n\nupper airway complications, including nasal polyps and sinusitis (prevalence increases with age)\n\nchronic liver disease (the prevalence increases with age until early adulthood)\n\nurinary stress incontinence\n\ncystic-fibrosis-related diabetes (uncommon in children under 10 years, but the prevalence increases with age and it affects up to 1 in 2 adults)\n\nreduced bone mineral density (including osteoporosis).\n\nBe aware that people with cystic fibrosis are at risk of the following less common complications:\n\ncystic-fibrosis-related arthritis\n\ndelayed puberty (associated with severe cystic fibrosis)\n\nrenal calculi (incidence increases with age and 1 in 20 adults are affected).\n\n# Annual and routine reviews\n\nBe aware that:\n\nthe aim of cystic fibrosis care is to prevent or limit symptoms and complications of the condition\n\nroutine monitoring and annual assessments are crucial in providing effective care.\n\nOffer people with cystic fibrosis a comprehensive annual review that includes the following:\n\na pulmonary assessment (see pulmonary monitoring)\n\nan assessment of nutrition and intestinal absorption (see nutritional interventions and exocrine pancreatic insufficiency)\n\nan assessment for liver disease (see liver disease)\n\ntesting for cystic-fibrosis-related diabetes, from 10 years of age (see cystic-fibrosis-related diabetes)\n\nan assessment for other potential or existing cystic fibrosis complications (see complications of cystic fibrosis)\n\na psychological assessment (see psychological assessment)\n\nassessments by a specialist nurse, physiotherapist, pharmacist and social worker (see service delivery)\n\na review of their exercise programme (see exercise).\n\nProvide regular routine reviews for people with cystic fibrosis, and do these more frequently immediately after diagnosis and in early life. For example:\n\nweekly in their first month of life\n\nevery 4 weeks when they are between 1 and 12 months old\n\nevery 6 to 8 weeks when they are between 1 and 5 years old\n\nevery 8 to 12 weeks when they are over 5 years old\n\nevery 3 to 6 months as adults.\n\n# Pulmonary monitoring, assessment and management\n\n## Pulmonary monitoring\n\nFor people with cystic fibrosis who have clinical evidence of lung disease, base the frequency of routine reviews on their clinical condition but review children and young people at least every 8 weeks and adults at least every 3 months. If appropriate, think about using the review schedules in recommendation 1.5.3.\n\nInclude the following at each routine review, in relation to pulmonary assessment, for people with cystic fibrosis:\n\na clinical assessment, including a review of clinical history and medicines adherence, and a physical examination with measurement of weight and length or height\n\nmeasurement of oxygen saturation\n\ntaking respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or nasal pharyngeal aspirate (NPA)\n\nlung function testing with spirometry (including forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and forced expiratory flow [FEF] 25–75%) in adults, and in children and young people who can do this.\n\nIf spirometry is normal at a routine review, consider measuring lung clearance index.\n\nInclude the following at each annual review in relation to pulmonary assessment for people with cystic fibrosis:\n\na clinical assessment, including a review of the clinical history and medicines adherence, and a physical examination, with measurement of weight and length or height\n\na physiotherapy assessment\n\nmeasurement of oxygen saturation\n\na chest X-ray\n\nblood tests, including white cell count, aspergillus serology and serum IgE\n\ntaking respiratory secretion samples for microbiological investigations (including non-tuberculous mycobacteria)\n\nlung function testing (for example with spirometry, including FEV1, FVC, and FEF 25–75%) in adults, and in children and young people who can do this.\n\nConsider measuring lung clearance index at each annual review if spirometry is normal.\n\nFor people with cystic fibrosis with lung disease who have symptoms that are concerning them or their family members or carers (as appropriate), consider which of the following may be useful:\n\nreview of clinical history\n\nphysical examination, including measurement of weight and length or height\n\nmeasurement of oxygen saturation\n\ntaking respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or NPA if not\n\nfor adults, blood tests to measure white cell count and inflammatory markers such as C‑reactive protein\n\nlung function testing, for example with spirometry (including FEV1, FVC, and FEF 25–75%) in adults, and in children and young people who can do this\n\nlung clearance index for people with normal spirometry results.Depending on the assessments that are needed, decide whether to provide a remote telemedicine or face-to-face assessment.\n\nThink about doing a low-dose chest CT scan for children with cystic fibrosis who have not had a chest CT scan before, to detect features that other tests (such as a plain chest X-ray) would miss (for example early bronchiectasis).\n\nThink about doing a chest X-ray for people with cystic fibrosis during or after treatment for an exacerbation of lung disease (taking account of severity), if:\n\nthe exacerbation does not respond to treatment or\n\na chest X-ray before treatment showed new radiological abnormalities.\n\nMonitor the treatment response during and after an exacerbation of lung disease by assessing whether the symptoms and signs have resolved, and as appropriate:\n\ntake respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or NPA if not\n\ntest lung function, for example with spirometry (including FEV1, FVC and FEF 25–75%) in adults, and in children and young people who can do this\n\nmeasure oxygen saturation.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nThink about using broncho-alveolar lavage to obtain airway samples for microbiological investigation in people with cystic fibrosis if:\n\nthey have lung disease that has not responded adequately to treatment and\n\nthe cause of the disease cannot be found with non-invasive upper airway respiratory secretion sampling (including sputum induction if appropriate).\n\n## Airway clearance techniques\n\nDiscuss the use of airway clearance techniques with people with cystic fibrosis who do not have clinical evidence of lung disease and their parents or carers (as appropriate). Provide them with training in airway clearance techniques and explain when to use them.\n\nOffer training in airway clearance techniques to people with cystic fibrosis who have clinical evidence of lung disease and their parents or carers (as appropriate).\n\nWhen choosing an airway clearance technique for people with cystic fibrosis:\n\nassess their ability to clear mucus from their lungs, and offer an individualised plan to optimise this\n\ntake account of their preferences and (if appropriate) those of their parents and carers\n\ntake account of any factors that may influence adherence.\n\nRegularly assess the effectiveness of airway clearance techniques, and modify the technique or use a different one if needed.\n\nDo not offer high-frequency chest wall oscillation as an airway clearance technique for people with cystic fibrosis except in exceptional clinical circumstances. The specialist cystic fibrosis team will decide whether these circumstances apply, and their decision would then be subject to the NHS England policy on Individual Funding Requests. Be aware that the evidence shows high-frequency chest wall oscillation is not as effective as other airway clearance techniques.\n\nConsider using non-invasive ventilation in people with cystic fibrosis who have moderate or severe lung disease and cannot clear their lungs using standard airway clearance techniques.\n\n## Mucoactive agents\n\nOffer a mucoactive agent to people with cystic fibrosis who have clinical evidence of lung disease.\n\nOffer rhDNase (dornase alfa; recombinant human deoxyribonuclease) as the first choice of mucoactive agent. October 2017: note that this was an off-label use for children under 5. See NICE's information on prescribing medicines.\n\nIf clinical evaluation or lung function testing indicates an inadequate response to rhDNase, consider both rhDNase and hypertonic sodium chloride or hypertonic sodium chloride alone. October 2017: note that this was an off-label use for children under 5. See NICE's information on prescribing medicines.\n\nConsider mannitol dry powder for inhalation for children and young people who cannot use rhDNase and hypertonic sodium chloride because of ineligibility, intolerance or inadequate response. October 2017: note that this was an off-label use of mannitol dry powder for children. See NICE's information on prescribing medicines.\n\nMannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:\n\nwho cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and\n\nwhose lung function is rapidly declining (forced expiratory volume in 1 second [FEV1] decline greater than 2% annually) and\n\nfor whom other osmotic agents are not considered appropriate.[This recommendation is from the NICE technology appraisal guidance on mannitol dry powder for inhalation for treating cystic fibrosis]\n\nPeople currently receiving mannitol whose cystic fibrosis does not meet the criteria in 1.6.21 should be able to continue treatment until they and their clinician consider it appropriate to stop.[This recommendation is the NICE technology appraisal guidance on mannitol dry powder for inhalation for treating cystic fibrosis]\n\nFor recommendations on using lumacaftor–ivacaftor, see the NICE technology appraisal guidance on\xa0lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation.\n\n## Pulmonary infection\n\nOffer flucloxacillin as antibiotic prophylaxis against respiratory Staphylococcus aureus infection for children with cystic fibrosis from the point of diagnosis up to age 3, and consider continuing up to 6 years of age. Before starting flucloxacillin, discuss the uncertainties and possible adverse effects with their parents or carers (as appropriate). For children who are allergic to penicillins, consider an alternative oral anti-Staphylococcus aureus agent. October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.\n\nFor children who are taking antibiotic prophylaxis and have a respiratory sample culture that is positive for Staphylococcus aureus:\n\nreview prophylaxis adherence and help the child's parents or carers (as appropriate) with any difficulties they are having\n\nstart treatment-dose anti-Staphylococcus aureus antibiotics\n\nrestart prophylaxis after treatment, even if treatment has not been successful.\n\nFor people who are not taking prophylaxis and have a new Staphylococcus aureus infection (that is, previous respiratory sample cultures did not show Staphylococcus aureus infection):\n\nif they are clinically well, consider an oral anti-Staphylococcus aureus agent\n\nif they are clinically unwell and have pulmonary disease, consider oral or intravenous (depending on infection severity) broad-spectrum antibiotics that include an anti-Staphylococcus aureus agent.\n\nConsider a long-term antibiotic to suppress chronic methicillin-sensitive Staphylococcus aureus (MSSA) respiratory infection in people whose pulmonary disease is stable.\n\nFor people with chronic MSSA respiratory infection who become clinically unwell with pulmonary disease, consider oral or intravenous broad-spectrum antibiotics (depending on infection severity) that include an anti-Staphylococcus aureus agent.\n\nFor people with new evidence of methicillin-resistant Staphylococcus aureus (MRSA) respiratory infection (with or without pulmonary exacerbation), seek specialist microbiological advice on treatment.\n\nDo not routinely use antibiotics to suppress chronic MRSA in people with stable pulmonary disease.\n\nIf a person with cystic fibrosis and chronic MRSA respiratory infection becomes unwell with a pulmonary exacerbation or shows a decline in pulmonary function, seek specialist microbiological advice.\n\nFor guidance on preventing the spread of infection, refer to the NICE guideline on healthcare-associated infections.\n\nIf a person with cystic fibrosis develops a new Pseudomonas aeruginosa infection (that is, recent respiratory secretion sample cultures showed no infection):\n\nif they are clinically well:\n\n\n\ncommence eradication therapy with a course of oral or intravenous antibiotics, together with an inhaled antibiotic\n\nfollow this with an extended course of oral and inhaled antibiotics\n\n\n\nif they are clinically unwell:\n\n\n\ncommence eradication therapy with a course of intravenous antibiotics together with an inhaled antibiotic\n\nfollow this with an extended course of oral and inhaled antibiotics.\n\n\n\nIf eradication treatment is not successful despite treatment as recommended in 1.6.33, offer sustained treatment with an inhaled antibiotic. Consider nebulised colistimethate sodium as first-line treatment. (See recommendation 1.6.37 on using colistimethate dry powder for inhalation).\n\nDepending on infection severity, use either an oral antibiotic or a combination of 2 intravenous antibiotics of different classes for people:\n\nwho have chronic Pseudomonas aeruginosa infection (when treatment has not eradicated the infection) and\n\nwho become clinically unwell with a pulmonary disease exacerbation.\n\nIf a person with chronic Pseudomonas aeruginosa infection repeatedly becomes clinically unwell with pulmonary disease exacerbations, consider changing the antibiotic regimens used to treat exacerbations.\n\nColistimethate sodium dry powder for inhalation (DPI) is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:\n\nthey would clinically benefit from continued colistimethate sodium but do not tolerate it in its nebulised form and thus tobramycin therapy would otherwise be considered and\n\nthe manufacturer provides colistimethate sodium DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.[This recommendation is from the NICE technology appraisal guidance on colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis]\n\nFor people with chronic Pseudomonas aeruginosa infection who are clinically deteriorating despite regular inhaled colistimethate sodium, consider nebulised aztreonam, nebulised tobramycin, or tobramycin DPI (see recommendation 1.6.39 on using tobramycin DPI).October 2017: note that this was an off-label use of all the drugs listed for children under 6. See NICE's information on prescribing medicines.\n\nTobramycin DPI is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:\n\nnebulised tobramycin is considered an appropriate treatment, that is, when colistimethate sodium is contraindicated, is not tolerated or has not produced an adequate clinical response and\n\nthe manufacturer provides tobramycin DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.[This recommendation is from the NICE technology appraisal guidance on colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis]\n\nPeople currently using tobramycin DPI or colistimethate sodium DPI that is not recommended according to recommendations 1.6.37 or 1.6.39 should be able to continue treatment until they and their clinician consider it appropriate to stop. For children and young people this decision should be made jointly by the clinician, the child or young person and their parents or carers.[This recommendation is from the NICE technology appraisal guidance on colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis]\n\nFor people with cystic fibrosis who develop a new Burkholderia cepacia complex infection (that is, recent respiratory sample cultures showed no Burkholderia cepacia infection):\n\nwhether they are clinically well or not, give antibiotic eradication therapy using a combination of intravenous antibiotics\n\nseek specialist microbiological advice on the choice of antibiotics to use.\n\nBe aware that there is no evidence to support using antibiotics to suppress chronic Burkholderia cepacia complex infection in people with cystic fibrosis who have stable pulmonary status. Discuss the possible risks (for example drug toxicity) of treating the infection with the person and their family members or carers (as appropriate).\n\nFor people with cystic fibrosis who have chronic Burkholderia cepacia complex infection (when treatment has not eradicated the infection) and who become clinically unwell with a pulmonary disease exacerbation:\n\ngive a combination of oral or intravenous antibiotics\n\nseek specialist microbiological advice on which antibiotics to use.\n\nFor people with cystic fibrosis who have chronic Burkholderia cepacia complex infection and declining pulmonary status:\n\nconsider sustained treatment with an inhaled antibiotic to suppress the infection\n\nseek specialist microbiological advice on which antibiotic to use\n\nstop this treatment if there is no observed benefit.\n\nFor people with cystic fibrosis who develop a Haemophilus influenzae infection (diagnosed by a positive respiratory sample culture) but do not have clinical evidence of pulmonary infection, treat with an appropriate oral antibiotic.\n\nFor people with cystic fibrosis who develop a Haemophilus influenzae infection (diagnosed by a positive respiratory sample culture) and are unwell with clinical evidence of pulmonary infection, treat with an appropriate antibiotic, given orally or intravenously depending on the severity of the illness.\n\nFor people with cystic fibrosis who are clinically well but whose airway secretions are persistently positive for non-tuberculous mycobacteria, discuss with them and their family members or carers (as appropriate):\n\nthe clinical uncertainties about non-tuberculous mycobacterial infection and\n\nthe possible benefits and risks (for example, drug toxicity) of treating it.\n\nIf a person with cystic fibrosis has a respiratory sample test positive for new non-tuberculous mycobacteria infection, repeat the test for confirmation.\n\nIf repeat testing confirms persistent non-tuberculous mycobacteria, do a chest CT scan to look for changes consistent with non-tuberculous mycobacteria disease.\n\nConsider non-tuberculous mycobacterial therapy aimed at eradication for people with cystic fibrosis:\n\nwhose airway secretions persistently test positive for non-tuberculous mycobacteria and\n\nwho are clinically unwell with pulmonary disease, or who have a chest CT scan showing changes consistent with non-tuberculous mycobacteria disease and\n\nwhose pulmonary disease has not responded to other recommended treatments.Seek specialist microbiological advice on which antibiotics to use and on the duration of treatment.\n\nDo not routinely use antifungal agents to suppress chronic Aspergillus fumigatus complex respiratory infection (diagnosed by persistently positive respiratory secretion sample cultures) in people with cystic fibrosis and stable pulmonary status.\n\nFor people with cystic fibrosis with chronic Aspergillus fumigatus complex respiratory infection and declining pulmonary status:\n\nconsider sustained treatment with an antifungal agent to suppress the infection\n\nseek specialist microbiological advice on which antifungal agent to use\n\nstop treatment or change to a different agent if there is no benefit.\n\nFor people with cystic fibrosis with elevated aspergillus serology (aspergillus-specific IgG and/or IgE) and declining pulmonary function despite optimised pulmonary treatment, think about treating for allergic bronchopulmonary aspergillosis or other aspergillus airway disease, especially if there are consistent chest X-ray or CT scan changes.\n\nFor people with cystic fibrosis who have a pulmonary disease exacerbation and no clear cause (based on recent respiratory secretion sample cultures):\n\nuse an oral or intravenous (depending on the exacerbation severity) broad-spectrum antibiotic\n\ncontinue collecting respiratory secretion samples, and change treatments if a pathogen is identified and a more appropriate treatment is available.\n\n## Immunomodulatory agents\n\nFor people with cystic fibrosis and deteriorating lung function or repeated pulmonary exacerbations, offer long-term treatment with azithromycin at an immunomodulatory dose. October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.\n\nFor people who have continued deterioration in lung function, or continuing pulmonary exacerbations while receiving long-term treatment with azithromycin, stop azithromycin and consider oral corticosteroids.\n\nDo not offer inhaled corticosteroids as an immunomodulatory treatment for cystic fibrosis.\n\n# Other monitoring, assessment and management\n\n## Nutritional interventions and exocrine pancreatic insufficiency\n\nThe cystic fibrosis specialist dietitian should offer advice on the benefits of optimal nutrition, and at the annual assessment review the person's:\n\ntotal nutritional intake, including energy intake (calories)\n\nestimated nutritional needs\n\npancreatic enzyme replacement therapy, if appropriate.\n\nEncourage people to increase calorie intake by increasing portion size and eating high-energy foods if there is concern about their nutrition (including weight loss and inadequate weight gain).\n\nIf increased portion size and high-energy foods are not effective, consider a trial of oral nutritional supplements.\n\nIf attempts to increase calorie intake are not effective, consider:\n\nsupplementation with enteral tube feeding or\n\nfor adults, a short-term trial of an appetite stimulant (for example up to 3 months).October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.\n\nTest for exocrine pancreatic insufficiency in people with cystic fibrosis, using a non-invasive technique such as stool elastase estimation. If the test result is normal, repeat it if symptoms or signs suggesting malabsorption occur.\n\nOffer oral pancreatic enzyme replacement therapy to people with exocrine pancreatic insufficiency. Adjust the dose as needed to minimise any symptoms or signs of malabsorption.\n\nConsider an acid suppression agent (for example an H2 receptor antagonist or a proton pump inhibitor) for people who have persistent symptoms or signs of malabsorption despite optimal pancreatic enzyme replacement therapy. October 2017: note that this was an off-label use. See NICE's information on prescribing medicines.\n\n## Distal intestinal obstruction syndrome\n\nBe aware that a variety of conditions can cause acute abdominal pain and resemble distal intestinal obstruction syndrome in people with cystic fibrosis, for example:\n\nconstipation\n\nappendicitis\n\nintussusception\n\ncholecystitis.\n\nSuspect distal intestinal obstruction syndrome in people with cystic fibrosis who have an acute onset of peri-umbilical or right lower quadrant abdominal pain and any of the following:\n\na palpable mass in the right lower quadrant\n\nfaecal loading in the right lower quadrant on a plain abdominal X-ray, especially if associated with small intestine air-fluid levels\n\nclinical features of partial or complete intestinal obstruction, such as vomiting (especially bilious) and abdominal distension.\n\nFor people who have an acute onset of peri-umbilical abdominal pain but no other clinical or radiological features of distal intestinal obstruction syndrome, consider further imaging, for example with an:\n\nabdominal ultrasound scan or\n\nabdominal CT scan.\n\nManage suspected distal intestinal obstruction syndrome in a specialist cystic fibrosis centre, with supervision from specialists who have expertise in recognising and treating the condition and its complications.\n\nOffer oral or intravenous fluids to ensure adequate hydration (and rehydration if needed) for people with distal intestinal obstruction syndrome.\n\nConsider diatrizoate meglumine and diatrizoate sodium solution (Gastrografin) (orally or via an enteral tube) as first-line treatment for distal intestinal obstruction syndrome.\n\nIf diatrizoate meglumine and diatrizoate sodium solution (Gastrografin) is not effective, consider an iso-osmotic polyethylene glycol and electrolyte (PEG) solution (macrogols) (orally or via an enteral tube) as a second-line treatment.\n\nConsider surgery as a last resort, if prolonged treatment with a PEG solution is not effective.\n\nTo reduce the risk of distal intestinal obstruction syndrome recurring:\n\nencourage people to drink plenty of fluids\n\noptimise pancreatic enzyme replacement therapy (see nutritional interventions and exocrine pancreatic insufficiency)\n\nconsider advising regular treatment with a stool-softening agent such as lactulose or a PEG solution.\n\n## Liver disease\n\nPerform a clinical assessment and liver function blood tests at the annual review for people with cystic fibrosis.\n\nIf liver function blood tests are abnormal, perform a liver ultrasound scan and consider ursodeoxycholic acid treatment. October 2017: note that this was an off-label use for adults. See NICE's information on prescribing medicines.\n\nThink about stopping ursodeoxycholic acid if liver function blood tests return to normal and clinical assessment and liver ultrasound scan show no liver disease.\n\nIf ursodeoxycholic acid is stopped, monitor for re-emergence of liver disease using clinical assessment and liver function blood tests.\n\nThink about referring people with cystic fibrosis to a liver specialist if the liver function blood test results are persistently abnormal despite treatment with ursodeoxycholic acid.\n\nRefer people with cystic fibrosis to a liver specialist if they have any of the following:\n\nchronic progressive liver disease, based on clinical assessment, liver function blood tests or the findings on a liver ultrasound scan\n\nliver failure, based on clinical assessment and liver function tests\n\nportal hypertension, haematemesis, splenomegaly or findings on a liver ultrasound scan.\n\n## Cystic-fibrosis-related diabetes\n\nDiagnose cystic-fibrosis-related diabetes using one of the following:\n\ncontinuous glucose monitoring (CGM)\n\nserial glucose testing over several days\n\noral glucose tolerance testing (OGTT) – if OGTT is abnormal perform CGM or serial glucose testing over several days to confirm the diagnosis.\n\nTest for cystic-fibrosis-related diabetes (as detailed in recommendation 1.7.23) in people with cystic fibrosis annually from 10 years of age.\n\nTest for cystic-fibrosis-related diabetes at the end of the first and second trimesters of pregnancy, using CGM or OGTT.\n\nTest for cystic-fibrosis-related diabetes in people with cystic fibrosis who are taking long-term systemic corticosteroids or receiving enteral tube feeding, using CGM or serial glucose monitoring.\n\nThink about testing for cystic-fibrosis-related diabetes in people who still have any of the following despite optimised cystic fibrosis treatment:\n\nunexplained weight loss\n\na deterioration in lung function as measured by spirometry\n\nincreased frequency of pulmonary exacerbations\n\nexcessive tiredness.\n\n## Bone mineral density\n\nConsider dual energy X-ray absorptiometry (DXA) bone density scans for people with cystic fibrosis who have factors that put them at high risk of low bone mineral density, such as:\n\nfrequent or long-term oral corticosteroid use\n\nfrequent intravenous antibiotic use\n\nsevere lung disease\n\nundernutrition\n\nprevious low-impact fractures\n\nprevious transplants\n\npost menopause.\n\nSeek specialist advice for people with a bone mineral density standard deviation below -2.0 (Z score) or -2.5 (T score).\n\n## Exercise\n\nAdvise people with cystic fibrosis and their family members or carers (as appropriate) that regular exercise improves both lung function and overall fitness.\n\nOffer people with cystic fibrosis an individualised exercise programme, taking into account their capability and preferences.\n\nRegularly review exercise programmes to monitor the person's progress and ensure that the programme continues to be appropriate for their needs.\n\nProvide people with cystic fibrosis who are having inpatient care with:\n\nan assessment of their exercise capacity\n\nthe facilities and support to continue their exercise programme (as appropriate), taking into account the need to prevent cross-infection (see preventing cross-infection) and local infection control guidelines.\n\n## Psychological assessment\n\nAt the annual review, the specialist clinical psychologist should include assessments of:\n\ngeneral mental health and wellbeing\n\nquality of life\n\nany factors that are making treatment adherence difficult\n\nindicators of emerging psychosocial problems\n\nbehaviours that affect health outcomes.\n\nIf a severe mental health condition is identified at any assessment performed by the cystic fibrosis clinical psychologist, refer the person with cystic fibrosis to a mental health practitioner. For guidance on treating mental health conditions, refer to the relevant NICE guideline.\n\nFor family members or carers of people with cystic fibrosis, the specialist clinical psychologist should:\n\nassess any cystic-fibrosis-related needs they have\n\nsupport their psychological wellbeing\n\nrefer them to mental health practitioners as needed.\n\n# Preventing cross-infection\n\nFor recommendations on preventing and controlling infection, see the NICE guidelines on infection control in primary and community care and healthcare-associated infections, and the NICE quality standard on infection prevention and control.\n\nTo prevent cross-infection among people with cystic fibrosis in outpatient and inpatient care, use microbiological surveillance and a local infection control strategy that includes cohorting.\n\nInform people with cystic fibrosis, their family members or carers (as appropriate) and staff involved in their care about the risk of cross-infection and how to avoid it.\n\nEach specialist cystic fibrosis clinic should be organised to prevent cross-infection. Separate people individually during the clinic, including by organising:\n\nthe use of communal areas\n\nattendance at diagnostic, treatment and pharmacy facilities.\n\nKeep people with transmissible or chronic Pseudomonas aeruginosa or Burkholderia cepacia complex infection separate from people who do not have these infections, for example by using separate outpatient clinics.\n\nConsider keeping people with cystic fibrosis who have intermittent isolation of Pseudomonas aeruginosa separate from people who do not have this infection, for example by using separate outpatient clinics. Help people with cystic fibrosis plan their inpatient attendance to avoid contact with each other, for example when they use:\n\nhospital restaurants, schools and recreation areas\n\ndiagnostic, treatment and pharmacy facilities (see information and support).\n\nDuring inpatient care, give people with cystic fibrosis individual rooms with en-suite facilities.\n\n# Terms used in this guideline\n\n## Immunomodulatory dose\n\nA dose of a drug that is less than the minimum inhibitory dose.\n\n## Outreach care\n\nA model of care in which the specialist multidisciplinary cystic fibrosis team provide outpatient clinics in local hospitals.\n\n## Pulmonary exacerbation\n\nThe sudden or recent worsening of clinical symptoms or signs. This is frequently caused by an acute pulmonary infection.\n\n## Pulmonary infection\n\nIn people with cystic fibrosis, this can be diagnosed based on symptoms or signs, or by identifying pathogens in respiratory secretion samples.\n\n## Shared-care model (network cystic fibrosis clinic)\n\nWhen a local hospital cares for people with cystic fibrosis, with oversight, support and direct involvement from members of a specialist cystic fibrosis multidisciplinary team.\n\n## Telemedicine\n\nProviding clinical services remotely, using phone and video messaging to communicate with the patient.\n\n## Young people\n\nAged 12 to 17 years.", 'Context': 'Cystic fibrosis is a multi-system genetic disorder affecting the lungs, pancreas, liver and intestine. It can have a significant impact on life expectancy and quality of life. The current median age of those who have died is 28 years and the median predicted survival is 45.1 years.\n\nDiagnosis is primarily made during newborn screening. The median age at diagnosis is 2 months, and 1 in every 2500 babies born in the UK has cystic fibrosis. Approximately 60% of people on the UK cystic fibrosis registry are aged over 16 years.\n\nMany different mutations are responsible for cystic fibrosis. The UK registry shows that 90.8% of people with cystic fibrosis have one known genotype; however 8.9% of people have at least one unknown genotype.\n\nLung function is often reduced in cystic fibrosis. The typical measure of lung function is forced expiratory volume in 1 second (FEV1). FEV1 is a key predictor of life expectancy in people with cystic fibrosis, and optimising lung function is a major goal of care.\n\nLung infections are a cause of significant morbidity in cystic fibrosis. Chronic infection (for example with Staphylococcus aureus and Pseudomonas aeruginosa) may need long-term use of antibiotics.\n\nThere is variation across the country in the multidisciplinary team structures used, the arrangements services make for providing care, and in the resources available to support services. Particular problems may arise with smaller shared-care clinic arrangements. In some centres, both inpatient and outpatient facilities are limited. For example, there may be problems in arranging admission to single rooms with en‑suite facilities. If adequate protocols are not in place, then there is a risk of cross-infection.\n\nBy making robust recommendations based on the available evidence and best practice in cystic fibrosis care, this guideline will help improve care for this highly complex condition.', 'Recommendations for research': "The committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Liver disease\n\nShould all children with meconium ileus receive ursodeoxycholic acid from diagnosis?\n\n## Why this is important\n\nLiver disease is the third most common cause of mortality in people with cystic fibrosis, and around 10 to 30% of people with cystic fibrosis will develop cystic-fibrosis-related liver disease. Children with meconium ileus are at an increased risk of liver disease, and starting treatment with ursodeoxycholic acid from diagnosis may reduce this risk. Ursodeoxycholic acid appears safe, is well tolerated and cheap. Routine use could increase people's overall quality of life and reduce the need for subsequent treatment for liver disease, but more research is needed into the effectiveness and safety of this treatment.\n\n# Airway clearance techniques\n\nHow effective are daily airway clearance techniques in maintaining lung function in infants and children with cystic fibrosis?\n\n## Why this is important\n\nThere has been debate about the level of physiotherapy needed to preserve lung health since healthcare systems started diagnosing cystic fibrosis through newborn screening. Some clinical teams teach parents airway clearance techniques and recommend using them daily, but others use alternatives such as parental respiratory assessment tools with structured exercise. Routine airway clearance from diagnosis takes up a lot of time and places considerable responsibility on the parents and carers. These techniques are also difficult to perform, particularly with an infant or young child who does not understand what is happening. It is important to find out whether daily airway clearance techniques are helping to maintain lung health or are creating an unnecessary burden on parents and carers. Future research should look at the impact on the lives of parents, family members and carers, as well as long-term clinical outcomes for infants and children with cystic fibrosis.\n\n# Monitoring pulmonary disease\n\nIs lung clearance index a useful and cost-effective tool for the routine assessment and monitoring of changes in pulmonary status in people with cystic fibrosis?\n\n## Why this is important\n\nAssessing the severity of lung disease is difficult in younger children. Not all children under 5 years can do spirometry tests and they are not sufficiently sensitive in people with good lung function, where CT scans can show pulmonary status changes before spirometry changes. A simple, sensitive and reproducible measurement such as lung clearance index allows assessment of respiratory status in people with cystic fibrosis, and could improve clinical decision-making.\n\n# Psychological assessment\n\nWhat is the most effective measure of psychological functioning to use as a test for thresholds of concern in people with cystic fibrosis?\n\n## Why this is important\n\nThere are no validated tools to assess psychological and behavioural problems in people with cystic fibrosis, and these would be useful to validate generic measures (for example for depression and anxiety). People with a long-term physical health condition are more likely to present with mental health problems. NHS England highlights that prevention of mental health problems is the most cost-effective service that can be provided. To prevent mental health problems, all people with cystic fibrosis would need to have their mental health status routinely and regularly assessed. People with cystic fibrosis would benefit, therefore, from having a routine test that would show who needs psychological intervention. This would allow early intervention to maintain or improve quality of life, prevent mental health problems from developing, and improve health outcomes through an improvement in wellbeing.\n\n# Monitoring for cystic-fibrosis-related diabetes\n\nWhat is the most effective strategy to detect diabetes in people with cystic fibrosis?\n\n## Why this is important\n\nDiabetes develops and presents very differently in people with cystic fibrosis. Although annual testing for cystic-fibrosis-related diabetes is recommended in this guideline for people over 10 with cystic fibrosis, there is a lack of evidence on how to diagnose the condition. There is currently variation in practice, with cystic fibrosis centres using different combinations of the oral glucose tolerance test, HbA1c, serial glucose testing, and continuous glucose monitoring systems. Identifying which strategy is most effective for early identification of cystic-fibrosis-related diabetes would help teams start prompt treatment and prevent the clinical decline associated with the condition.\n\n# Mucoactive agents\n\nWhat is the most clinically and cost-effective dose of rhDNase (dornase alfa; recombinant human deoxyribonuclease) for people with cystic fibrosis?\n\n## Why this is important\n\nPeople with cystic fibrosis often have complex treatment schedules, which can include multiple nebulised treatments. Taking daily rhDNase increases the burden on them. Because of this, it is essential to find out whether rhDNase needs to be taken this often to provide clinical benefit. There is some evidence that alternate-day rhDNase is just as effective, and if this is confirmed then overall treatment adherence may improve and cost savings would be made. The current evidence base is mostly small, underpowered, short-term trials, in people who have had this treatment before. Consequently, it is not clear what the long-term impact of different doses of rhDNase are for people with cystic fibrosis. It may be cost effective to switch to alternate-day rhDNase if it is shown to be as effective as daily rhDNase."}
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https://www.nice.org.uk/guidance/ng78
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This guideline covers diagnosing and managing cystic fibrosis. It specifies how to monitor the condition and manage the symptoms to improve quality of life. There are also detailed recommendations on treating the most common infections in people with cystic fibrosis.
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cd23368f91e53ff74bb713fc7c1b3211cc7db262
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nice
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Hepatitis B (chronic): diagnosis and management
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Hepatitis B (chronic): diagnosis and management
This guideline covers assessing and managing chronic hepatitis B in children, young people and adults. It aims to improve care for people with hepatitis B by specifying which tests and treatments to use for people of different ages and with different disease severities.
# Context
Chronic hepatitis B describes a spectrum of disease usually characterised by the presence of detectable hepatitis B surface antigen (HBsAg) in the blood or serum for longer than 6 months. In some people, chronic hepatitis B is inactive and does not present significant health problems, but others may progress to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver disease is associated with hepatitis B virus (HBV) DNA levels in the blood. Without antiviral treatment, the 5-year cumulative incidence of cirrhosis ranges from 8 to 20%. People with cirrhosis face a significant risk of decompensated liver disease if they remain untreated. Five-year survival rates among people with untreated decompensated cirrhosis can be as low as 15%. Chronic hepatitis B can be divided into e antigen- (HBeAg) positive or HBeAg-negative disease based on the presence or absence of e antigen. The presence of HBeAg is typically associated with higher rates of viral replication and therefore increased infectivity.
The goal of treatment for chronic hepatitis B is to prevent cirrhosis, HCC and liver failure. In clinical practice surrogate markers are used to monitor progression of disease and treatment response, and include normalisation of serum alanine aminotransferase (ALT) levels, decrease in inflammation scores with no worsening or improvement in fibrosis on liver biopsies, suppression of serum HBV DNA to undetectable levels, loss of HBeAg and seroconversion to HBe antibody (anti-HBe), and loss of HBsAg and seroconversion to HBs antibody (anti-HBs).
Antiviral therapy suppresses HBV replication and decreases hepatic inflammation and fibrosis, thereby reducing the likelihood of serious clinical disease. Since the introduction of effective treatment in the form of interferon alfa, several nucleoside and nucleotide analogues are now approved for use in adults with chronic hepatitis B, together with a pegylated form of interferon alfa. With multiple treatment options that are efficacious and safe, the key questions are which patients need immediate treatment and what sequence and combination of drug regimens should be used, and which patients can be monitored and delay treatment.
In this guideline we cover the following:
information needs of people with chronic hepatitis B and their carers
where children, young people and adults with chronic hepatitis B should be assessed
assessment of liver disease, including the use of non-invasive tests and genotype testing
criteria for offering antiviral treatment
the efficacy, safety and cost effectiveness of currently available treatments
selection of first-line therapy
management of treatment failure or drug resistance
whether there is a role for combination therapy
when it is possible to stop treatment
managing the care of pregnant and breastfeeding women and prevention of vertical transmission
prophylactic treatment during immunosuppressive therapy
monitoring for treatment response, severity of fibrosis and development of HCC.
The spontaneous mutation rate of HBV DNA is high. Exposure of HBV to nucleoside or nucleotide analogues selects for mutations in the polymerase gene that confer resistance or decreased susceptibility to the drugs. The relative risk of drug resistance must be taken into account when considering treatment with nucleoside or nucleotide analogues, including the level of cross resistance between different agents.
Figure 1 depicts the natural history of chronic HBV infection. The immune-tolerance phase is seen in HBeAg-positive disease and is characterised by high levels of HBV replication with normal ALT levels and limited liver necroinflammation. Because there is minimal immune response to the virus it is unusual for spontaneous HBeAg loss to occur. This phase is commonly seen in children. It is followed by an immune-clearance or immune-reactive phase in which the immune system recognises and starts to clear the virus. ALT levels are typically elevated or fluctuating, and there is a higher risk of liver fibrosis. This tends to be the initial phase in people infected with HBV as adults. It lasts from weeks to years and ends with HBeAg seroconversion.
With the loss of HBeAg the person may enter an immune-control phase with very low or undetectable HBV DNA levels, normal ALT and minimal fibrosis progression. However, some people may experience rising HBV DNA levels despite HBeAg negativity. This is caused by virions that do not express HBeAg because of genetic mutations. This immune-escape phase can lead to active necroinflammation and progression of fibrosis.
Substantial progress has been made in the treatment of chronic hepatitis B in the past decade but the appropriate time for starting treatment remains a topic of debate. Although currently available treatment is effective in suppressing HBV replication, it fails to eradicate the virus necessitating long treatment duration and perhaps lifelong treatment.
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
In this guideline, children and young people are defined as aged up to 18 years. Please follow the recommendations for women who are pregnant for young people with chronic hepatitis B who are pregnant.
# Patient information
Provide information on the following topics to people with chronic hepatitis B and to family members or carers (if appropriate) before assessment for antiviral treatment:
the natural history of chronic hepatitis B, including stages of disease and long-term prognosis
lifestyle issues such as alcohol, diet and weight
family planning
monitoring
routes of hepatitis B virus (HBV) transmission
the benefits of antiviral treatment, including reduced risk of serious liver disease and death and reduced risk of transmission of HBV to others
treatment options and contraindications based on the patient's circumstances, including peginterferon alfa-2a and nucleoside or nucleotide analogues
short- and long-term treatment goals
causes of treatment failure, including non-adherence to prescribed medicines, and options for re-treatment
risks of treatment, including adverse effects and drug resistance.
Offer a copy of the personalised care plan to people with chronic hepatitis B and to family members or carers (if appropriate) outlining proposed treatment and long-term management, for example, a copy of the hospital consultation summary.
Provide information on self-injection techniques to people beginning peginterferon alfa-2a or to family members or carers.
NICE has produced public health guidance on ways to promote and offer testing to people at increased risk of infection with hepatitis B. All healthcare professionals should follow the recommendations in the NICE guideline on hepatitis B and C testing.
NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services.
# Assessment and referral in primary care
## Adults who are HBsAg positive
Arrange the following tests in primary care for adults who are hepatitis B surface antigen (HBsAg) positive:
hepatitis B e antigen (HBeAg)/antibody (anti-HBe) status
HBV DNA level
IgM antibody to hepatitis B core antigen (anti-HBc lgM)
hepatitis C virus antibody (anti-HCV)
hepatitis delta virus antibody (anti-HDV)
HIV antibody (anti-HIV)
lgG antibody to hepatitis A virus (anti-HAV)
additional laboratory tests including alanine aminotransferase (ALT) or aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), serum albumin, total bilirubin, total globulins, full blood count and prothrombin time
tests for hepatocellular carcinoma (HCC), including hepatic ultrasound and alpha-fetoprotein testing.
Refer all adults who are HBsAg positive to a hepatologist or to a gastroenterologist or infectious disease specialist with an interest in hepatology.
Include the results of the initial tests with the referral (see recommendation 1.2.1).
## Pregnant women who test HBsAg positive at antenatal screening
Refer pregnant women who are HBsAg positive to a hepatologist, or to a gastroenterologist or infectious disease specialist with an interest in hepatology, for assessment within 6 weeks of receiving the screening test result and to allow treatment in the third trimester (see recommendation 1.5.39 in the section on women who are pregnant or breastfeeding).
## Adults with decompensated liver disease
Refer adults who develop decompensated liver disease immediately to a hepatologist or to a gastroenterologist with an interest in hepatology. Symptoms of decompensated liver disease include (but are not limited to) ascites, encephalopathy and gastrointestinal haemorrhage.
## Children and young people who are HBsAg positive
Arrange the following tests for children and young people who are HBsAg positive:
HBeAg/anti-HBe status
HBV DNA level
anti-HBc lgM
anti-HCV
anti-HDV
anti-HIV
anti-HAV
additional laboratory tests, including ALT or AST, GGT, serum albumin, total bilirubin, total globulins, full blood count and prothrombin time
tests for HCC, including hepatic ultrasound and alpha-fetoprotein testing.
Refer all children and young people who are HBsAg positive to a paediatric hepatologist or to a gastroenterologist or infectious disease specialist with an interest in hepatology.
Include the results of the initial tests with the referral (see recommendation 1.2.6).
# Assessment of liver disease in secondary specialist care
## Adults with chronic hepatitis B
Refer to recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B for detailed guidance on offering antiviral treatment.
Ensure all healthcare professionals who refer adults for non-invasive tests for liver disease are trained to interpret the results and aware of co-factors that influence liver elasticity (for example, fatty liver caused by obesity or alcohol misuse).
Discuss the accuracy, limitations and risks of the different tests for liver disease with the patient.
Offer transient elastography as the initial test for liver disease in adults newly referred for assessment.
Offer antiviral treatment without a liver biopsy to adults with a transient elastography score greater than or equal to 11 kPa, in line with recommendation 1.5.6 in the section on adults with chronic hepatitis B (adults with a transient elastography score greater than or equal to 11 kPa are very likely to have cirrhosis and confirmation by liver biopsy is not needed).
Consider liver biopsy to confirm the level of fibrosis in adults with a transient elastography score between 6 and 10 kPa (the degree of fibrosis cannot be accurately predicted in adults with a transient elastography score between 6 to 10 kPa; some people may choose to have a liver biopsy in these circumstances to confirm the extent of liver disease). Offer antiviral treatment in line with recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B.
Offer liver biopsy to adults with a transient elastography score less than 6 kPa if they are younger than 30 years and have HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart (adults with a transient elastography score less than 6 kPa are unlikely to have significant fibrosis). Offer antiviral treatment in line with recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B.
Do not offer liver biopsy to adults with a transient elastography score less than 6 kPa who have normal ALT (less than 30 IU/L in males and less than 19 IU/L in females) and HBV DNA less than 2000 IU/ml as they are unlikely to have advanced liver disease or need antiviral treatment (see recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B). Adults with a transient elastography score less than 6 kPa are unlikely to have significant fibrosis.
Offer an annual reassessment of liver disease using transient elastography to adults who are not taking antiviral treatment.
## Children and young people with chronic hepatitis B
Discuss the accuracy, limitations and risks of liver biopsy in determining the need for antiviral treatment with the child or young person and with parents or carers (if appropriate).
Consider liver biopsy to assess liver disease and the need for antiviral treatment in children and young people with HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart. Offer biopsy under a general anaesthetic to children who are too young to tolerate the procedure under a local anaesthetic.
# Genotype testing
Do not offer genotype testing to determine initial treatment in people with chronic hepatitis B.
# Antiviral treatment
Recommendations 1.5.8 to 1.5.43 do not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or HIV.
## Adults with chronic hepatitis B
Discuss treatment options, adverse effects and long-term prognosis with the patient before starting treatment.
Re-assess the person's risk of exposure to HIV before starting treatment and offer repeat testing if needed.
Offer antiviral treatment to adults aged 30 years and older who have HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L in males and greater than or equal to 19 IU/L in females) on 2 consecutive tests conducted 3 months apart.
Offer antiviral treatment to adults younger than 30 years who have HBV DNA greater than 2000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L in males and greater than or equal to 19 IU/L in females) on 2 consecutive tests conducted 3 months apart if there is evidence of necroinflammation or fibrosis on liver biopsy or a transient elastography score greater than 6 kPa.
Offer antiviral treatment to adults who have HBV DNA greater than 20,000 IU/ml and abnormal ALT (greater than or equal to 30 IU/L in males and greater than or equal to 19 IU/L in females) on 2 consecutive tests conducted 3 months apart regardless of age or the extent of liver disease.
Offer antiviral treatment to adults with cirrhosis and detectable HBV DNA, regardless of HBeAg status, HBV DNA and ALT levels.
Consider antiviral treatment in adults with HBV DNA greater than 2000 IU/ml and evidence of necroinflammation or fibrosis on liver biopsy.
Peginterferon alfa-2a is recommended as an option for the initial treatment of adults with chronic hepatitis B (HBeAg-positive or HBeAg-negative), within its licensed indications. (This recommendation is from NICE's technology appraisal guidance on adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B.)
Entecavir, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated. (This recommendation is from NICE's technology appraisal guidance on entecavir for the treatment of chronic hepatitis B.)
Tenofovir disoproxil, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated. (This recommendation is from NICE's technology appraisal guidance on tenofovir disoproxil fumarate for the treatment of hepatitis B.)
Telbivudine is not recommended for the treatment of chronic hepatitis B. (This recommendation is from NICE's technology appraisal guidance on telbivudine for the treatment of chronic hepatitis B.)
People currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop. (This recommendation is from NICE's technology appraisal guidance on telbivudine for the treatment of chronic hepatitis B.)
Do not offer adefovir dipivoxil for treatment of chronic hepatitis B.
People currently receiving adefovir dipivoxil should be offered the option to switch to a different treatment. Offer tenofovir disoproxil or entecavir, depending on previous antiviral exposure:
-ffer tenofovir disoproxil to people with a history of lamivudine resistance.
Antiviral treatment should be initiated only by an appropriately qualified healthcare professional with expertise in the management of viral hepatitis. Continuation of therapy under shared-care arrangements with a GP is appropriate.
## Treatment sequence in adults with HBeAg-positive chronic hepatitis B and compensated liver disease
Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-positive chronic hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.
Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level has decreased by less than 2 log10 IU/ml and/or if HBsAg is greater than 20,000 IU/ml, and offer second-line treatment in line with recommendations 1.5.18 and 1.5.19.
Offer tenofovir disoproxil as second-line treatment to people who do not undergo HBeAg seroconversion or who relapse (revert to being HBeAg positive following seroconversion) after first-line treatment with peginterferon alfa-2a.
Offer entecavir as an alternative second-line treatment to people who cannot tolerate tenofovir disoproxil or if it is contraindicated.
Review adherence in people taking tenofovir disoproxil who have detectable HBV DNA at 48 weeks of treatment and, if appropriate, provide support in line with NICE's guideline on medicines adherence.
If HBV DNA remains detectable at 96 weeks, and there is no history of lamivudine resistance, consider adding lamivudine to tenofovir disoproxil.
In people with a history of lamivudine resistance, consider adding entecavir to tenofovir disoproxil.
Consider stopping nucleoside or nucleotide analogue treatment 12 months after HBeAg seroconversion in people without cirrhosis.
Do not stop nucleoside or nucleotide analogue treatment 12 months after HBeAg seroconversion in people with cirrhosis.
## Treatment sequence in adults with HBeAg-negative chronic hepatitis B and compensated liver disease
Offer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-negative chronic hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.
Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level has decreased by less than 2 log10 IU/ml and HBsAg has not decreased, and consider second-line treatment in line with recommendation 1.5.25.
Offer entecavir or tenofovir disoproxil as second-line treatment to people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a.
Consider switching from tenofovir disoproxil to entecavir, or from entecavir to tenofovir disoproxil, as third-line treatment in people who have detectable HBV DNA at 48 weeks of treatment.
Consider stopping nucleoside or nucleotide analogue treatment 12 months after achieving undetectable HBV DNA and HBsAg seroconversion in people without cirrhosis.
Do not stop nucleoside or nucleotide analogue treatment after achieving undetectable HBV DNA and HBsAg seroconversion in patients with cirrhosis.
## Children and young people with chronic hepatitis B and compensated liver disease
Discuss treatment options, adverse effects and long-term prognosis with the child or young person and with parents or carers (if appropriate) before starting treatment.
Re-assess the child or young person's risk of exposure to HIV before starting treatment and offer repeat testing if necessary.
Offer antiviral treatment if there is evidence of significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3) or abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3 months apart.
Consider a 48-week course of peginterferon alfa-2a as first-line treatment in children and young people with chronic hepatitis B and compensated liver disease.Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.In June 2013, this was an off-label use of peginterferon alfa-2a in children. See NICE's information on prescribing medicines.
Consider stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level has decreased by less than 2 log10 IU/ml and/or if HBsAg is greater than 20,000 IU/ml.
Consider a nucleoside or nucleotide analogue as second-line treatment in children and young people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a. In October 2017, this was an off-label use of peginterferon alfa-2a in children. See NICE's information on prescribing medicines.
## Adults with decompensated liver disease
Manage decompensated liver disease in adults in conjunction with a liver transplant centre.
Do not offer peginterferon alfa-2a to people with chronic hepatitis B and decompensated liver disease.
Offer entecavir as first-line treatment in people with decompensated liver disease if there is no history of lamivudine resistance.
Offer tenofovir disoproxil to people with a history of lamivudine resistance.
Reduce the dose of tenofovir disoproxil in people with renal impairment, in line with guidance in the summary of product characteristics.
## Women who are pregnant or breastfeeding
Discuss with pregnant women the benefits and risks of antiviral treatment for them and their baby.
Offer tenofovir disoproxil to women with HBV DNA greater than 107 IU/ml in the third trimester to reduce the risk of transmission of HBV to the baby.In June 2013, this was an off-label use of tenofovir disoproxil. See NICE's information on prescribing medicines.
Monitor quantitative HBV DNA 2 months after starting tenofovir disoproxil and ALT monthly after the birth to detect postnatal HBV flares in the woman.
Stop tenofovir disoproxil 4 to 12 weeks after the birth unless the mother meets criteria for long-term treatment (see recommendations 1.5.4 to 1.5.8).
Offer active and passive hepatitis B immunisation in infants and follow up in line with the guidance below:
Department of Health and Social Care's best practice guidance on Hepatitis B antenatal screening and newborn immunisation programme
Immunisation against infectious disease (the Green book)
NICE's guideline on hepatitis B and C testing
NICE's guideline on vaccine uptake in the general population.
Advise women that there is no risk of transmitting HBV to their babies through breastfeeding if guidance on hepatitis B immunisation has been followed, and that they may continue antiviral treatment while they are breastfeeding.
## Adults who are co-infected with hepatitis C
Offer peginterferon alfa and ribavirin in adults co-infected with chronic hepatitis B and C. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.
## Adults who are co-infected with hepatitis D
Offer a 48-week course of peginterferon alfa-2a in people co-infected with chronic hepatitis B and hepatitis delta infection who have evidence of significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3). Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.
Consider stopping peginterferon alfa-2a if there is no decrease in HDV RNA after 6 months to 1 year of treatment. Otherwise, continue treatment and re-evaluate treatment response annually.
Stop treatment after HBsAg seroconversion.
## Prophylactic treatment during immunosuppressive therapy
In June 2013, the use of entecavir, lamivudine and tenofovir disoproxil as prophylactic treatments during immunosuppressive therapy was off-label. See NICE's information on prescribing medicines.
Perform the following tests in people who are HBsAg and/or anti-HBc positive before starting immunosuppressive therapy for autoimmune or atopic diseases, chemotherapy, bone marrow or solid organ transplantation:
antibody to hepatitis B surface antigen (anti-HBs)
plasma or serum HBV DNA level
ALT.
In people who are HBsAg positive and have HBV DNA greater than 2000 IU/ml, offer prophylaxis with entecavir or tenofovir disoproxil.
Start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after HBeAg seroconversion and HBV DNA is undetectable.
In people who are HBsAg positive and have HBV DNA less than 2000 IU/ml, offer prophylaxis.
Consider lamivudine if immunosuppressive therapy is expected to last less than 6 months.
Monitor HBV DNA monthly in people treated with lamivudine and change to tenofovir disoproxil if HBV DNA remains detectable after 3 months.
Consider entecavir or tenofovir disoproxil if immunosuppressive therapy is expected to last longer than 6 months.
Start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after stopping immunosuppressive therapy.
In people who are HBsAg negative and anti-HBc positive (regardless of anti-HBs status) and are starting rituximab or other B cell-depleting therapies:
-ffer prophylaxis with lamivudine
start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after stopping immunosuppressive therapy.
In people who are HBsAg negative, anti-HBc positive and anti-HBs negative and are not taking rituximab or other B cell-depleting therapies:
monitor HBV DNA monthly and offer prophylaxis to people whose HBV DNA becomes detectable
consider lamivudine in people with HBV DNA less than 2000 IU/ml and for whom immunosuppressive therapy is expected to last less than 6 months; change to tenofovir disoproxil if HBV DNA remains detectable after 6 months
consider entecavir or tenofovir disoproxil in people with HBV DNA greater than 2000 IU/ml and for whom immunosuppressive therapy is expected to last longer than 6 months
continue antiviral therapy for a minimum of 6 months after stopping immunosuppressive therapy.
Do not offer prophylaxis to people who are HBsAg negative and anti-HBc and anti-HBs positive who are not taking rituximab or other B cell-depleting therapies.
# Monitoring
## Monitoring in people who do not meet criteria for antiviral treatment
Further information on the progression of chronic hepatitis B can be found in the context section.
Monitor ALT levels every 24 weeks in adults with HBeAg-positive disease who are in the immune-tolerant phase (defined by active viral replication and normal ALT levels ).
Monitor ALT every 12 weeks on at least 3 consecutive occasions if there is an increase in ALT levels.
Monitor ALT and HBV DNA levels every 48 weeks in adults with inactive chronic hepatitis B infection (defined as HBeAg negative on 2 consecutive tests with normal ALT and HBV DNA less than 2000 IU/ml).
Consider monitoring more frequently (for example, every 12–24 weeks) in people with cirrhosis who have undetectable HBV DNA.
Monitor ALT levels every 24 weeks in children and young people with HBeAg-positive disease who have normal ALT levels (less than 30 IU/L for males and less than 19 IU/L for females) and no evidence of significant fibrosis (METAVIR stage less than F2 or Ishak stage less than 3).
Review annually children and young people with HBeAg-negative disease who have normal ALT (less than 30 IU/L for males and less than 19 IU/L for females), no evidence of significant fibrosis (METAVIR stage less than F2 or Ishak stage less than 3) and HBV DNA less than 2000 IU/ml.
Review every 12 weeks children and young people with HBeAg-negative disease who have abnormal ALT (greater than or equal to 30 IU/L for males and greater than or equal to 19 IU/L for females) and HBV DNA greater than 2000 IU/ml.
In people with HBeAg seroconversion after antiviral treatment, monitor HBeAg, anti-HBe, HBV DNA level and liver function at 4, 12 and 24 weeks after HBeAg seroconversion and then every 6 months.
Monitor HBsAg and anti-HBs annually in people with HBsAg seroconversion after antiviral treatment and discharge people who are anti-HBs positive on 2 consecutive tests.
## Monitoring in people taking antiviral treatment
In October 2017, the use of peginterferon alfa-2a as an antiviral treatment in children with chronic hepatitis B was off-label. See NICE's information on prescribing medicines.
Review injection technique and adverse effects weekly during the first month of treatment in people taking peginterferon alfa-2a.
Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels) and thyroid function (and in children, weight and height) before starting peginterferon alfa-2a and 2, 4, 12, 24, 36 and 48 weeks after starting treatment to detect adverse effects.
Monitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting peginterferon alfa-2a at 12, 24 and 48 weeks after starting treatment to determine treatment response.
In October 2017, the use of entecavir in children younger than 2 years with chronic hepatitis B and compensated liver disease was off-label. See NICE's information on prescribing medicines.
Monitor full blood count, liver function (including bilirubin, albumin and ALT) and renal function (including urea and electrolyte levels) in people with compensated liver disease before starting entecavir or lamivudine, 4 weeks after starting treatment and then every 3 months to detect adverse effects.
Monitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting entecavir or lamivudine, 12, 24 and 48 weeks after starting treatment and then every 6 months to determine treatment response and medicines adherence.
Monitor HBV DNA levels every 12 weeks in people with HBeAg-negative disease who have been taking lamivudine for 5 years or longer.
In October 2017, the use of tenofovir disoproxil in children younger than 12 years with chronic hepatitis B and compensated liver disease was off-label. See NICE's information on prescribing medicines.
Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio), and phosphate levels in people with compensated liver disease before starting tenofovir disoproxil, 4 weeks after starting treatment and then every 3 months to detect adverse effects.
Monitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting tenofovir disoproxil, 12, 24 and 48 weeks after starting treatment and then every 6 months to determine treatment response and medicines adherence.
Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio), blood clotting, HBV DNA level and HBeAg status in people with decompensated liver disease before starting entecavir or lamivudine and weekly after starting treatment to assess treatment response and adverse effects. When the person is no longer decompensated, follow the recommendations in the section on children, young people and adults with compensated liver disease taking entecavir or lamivudine.In October 2017, the use of entecavir in children younger than 2 years was off-label. See NICE's information on prescribing medicines..
Monitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio) and phosphate, blood clotting, HBV DNA level and HBeAg status in people with decompensated liver disease before starting tenofovir disoproxil and weekly after starting treatment to assess treatment response and adverse effects. When the person is no longer decompensated, follow the recommendations in the section on children, young people and adults with compensated liver disease taking tenofovir disoproxil'.In October 2017, the use of entecavir in children younger than 2 years was off-label. See NICE's information on prescribing medicines.
# Surveillance testing for hepatocellular carcinoma in adults with chronic hepatitis B
Perform 6-monthly surveillance for HCC by hepatic ultrasound and alpha-fetoprotein testing in people with significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3) or cirrhosis.
In people without significant fibrosis or cirrhosis (METAVIR stage less than F2 or Ishak stage less than 3), consider 6-monthly surveillance for HCC if the person is older than 40 years and has a family history of HCC and HBV DNA greater than or equal to 20,000 IU/ml.
Do not offer surveillance for HCC in people without significant fibrosis or cirrhosis (METAVIR stage less than F2 or Ishak stage less than 3) who have HBV DNA less than 20,000 IU/ml and are younger than 40 years.
# Terms used in this guidance
## Chronic hepatitis B
Chronic hepatitis B is defined as persistence of hepatitis B surface antigen (HBsAg) for 6 months or more after acute infection with hepatitis B virus (HBV).
## HBV DNA
HBV DNA level, or 'viral load', is an indicator of viral replication. Higher HBV DNA levels are usually associated with an increased risk of liver disease and hepatocellular carcinoma. HBV DNA level typically falls in response to effective antiviral treatment.
## Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antigen (HBsAg) is a viral protein detectable in the blood in acute and chronic hepatitis B infection.
## HBsAg seroconversion
The development of antibodies against HBsAg is known as HBsAg seroconversion. It signifies clearance of HBsAg and resolution of the chronic infection.
## Hepatitis B e antigen (HBeAg)
Hepatitis B e antigen (HBeAg) is an indicator of viral replication, although some variant forms of the virus do not express HBeAg (see HBeAg-negative chronic hepatitis B in this section). Active infection can be described as HBeAg-positive or HBeAg-negative according to whether HBeAg is secreted.
## HBeAg-negative chronic hepatitis B
HBeAg-negative hepatitis B is a form of the virus that does not cause infected cells to secrete HBeAg. People can be infected with the HBeAg-negative form of the virus from the beginning, or the viral mutation can emerge later in the course of infection in people initially infected with the HBeAg-positive form of the virus.
## HBeAg seroconversion
HBeAg seroconversion occurs when people infected with the HBeAg-positive form of the virus develop antibodies against the 'e' antigen. The seroconverted disease state is referred to as the 'inactive HBV carrier state' when HBeAg has been cleared, anti-HBe is present and HBV DNA is undetectable or less than 2000 IU/ml. Once seroconversion has taken place, most people remain in the inactive HBV carrier state (the immune-control phase; see the information about the natural history of chronic HBV infection in the context section). However, increasing HBV DNA and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus (the immune-escape phase; see the information about the natural history of chronic HBV infection in the context section).# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Stopping antiviral treatment in HBeAg-negative disease
Further research should be undertaken to evaluate the clinical and cost effectiveness of hepatitis B surface antigen (HBsAg) quantitative assays in determining treatment duration in hepatitis B e antigen- (HBeAg) negative disease.
## Why this is important
In HBeAg-positive disease, HBeAg seroconversion is a predictor of durable response to antiviral treatment and can be used as a milestone after which treatment can be stopped. At present, similar parameters have not been defined in HBeA'g-negative disease. Quantitative HBsAg may have a role in determining treatment duration in this setting. Establishing threshold levels for HBsAg titre associated with durable off-treatment control in HBeAg-negative disease would transform current treatment strategies. People on long-term nucleoside or nucleotide analogues could safely stop treatment once they achieved a threshold level of HBsAg. Further research is needed to define these levels of HBsAg and to determine when treatment in HBeAg-negative disease can be safely stopped.
# ALT values for children and young people
Further research should be undertaken to examine whether the upper limit of normal ALT values for adults (below 30 IU/L for males and below 19 IU/L for females) are appropriate for use in children and young people with chronic hepatitis B when making decisions on when to initiate treatment.
## Why this is important
Recent studies have highlighted the imprecision of using biochemical activity as a measure of immune activity in children and young people with chronic hepatitis B. Researchers have found T-cell exhaustion and even HBV-specific immune responses in children and young people considered to have immune-tolerant disease. These findings need to be validated in larger studies to see if upper limit of normal ALT values derived from adults accurately reflect disease activity in children and young people. Further research is needed to investigate whether there is a genuine state of immune tolerance in children and young people reflected in lower levels of biochemical activity and a lower upper limit of normal ALT value.
# Long-term safety of tenofovir disoproxil in chronic hepatitis B
Further research should be undertaken to determine the long-term safety of tenofovir disoproxil, including the risk of clinically significant hypophosphataemia and related bone toxicity, in people with chronic hepatitis B. The cost effectiveness of routine monitoring for phosphate loss and bone disease in people with chronic hepatitis B who are receiving tenofovir disoproxil treatment needs further evaluation.
## Why this is important
Tenofovir disoproxil is recommended as an option for treatment of people with chronic hepatitis B, and is typically prescribed for long-term use. Kidney dysfunction has been reported in people treated with tenofovir disoproxil, including rare cases of proximal renal tubular dysfunction that appear related to long-term exposure but are not well understood. Adverse renal effects such as hypophosphataemia may have an impact on bone architecture which could result in clinical problems such as fragility fractures. Monitoring for phosphate loss and bone disease could have a role in preventing clinically significant bone problems in people with chronic hepatitis B receiving long-term tenofovir disoproxil. However, the cost effectiveness and clinical utility of routine monitoring needs to be established before recommendations can be made about its use.
# Prophylactic treatment in people receiving immunosuppressive therapy
Further research should be undertaken to determine whether long-term use of mild immunosuppressive agents for autoimmune and allergic problems presents a risk for reactivation of HBV infection in people with previous or current chronic hepatitis B, including occult HBV infection. The cost effectiveness of routine tests for HBV in this population, including HBV DNA for occult HBV infection, and the need for prophylactic treatment with nucleoside or nucleotide analogues needs further evaluation.
## Why this is important
Reactivation of HBV may occur spontaneously or arise during immunosuppression. Solid organ transplantation, chemotherapy and immunosuppressive drugs used to treat autoimmune diseases are key causes of HBV reactivation. Antiviral agents can be used as prophylaxis to prevent reactivation of HBV infection in people receiving immunosuppressive therapy but the optimal treatment and duration of therapy are unknown. Decision-making and cost-effectiveness studies are needed to determine optimal screening strategies to identify people at risk of HBV reactivation. People with occult HBV (including people coming from high endemicity regions) might carry a low, but not negligible, risk of viral reactivation. Prospective studies are needed to assess the risk of HBV reactivation in people receiving mild immunosuppressants or biological treatment for autoimmune diseases, to identify risk factors that predict HBV reactivation in this population, and evaluate treatment or pre-emptive strategies using existing nucleoside and nucleotide analogues.
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{'Context': "Chronic hepatitis B describes a spectrum of disease usually characterised by the presence of detectable hepatitis B surface antigen (HBsAg) in the blood or serum for longer than 6\xa0months. In some people, chronic hepatitis B is inactive and does not present significant health problems, but others may progress to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver disease is associated with hepatitis B virus (HBV) DNA levels in the blood. Without antiviral treatment, the 5-year cumulative incidence of cirrhosis ranges from 8 to 20%. People with cirrhosis face a significant risk of decompensated liver disease if they remain untreated. Five-year survival rates among people with untreated decompensated cirrhosis can be as low as 15%. Chronic hepatitis B can be divided into e antigen- (HBeAg) positive or HBeAg-negative disease based on the presence or absence of e antigen. The presence of HBeAg is typically associated with higher rates of viral replication and therefore increased infectivity.\n\nThe goal of treatment for chronic hepatitis B is to prevent cirrhosis, HCC and liver failure. In clinical practice surrogate markers are used to monitor progression of disease and treatment response, and include normalisation of serum alanine aminotransferase (ALT) levels, decrease in inflammation scores with no worsening or improvement in fibrosis on liver biopsies, suppression of serum HBV DNA to undetectable levels, loss of HBeAg and seroconversion to HBe antibody (anti-HBe), and loss of HBsAg and seroconversion to HBs antibody (anti-HBs).\n\nAntiviral therapy suppresses HBV replication and decreases hepatic inflammation and fibrosis, thereby reducing the likelihood of serious clinical disease. Since the introduction of effective treatment in the form of interferon alfa, several nucleoside and nucleotide analogues are now approved for use in adults with chronic hepatitis B, together with a pegylated form of interferon alfa. With multiple treatment options that are efficacious and safe, the key questions are which patients need immediate treatment and what sequence and combination of drug regimens should be used, and which patients can be monitored and delay treatment.\n\nIn this guideline we cover the following:\n\ninformation needs of people with chronic hepatitis B and their carers\n\nwhere children, young people and adults with chronic hepatitis B should be assessed\n\nassessment of liver disease, including the use of non-invasive tests and genotype testing\n\ncriteria for offering antiviral treatment\n\nthe efficacy, safety and cost effectiveness of currently available treatments\n\nselection of first-line therapy\n\nmanagement of treatment failure or drug resistance\n\nwhether there is a role for combination therapy\n\nwhen it is possible to stop treatment\n\nmanaging the care of pregnant and breastfeeding women and prevention of vertical transmission\n\nprophylactic treatment during immunosuppressive therapy\n\nmonitoring for treatment response, severity of fibrosis and development of HCC.\n\nThe spontaneous mutation rate of HBV DNA is high. Exposure of HBV to nucleoside or nucleotide analogues selects for mutations in the polymerase gene that confer resistance or decreased susceptibility to the drugs. The relative risk of drug resistance must be taken into account when considering treatment with nucleoside or nucleotide analogues, including the level of cross resistance between different agents.\n\nFigure 1 depicts the natural history of chronic HBV infection. The immune-tolerance phase is seen in HBeAg-positive disease and is characterised by high levels of HBV replication with normal ALT levels and limited liver necroinflammation. Because there is minimal immune response to the virus it is unusual for spontaneous HBeAg loss to occur. This phase is commonly seen in children. It is followed by an immune-clearance or immune-reactive phase in which the immune system recognises and starts to clear the virus. ALT levels are typically elevated or fluctuating, and there is a higher risk of liver fibrosis. This tends to be the initial phase in people infected with HBV as adults. It lasts from weeks to years and ends with HBeAg seroconversion.\n\nWith the loss of HBeAg the person may enter an immune-control phase with very low or undetectable HBV DNA levels, normal ALT and minimal fibrosis progression. However, some people may experience rising HBV DNA levels despite HBeAg negativity. This is caused by virions that do not express HBeAg because of genetic mutations. This immune-escape phase can lead to active necroinflammation and progression of fibrosis.\n\nSubstantial progress has been made in the treatment of chronic hepatitis B in the past decade but the appropriate time for starting treatment remains a topic of debate. Although currently available treatment is effective in suppressing HBV replication, it fails to eradicate the virus necessitating long treatment duration and perhaps lifelong treatment.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nThis guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient (or those with authority to give consent on their behalf) should provide informed consent, which should be documented. See the General Medical Council's good practice in prescribing and managing medicines and devices for further information. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nIn this guideline, children and young people are defined as aged up to 18 years. Please follow the recommendations for women who are pregnant for young people with chronic hepatitis B who are pregnant.\n\n# Patient information\n\nProvide information on the following topics to people with chronic hepatitis B and to family members or carers (if appropriate) before assessment for antiviral treatment:\n\nthe natural history of chronic hepatitis B, including stages of disease and long-term prognosis\n\nlifestyle issues such as alcohol, diet and weight\n\nfamily planning\n\nmonitoring\n\nroutes of hepatitis B virus (HBV) transmission\n\nthe benefits of antiviral treatment, including reduced risk of serious liver disease and death and reduced risk of transmission of HBV to others\n\ntreatment options and contraindications based on the patient's circumstances, including peginterferon alfa-2a and nucleoside or nucleotide analogues\n\nshort- and long-term treatment goals\n\ncauses of treatment failure, including non-adherence to prescribed medicines, and options for re-treatment\n\nrisks of treatment, including adverse effects and drug resistance.\n\nOffer a copy of the personalised care plan to people with chronic hepatitis B and to family members or carers (if appropriate) outlining proposed treatment and long-term management, for example, a copy of the hospital consultation summary.\n\nProvide information on self-injection techniques to people beginning peginterferon alfa-2a or to family members or carers.\n\nNICE has produced public health guidance on ways to promote and offer testing to people at increased risk of infection with hepatitis B. All healthcare professionals should follow the recommendations in the NICE guideline on hepatitis B and C testing.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services.\n\n# Assessment and referral in primary care\n\n## Adults who are HBsAg positive\n\nArrange the following tests in primary care for adults who are hepatitis B surface antigen (HBsAg) positive:\n\nhepatitis B e antigen (HBeAg)/antibody (anti-HBe) status\n\nHBV DNA level\n\nIgM antibody to hepatitis B core antigen (anti-HBc lgM)\n\nhepatitis C virus antibody (anti-HCV)\n\nhepatitis delta virus antibody (anti-HDV)\n\nHIV antibody (anti-HIV)\n\nlgG antibody to hepatitis A virus (anti-HAV)\n\nadditional laboratory tests including alanine aminotransferase (ALT) or aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), serum albumin, total bilirubin, total globulins, full blood count and prothrombin time\n\ntests for hepatocellular carcinoma (HCC), including hepatic ultrasound and alpha-fetoprotein testing.\n\nRefer all adults who are HBsAg positive to a hepatologist or to a gastroenterologist or infectious disease specialist with an interest in hepatology.\n\nInclude the results of the initial tests with the referral (see recommendation 1.2.1).\n\n## Pregnant women who test HBsAg positive at antenatal screening\n\nRefer pregnant women who are HBsAg positive to a hepatologist, or to a gastroenterologist or infectious disease specialist with an interest in hepatology, for assessment within 6 weeks of receiving the screening test result and to allow treatment in the third trimester (see recommendation 1.5.39 in the section on women who are pregnant or breastfeeding).\n\n## Adults with decompensated liver disease\n\nRefer adults who develop decompensated liver disease immediately to a hepatologist or to a gastroenterologist with an interest in hepatology. Symptoms of decompensated liver disease include (but are not limited to) ascites, encephalopathy and gastrointestinal haemorrhage.\n\n## Children and young people who are HBsAg positive\n\nArrange the following tests for children and young people who are HBsAg positive:\n\nHBeAg/anti-HBe status\n\nHBV DNA level\n\nanti-HBc lgM\n\nanti-HCV\n\nanti-HDV\n\nanti-HIV\n\nanti-HAV\n\nadditional laboratory tests, including ALT or AST, GGT, serum albumin, total bilirubin, total globulins, full blood count and prothrombin time\n\ntests for HCC, including hepatic ultrasound and alpha-fetoprotein testing.\n\nRefer all children and young people who are HBsAg positive to a paediatric hepatologist or to a gastroenterologist or infectious disease specialist with an interest in hepatology.\n\nInclude the results of the initial tests with the referral (see recommendation 1.2.6).\n\n# Assessment of liver disease in secondary specialist care\n\n## Adults with chronic hepatitis B\n\nRefer to recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B for detailed guidance on offering antiviral treatment.\n\nEnsure all healthcare professionals who refer adults for non-invasive tests for liver disease are trained to interpret the results and aware of co-factors that influence liver elasticity (for example, fatty liver caused by obesity or alcohol misuse).\n\nDiscuss the accuracy, limitations and risks of the different tests for liver disease with the patient.\n\nOffer transient elastography as the initial test for liver disease in adults newly referred for assessment.\n\nOffer antiviral treatment without a liver biopsy to adults with a transient elastography score greater than or equal to 11\xa0kPa, in line with recommendation 1.5.6 in the section on adults with chronic hepatitis B (adults with a transient elastography score greater than or equal to 11 kPa are very likely to have cirrhosis and confirmation by liver biopsy is not needed).\n\nConsider liver biopsy to confirm the level of fibrosis in adults with a transient elastography score between 6 and 10\xa0kPa (the degree of fibrosis cannot be accurately predicted in adults with a transient elastography score between 6 to 10\xa0kPa; some people may choose to have a liver biopsy in these circumstances to confirm the extent of liver disease). Offer antiviral treatment in line with recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B.\n\nOffer liver biopsy to adults with a transient elastography score less than 6\xa0kPa if they are younger than 30\xa0years and have HBV DNA greater than 2000\xa0IU/ml and abnormal ALT (greater than or equal to 30\xa0IU/L for males and greater than or equal to 19 IU/L for females) on 2 consecutive tests conducted 3\xa0months apart (adults with a transient elastography score less than 6\xa0kPa are unlikely to have significant fibrosis). Offer antiviral treatment in line with recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B.\n\nDo not offer liver biopsy to adults with a transient elastography score less than 6\xa0kPa who have normal ALT (less than 30\xa0IU/L in males and less than 19\xa0IU/L in females) and HBV DNA less than 2000\xa0IU/ml as they are unlikely to have advanced liver disease or need antiviral treatment (see recommendations 1.5.3 to 1.5.7 in the section on adults with chronic hepatitis B). Adults with a transient elastography score less than 6\xa0kPa are unlikely to have significant fibrosis.\n\nOffer an annual reassessment of liver disease using transient elastography to adults who are not taking antiviral treatment.\n\n## Children and young people with chronic hepatitis B\n\nDiscuss the accuracy, limitations and risks of liver biopsy in determining the need for antiviral treatment with the child or young person and with parents or carers (if appropriate).\n\nConsider liver biopsy to assess liver disease and the need for antiviral treatment in children and young people with HBV DNA greater than 2000\xa0IU/ml and abnormal ALT (greater than or equal to 30\xa0IU/L for males and greater than or equal to 19\xa0IU/L for females) on 2 consecutive tests conducted 3\xa0months apart. Offer biopsy under a general anaesthetic to children who are too young to tolerate the procedure under a local anaesthetic.\n\n# Genotype testing\n\nDo not offer genotype testing to determine initial treatment in people with chronic hepatitis B.\n\n# Antiviral treatment\n\nRecommendations 1.5.8 to 1.5.43 do not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or HIV.\n\n## Adults with chronic hepatitis B\n\nDiscuss treatment options, adverse effects and long-term prognosis with the patient before starting treatment.\n\nRe-assess the person's risk of exposure to HIV before starting treatment and offer repeat testing if needed.\n\nOffer antiviral treatment to adults aged 30\xa0years and older who have HBV DNA greater than 2000\xa0IU/ml and abnormal ALT (greater than or equal to 30\xa0IU/L in males and greater than or equal to 19\xa0IU/L in females) on 2 consecutive tests conducted 3\xa0months apart.\n\nOffer antiviral treatment to adults younger than 30\xa0years who have HBV DNA greater than 2000\xa0IU/ml and abnormal ALT (greater than or equal to 30\xa0IU/L in males and greater than or equal to 19\xa0IU/L in females) on 2 consecutive tests conducted 3\xa0months apart if there is evidence of necroinflammation or fibrosis on liver biopsy or a transient elastography score greater than 6\xa0kPa.\n\nOffer antiviral treatment to adults who have HBV DNA greater than 20,000\xa0IU/ml and abnormal ALT (greater than or equal to 30\xa0IU/L in males and greater than or equal to 19\xa0IU/L in females) on 2 consecutive tests conducted 3\xa0months apart regardless of age or the extent of liver disease.\n\nOffer antiviral treatment to adults with cirrhosis and detectable HBV DNA, regardless of HBeAg status, HBV DNA and ALT levels.\n\nConsider antiviral treatment in adults with HBV DNA greater than 2000\xa0IU/ml and evidence of necroinflammation or fibrosis on liver biopsy.\n\nPeginterferon alfa-2a is recommended as an option for the initial treatment of adults with chronic hepatitis B (HBeAg-positive or HBeAg-negative), within its licensed indications. (This recommendation is from NICE's technology appraisal guidance on adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B.)\n\nEntecavir, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated. (This recommendation is from NICE's technology appraisal guidance on entecavir for the treatment of chronic hepatitis B.)\n\nTenofovir disoproxil, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated. (This recommendation is from NICE's technology appraisal guidance on tenofovir disoproxil fumarate for the treatment of hepatitis B.)\n\nTelbivudine is not recommended for the treatment of chronic hepatitis B. (This recommendation is from NICE's technology appraisal guidance on telbivudine for the treatment of chronic hepatitis B.)\n\nPeople currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop. (This recommendation is from NICE's technology appraisal guidance on telbivudine for the treatment of chronic hepatitis B.)\n\nDo not offer adefovir dipivoxil for treatment of chronic hepatitis B.\n\nPeople currently receiving adefovir dipivoxil should be offered the option to switch to a different treatment. Offer tenofovir disoproxil or entecavir, depending on previous antiviral exposure:\n\noffer tenofovir disoproxil to people with a history of lamivudine resistance.\n\nAntiviral treatment should be initiated only by an appropriately qualified healthcare professional with expertise in the management of viral hepatitis. Continuation of therapy under shared-care arrangements with a GP is appropriate.\n\n## Treatment sequence in adults with HBeAg-positive chronic hepatitis B and compensated liver disease\n\nOffer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-positive chronic hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.\n\nConsider stopping peginterferon alfa-2a 24\xa0weeks after starting treatment if HBV DNA level has decreased by less than 2\xa0log10\xa0IU/ml and/or if HBsAg is greater than 20,000\xa0IU/ml, and offer second-line treatment in line with recommendations 1.5.18 and 1.5.19.\n\nOffer tenofovir disoproxil as second-line treatment to people who do not undergo HBeAg seroconversion or who relapse (revert to being HBeAg positive following seroconversion) after first-line treatment with peginterferon alfa-2a.\n\nOffer entecavir as an alternative second-line treatment to people who cannot tolerate tenofovir disoproxil or if it is contraindicated.\n\nReview adherence in people taking tenofovir disoproxil who have detectable HBV DNA at 48\xa0weeks of treatment and, if appropriate, provide support in line with NICE's guideline on medicines adherence.\n\nIf HBV DNA remains detectable at 96\xa0weeks, and there is no history of lamivudine resistance, consider adding lamivudine to tenofovir disoproxil.\n\nIn people with a history of lamivudine resistance, consider adding entecavir to tenofovir disoproxil.\n\nConsider stopping nucleoside or nucleotide analogue treatment 12\xa0months after HBeAg seroconversion in people without cirrhosis.\n\nDo not stop nucleoside or nucleotide analogue treatment 12\xa0months after HBeAg seroconversion in people with cirrhosis.\n\n## Treatment sequence in adults with HBeAg-negative chronic hepatitis B and compensated liver disease\n\nOffer a 48-week course of peginterferon alfa-2a as first-line treatment in adults with HBeAg-negative chronic hepatitis B and compensated liver disease. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.\n\nConsider stopping peginterferon alfa-2a 24\xa0weeks after starting treatment if HBV DNA level has decreased by less than 2\xa0log10\xa0IU/ml and HBsAg has not decreased, and consider second-line treatment in line with recommendation 1.5.25.\n\nOffer entecavir or tenofovir disoproxil as second-line treatment to people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a.\n\nConsider switching from tenofovir disoproxil to entecavir, or from entecavir to tenofovir disoproxil, as third-line treatment in people who have detectable HBV DNA at 48\xa0weeks of treatment.\n\nConsider stopping nucleoside or nucleotide analogue treatment 12\xa0months after achieving undetectable HBV DNA and HBsAg seroconversion in people without cirrhosis.\n\nDo not stop nucleoside or nucleotide analogue treatment after achieving undetectable HBV DNA and HBsAg seroconversion in patients with cirrhosis.\n\n## Children and young people with chronic hepatitis B and compensated liver disease\n\nDiscuss treatment options, adverse effects and long-term prognosis with the child or young person and with parents or carers (if appropriate) before starting treatment.\n\nRe-assess the child or young person's risk of exposure to HIV before starting treatment and offer repeat testing if necessary.\n\nOffer antiviral treatment if there is evidence of significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3) or abnormal ALT (greater than or equal to 30\xa0IU/L for males and greater than or equal to 19\xa0IU/L for females) on 2 consecutive tests conducted 3\xa0months apart.\n\nConsider a 48-week course of peginterferon alfa-2a as first-line treatment in children and young people with chronic hepatitis B and compensated liver disease.Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.In June 2013, this was an off-label use of peginterferon alfa-2a in children. See NICE's information on prescribing medicines.\n\nConsider stopping peginterferon alfa-2a 24\xa0weeks after starting treatment if HBV DNA level has decreased by less than 2\xa0log10\xa0IU/ml and/or if HBsAg is greater than 20,000\xa0IU/ml.\n\nConsider a nucleoside or nucleotide analogue as second-line treatment in children and young people with detectable HBV DNA after first-line treatment with peginterferon alfa-2a. In October 2017, this was an off-label use of peginterferon alfa-2a in children. See NICE's information on prescribing medicines.\n\n## Adults with decompensated liver disease\n\nManage decompensated liver disease in adults in conjunction with a liver transplant centre.\n\nDo not offer peginterferon alfa-2a to people with chronic hepatitis B and decompensated liver disease.\n\nOffer entecavir as first-line treatment in people with decompensated liver disease if there is no history of lamivudine resistance.\n\nOffer tenofovir disoproxil to people with a history of lamivudine resistance.\n\nReduce the dose of tenofovir disoproxil in people with renal impairment, in line with guidance in the summary of product characteristics.\n\n## Women who are pregnant or breastfeeding\n\nDiscuss with pregnant women the benefits and risks of antiviral treatment for them and their baby.\n\nOffer tenofovir disoproxil to women with HBV DNA greater than 107\xa0IU/ml in the third trimester to reduce the risk of transmission of HBV to the baby.In June 2013, this was an off-label use of tenofovir disoproxil. See NICE's information on prescribing medicines.\n\nMonitor quantitative HBV DNA 2\xa0months after starting tenofovir disoproxil and ALT monthly after the birth to detect postnatal HBV flares in the woman.\n\nStop tenofovir disoproxil 4 to 12\xa0weeks after the birth unless the mother meets criteria for long-term treatment (see recommendations 1.5.4 to 1.5.8).\n\nOffer active and passive hepatitis B immunisation in infants and follow up in line with the guidance below:\n\nDepartment of Health and Social Care's best practice guidance on Hepatitis B antenatal screening and newborn immunisation programme\n\nImmunisation against infectious disease (the Green book)\n\nNICE's guideline on hepatitis B and C testing\n\nNICE's guideline on vaccine uptake in the general population.\n\nAdvise women that there is no risk of transmitting HBV to their babies through breastfeeding if guidance on hepatitis B immunisation has been followed, and that they may continue antiviral treatment while they are breastfeeding.\n\n## Adults who are co-infected with hepatitis C\n\nOffer peginterferon alfa and ribavirin in adults co-infected with chronic hepatitis B and C. Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.\n\n## Adults who are co-infected with hepatitis D\n\nOffer a 48-week course of peginterferon alfa-2a in people co-infected with chronic hepatitis B and hepatitis delta infection who have evidence of significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3). Avoid use of peginterferon alfa-2a in pregnancy unless the potential benefit outweighs risk. Women of childbearing potential must use effective contraception throughout therapy.\n\nConsider stopping peginterferon alfa-2a if there is no decrease in HDV RNA after 6\xa0months to 1\xa0year of treatment. Otherwise, continue treatment and re-evaluate treatment response annually.\n\nStop treatment after HBsAg seroconversion.\n\n## Prophylactic treatment during immunosuppressive therapy\n\nIn June 2013, the use of entecavir, lamivudine and tenofovir disoproxil as prophylactic treatments during immunosuppressive therapy was off-label. See NICE's information on prescribing medicines.\n\nPerform the following tests in people who are HBsAg and/or anti-HBc positive before starting immunosuppressive therapy for autoimmune or atopic diseases, chemotherapy, bone marrow or solid organ transplantation:\n\nantibody to hepatitis B surface antigen (anti-HBs)\n\nplasma or serum HBV DNA level\n\nALT.\n\nIn people who are HBsAg positive and have HBV DNA greater than 2000\xa0IU/ml, offer prophylaxis with entecavir or tenofovir disoproxil.\n\nStart prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6\xa0months after HBeAg seroconversion and HBV DNA is undetectable.\n\nIn people who are HBsAg positive and have HBV DNA less than 2000\xa0IU/ml, offer prophylaxis.\n\nConsider lamivudine if immunosuppressive therapy is expected to last less than 6\xa0months.\n\n\n\nMonitor HBV DNA monthly in people treated with lamivudine and change to tenofovir disoproxil if HBV DNA remains detectable after 3\xa0months.\n\n\n\nConsider entecavir or tenofovir disoproxil if immunosuppressive therapy is expected to last longer than 6\xa0months.\n\nStart prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6\xa0months after stopping immunosuppressive therapy.\n\nIn people who are HBsAg negative and anti-HBc positive (regardless of anti-HBs status) and are starting rituximab or other B cell-depleting therapies:\n\noffer prophylaxis with lamivudine\n\nstart prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6\xa0months after stopping immunosuppressive therapy.\n\nIn people who are HBsAg negative, anti-HBc positive and anti-HBs negative and are not taking rituximab or other B cell-depleting therapies:\n\nmonitor HBV DNA monthly and offer prophylaxis to people whose HBV DNA becomes detectable\n\n\n\nconsider lamivudine in people with HBV DNA less than 2000\xa0IU/ml and for whom immunosuppressive therapy is expected to last less than 6\xa0months; change to tenofovir disoproxil if HBV DNA remains detectable after 6\xa0months\n\nconsider entecavir or tenofovir disoproxil in people with HBV DNA greater than 2000\xa0IU/ml and for whom immunosuppressive therapy is expected to last longer than 6\xa0months\n\ncontinue antiviral therapy for a minimum of 6\xa0months after stopping immunosuppressive therapy.\n\n\n\nDo not offer prophylaxis to people who are HBsAg negative and anti-HBc and anti-HBs positive who are not taking rituximab or other B cell-depleting therapies.\n\n# Monitoring\n\n## Monitoring in people who do not meet criteria for antiviral treatment\n\nFurther information on the progression of chronic hepatitis B can be found in the context section.\n\nMonitor ALT levels every 24\xa0weeks in adults with HBeAg-positive disease who are in the immune-tolerant phase (defined by active viral replication and normal ALT levels [less than 30\xa0IU/L in males and less than 19\xa0IU/L in females]).\n\nMonitor ALT every 12\xa0weeks on at least 3 consecutive occasions if there is an increase in ALT levels.\n\nMonitor ALT and HBV DNA levels every 48\xa0weeks in adults with inactive chronic hepatitis B infection (defined as HBeAg negative on 2 consecutive tests with normal ALT [less than 30\xa0IU/L in males and less than 19\xa0IU/L in females] and HBV DNA less than 2000\xa0IU/ml).\n\nConsider monitoring more frequently (for example, every 12–24 weeks) in people with cirrhosis who have undetectable HBV DNA.\n\nMonitor ALT levels every 24\xa0weeks in children and young people with HBeAg-positive disease who have normal ALT levels (less than 30\xa0IU/L for males and less than 19\xa0IU/L for females) and no evidence of significant fibrosis (METAVIR stage less than F2 or Ishak stage less than 3).\n\nReview annually children and young people with HBeAg-negative disease who have normal ALT (less than 30\xa0IU/L for males and less than 19\xa0IU/L for females), no evidence of significant fibrosis (METAVIR stage less than F2 or Ishak stage less than 3) and HBV DNA less than 2000\xa0IU/ml.\n\nReview every 12\xa0weeks children and young people with HBeAg-negative disease who have abnormal ALT (greater than or equal to 30\xa0IU/L for males and greater than or equal to 19\xa0IU/L for females) and HBV DNA greater than 2000\xa0IU/ml.\n\nIn people with HBeAg seroconversion after antiviral treatment, monitor HBeAg, anti-HBe, HBV DNA level and liver function at 4, 12 and 24\xa0weeks after HBeAg seroconversion and then every 6\xa0months.\n\nMonitor HBsAg and anti-HBs annually in people with HBsAg seroconversion after antiviral treatment and discharge people who are anti-HBs positive on 2 consecutive tests.\n\n## Monitoring in people taking antiviral treatment\n\nIn October 2017, the use of peginterferon alfa-2a as an antiviral treatment in children with chronic hepatitis B was off-label. See NICE's information on prescribing medicines.\n\nReview injection technique and adverse effects weekly during the first month of treatment in people taking peginterferon alfa-2a.\n\nMonitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels) and thyroid function (and in children, weight and height) before starting peginterferon alfa-2a and 2, 4, 12, 24, 36 and 48\xa0weeks after starting treatment to detect adverse effects.\n\nMonitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting peginterferon alfa-2a at 12, 24 and 48\xa0weeks after starting treatment to determine treatment response.\n\nIn October 2017, the use of entecavir in children younger than 2 years with chronic hepatitis B and compensated liver disease was off-label. See NICE's information on prescribing medicines.\n\nMonitor full blood count, liver function (including bilirubin, albumin and ALT) and renal function (including urea and electrolyte levels) in people with compensated liver disease before starting entecavir or lamivudine, 4\xa0weeks after starting treatment and then every 3\xa0months to detect adverse effects.\n\nMonitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting entecavir or lamivudine, 12, 24 and 48\xa0weeks after starting treatment and then every 6\xa0months to determine treatment response and medicines adherence.\n\nMonitor HBV DNA levels every 12\xa0weeks in people with HBeAg-negative disease who have been taking lamivudine for 5\xa0years or longer.\n\nIn October 2017, the use of tenofovir disoproxil in children younger than 12 years with chronic hepatitis B and compensated liver disease was off-label. See NICE's information on prescribing medicines.\n\nMonitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio), and phosphate levels in people with compensated liver disease before starting tenofovir disoproxil, 4\xa0weeks after starting treatment and then every 3\xa0months to detect adverse effects.\n\nMonitor HBV DNA and quantitative HBsAg levels and HBeAg status before starting tenofovir disoproxil, 12, 24 and 48\xa0weeks after starting treatment and then every 6\xa0months to determine treatment response and medicines adherence.\n\nMonitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio), blood clotting, HBV DNA level and HBeAg status in people with decompensated liver disease before starting entecavir or lamivudine and weekly after starting treatment to assess treatment response and adverse effects. When the person is no longer decompensated, follow the recommendations in the section on children, young people and adults with compensated liver disease taking entecavir or lamivudine.In October 2017, the use of entecavir in children younger than 2 years was off-label. See NICE's information on prescribing medicines..\n\nMonitor full blood count, liver function (including bilirubin, albumin and ALT), renal function (including urea and electrolyte levels and urine protein/creatinine ratio) and phosphate, blood clotting, HBV DNA level and HBeAg status in people with decompensated liver disease before starting tenofovir disoproxil and weekly after starting treatment to assess treatment response and adverse effects. When the person is no longer decompensated, follow the recommendations in the section on children, young people and adults with compensated liver disease taking tenofovir disoproxil'.In October 2017, the use of entecavir in children younger than 2 years was off-label. See NICE's information on prescribing medicines.\n\n# Surveillance testing for hepatocellular carcinoma in adults with chronic hepatitis B\n\nPerform 6-monthly surveillance for HCC by hepatic ultrasound and alpha-fetoprotein testing in people with significant fibrosis (METAVIR stage greater than or equal to F2 or Ishak stage greater than or equal to 3) or cirrhosis.\n\nIn people without significant fibrosis or cirrhosis (METAVIR stage less than F2 or Ishak stage less than 3), consider 6-monthly surveillance for HCC if the person is older than 40\xa0years and has a family history of HCC and HBV DNA greater than or equal to 20,000\xa0IU/ml.\n\nDo not offer surveillance for HCC in people without significant fibrosis or cirrhosis (METAVIR stage less than F2 or Ishak stage less than 3) who have HBV DNA less than 20,000\xa0IU/ml and are younger than 40\xa0years.\n\n# Terms used in this guidance\n\n## Chronic hepatitis B\n\nChronic hepatitis B is defined as persistence of hepatitis B surface antigen (HBsAg) for 6\xa0months or more after acute infection with hepatitis B virus (HBV).\n\n## HBV DNA\n\nHBV DNA level, or 'viral load', is an indicator of viral replication. Higher HBV DNA levels are usually associated with an increased risk of liver disease and hepatocellular carcinoma. HBV DNA level typically falls in response to effective antiviral treatment.\n\n## Hepatitis B surface antigen (HBsAg)\n\nHepatitis B surface antigen (HBsAg) is a viral protein detectable in the blood in acute and chronic hepatitis B infection.\n\n## HBsAg seroconversion\n\nThe development of antibodies against HBsAg is known as HBsAg seroconversion. It signifies clearance of HBsAg and resolution of the chronic infection.\n\n## Hepatitis B e antigen (HBeAg)\n\nHepatitis B e antigen (HBeAg) is an indicator of viral replication, although some variant forms of the virus do not express HBeAg (see HBeAg-negative chronic hepatitis B in this section). Active infection can be described as HBeAg-positive or HBeAg-negative according to whether HBeAg is secreted.\n\n## HBeAg-negative chronic hepatitis B\n\nHBeAg-negative hepatitis B is a form of the virus that does not cause infected cells to secrete HBeAg. People can be infected with the HBeAg-negative form of the virus from the beginning, or the viral mutation can emerge later in the course of infection in people initially infected with the HBeAg-positive form of the virus.\n\n## HBeAg seroconversion\n\nHBeAg seroconversion occurs when people infected with the HBeAg-positive form of the virus develop antibodies against the 'e' antigen. The seroconverted disease state is referred to as the 'inactive HBV carrier state' when HBeAg has been cleared, anti-HBe is present and HBV DNA is undetectable or less than 2000\xa0IU/ml. Once seroconversion has taken place, most people remain in the inactive HBV carrier state (the immune-control phase; see the information about the natural history of chronic HBV infection in the context section). However, increasing HBV DNA and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus (the immune-escape phase; see the information about the natural history of chronic HBV infection in the context section).", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Stopping antiviral treatment in HBeAg-negative disease\n\nFurther research should be undertaken to evaluate the clinical and cost effectiveness of hepatitis B surface antigen (HBsAg) quantitative assays in determining treatment duration in hepatitis B e antigen- (HBeAg) negative disease.\n\n## Why this is important\n\nIn HBeAg-positive disease, HBeAg seroconversion is a predictor of durable response to antiviral treatment and can be used as a milestone after which treatment can be stopped. At present, similar parameters have not been defined in HBeA'g-negative disease. Quantitative HBsAg may have a role in determining treatment duration in this setting. Establishing threshold levels for HBsAg titre associated with durable off-treatment control in HBeAg-negative disease would transform current treatment strategies. People on long-term nucleoside or nucleotide analogues could safely stop treatment once they achieved a threshold level of HBsAg. Further research is needed to define these levels of HBsAg and to determine when treatment in HBeAg-negative disease can be safely stopped.\n\n# ALT values for children and young people\n\nFurther research should be undertaken to examine whether the upper limit of normal ALT values for adults (below 30\xa0IU/L for males and below 19\xa0IU/L for females) are appropriate for use in children and young people with chronic hepatitis B when making decisions on when to initiate treatment.\n\n## Why this is important\n\nRecent studies have highlighted the imprecision of using biochemical activity as a measure of immune activity in children and young people with chronic hepatitis B. Researchers have found T-cell exhaustion and even HBV-specific immune responses in children and young people considered to have immune-tolerant disease. These findings need to be validated in larger studies to see if upper limit of normal ALT values derived from adults accurately reflect disease activity in children and young people. Further research is needed to investigate whether there is a genuine state of immune tolerance in children and young people reflected in lower levels of biochemical activity and a lower upper limit of normal ALT value.\n\n# Long-term safety of tenofovir disoproxil in chronic hepatitis B\n\nFurther research should be undertaken to determine the long-term safety of tenofovir disoproxil, including the risk of clinically significant hypophosphataemia and related bone toxicity, in people with chronic hepatitis B. The cost effectiveness of routine monitoring for phosphate loss and bone disease in people with chronic hepatitis B who are receiving tenofovir disoproxil treatment needs further evaluation.\n\n## Why this is important\n\nTenofovir disoproxil is recommended as an option for treatment of people with chronic hepatitis B, and is typically prescribed for long-term use. Kidney dysfunction has been reported in people treated with tenofovir disoproxil, including rare cases of proximal renal tubular dysfunction that appear related to long-term exposure but are not well understood. Adverse renal effects such as hypophosphataemia may have an impact on bone architecture which could result in clinical problems such as fragility fractures. Monitoring for phosphate loss and bone disease could have a role in preventing clinically significant bone problems in people with chronic hepatitis B receiving long-term tenofovir disoproxil. However, the cost effectiveness and clinical utility of routine monitoring needs to be established before recommendations can be made about its use.\n\n# Prophylactic treatment in people receiving immunosuppressive therapy\n\nFurther research should be undertaken to determine whether long-term use of mild immunosuppressive agents for autoimmune and allergic problems presents a risk for reactivation of HBV infection in people with previous or current chronic hepatitis B, including occult HBV infection. The cost effectiveness of routine tests for HBV in this population, including HBV DNA for occult HBV infection, and the need for prophylactic treatment with nucleoside or nucleotide analogues needs further evaluation.\n\n## Why this is important\n\nReactivation of HBV may occur spontaneously or arise during immunosuppression. Solid organ transplantation, chemotherapy and immunosuppressive drugs used to treat autoimmune diseases are key causes of HBV reactivation. Antiviral agents can be used as prophylaxis to prevent reactivation of HBV infection in people receiving immunosuppressive therapy but the optimal treatment and duration of therapy are unknown. Decision-making and cost-effectiveness studies are needed to determine optimal screening strategies to identify people at risk of HBV reactivation. People with occult HBV (including people coming from high endemicity regions) might carry a low, but not negligible, risk of viral reactivation. Prospective studies are needed to assess the risk of HBV reactivation in people receiving mild immunosuppressants or biological treatment for autoimmune diseases, to identify risk factors that predict HBV reactivation in this population, and evaluate treatment or pre-emptive strategies using existing nucleoside and nucleotide analogues."}
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https://www.nice.org.uk/guidance/cg165
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This guideline covers assessing and managing chronic hepatitis B in children, young people and adults. It aims to improve care for people with hepatitis B by specifying which tests and treatments to use for people of different ages and with different disease severities.
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fc3aa7887077765b23de9410e9779269020a1fbb
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nice
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Tofacitinib for moderate to severe rheumatoid arthritis
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Tofacitinib for moderate to severe rheumatoid arthritis
Evidence-based recommendations on tofacitinib (Xeljanz) for treating moderate to severe rheumatoid arthritis in adults.
# Recommendations
Tofacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying anti-rheumatic drugs (DMARDs), only if:
disease is severe (a disease activity score of more than 5.1) and
the company provides tofacitinib with the discount agreed in the patient access scheme.
Tofacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot have, other DMARDs, including at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
they cannot have rituximab and
the company provides tofacitinib with the discount agreed in the patient access scheme.
Tofacitinib can be used as monotherapy for adults who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections 1.1 or 1.2 are met.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. After an initial response within 6 months, withdraw treatment if at least a moderate EULAR response is not maintained.
When using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with tofacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trial evidence shows tofacitinib plus conventional DMARDs is more effective than conventional DMARDs alone for treating moderate and severe active rheumatoid arthritis that has not responded adequately to conventional or biological DMARDs.
Clinical trial evidence also shows that tofacitinib plus methotrexate is not worse in effectiveness than the biological DMARD adalimumab plus conventional DMARDs in people whose disease has responded inadequately to conventional DMARDs. Because there are no trials comparing tofacitinib with other biological DMARDs, the company did an indirect comparison. This shows that tofacitinib works as well as most of the biological DMARDs which NICE has already recommended in this indication.
Based on the health-related benefits and costs compared with conventional and biological DMARDs, tofacitinib plus conventional DMARDs is recommended as a cost-effective treatment for severe active rheumatoid arthritis, in line with previous recommendations in:
NICE technology appraisal guidance on baricitinib
certolizumab pegol (after a TNF-alpha inhibitor)
adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (after conventional DMARDs)
tocilizumab
golimumab (after DMARDs)
adalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha inhibitor).Tofacitinib for moderate active rheumatoid arthritis that has responded inadequately to conventional DMARDs is not cost effective based on what NICE normally considers acceptable, that is, £30,000 per quality-adjusted life year gained.# The technology
Marketing authorisation
Tofacitinib (Xeljanz, Pfizer) in combination with methotrexate has a marketing authorisation in the UK for the 'treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs'. Tofacitinib can be given as monotherapy in patients who are intolerant to methotrexate or when treatment with methotrexate is inappropriate.
Recommended dose and schedule
The recommended dose of tofacitinib is 5 mg twice daily. A dose of 5 mg once daily is appropriate for patients with severe renal impairment (creatinine clearance less than 30 ml/min). A dose of 5 mg once daily is appropriate for patients with moderate hepatic impairment (Child–Pugh B). Tofacitinib should not be used in patients with severe hepatic impairment (Child–Pugh C). Tofacitinib should be interrupted if a patient develops a serious infection, until the infection is controlled.
Price
The list price of a 56‑tablet pack of 5 mg tofacitinib is £690.03 (excluding VAT; British national formulary online ). The average cost per patient for the first 6 months is estimated at £4,050.60 based on the list price. The average cost per patient for subsequent years is estimated at £9,001.19 based on the list price.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of tofacitinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatment pathway
## Tofacitinib can be used at 4 different points in the pathway
Tofacitinib's marketing authorisation covers its use at 4 points in the treatment pathway, specifically in adults with:
moderate, active rheumatoid arthritis that has not responded adequately to conventional disease-modifying anti-rheumatic drugs (DMARDs)
severe, active rheumatoid arthritis that has not responded adequately to conventional DMARDs
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1 tumour necrosis factor-alpha (TNF‑alpha) inhibitor
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1 TNF‑alpha inhibitor and when rituximab is contraindicated or withdrawn because of adverse events.The committee also noted that the marketing authorisation includes the use of tofacitinib alone or with methotrexate.
## NICE technology appraisal guidance exists for these points in the rheumatoid arthritis treatment pathway
NICE currently recommends the use of the biological DMARDs in its technology appraisal guidance on baricitinib, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are TNF‑alpha inhibitors), in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, less than 3.2 but more than 2.6 indicates mild disease and less than 2.6 indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that baricitinib, adalimumab, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy. The guidance recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose) and should only be continued according to European League Against Rheumatism (EULAR) response at 6 months.
For people with severe rheumatoid arthritis who have already had at least 1 TNF‑alpha inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommends the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends tocilizumab, certolizumab pegol, baricitinib, abatacept, adalimumab, etanercept, infliximab or golimumab, in combination with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance on abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol or baricitinib recommends adalimumab, etanercept, tocilizumab, certolizumab pegol or baricitinib as monotherapy. NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha inhibitors nor rituximab have worked.
## A range of treatment options is important in rheumatoid arthritis
The committee heard from the patient experts that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional DMARDs such as methotrexate are inadequate for many people. They added that the disease sometimes does not respond adequately to the first biological DMARD prescribed. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological DMARDs after failure of conventional DMARDs. The clinical and patient experts agreed that methotrexate is often not well tolerated; the clinical experts noted that up to a third of people who are prescribed methotrexate with biological DMARDs do not take the drug because of side effects. The committee concluded that a range of treatment options is important in rheumatoid arthritis.
## Tofacitinib offers a potentially important new treatment option for people with rheumatoid arthritis
The clinical experts emphasised that tofacitinib is a novel treatment with a different mode of action to the biological DMARDs. They noted that the selective inhibition of Janus kinase 1 and 3 will affect a broad range of cytokines involved in the pathogenesis of rheumatoid arthritis. The clinical experts noted that there are subtly different adverse effects across the different classes of drugs for rheumatoid arthritis, but the adverse effects associated with Janus kinase inhibitors are unlikely to influence their desire to prescribe the drug. The patient experts noted that the potential benefits of treatment with Janus kinase inhibitors are likely to outweigh the adverse effects. The clinical experts also noted the similar kinetic action of tofacitinib compared with biological DMARDs, specifically TNF‑alpha inhibitors. Both the clinical and patient experts also highlighted that tofacitinib is given orally, which has major benefits for both patients and the health system. The patient experts emphasised that this is an important factor for people who have difficulty injecting themselves because of the disease affecting their hands. The patient experts also noted that some current treatments have to be stopped if the person gets an infection, and that some treatments may cause injection site reactions. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological DMARDs.
# Subgroups
## The company's subgroups and comparators were appropriate
The committee was aware that the company had analysed 5 distinct subgroups for whom tofacitinib could be used:
people with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs
people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs and for whom methotrexate is a treatment option
people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs and for whom methotrexate isn't an option
people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option
people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated.The relevant comparators varied by subgroup. The committee concluded that it was appropriate to consider the 5 groups separately and that the company had broadly included the appropriate comparators.
# Clinical effectiveness
## The trials were adequate and suitable for decision-making
The company's clinical evidence came mainly from 4 phase III randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.6. The trials were:
ORAL Standard, which included people whose disease responded inadequately to methotrexate and who had not had biological DMARDs. Tofacitinib 5 mg was given twice daily in combination with methotrexate and the comparators were placebo and adalimumab, both in combination with methotrexate.
ORAL Scan, which included people whose disease responded inadequately to methotrexate and who had not had biological DMARDs. Tofacitinib 5 mg was given twice daily in combination with methotrexate and the comparator was placebo plus methotrexate.
ORAL Sync, which included people whose disease responded inadequately to conventional or biological DMARDs. Tofacitinib 5 mg was given twice daily in combination with at least 1 conventional DMARD and the comparator was placebo plus methotrexate.
ORAL Solo, which included people whose disease responded inadequately to conventional or biological DMARDs. Tofacitinib 5 mg alone was given twice daily and the comparator was placebo.The primary outcomes of all the randomised controlled trials, measured at month 3 or 6, were:
proportion of people with a 20% improvement in the American College of Rheumatology response criteria (ACR20)
mean change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI)
proportion of people with a DAS28 of less than 2.6.The key secondary outcomes included the proportion of people with a 50% or 70% improvement in the response criteria (ACR50 and ACR70 respectively).
Additional clinical evidence came from ORAL Strategy, a phase III/IVb randomised controlled trial. It included people with moderate to severe rheumatoid arthritis, and measured ACR50 at month 6, as its primary outcome. The committee concluded that the trials were adequate and suitable for decision-making.
## EULAR response was derived from DAS28 score
The committee noted that because the ORAL trials did not collect the EULAR response criteria, EULAR response was derived from the DAS28 scores for each trial, at month 3 or 6. The EULAR response criteria use the individual change in DAS28 and the absolute DAS28 score to classify a EULAR response as good, moderate, or none. The committee accepted the company's estimation of the EULAR response and concluded that the trials were relevant and adequate for its decision-making.
## The company adjusted for crossover using 2 approaches considered suitable for decision-making
The committee noted that the design of the ORAL trials allowed all the patients having placebo or all patients whose condition did not respond to placebo to have tofacitinib after month 3 (response was defined as a 20% reduction in the number of tender and swollen joints). The committee heard from the ERG that, to adjust for crossover, 2 approaches were applied. The first approach estimated the treatment effect (estimate 1) by imputing the number of patients from the placebo arm whose condition did not respond at month 3 (also known as non-responder imputation without advancement penalty). The second approach estimated the treatment effect (estimate 2) by imputing the number of patients from the placebo arm whose condition did not respond at month 3 as well as the patients from the tofacitinib arm whose condition did not respond (also known as non-responder imputation with advancement penalty). The committee noted that the primary analysis for the ORAL Standard, Scan and Sync trials was based on non-responder imputation with advancement penalty (estimate 2) and therefore clinical results are reported for a combined placebo group (that is, the group who crossed over to have either 5 mg or 10 mg of tofacitinib, because the results were not provided separately for the licensed 5 mg dose). Because fewer patients from the placebo arm whose condition did not respond at month 3 later developed a response at month 6 compared with patients from the tofacitinib arm, the ERG agreed that the true treatment effect was likely to lie between these 2 estimates, but closer to estimate 1 than to estimate 2. The committee was satisfied with the approaches used to adjust for crossover and agreed with the ERG on their estimation of the true treatment effect.
Tofacitinib with methotrexate is more clinically effective than conventional DMARDs for moderate to severe disease that has responded inadequately to conventional DMARDs
The committee considered ORAL Standard and ORAL Scan, which included people with moderate to severe rheumatoid arthritis whose disease responded inadequately to conventional DMARDs. In both trials, there was a statistically significant increase in the proportion of people having tofacitinib who met the ACR20 criteria at month 6 compared with the combined placebo group (see section 3.9): ORAL Standard 51.5% compared with 28.3% respectively, p<0.001; ORAL Scan 51.5% compared with 25.3% respectively, p<0.001. In ORAL Standard, there was also a statistically significant increase in the proportion of people having adalimumab who met the ACR20 criteria at month 6 compared with the combined placebo group: 47.2% compared with 28.3% respectively, p<0.001. Statistically significant improvements in the mean change from baseline in HAQ-DI scores and the proportion of patients achieving a DAS28 of less than 2.6 were also seen in ORAL Standard for tofacitinib compared with the combined placebo group (−0.55 compared with −0.24, p<0.001; 6.2% compared with 1.1%, p value is confidential). For ORAL Scan, no statements about statistical significance could be made for the HAQ‑DI score or DAS28 outcomes. The committee considered ORAL Strategy, which included people with moderate to severe rheumatoid arthritis that responded inadequately to conventional DMARDs. For the proportion of people meeting the ACR50 criteria at 6 months, tofacitinib plus conventional DMARDs was non-inferior to adalimumab plus conventional DMARDs, and tofacitinib monotherapy was less effective than both tofacitinib and adalimumab, both in combination with conventional DMARDs. The committee concluded that in people with moderate to severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, tofacitinib plus conventional DMARDs is not worse in effectiveness than adalimumab plus conventional DMARDs, and is more effective than conventional DMARDs alone.
Tofacitinib alone and with methotrexate is more clinically effective than conventional DMARDs for moderate to severe disease that has responded inadequately to conventional or biological DMARDs
The committee considered ORAL Sync (combination therapy) and ORAL Solo (monotherapy), which included people with moderate to severe rheumatoid arthritis whose disease responded inadequately to conventional or biological DMARDs. For ORAL Sync, in the tofacitinib plus methotrexate group compared with the combined placebo group, there was a statistically significant increase in the proportion of people meeting the ACR20 criteria at 6 months (52.7% compared with 31.2%, p<0.001) and in the mean change from baseline in HAQ-DI scores at 3 months (−0.46 compared with −0.21, p<0.01) respectively. The proportion achieving remission using a DAS28 less than 2.6 response at 3 months was 9.1% compared with 2.7% for tofacitinib plus methotrexate compared with combined placebo (p=0.0038). In ORAL Solo, the proportion of people meeting the ACR20 criteria and the mean change from baseline in HAQ-DI scores at 3 months was statistically significantly higher for tofacitinib monotherapy compared with combined placebo at 3 months (ACR20 59.8% compared with 26.7%, p<0.001; HAQ-DI −0.50 compared with −0.19, p<0.001). The proportion of patients in the tofacitinib monotherapy group compared with the combined placebo group who went into remission, based on a DAS28 response of less than 2.6 at 3 months, was not statistically significantly different (5.6% compared with 4.4%; p=0.62). The committee concluded that tofacitinib plus conventional DMARDs is more effective than conventional DMARDs alone, and tofacitinib alone is more effective than placebo in people with moderate to severe rheumatoid arthritis whose disease has responded inadequately to conventional or biological DMARDs.
## Tofacitinib has a similar safety profile to conventional DMARDs
The committee noted that the safety profiles of tofacitinib and conventional DMARDs were similar. It heard from the ERG that a safety review by Curtis et al. (2016) showed that the incidence of herpes zoster was significantly higher in people who had previously had tofacitinib than those who had previously had biological DMARDs. The committee heard from clinical experts that this adverse effect was specific to the class of Janus kinase inhibitors rather than tofacitinib. It also heard that the higher incidence of herpes zoster in the review was not associated with a higher rate of patients stopping treatment with tofacitinib because it is considered as a manageable infection. The committee concluded that tofacitinib's safety profile was acceptable and similar to that of conventional DMARDs.
# Indirect comparison
## Network meta-analyses show that tofacitinib works as well as biological DMARDs
The committee was aware that other than the direct comparison with adalimumab, the only evidence available on the comparative effectiveness of tofacitinib and the biological DMARDs was from the company's network meta-analyses. The company did separate analyses for patients whose disease responded inadequately to either conventional or biological DMARDs, using change in HAQ-DI from baseline and EULAR response outcome measures, together with estimate 1 (see section 3.9) in the base case.At the 20- to 30‑week follow-up, for patients whose disease responded inadequately to conventional DMARDs, the network meta-analysis showed that:
tofacitinib plus conventional DMARDs gave better EULAR response rates than conventional DMARDs alone
tofacitinib plus conventional DMARDs gave similar EULAR response rates to biological DMARDs plus conventional DMARDs
estimates 1 were higher than estimates 2.At the 20- to 30‑week follow-up, for patients whose disease responded inadequately to biological DMARDs, the network meta-analysis provided only used estimate 2 and showed that tofacitinib plus conventional DMARDs gave similar EULAR response rates to biological DMARDs plus conventional DMARDs.
## The company's and ERG's network meta-analysis results were broadly comparable
The committee heard from the ERG that there were problems with the methods used in the company's network meta-analysis. These included:
different models for EULAR response in the 2 populations
a random effects model for patients whose disease responded inadequately to conventional DMARDs and a fixed effects model for patients whose disease responded inadequately to biological DMARDs
a uniform prior in the random effects model
using estimate 1 in their base case and
the method of linking etanercept to the network.Also, studies reporting EULAR responses were synthesised with converted EULAR response outcomes from studies that only reported ACR responses. At the clarification stage, the company corrected the errors in their network meta-analysis. The committee was satisfied that the corrected network meta-analysis was suitable for decision-making.
# Cost effectiveness
## The economic model structure was appropriate for decision-making
The company used an individual patient-based discrete event simulation model for its economic evaluation. The model simulates patients' disease progression through the sequences of treatments being compared. It was based on the model used by the assessment group during the production of NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The model categorised patients based on their EULAR response (good, moderate or no response) at 6 months. Response rates were based on a regression model using ORAL trial data (for tofacitinib and tofacitinib plus methotrexate) and the company's network meta-analysis (for the comparators). The treatment stopped if the patient did not have at least a moderate EULAR response at 6 months. The company analysed cost effectiveness for each of the subgroups described in section 3.6. The committee concluded that the model structure was appropriate for its decision-making.
## The model was adequate for decision-making
After corrections by the company (at the clarification stage and a later correction of an error in the company submission), the ERG identified several issues with the company's economic analyses including:
exclusion of relevant comparators that have previously been recommended by NICE
using inappropriate sequences of treatment
assuming that the efficacy for sulfasalazine is the same as the efficacy for placebo
deterministic rounding of HAQ scores to the nearest valid HAQ score, rather than allowing HAQ scores to be sampled based on a continuous HAQ value
excluding intravenous abatacept and subcutaneous tocilizumab from the list of comparators.The ERG amended the company's model by using the appropriate sequencing and applying a probabilistic HAQ rounding (instead of deterministic) and stated that the other errors were unlikely to change the broad conclusions of the company's model. The committee concluded that the ERG's amended model was adequate for its decision-making.
# Cost-effectiveness results
## Tofacitinib is not cost effective for moderate disease after conventional DMARDs
In the moderate active rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the ERG's incremental cost-effectiveness ratio (ICER) for the tofacitinib sequence compared with the conventional DMARD sequence, including the confidential comparator patient access scheme, was above £30,000 per quality-adjusted life year (QALY) gained. The committee considered that tofacitinib plus conventional DMARDs was not cost effective in people with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.
## Tofacitinib, with methotrexate, is cost effective for severe active disease after conventional DMARDs
In the ERG's analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the clinical and cost-effectiveness estimates for tofacitinib plus conventional DMARDs were very similar to what had previously been seen in rheumatoid arthritis. The committee concluded that it could recommend tofacitinib plus methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.
## Tofacitinib monotherapy is cost effective for severe active disease after conventional DMARDs
In the ERG's analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, tofacitinib monotherapy produced very similar clinical and cost-effectiveness estimates compared with what had previously been seen in rheumatoid arthritis. The committee concluded that it could recommend tofacitinib monotherapy as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.
## Tofacitinib is not cost effective for severe disease after biological DMARDs if rituximab is a treatment option
For the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option, the only sequence recommended by NICE is rituximab followed by tocilizumab. In the ERG's analysis, ICERs were presented for alternative sequences compared with the recommended sequence. It showed that when using estimate 1, tofacitinib followed by tocilizumab was dominated by rituximab followed by tocilizumab, whereas the sequence of rituximab followed by tofacitinib gives cost savings but also loss of QALYs, resulting in ICERs that reflect 'savings per QALY lost'. For example, in the ERG's analysis, when comparing the sequence starting with rituximab followed by tofacitinib with the sequence starting with rituximab followed by tocilizumab, there was a cost saving of £15,284 in the tofacitinib sequence, but a QALY loss of −0.19, resulting in an ICER of £80,442 saved per QALY lost. When using estimate 2, the sequence of tofacitinib followed by tocilizumab was dominated by rituximab followed by tocilizumab (less costly and more effective) whereas rituximab followed by tofacitinib resulted in cost savings but also loss of QALYs (£137,483 saved per QALY lost). The committee noted that a confidential patient access scheme is in place for tocilizumab, which was not included in this analysis. The committee considered the ICERs that incorporated confidential patient access schemes for tocilizumab and tofacitinib, but the results are confidential and cannot be reported here (to protect the confidentiality of the discounts in the patient access schemes). The committee noted that when using estimate 1, the sequence of tofacitinib followed by tocilizumab remained dominated by NICE's recommended sequence, and although the ICER for rituximab followed by tofacitinib was lower, the cost savings were at a less acceptable level given the QALYs that would be lost. When using estimate 2, the sequence of tofacitinib followed by tocilizumab resulted in cost savings and loss of QALYs. The ICER for rituximab followed by tofacitinib no longer resulted in cost savings and was dominated by the recommended sequence. Therefore there was a high degree of uncertainty around the cost-effectiveness estimates in this population. Taking into account all of the information presented, the committee concluded that tofacitinib was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs if rituximab is a treatment option.
## Tofacitinib, with methotrexate, is cost effective for severe disease after biological DMARDs if rituximab is not a treatment option
The committee noted that adalimumab, infliximab and certolizumab pegol, all in combination with methotrexate, have not been included in the analyses despite this being recommended by NICE. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness compared with those previously seen in appraisals of rheumatoid arthritis. It concluded that tofacitinib plus methotrexate was a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is not a treatment option.
## The recommendations also apply to tofacitinib for severe disease after biological DMARDs if methotrexate is not a treatment option
The committee was aware that the marketing authorisation for tofacitinib includes its use as a monotherapy. But the company did not present an economic analysis for tofacitinib alone for severe disease, after biological DMARDs, in patients who cannot have methotrexate. The committee recognised the considerable uncertainty about the effectiveness of tofacitinib alone in people whose disease has responded inadequately to conventional or biological DMARDs. The committee was aware that in the appraisal of baricitinib, the committee concluded that baricitinib monotherapy has similar clinical effectiveness to baricitinib plus conventional DMARDs. The committee heard from the clinical experts that, although the preference is to give tofacitinib plus methotrexate, if a person cannot take methotrexate, tofacitinib will be given alone. The clinical experts also noted that Janus kinase inhibitors seem to have similar clinical effectiveness. The committee concluded that its recommendations for tofacitinib plus conventional DMARDs should also apply to tofacitinib alone for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and who cannot take methotrexate because it is contraindicated or not tolerated.
|
{'Recommendations': 'Tofacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying anti-rheumatic drugs (DMARDs), only if:\n\ndisease is severe (a disease activity score [DAS28] of more than\xa05.1) and\n\nthe company provides tofacitinib with the discount agreed in the patient access scheme.\n\nTofacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot have, other DMARDs, including at least 1\xa0biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than\xa05.1) and\n\nthey cannot have rituximab and\n\nthe company provides tofacitinib with the discount agreed in the patient access scheme.\n\nTofacitinib can be used as monotherapy for adults who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections\xa01.1 or\xa01.2 are met.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. After an initial response within 6\xa0months, withdraw treatment if at least a moderate EULAR response is not maintained.\n\nWhen using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with tofacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trial evidence shows tofacitinib plus conventional DMARDs is more effective than conventional DMARDs alone for treating moderate and severe active rheumatoid arthritis that has not responded adequately to conventional or biological DMARDs.\n\nClinical trial evidence also shows that tofacitinib plus methotrexate is not worse in effectiveness than the biological DMARD adalimumab plus conventional DMARDs in people whose disease has responded inadequately to conventional DMARDs. Because there are no trials comparing tofacitinib with other biological DMARDs, the company did an indirect comparison. This shows that tofacitinib works as well as most of the biological DMARDs which NICE has already recommended in this indication.\n\nBased on the health-related benefits and costs compared with conventional and biological DMARDs, tofacitinib plus conventional DMARDs is recommended as a cost-effective treatment for severe active rheumatoid arthritis, in line with previous recommendations in:\n\nNICE technology appraisal guidance on baricitinib\n\ncertolizumab pegol (after a TNF-alpha inhibitor)\n\nadalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (after conventional DMARDs)\n\ntocilizumab\n\ngolimumab (after DMARDs)\n\nadalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha inhibitor).Tofacitinib for moderate active rheumatoid arthritis that has responded inadequately to conventional DMARDs is not cost effective based on what NICE normally considers acceptable, that is, £30,000 per quality-adjusted life year gained.', 'The technology': "Marketing authorisation\n\nTofacitinib (Xeljanz, Pfizer) in combination with methotrexate has a marketing authorisation in the UK for the 'treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs'. Tofacitinib can be given as monotherapy in patients who are intolerant to methotrexate or when treatment with methotrexate is inappropriate.\n\nRecommended dose and schedule\n\nThe recommended dose of tofacitinib is 5\xa0mg twice daily. A dose of 5\xa0mg once daily is appropriate for patients with severe renal impairment (creatinine clearance less than 30\xa0ml/min). A dose of 5\xa0mg once daily is appropriate for patients with moderate hepatic impairment (Child–Pugh\xa0B). Tofacitinib should not be used in patients with severe hepatic impairment (Child–Pugh\xa0C). Tofacitinib should be interrupted if a patient develops a serious infection, until the infection is controlled.\n\nPrice\n\nThe list price of a 56‑tablet pack of 5\xa0mg tofacitinib is £690.03 (excluding VAT; British national formulary [BNF] online ). The average cost per patient for the first 6\xa0months is estimated at £4,050.60 based on the list price. The average cost per patient for subsequent years is estimated at £9,001.19 based on the list price.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of tofacitinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Tofacitinib can be used at 4\xa0different points in the pathway\n\nTofacitinib's marketing authorisation covers its use at 4\xa0points in the treatment pathway, specifically in adults with:\n\nmoderate, active rheumatoid arthritis that has not responded adequately to conventional disease-modifying anti-rheumatic drugs (DMARDs)\n\nsevere, active rheumatoid arthritis that has not responded adequately to conventional DMARDs\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1\xa0tumour necrosis factor-alpha (TNF‑alpha) inhibitor\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1\xa0TNF‑alpha inhibitor and when rituximab is contraindicated or withdrawn because of adverse events.The committee also noted that the marketing authorisation includes the use of tofacitinib alone or with methotrexate.\n\n## NICE technology appraisal guidance exists for these points in the rheumatoid arthritis treatment pathway\n\nNICE currently recommends the use of the biological DMARDs in its technology appraisal guidance on baricitinib, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are TNF‑alpha inhibitors), in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than\xa05.1 indicates severe disease (between\xa03.2 and\xa05.1 indicates moderate disease, less than\xa03.2 but more than\xa02.6 indicates mild disease and less than\xa02.6 indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that baricitinib, adalimumab, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy. The guidance recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose) and should only be continued according to European League Against Rheumatism (EULAR) response at 6\xa0months.\n\nFor people with severe rheumatoid arthritis who have already had at least 1\xa0TNF‑alpha inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommends the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends tocilizumab, certolizumab pegol, baricitinib, abatacept, adalimumab, etanercept, infliximab or golimumab, in combination with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance on abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol or baricitinib recommends adalimumab, etanercept, tocilizumab, certolizumab pegol or baricitinib as monotherapy. NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha inhibitors nor rituximab have worked.\n\n## A range of treatment options is important in rheumatoid arthritis\n\nThe committee heard from the patient experts that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional DMARDs such as methotrexate are inadequate for many people. They added that the disease sometimes does not respond adequately to the first biological DMARD prescribed. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological DMARDs after failure of conventional DMARDs. The clinical and patient experts agreed that methotrexate is often not well tolerated; the clinical experts noted that up to a third of people who are prescribed methotrexate with biological DMARDs do not take the drug because of side effects. The committee concluded that a range of treatment options is important in rheumatoid arthritis.\n\n## Tofacitinib offers a potentially important new treatment option for people with rheumatoid arthritis\n\nThe clinical experts emphasised that tofacitinib is a novel treatment with a different mode of action to the biological DMARDs. They noted that the selective inhibition of Janus kinase\xa01 and\xa03 will affect a broad range of cytokines involved in the pathogenesis of rheumatoid arthritis. The clinical experts noted that there are subtly different adverse effects across the different classes of drugs for rheumatoid arthritis, but the adverse effects associated with Janus kinase inhibitors are unlikely to influence their desire to prescribe the drug. The patient experts noted that the potential benefits of treatment with Janus kinase inhibitors are likely to outweigh the adverse effects. The clinical experts also noted the similar kinetic action of tofacitinib compared with biological DMARDs, specifically TNF‑alpha inhibitors. Both the clinical and patient experts also highlighted that tofacitinib is given orally, which has major benefits for both patients and the health system. The patient experts emphasised that this is an important factor for people who have difficulty injecting themselves because of the disease affecting their hands. The patient experts also noted that some current treatments have to be stopped if the person gets an infection, and that some treatments may cause injection site reactions. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological DMARDs.\n\n# Subgroups\n\n## The company's subgroups and comparators were appropriate\n\nThe committee was aware that the company had analysed 5\xa0distinct subgroups for whom tofacitinib could be used:\n\npeople with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs\n\npeople with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs and for whom methotrexate is a treatment option\n\npeople with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs and for whom methotrexate isn't an option\n\npeople with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option\n\npeople with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated.The relevant comparators varied by subgroup. The committee concluded that it was appropriate to consider the 5\xa0groups separately and that the company had broadly included the appropriate comparators.\n\n# Clinical effectiveness\n\n## The trials were adequate and suitable for decision-making\n\nThe company's clinical evidence came mainly from 4\xa0phase\xa0III randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis, as defined in section\xa03.6. The trials were:\n\nORAL Standard, which included people whose disease responded inadequately to methotrexate and who had not had biological DMARDs. Tofacitinib 5\xa0mg was given twice daily in combination with methotrexate and the comparators were placebo and adalimumab, both in combination with methotrexate.\n\nORAL Scan, which included people whose disease responded inadequately to methotrexate and who had not had biological DMARDs. Tofacitinib 5\xa0mg was given twice daily in combination with methotrexate and the comparator was placebo plus methotrexate.\n\nORAL Sync, which included people whose disease responded inadequately to conventional or biological DMARDs. Tofacitinib 5\xa0mg was given twice daily in combination with at least 1\xa0conventional DMARD and the comparator was placebo plus methotrexate.\n\nORAL Solo, which included people whose disease responded inadequately to conventional or biological DMARDs. Tofacitinib 5\xa0mg alone was given twice daily and the comparator was placebo.The primary outcomes of all the randomised controlled trials, measured at month\xa03 or\xa06, were:\n\nproportion of people with a 20% improvement in the American College of Rheumatology response criteria (ACR20)\n\nmean change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI)\n\nproportion of people with a DAS28 of less than\xa02.6.The key secondary outcomes included the proportion of people with a 50% or 70% improvement in the response criteria (ACR50 and ACR70 respectively).\n\nAdditional clinical evidence came from ORAL Strategy, a phase\xa0III/IVb randomised controlled trial. It included people with moderate to severe rheumatoid arthritis, and measured ACR50 at month\xa06, as its primary outcome. The committee concluded that the trials were adequate and suitable for decision-making.\n\n## EULAR response was derived from DAS28 score\n\nThe committee noted that because the ORAL trials did not collect the EULAR response criteria, EULAR response was derived from the DAS28 scores for each trial, at month\xa03 or\xa06. The EULAR response criteria use the individual change in DAS28 and the absolute DAS28 score to classify a EULAR response as good, moderate, or none. The committee accepted the company's estimation of the EULAR response and concluded that the trials were relevant and adequate for its decision-making.\n\n## The company adjusted for crossover using 2\xa0approaches considered suitable for decision-making\n\nThe committee noted that the design of the ORAL trials allowed all the patients having placebo or all patients whose condition did not respond to placebo to have tofacitinib after month\xa03 (response was defined as a 20% reduction in the number of tender and swollen joints). The committee heard from the ERG that, to adjust for crossover, 2\xa0approaches were applied. The first approach estimated the treatment effect (estimate\xa01) by imputing the number of patients from the placebo arm whose condition did not respond at month\xa03 (also known as non-responder imputation without advancement penalty). The second approach estimated the treatment effect (estimate\xa02) by imputing the number of patients from the placebo arm whose condition did not respond at month\xa03 as well as the patients from the tofacitinib arm whose condition did not respond (also known as non-responder imputation with advancement penalty). The committee noted that the primary analysis for the ORAL Standard, Scan and Sync trials was based on non-responder imputation with advancement penalty (estimate\xa02) and therefore clinical results are reported for a combined placebo group (that is, the group who crossed over to have either 5\xa0mg or 10\xa0mg of tofacitinib, because the results were not provided separately for the licensed 5\xa0mg dose). Because fewer patients from the placebo arm whose condition did not respond at month\xa03 later developed a response at month\xa06 compared with patients from the tofacitinib arm, the ERG agreed that the true treatment effect was likely to lie between these 2\xa0estimates, but closer to estimate\xa01 than to estimate\xa02. The committee was satisfied with the approaches used to adjust for crossover and agreed with the ERG on their estimation of the true treatment effect.\n\nTofacitinib with methotrexate is more clinically effective than conventional DMARDs for moderate to severe disease that has responded inadequately to conventional DMARDs\n\nThe committee considered ORAL Standard and ORAL Scan, which included people with moderate to severe rheumatoid arthritis whose disease responded inadequately to conventional DMARDs. In both trials, there was a statistically significant increase in the proportion of people having tofacitinib who met the ACR20 criteria at month\xa06 compared with the combined placebo group (see section\xa03.9): ORAL Standard 51.5% compared with 28.3% respectively, p<0.001; ORAL Scan 51.5% compared with 25.3% respectively, p<0.001. In ORAL Standard, there was also a statistically significant increase in the proportion of people having adalimumab who met the ACR20 criteria at month\xa06 compared with the combined placebo group: 47.2% compared with 28.3% respectively, p<0.001. Statistically significant improvements in the mean change from baseline in HAQ-DI scores and the proportion of patients achieving a DAS28 of less than\xa02.6 were also seen in ORAL Standard for tofacitinib compared with the combined placebo group (−0.55 compared with −0.24, p<0.001; 6.2% compared with 1.1%, p\xa0value is confidential). For ORAL Scan, no statements about statistical significance could be made for the HAQ‑DI score or DAS28 outcomes. The committee considered ORAL Strategy, which included people with moderate to severe rheumatoid arthritis that responded inadequately to conventional DMARDs. For the proportion of people meeting the ACR50 criteria at 6\xa0months, tofacitinib plus conventional DMARDs was non-inferior to adalimumab plus conventional DMARDs, and tofacitinib monotherapy was less effective than both tofacitinib and adalimumab, both in combination with conventional DMARDs. The committee concluded that in people with moderate to severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, tofacitinib plus conventional DMARDs is not worse in effectiveness than adalimumab plus conventional DMARDs, and is more effective than conventional DMARDs alone.\n\nTofacitinib alone and with methotrexate is more clinically effective than conventional DMARDs for moderate to severe disease that has responded inadequately to conventional or biological DMARDs\n\nThe committee considered ORAL Sync (combination therapy) and ORAL Solo (monotherapy), which included people with moderate to severe rheumatoid arthritis whose disease responded inadequately to conventional or biological DMARDs. For ORAL Sync, in the tofacitinib plus methotrexate group compared with the combined placebo group, there was a statistically significant increase in the proportion of people meeting the ACR20 criteria at 6\xa0months (52.7% compared with 31.2%, p<0.001) and in the mean change from baseline in HAQ-DI scores at 3\xa0months (−0.46 compared with −0.21, p<0.01) respectively. The proportion achieving remission using a DAS28 less than\xa02.6 response at 3\xa0months was 9.1% compared with 2.7% for tofacitinib plus methotrexate compared with combined placebo (p=0.0038). In ORAL Solo, the proportion of people meeting the ACR20 criteria and the mean change from baseline in HAQ-DI scores at 3\xa0months was statistically significantly higher for tofacitinib monotherapy compared with combined placebo at 3\xa0months (ACR20 59.8% compared with 26.7%, p<0.001; HAQ-DI −0.50 compared with −0.19, p<0.001). The proportion of patients in the tofacitinib monotherapy group compared with the combined placebo group who went into remission, based on a DAS28 response of less than\xa02.6 at 3\xa0months, was not statistically significantly different (5.6% compared with 4.4%; p=0.62). The committee concluded that tofacitinib plus conventional DMARDs is more effective than conventional DMARDs alone, and tofacitinib alone is more effective than placebo in people with moderate to severe rheumatoid arthritis whose disease has responded inadequately to conventional or biological DMARDs.\n\n## Tofacitinib has a similar safety profile to conventional DMARDs\n\nThe committee noted that the safety profiles of tofacitinib and conventional DMARDs were similar. It heard from the ERG that a safety review by Curtis et al. (2016) showed that the incidence of herpes zoster was significantly higher in people who had previously had tofacitinib than those who had previously had biological DMARDs. The committee heard from clinical experts that this adverse effect was specific to the class of Janus kinase inhibitors rather than tofacitinib. It also heard that the higher incidence of herpes zoster in the review was not associated with a higher rate of patients stopping treatment with tofacitinib because it is considered as a manageable infection. The committee concluded that tofacitinib's safety profile was acceptable and similar to that of conventional DMARDs.\n\n# Indirect comparison\n\n## Network meta-analyses show that tofacitinib works as well as biological DMARDs\n\nThe committee was aware that other than the direct comparison with adalimumab, the only evidence available on the comparative effectiveness of tofacitinib and the biological DMARDs was from the company's network meta-analyses. The company did separate analyses for patients whose disease responded inadequately to either conventional or biological DMARDs, using change in HAQ-DI from baseline and EULAR response outcome measures, together with estimate\xa01 (see section\xa03.9) in the base case.At the 20- to 30‑week follow-up, for patients whose disease responded inadequately to conventional DMARDs, the network meta-analysis showed that:\n\ntofacitinib plus conventional DMARDs gave better EULAR response rates than conventional DMARDs alone\n\ntofacitinib plus conventional DMARDs gave similar EULAR response rates to biological DMARDs plus conventional DMARDs\n\nestimates\xa01 were higher than estimates\xa02.At the 20- to 30‑week follow-up, for patients whose disease responded inadequately to biological DMARDs, the network meta-analysis provided only used estimate\xa02 and showed that tofacitinib plus conventional DMARDs gave similar EULAR response rates to biological DMARDs plus conventional DMARDs.\n\n## The company's and ERG's network meta-analysis results were broadly comparable\n\nThe committee heard from the ERG that there were problems with the methods used in the company's network meta-analysis. These included:\n\ndifferent models for EULAR response in the 2\xa0populations\n\na random effects model for patients whose disease responded inadequately to conventional DMARDs and a fixed effects model for patients whose disease responded inadequately to biological DMARDs\n\na uniform prior in the random effects model\n\nusing estimate\xa01 in their base case and\n\nthe method of linking etanercept to the network.Also, studies reporting EULAR responses were synthesised with converted EULAR response outcomes from studies that only reported ACR responses. At the clarification stage, the company corrected the errors in their network meta-analysis. The committee was satisfied that the corrected network meta-analysis was suitable for decision-making.\n\n# Cost effectiveness\n\n## The economic model structure was appropriate for decision-making\n\nThe company used an individual patient-based discrete event simulation model for its economic evaluation. The model simulates patients' disease progression through the sequences of treatments being compared. It was based on the model used by the assessment group during the production of NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The model categorised patients based on their EULAR response (good, moderate or no response) at 6\xa0months. Response rates were based on a regression model using ORAL trial data (for tofacitinib and tofacitinib plus methotrexate) and the company's network meta-analysis (for the comparators). The treatment stopped if the patient did not have at least a moderate EULAR response at\xa06 months. The company analysed cost effectiveness for each of the subgroups described in section\xa03.6. The committee concluded that the model structure was appropriate for its decision-making.\n\n## The model was adequate for decision-making\n\nAfter corrections by the company (at the clarification stage and a later correction of an error in the company submission), the ERG identified several issues with the company's economic analyses including:\n\nexclusion of relevant comparators that have previously been recommended by NICE\n\nusing inappropriate sequences of treatment\n\nassuming that the efficacy for sulfasalazine is the same as the efficacy for placebo\n\ndeterministic rounding of HAQ scores to the nearest valid HAQ score, rather than allowing HAQ scores to be sampled based on a continuous HAQ value\n\nexcluding intravenous abatacept and subcutaneous tocilizumab from the list of comparators.The ERG amended the company's model by using the appropriate sequencing and applying a probabilistic HAQ rounding (instead of deterministic) and stated that the other errors were unlikely to change the broad conclusions of the company's model. The committee concluded that the ERG's amended model was adequate for its decision-making.\n\n# Cost-effectiveness results\n\n## Tofacitinib is not cost effective for moderate disease after conventional DMARDs\n\nIn the moderate active rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the ERG's incremental cost-effectiveness ratio (ICER) for the tofacitinib sequence compared with the conventional DMARD sequence, including the confidential comparator patient access scheme, was above £30,000 per quality-adjusted life year (QALY) gained. The committee considered that tofacitinib plus conventional DMARDs was not cost effective in people with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.\n\n## Tofacitinib, with methotrexate, is cost effective for severe active disease after conventional DMARDs\n\nIn the ERG's analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the clinical and cost-effectiveness estimates for tofacitinib plus conventional DMARDs were very similar to what had previously been seen in rheumatoid arthritis. The committee concluded that it could recommend tofacitinib plus methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.\n\n## Tofacitinib monotherapy is cost effective for severe active disease after conventional DMARDs\n\nIn the ERG's analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, tofacitinib monotherapy produced very similar clinical and cost-effectiveness estimates compared with what had previously been seen in rheumatoid arthritis. The committee concluded that it could recommend tofacitinib monotherapy as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.\n\n## Tofacitinib is not cost effective for severe disease after biological DMARDs if rituximab is a treatment option\n\nFor the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option, the only sequence recommended by NICE is rituximab followed by tocilizumab. In the ERG's analysis, ICERs were presented for alternative sequences compared with the recommended sequence. It showed that when using estimate\xa01, tofacitinib followed by tocilizumab was dominated by rituximab followed by tocilizumab, whereas the sequence of rituximab followed by tofacitinib gives cost savings but also loss of QALYs, resulting in ICERs that reflect 'savings per QALY lost'. For example, in the ERG's analysis, when comparing the sequence starting with rituximab followed by tofacitinib with the sequence starting with rituximab followed by tocilizumab, there was a cost saving of £15,284 in the tofacitinib sequence, but a QALY loss of −0.19, resulting in an ICER of £80,442 saved per QALY lost. When using estimate\xa02, the sequence of tofacitinib followed by tocilizumab was dominated by rituximab followed by tocilizumab (less costly and more effective) whereas rituximab followed by tofacitinib resulted in cost savings but also loss of QALYs (£137,483 saved per QALY lost). The committee noted that a confidential patient access scheme is in place for tocilizumab, which was not included in this analysis. The committee considered the ICERs that incorporated confidential patient access schemes for tocilizumab and tofacitinib, but the results are confidential and cannot be reported here (to protect the confidentiality of the discounts in the patient access schemes). The committee noted that when using estimate\xa01, the sequence of tofacitinib followed by tocilizumab remained dominated by NICE's recommended sequence, and although the ICER for rituximab followed by tofacitinib was lower, the cost savings were at a less acceptable level given the QALYs that would be lost. When using estimate\xa02, the sequence of tofacitinib followed by tocilizumab resulted in cost savings and loss of QALYs. The ICER for rituximab followed by tofacitinib no longer resulted in cost savings and was dominated by the recommended sequence. Therefore there was a high degree of uncertainty around the cost-effectiveness estimates in this population. Taking into account all of the information presented, the committee concluded that tofacitinib was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs if rituximab is a treatment option.\n\n## Tofacitinib, with methotrexate, is cost effective for severe disease after biological DMARDs if rituximab is not a treatment option\n\nThe committee noted that adalimumab, infliximab and certolizumab pegol, all in combination with methotrexate, have not been included in the analyses despite this being recommended by NICE. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness compared with those previously seen in appraisals of rheumatoid arthritis. It concluded that tofacitinib plus methotrexate was a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is not a treatment option.\n\n## The recommendations also apply to tofacitinib for severe disease after biological DMARDs if methotrexate is not a treatment option\n\nThe committee was aware that the marketing authorisation for tofacitinib includes its use as a monotherapy. But the company did not present an economic analysis for tofacitinib alone for severe disease, after biological DMARDs, in patients who cannot have methotrexate. The committee recognised the considerable uncertainty about the effectiveness of tofacitinib alone in people whose disease has responded inadequately to conventional or biological DMARDs. The committee was aware that in the appraisal of baricitinib, the committee concluded that baricitinib monotherapy has similar clinical effectiveness to baricitinib plus conventional DMARDs. The committee heard from the clinical experts that, although the preference is to give tofacitinib plus methotrexate, if a person cannot take methotrexate, tofacitinib will be given alone. The clinical experts also noted that Janus kinase inhibitors seem to have similar clinical effectiveness. The committee concluded that its recommendations for tofacitinib plus conventional DMARDs should also apply to tofacitinib alone for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and who cannot take methotrexate because it is contraindicated or not tolerated."}
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https://www.nice.org.uk/guidance/ta480
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Evidence-based recommendations on tofacitinib (Xeljanz) for treating moderate to severe rheumatoid arthritis in adults.
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70dcaec9e5ed7cfdfc0b4fc108bd778aa30a17d0
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nice
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Immunosuppressive therapy for kidney transplant in adults
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Immunosuppressive therapy for kidney transplant in adults
Evidence-based recommendations on immunosuppressive therapies for preventing kidney rejection in adults. The therapies are basiliximab (Simulect), immediate-release tacrolimus (Adoport, Capexion, Modigraf, Prograf, Tacni, Vivadex), mycophenolate mofetil (Cellcept and non-branded versions), rabbit anti-human thymocyte immunoglobulin (Thymoglobuline), prolonged-release tacrolimus (Advagraf, Envarsus), mycophenolate sodium (Myfortic, Ceptava), sirolimus (Rapamune), everolimus (Certican) and belatacept (Nulojix).
# Recommendations
This guidance makes recommendations on using basiliximab, rabbit anti-human thymocyte immunoglobulin, tacrolimus (immediate-release and prolonged-release), mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept after kidney transplant in adults. The recommendations apply only to the initial immunosuppressive therapy (induction and maintenance therapy) started around the time of kidney transplant.
It was outside the scope of the appraisal to make recommendations on using the standard triple therapy regimen of ciclosporin, azathioprine and a corticosteroid after kidney transplant in adults.
Under an exceptional directive from the Department of Health, the appraisal committee was allowed to make recommendations about using drugs outside the terms of their marketing authorisations if there was compelling evidence of their safety and effectiveness.
Basiliximab, when used as part of an immunosuppressive regimen that includes a calcineurin inhibitor, is recommended as an initial option to prevent organ rejection in adults having a kidney transplant.,
Immediate-release tacrolimus, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in adults having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the person is not able to swallow capsules as a result of a disability or they are unable to have a particular ingredient because of allergy or religious reasons). Tacrolimus granules for oral suspension (Modigraf) should be used only if the company provides it at the same price or lower than that agreed with the Commercial Medicines Unit.
Mycophenolate mofetil, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in adults having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the person is not able to swallow capsules as a result of a disability or they are unable to have a particular ingredient because of allergy or religious reasons).,
Rabbit anti-human thymocyte immunoglobulin, prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in adults having a kidney transplant.
The committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in adults who are, or become, unable to have the technologies recommended in sections 1.1 to 1.3 or standard triple therapy with ciclosporin, azathioprine and a corticosteroid (for example, because of treatment failure, contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes adults who:
are unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or
have a second or subsequent transplant, having previously found that 1 or more of the recommended initial treatments or standard treatments are clinically unsuitable for example, because of treatment failure, contraindications or intolerance.
These recommendations are not intended to affect treatment with any of the technologies in this appraisal that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations, or for whom the committee were unable to make a recommendation, may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
August 2017: the use of basiliximab (with tacrolimus) and mycophenolate mofetil (with tacrolimus) is outside the terms of the marketing authorisations for basiliximab and for mycophenolate mofetil. If these combinations are prescribed, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. For further information, see the General Medical Council's guidance on Good practice in prescribing and managing medicines and devices.
The Department of Health has stated that the statutory funding requirement does not apply to drugs that are used outside the terms of their marketing authorisation.
The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that to maintain therapeutic response when a patient is stabilised on a particular brand, oral tacrolimus products should be prescribed and dispensed by brand name only. If a prescriber considers that switching to a different brand of oral tacrolimus would be of benefit, the change requires careful supervision and therapeutic monitoring by an appropriate specialist. See the MHRA's advice on oral tacrolimus products.# Clinical need and practice
Kidney transplant is used to treat established kidney failure, which is severe and irreversible impairment of kidney function. After a kidney transplant, immunosuppressive therapy is used to reduce the risk of rejection of the transplanted kidney (or 'graft') and prolong its survival.
Between April 2016 and March 2017, 3,042 kidney transplants were done in adults in the UK; 2,682 of these were in England. At the end of 2014, approximately 31,150 people in the UK were having immunosuppressive therapy after a kidney transplant, including 26,100 people in England.
Immunosuppressive therapy aims to prevent acute rejection and optimise the function of the transplanted kidney, while minimising the adverse effects of immunosuppression (such as increased risk of infection, cancer, diabetes and cardiovascular disease). Immunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2 weeks around the time of transplant and may include polyclonal or monoclonal antibodies. Maintenance therapy starts immediately after transplant and continues for life.
NICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults was published in 2004. It recommended basiliximab, daclizumab, tacrolimus, mycophenolate mofetil and sirolimus, in certain circumstances, as options for immunosuppressive therapy for kidney transplant in adults. Since that appraisal, the marketing authorisation for daclizumab has been withdrawn, new technologies (rabbit anti-human thymocyte immunoglobulin, mycophenolate sodium, belatacept, a prolonged-release formulation of tacrolimus, and everolimus) have received marketing authorisations, and some of the technologies are available as generics.# The technologies
# Induction therapy
## Basiliximab
Basiliximab (Simulect, Novartis Pharmaceuticals) is a monoclonal antibody that acts as an interleukin‑2 receptor antagonist. It has a marketing authorisation in the UK for the prophylaxis of acute organ rejection in adults having a kidney transplant. The summary of product characteristics states that basiliximab is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression, in patients with panel-reactive antibodies less than 80%, or in a triple maintenance immunosuppressive regimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine or mycophenolate mofetil.
Basiliximab is administered intravenously, in 2 doses of 20 mg each (one 2 hours before the surgery and the second 4 days after).
Basiliximab is available in 10‑mg and 20‑mg vials, at a price of £758.69 and £842.38 respectively (excluding VAT; British national formulary online ), equating to £1,685 per course of treatment (2 doses of 20 mg).
## Rabbit anti-human thymocyte immunoglobulin
Rabbit anti-human thymocyte immunoglobulin (r‑ATG; Thymoglobuline, Sanofi) is made by injecting human thymus cells into rabbits. The drug contains immunoglobulins (antibodies) that attach to and destroy some of the cells of the immune system. It has a marketing authorisation in the UK for the prevention of graft rejection in kidney transplant. The summary of product characteristics states that it is usually used with other immunosuppressive drugs.
r‑ATG is administered intravenously, at a dose of 1 to 1.5 mg/kg/day for 3 to 9 days after a kidney transplant (a cumulative dose of 3 to 13.5 mg/kg).
r‑ATG is available in 25 mg vials, at a price of £158.77 (excluding VAT; BNF online ), equating to £1,428.93 to £7,144.65 per course for a 70‑kg person.
# Maintenance therapy
Some drugs in this appraisal contain the same active ingredient but in different formulations. Tacrolimus is a calcineurin inhibitor and is available in an immediate-release formulation and a prolonged-release formulation. Mycophenolic acid is an antiproliferative agent. It is available as a prodrug called mycophenolate mofetil and a sodium salt called mycophenolate sodium.
## Immediate-release tacrolimus
Brands of immediate-release tacrolimus include Adoport (Sandoz), Capexion (Mylan), Modigraf (Astellas Pharma), Perixis (Accord Healthcare), Prograf (Astellas Pharma), Tacni (Teva) and Vivadex (Dexcel Pharma). All of these formulations have marketing authorisations in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. Adoport, Capexion, Perixis, Prograf, Tacni and Vivadex are administered orally as capsules, twice a day. Prograf can also be administered intravenously. Modigraf consists of granules for oral suspension.
For all brands of immediate-release tacrolimus, the summary of product characteristics recommends an initial dose of 0.2 to 0.3 mg/kg/day orally or 0.05 to 0.1 mg/kg/day intravenously, and states that the dosage is usually reduced in the period after the transplant.
Modigraf (tacrolimus granules for oral suspension) is available in sachets of 0.2 mg and 1 mg at a price of £7.13 per mg (excluding VAT; BNF online ). The company has agreed a nationally available price reduction for Modigraf with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. Tacrolimus immediate-release capsules are available as 0.5‑mg, 0.75‑mg, 1‑mg, 2‑mg and 5‑mg capsules (depending on the brand), the price of which varies by brand. The assessment group (AG) calculated that the average cost paid by the NHS for immediate-release tacrolimus capsules is £0.52 per mg (excluding VAT; data from the Electronic Market Information Tool , Commercial Medicines Unit). This equates to £50.96 to £76.44 per week for an initial dose of 0.2 to 0.3 mg/kg/day in a 70‑kg person. Adoport is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
## Prolonged-release tacrolimus
Prolonged-release tacrolimus (Advagraf, Astellas Pharma) is administered orally as a capsule, once a day. It has a marketing authorisation in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. The summary of product characteristics recommends an initial dose for adults of 0.2 to 0.3 mg/kg/day. The dosage is usually reduced in the period after the transplant.
Prolonged-release tacrolimus (Advagraf) is available as 0.5‑mg, 1‑mg, 3‑mg and 5‑mg capsules, at a price of £1.07 to £1.43 per mg (excluding VAT; BNF online ). This equates to £112.11 to £210.47 per week for an initial dose of 0.2 to 0.3 mg/kg/day in a 70‑kg person. Advagraf is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
Another brand of prolonged-release tacrolimus, Envarsus (Chiesi), obtained a marketing authorisation after the scope for this appraisal was finalised. The brand name Envarsus was not included in the AG's search for evidence and Chiesi was not asked to submit evidence for the appraisal.
## Belatacept
Belatacept (Nulojix, Bristol-Myers Squibb) is a soluble fusion protein designed to selectively inhibit CD28-mediated co-stimulation of T‑cells. Belatacept, in combination with corticosteroids and a mycophenolic acid, has a marketing authorisation in the UK for prophylaxis of graft rejection in adults having a kidney transplant. The summary of product characteristics recommends that an interleukin‑2 receptor antagonist is added to this belatacept-based regimen.
Belatacept is administered intravenously. The recommended dose is 10 mg/kg on the day of the transplant, followed by 10 mg/kg on days 5, 14, 28, 56 and 84 and then 5 mg/kg every 4 weeks from then on.
Belatacept is available in 250‑mg vials at a price of £354.52 (excluding VAT; BNF online ). For a 70‑kg person, this equates to £6,381.36 for the first 12 weeks and £709.04 every 4 weeks from week 16 onwards.
## Mycophenolate mofetil
Mycophenolate mofetil (generic) has a marketing authorisation in the UK, in combination with ciclosporin and corticosteroids, for the prophylaxis of acute transplant rejection in people having a kidney transplant. It can be administered orally (capsules or an oral suspension) or intravenously, at a recommended dose of 2 g/day.
The price of mycophenolate mofetil varies by brand. The oral suspension (CellCept) is available in 175‑ml containers of 1 g/5 ml suspension at a price of £3.29 per g (excluding VAT; BNF online ). At the time of the initial committee discussion (July 2015), the average cost paid by the NHS for mycophenolate mofetil capsules was £0.38 per g (excluding VAT; data from eMIT, Commercial Medicines Unit), equating to £5.28 per week.
## Mycophenolate sodium
Mycophenolate sodium (Myfortic, Novartis Pharmaceuticals), in combination with ciclosporin and corticosteroids, has a marketing authorisation in the UK for the prophylaxis of acute transplant rejection in adults having a kidney transplant. It is administered orally, at a recommended dose of 1.44 g per day.
Mycophenolate sodium is available in 180‑mg and 360‑mg tablets, at a price of £4.48 per g (excluding VAT; BNF online ), equating to £45.13 per week.
## Sirolimus
Sirolimus (Rapamune, Pfizer) is an antiproliferative that blocks a protein called mammalian target of rapamycin (mTOR). It has a marketing authorisation in the UK for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. It is recommended to be used initially with ciclosporin and corticosteroids for 2 to 3 months, and may be continued only if ciclosporin can be progressively discontinued.
Sirolimus is administered orally as a tablet or solution. The recommended dose is 6 mg initially, followed by 2 mg per day for 2 to 3 months, then adjusted to obtain blood trough levels of 4 to 12 nanograms/ml.
Sirolimus is available as 0.5‑mg, 1‑mg and 2‑mg tablets and a 1 mg/ml oral solution, at a net price of £2.71 to £4.60 per mg (excluding VAT; BNF online ), equating to £16.24 to £27.60 initially, followed by £37.90 to £64.40 per week.
## Everolimus
Everolimus (Certican, Novartis Pharmaceuticals) is an antiproliferative that blocks mTOR. It has a marketing authorisation for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. The summary of product characteristics states that everolimus should be used with ciclosporin and corticosteroids. Everolimus is administered orally at an initial dose of 1.5 mg/day.
Everolimus is available in 0.25‑mg, 0.5‑mg and 0.75‑mg tablets, at a net price of £9.90 per mg (excluding VAT; BNF online ). This equates to £103.95 per week.
Costs for all of the technologies may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 6) considered evidence from a number of sources. See the committee papers for full details of the evidence. The appraisal included 9 drugs for immunosuppression after kidney transplant in adults. Basiliximab and rabbit anti-human thymocyte immunoglobulin (r‑ATG) are both induction therapies. The other drugs are maintenance therapies: immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept.
The appraisal committee reviewed the data available on the clinical and cost effectiveness of the technologies, having considered evidence on the nature of kidney transplant and organ rejection and the value placed on the benefits of immunosuppressive therapy by people with a kidney transplant, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee heard from the clinical experts that the key priority for clinicians is to prolong graft survival for as long as possible, while minimising adverse effects, with the ultimate goal of allowing people to return to normal life. The clinical experts considered that both quality of life and survival are better with a functioning kidney transplant than with dialysis. The patient experts described their experiences of kidney transplants and immunosuppressive regimens, and emphasised the value of maintaining a functioning kidney transplant. The committee understood that effective immunosuppressive therapies are important to prevent organ rejection in adults having kidney transplants.
The committee heard from the clinical experts that the choice of immunosuppressive therapy is affected by a number of factors, including the characteristics and preferences of the person having treatment. The committee heard that the side-effect profiles of each drug and the risk profile of the kidney donor and recipient are important considerations. In particular, the risks of new-onset diabetes, delayed graft function and nephrotoxicity may be key priorities for some people (for example, people of African-Caribbean and Asian family origins have a higher risk of developing diabetes), whereas the level of immunological risk may be a priority for others. The clinical and patient experts therefore emphasised the importance of having access to a choice of treatment options to meet the needs of different people. The committee acknowledged that immunosuppressive therapies are chosen based on a number of factors, and that some treatments may be particularly beneficial for individual people or groups of people.
The committee discussed the technologies included in the assessment report. It noted that the final guidance would apply to the interventions listed in the scope and would not affect the current use in the NHS of ciclosporin, azathioprine and prednisolone (the standard triple therapy regimen), which were included as comparators only. A clinical expert suggested that the appraisal should consider alemtuzumab as an induction therapy. The committee was aware that alemtuzumab does not have a marketing authorisation in the UK for immunosuppression after kidney transplant and is not routinely available for transplant patients (it is available on a 'named patient' basis). It was therefore not included in the scope for this appraisal.
# Clinical effectiveness
The committee considered the clinical effectiveness evidence presented by the AG and companies. The AG's systematic review found 86 randomised controlled trials, of which 23 were included in NICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults, and 63 were identified in the updated systematic review for the current appraisal. The systematic review included 11 studies of induction therapies, 73 studies of maintenance therapies and 2 studies examining both induction and maintenance therapies. The AG considered that only 11 trials adequately matched the population and current practice in the NHS in England. The committee accepted that the AG's systematic review was comprehensive and concluded that all the relevant clinical effectiveness randomised controlled trials had been taken into account. The committee heard from the clinical experts that additional observational evidence is available from the UK Transplant Registry. The AG stated that this evidence had been used in its economic model to inform the natural history of the condition. However, the committee heard from the AG that there were some challenges with the recording of immunosuppressive regimens in the registry. Also there were relatively fewer people having the newer drugs in the registry than in the clinical trials, and so the clinical effectiveness evidence available from this source was limited. The committee understood that the clinical experts were not aware of any additional evidence, and concluded that all the relevant randomised controlled trial evidence had been taken into account.
The committee discussed the findings of the pooled head-to-head analyses and network meta-analyses for the induction therapies. It understood that both basiliximab and r‑ATG were associated with statistically significant reductions in the incidence of acute rejection compared with placebo or treatment without induction. The committee saw no evidence of a statistically significant difference between basiliximab and r‑ATG, either in head-to-head comparisons or in the network meta-analysis. The committee concluded that basiliximab and r‑ATG are effective induction therapies, but there was no evidence of a difference in clinical effectiveness between them.
The committee discussed the findings of the clinical effectiveness analyses for the maintenance therapies. It noted that head-to-head comparisons suggested that calcineurin inhibitors (tacrolimus and ciclosporin) were associated with statistically significant reductions in the incidence of acute rejection compared with belatacept, everolimus and sirolimus. It also noted that tacrolimus reduced the incidence of acute rejection compared with ciclosporin. The committee noted that both belatacept and mycophenolate mofetil were associated with improved graft function compared with calcineurin inhibitors. The committee noted that there were no consistent differences between immediate- and prolonged-release tacrolimus, or between mycophenolate mofetil and mycophenolate sodium. The committee noted that the AG's network meta-analysis presented a systematic comparison of maintenance regimens across 4 outcomes (mortality, graft loss, acute rejection and graft function). It noted that all regimens except belatacept plus mycophenolate mofetil showed evidence of improvement in acute rejection compared with ciclosporin plus azathioprine. However, belatacept plus mycophenolate mofetil statistically significantly increased graft function compared with ciclosporin plus azathioprine. The committee understood that there was substantial heterogeneity in the AG's network meta-analysis, and none of the maintenance regimens performed consistently well across all 4 outcomes. The committee concluded that the maintenance therapies included in this appraisal are effective options for immunosuppression in adults having a kidney transplant, although limited conclusions on differences between these options can be drawn from the AG's network meta-analysis.
# Cost effectiveness
The committee reviewed the economic models presented by the AG and 3 companies, Astellas, Bristol-Myers Squibb and Novartis. The AG presented an economic model based on a discrete-time state transition structure. The model was independent of that built for NICE's technology appraisal guidance on immunosuppressive therapy for renal transplantation in adults. The AG highlighted that the previous analysis had not fully accounted for uncertainty and had not taken into account the effect of kidney function on clinical and economic outcomes. Since the original appraisal, some of the technologies have become available as generics. Astellas submitted a Markov model and presented results for each immunosuppressive drug compared with immediate-release tacrolimus. Bristol-Myers Squibb presented an analysis of the cost effectiveness of belatacept compared with tacrolimus and ciclosporin, based on a 36-month initial phase followed by a longer-term Markov model. Novartis presented a patient-level simulation model to capture the cost effectiveness of everolimus plus reduced-dose ciclosporin and mycophenolate sodium plus standard-dose ciclosporin, compared with mycophenolate mofetil plus standard-dose ciclosporin or tacrolimus. The committee heard from the clinical experts that they considered the AG's model to represent current practice. The committee considered in particular the modelling of quality of life, kidney donor types and maintenance therapy dosing.
The committee noted that the AG modelled quality of life using fixed utility decrements for each health state, whereas Novartis assumed that quality of life would decrease as graft function decreased. The committee heard from the clinical experts that people with kidney disease often have few symptoms until their kidney function (estimated glomerular filtration rate; eGFR) reaches about 25 ml/min/1.73 m2. Similarly, the patient experts reported good quality of life until they approached the end stages of kidney disease. The committee understood that the Novartis model suggested that the cost-effectiveness results were very sensitive to the utility assumptions. It considered that Novartis's analyses implied that the benefits had been underestimated for all treatments, and would be most underestimated for treatments with the largest beneficial effect on eGFR (such as belatacept plus mycophenolate mofetil and tacrolimus plus azathioprine).
The committee heard from the clinical experts that a major factor influencing graft survival is the type of organ donor and their age. The experts stated that kidney transplants from living donors have become more common in recent years, and are associated with longer graft survival than kidneys from donors who have died. The AG confirmed that its model included a mix of kidney donor types, and the committee heard that the patterns of graft survival predicted by the model were consistent with the clinical experts' expectations.
The committee noted comments from consultees stating that the dosage of maintenance therapies used in clinical practice is often lower than is recommended in their marketing authorisations, and often decreases over time. It heard from the clinical experts that the lower doses may be associated with a decrease in the incidence of new-onset diabetes. The AG stated that the model included a reduction in maintenance dosing over time, with the dosage stabilising after 1 to 3 years. The committee accepted that the maintenance therapy dosages and the clinical outcomes associated with them in the AG's model were based on clinical trials.
The committee discussed the drug costs used in the AG's model and agreed that it was appropriate to use prices from the Electronic Market Information Tool (eMIT), if available, because these reflect the prices paid by the NHS (see NICE's guide to the methods of technology appraisal, section 5.5.2). The committee agreed that it was appropriate to consider the prices agreed with the Commercial Medicines Unit for Advagraf (prolonged-release tacrolimus capsules), Modigraf (tacrolimus granules for oral suspension) and Adoport (immediate-release tacrolimus) when making its recommendations, because these prices are nationally available to the NHS. The committee concluded that its preferred analysis used eMIT prices when available and the prices agreed with the Commercial Medicines Unit for Advagraf, Modigraf and Adoport.The committee concluded that the AG's model was the most informative model for decision-making.
The committee understood that in clinical practice, some treatments may be considered particularly valuable for certain groups of people (see section 4.2). It therefore considered whether there was any clinical and cost-effectiveness evidence for specific subgroups. The committee noted that there were very little subgroup data for any of the interventions, and highlighted that the AG had not found enough evidence in its systematic review to inform robust subgroup analyses. The clinical experts acknowledged that there is limited evidence in this area. The committee considered that there are likely to be some subgroups of people for whom individual treatment options may be particularly beneficial, but it had not seen sufficient evidence of clinical or cost effectiveness in specific subgroups. Therefore the committee concluded that it was unable to make recommendations for any of the interventions in specific subgroups (see sections 4.20 and 4.21).
The committee considered the effect of adherence on the clinical and cost effectiveness of immunosuppressive regimens. The committee heard from patient experts that, although it took some adjustment, taking the medicines could be fitted into a daily routine. The patient experts described some people who may find adherence more difficult, such as people at university and those who need to take a lot of medicines for other conditions. The clinical experts also noted that it is the evening dose of tacrolimus that is most often missed. The clinical experts stated that once-daily dosing of tacrolimus (using the prolonged-release formulation) is likely to be helpful for some people, although there are others for whom it makes little difference. The committee understood that there is limited evidence on the effect of once-daily dosing on adherence or clinical outcomes, and that it would be difficult to identify people who would benefit. The committee noted that improved adherence associated with prolonged-release tacrolimus had been modelled by Astellas. It noted that this model was based on a single trial demonstrating the effect of once-daily tacrolimus on adherence, combined with a meta-analysis showing the effect of improved adherence on clinical outcomes. The committee considered that the quality of the evidence informing this meta-analysis varied. The committee also highlighted that it was unclear whether the company had captured the different effects of missing a dose of a once-daily or a twice-daily therapy, and that Astellas's approach assumed the effectiveness of the whole regimen would be increased by improving adherence to tacrolimus. Therefore, the committee considered that there were limitations in Astellas's analysis. The committee noted the additional evidence received from Astellas during consultation. The company highlighted a randomised controlled study by Kuypers et al. (2013) that had been included in its original submission, which compared adherence between tacrolimus once-daily and twice-daily regimens. The company stated that non-randomised evidence was also available, which suggested that prolonged-release tacrolimus improved adherence and reduced within-patient variation in blood levels of tacrolimus. The company stated that these outcomes were associated with graft survival. The AG highlighted that the study by Kuypers et al. (2013) had a number of strengths, but also weaknesses, which limited its generalisability. The committee noted that the study did not report patient-related outcomes such as graft survival. It also noted the AG's view that people had more contact with clinicians when they were transferred from immediate-release tacrolimus to prolonged-release tacrolimus, which could be a potential reason for better adherence. The committee considered that there may be some people for whom once-daily prolonged-release tacrolimus could improve adherence. However considering all the evidence, the committee concluded that it would be difficult to identify the people who would benefit from prolonged-release tacrolimus, and that the effect on clinical outcomes was uncertain.
## Basiliximab
The committee considered that basiliximab is a clinically effective treatment option. It noted that the AG's economic model showed that basiliximab dominated (that is, provides more quality-adjusted life years at a lower cost) both treatment without induction and r‑ATG, when used with either tacrolimus-based or ciclosporin-based maintenance regimens. Therefore the committee concluded that basiliximab was cost effective and could be recommended as part of a calcineurin-inhibitor-based immunosuppressive regimen, as an option to prevent organ rejection in adults having a kidney transplant. The committee was aware that treatment with basiliximab plus tacrolimus was outside the terms of the marketing authorisation, and noted the exceptional directive from the Department of Health for this appraisal that covers this situation. The committee was convinced that there was sufficient evidence to support this recommendation.
## Rabbit anti-human thymocyte immunoglobulin
The committee considered r‑ATG to be a clinically effective induction therapy. It noted that in the AG's economic model, r‑ATG was dominated by basiliximab and was associated with incremental cost-effectiveness ratios (ICERs) of £63,200 to £333,000 per QALY gained compared with treatment without induction. The committee understood that the AG's model had assumed vials of r‑ATG would be shared and there was no wastage of partially used vials. It heard from the clinical experts that this was unlikely, so considered that the costs of r‑ATG could have been underestimated. The committee also heard from the clinical experts that r‑ATG causes short-term side effects and so can be unpleasant to take. The committee acknowledged that there may be some subgroups of people, such as people with high immunological risk or delayed graft function, for whom r‑ATG may provide additional benefits. The committee noted comments received during consultation about evidence demonstrating r‑ATG's efficacy in people with high immunological risk and its effect on the incidence of antibody-treated acute rejection. The committee noted the Brennan (2006) study in which the mean peak panel-reactive antibody was approximately 14% in both groups, with a mean value of about 6% at the time of transplant. The committee recognised that immunological risk is influenced by a number of factors as well as panel-reactive antibody levels, but questioned whether the study had included a high immunological risk group and considered that there was not enough evidence to support recommendations in people with high immunological risk. The committee concluded that the evidence it had seen showed that r‑ATG is not cost effective for preventing organ rejection in adults having a kidney transplant.
## Tacrolimus
The committee heard from the clinical experts that tacrolimus is a potent immunosuppressive therapy, and noted that the immediate-release formulation was cost effective in all comparisons presented by the AG. Therefore the committee concluded that immediate-release tacrolimus could be recommended as an option as part of an immunosuppressive regimen for preventing organ rejection in adults having a kidney transplant.
The committee heard that there were no consistent statistically significant differences in clinical effectiveness between prolonged-release and immediate-release tacrolimus. It noted that prolonged-release tacrolimus was dominated by both immediate-release tacrolimus and ciclosporin in the AG's economic analyses. Therefore the committee did not consider prolonged-release tacrolimus to be cost effective, based on the evidence it had seen. The committee noted that Astellas's submission stated that its formulation of prolonged-release tacrolimus (Advagraf) is available at a discount through an agreement with the Commercial Medicines Unit, and discussed a scenario analysis presented by the AG using this discount. The discount and the results of the scenario analysis are commercial in confidence and so cannot be reported here. The committee considered that this scenario analysis did not affect its conclusion about the cost effectiveness of prolonged-release tacrolimus.
## Belatacept
The committee acknowledged that belatacept was likely to be a clinically effective treatment, based on the evidence it had seen. In particular, it noted that belatacept plus mycophenolate mofetil increased graft function compared with ciclosporin plus azathioprine in the AG's network meta-analysis. The committee accepted that belatacept was associated with ICERs ranging from £241,000 to £424,000 per QALY gained, compared with immediate-release tacrolimus, sirolimus and ciclosporin, and that these ICERs were substantially higher than the range normally considered cost effective. The committee acknowledged that there may be some subgroups of people for whom belatacept may provide additional benefits, for example, people with nephrotoxicity or microangiopathy resulting from previous immunosuppressive treatment. However, it considered that there was limited evidence to support recommendations in specific subgroups (see sections 4.20 and 4.21).
## Mycophenolic acid
The committee noted that in the AG's economic analysis, mycophenolate mofetil dominated both sirolimus and azathioprine, and was less costly and less effective than mycophenolate sodium and everolimus; it noted that the ICERs for these comparisons were £144,000 and £1,530,000 per QALY lost respectively. The committee considered that mycophenolate mofetil was a clinically effective option, and was cost effective in all the comparisons presented. The committee concluded that mycophenolate mofetil was a cost-effective use of NHS resources and could be recommended as an option as part of a calcineurin-inhibitor-based immunosuppressive regimen to prevent organ rejection in adults having a kidney transplant.
The committee heard that there were no noticeable differences in clinical effectiveness between mycophenolate mofetil and mycophenolate sodium. It noted that mycophenolate sodium was associated with an ICER of £56,600 per QALY gained compared with azathioprine, and £144,000 per QALY gained compared with mycophenolate mofetil. The committee concluded that mycophenolate sodium was not cost effective, based on the evidence it had seen.
## Sirolimus
The committee heard from the clinical experts that treatment with sirolimus can be difficult to manage in clinical practice, and may be associated with a range of adverse effects including peripheral oedema and bone marrow suppression. It also heard that anaemia may be more common with sirolimus and everolimus than with other immunosuppressive therapies (although the AG had assumed the rate would be equal across all regimens). The committee noted that in the AG's base-case economic analyses, sirolimus was dominated by immediate-release tacrolimus and mycophenolate mofetil. The committee considered that this evidence suggested that sirolimus was not cost effective, and noted that the cost effectiveness of sirolimus would worsen if the incidence of anaemia increased.
## Everolimus
The committee noted that the AG's economic model suggested that everolimus may be more effective than mycophenolate mofetil and azathioprine, although it was also associated with higher costs. The committee noted that the ICERs were £1,530,000 and £383,000 per QALY gained respectively, and were well above the range normally considered cost effective. The committee was also aware that anaemia may be more common with sirolimus and everolimus than with other immunosuppressive therapies, and that this would worsen the cost effectiveness of everolimus in these comparisons.
# Additional considerations
Following an appeal, the committee considered in detail the scope of the appraisal and the populations and clinical situations to which its recommendations would apply. It noted that its intention at the time of the first final appraisal determination was that the recommendations would apply to the initial treatments for people having kidney transplants, and explained that this was based on its interpretation of the scope at that time and the evidence available from the systematic review and economic modelling. However, on further review the committee recognised that the scope included immunosuppressive treatments given immediately after transplant and at subsequent stages, in people having a kidney transplant and in people who have had a re-transplant in the last 2 years. The committee therefore acknowledged that the scope for this appraisal includes, in addition to initial treatments, subsequent therapies during the life of a graft and treatments for people having second and subsequent transplants. The committee concluded that the scope was broader than its original recommendations, and discussed the recommendations it could make for these additional clinical scenarios.
The committee noted that the protocol and systematic review did not include the use of subsequent treatments during the life of the graft and only included studies in which randomisation took place at the time of the transplant. As a result, none of the studies considered during the appraisal investigated the effect of switching regimens during the life of a functioning graft. It also noted that the AG's economic model did not provide estimates of the cost effectiveness of switching to alternative interventions during the life of a graft. The committee considered that the systematic review and economic modelling were suitable to provide evidence on the initial treatments started around the time of transplant. The committee heard from the clinical experts that between 10% and 20% of people cannot continue on their initial immunosuppressive treatments. This may result from intolerance because of nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy associated with ciclosporin, tacrolimus, sirolimus or everolimus, for example. The clinical and patient experts highlighted the need for other treatments to be available to ensure continued immunosuppressive therapy for people unable to continue taking their initial treatment. They also highlighted recent studies which showed that tacrolimus withdrawal should be avoided. They therefore emphasised the need for alternative immunosuppressants if tacrolimus has to be stopped. The committee was aware that returning to dialysis if a transplant fails can have a significant effect on quality of life as well as incurring costs to the NHS. It noted that sirolimus could be a cost-effective option for people with calcineurin inhibitor nephrotoxicity because the only alternative would be dialysis, although it understood that sirolimus is currently routinely commissioned by NHS England for nephrotoxicity. The committee also heard that although thrombotic microangiopathy is rare, it results in graft loss and the person needing dialysis. The clinical experts noted that belatacept is the only immunosuppressant that can be given in these circumstances. The committee recognised the need for urgency in this situation and that individual funding requests might not be suitable or approved quickly enough. It also recognised that belatacept could potentially be a cost-effective use of NHS resources when thrombotic microangiopathy develops because the only alternative would be dialysis. The committee heard from the clinical experts and the AG that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review. The committee recalled that the limited analysis it had seen on treatment switching, submitted by Novartis, was highly uncertain. In addition, it heard that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the clinical and cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee considered that any outstanding clinical and commissioning issues would be better addressed through other routes, such as other NICE programmes or clinical commissioning policies. They noted that the consultees agreed with this approach. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment started around the time of kidney transplant.
The committee understood that the systematic review was not restricted to people having their first kidney transplant, and heard from the AG that about 30% of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee also heard from the AG that the economic model gives the same results whether it considers the first or second transplant. It was aware that the conclusions from the economic model might change if individual interventions were removed because, at the time of the second transplant, they had previously been found to be clinically inappropriate. However, it had not seen evidence for this situation, and considered that it was unlikely that sufficient evidence to inform a robust analysis could be obtained. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.
The committee considered the bioequivalence of generic immunosuppressive therapies. It noted that calcineurin inhibitors have a narrow therapeutic index. It understood that the Commission on Human Medicines recommends that oral tacrolimus should be prescribed by brand name, and that care is needed when switching between drugs with a narrow therapeutic index (see the Medicines and Healthcare products Regulatory Agency's drug safety update on oral tacrolimus products). The committee heard from the clinical experts that this primarily applies to the drugs that are dosed based on plasma levels, such as tacrolimus, and that clinicians are aware of the risks associated with generic prescribing and switching formulations. The committee understood that guidance on good practice in prescribing generic immunosuppressive therapies is routinely followed in clinical practice. The committee also heard that clinicians are aware of cost differences between the different brands of immunosuppressive therapies, and take into account local costs in their prescribing decisions. The committee concluded that it did not need to make additional recommendations about the bioequivalence of generic immunosuppressive therapies, and considered that if different preparations are equally suitable, it would be reasonable to recommend using the least expensive product when starting treatment.
The committee noted the potential equality issue raised by consultees during scoping, in submissions and during the committee meeting. It understood that some Jehovah's Witnesses are unwilling to have human blood products, but noted that none of the recommended technologies are based on human blood products. The committee understood that effective immunosuppression may be particularly beneficial for people from black, Asian and minority ethnic groups, and noted that a number of effective treatment options are available. The committee also heard that mycophenolate mofetil cannot be taken by women who are pregnant and noted that alternative effective treatment options are available.
The committee discussed providing immunosuppressive therapy for adults who cannot swallow capsules as a result of a disability, or who cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin. The committee noted that these people might need alternative formulations (such as oral suspensions or gelatine-free formulations) instead. The committee noted that oral suspensions and gelatine-free formulations are available for both immediate-release tacrolimus and mycophenolate mofetil, and that these products have marketing authorisations in the UK. The suspensions are more expensive than the capsules, although there is a nationally available price agreed with the Commercial Medicines Unit for Modigraf (see section 3.10 and section 3.18). The committee recognised that, given its recommendations (see section 4.12 and section 4.15) covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might discriminate against adults with protected characteristics. The committee reiterated that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product (see section 4.22), but concluded that it could be started with an alternative dosage form if the least expensive product is not suitable. The committee agreed that Modigraf should be used only if the company provides Modigraf at the price agreed with the Commercial Medicines Unit.
# Summary of appraisal committee's key conclusions
TA481
Appraisal title: Immunosuppressive therapy for kidney transplant in adults
Section
Key conclusion
Basiliximab, immediate-release tacrolimus and mycophenolate mofetil are recommended as initial options to prevent organ rejection in adults having a kidney transplant.
The committee considered that basiliximab is a clinically effective treatment option, and provided more quality-adjusted life years (QALYs) at a lower cost than treatment without induction and rabbit anti-human thymocyte immunoglobulin (r‑ATG).
The committee heard that tacrolimus is a potent immunosuppressive therapy, and considered that immediate-release tacrolimus was cost effective.
The committee considered that mycophenolate mofetil was a clinically effective option, and was cost effective in all the comparisons presented.
r‑ATG, prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in adults having a kidney transplant.
The committee considered that r‑ATG was clinically effective, but concluded that it was not cost effective.
The committee noted that there were no consistent differences in clinical effectiveness between immediate- and prolonged-release tacrolimus. It considered that prolonged-release tacrolimus was not cost effective.
The committee noted that belatacept was likely to be clinically effective, but was associated with incremental cost-effectiveness ratios (ICERs) substantially higher than the range normally considered cost effective.
The committee heard that there were no noticeable differences in clinical effectiveness between mycophenolate mofetil and mycophenolate sodium, and concluded that mycophenolate sodium was not cost effective.
The committee noted that sirolimus was not a cost-effective treatment option.
The committee noted the economic modelling suggested that everolimus may be more effective than mycophenolate mofetil and azathioprine, although it was not cost effective.
The committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in adults who are, or become, unable to have the technologies recommended in sections 1.1 to 1.3 or the standard triple therapy regimen of ciclosporin, azathioprine and a corticosteroid (for example, because of treatment failure, contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes adults who:
are unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or
have a second or subsequent transplant, having previously found that 1 or more of the recommended initial treatments or standard treatments are clinically unsuitable for example, because of treatment failure, contraindications or intolerance.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee understood that effective immunosuppressive therapies are important to prevent organ rejection in adults having kidney transplants.
The committee heard that the choice of immunosuppressive therapy is affected by a number of factors, including the characteristics and preferences of the person having treatment. The committee understood the value of having a choice of immunosuppressive therapies.
The technologies
Proposed benefits of the technologies
How innovative are the technologies in their potential to make a significant and substantial impact on health-related benefits?
The committee heard that the key priority for immunosuppressive therapy is to prolong graft survival for as long as possible, while minimising adverse effects. The clinical experts considered that both quality of life and survival are better with a functioning kidney transplant than with dialysis, and the patient experts emphasised the value of maintaining a functioning kidney transplant.
What are the positions of the treatments in the pathway of care for the condition?
Immunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2 weeks around the time of transplant and may include polyclonal or monoclonal antibodies. Maintenance therapy starts immediately after transplant and continues for life.
Basiliximab and r‑ATG are options for induction therapy. Tacrolimus, belatacept, mycophenolate mofetil, mycophenolate sodium, sirolimus and everolimus are options for maintenance therapy.
The committee understood that in clinical practice, some treatments may be considered particularly valuable for certain groups of people.
Adverse reactions
The committee heard that sirolimus may be associated with a range of adverse effects including peripheral oedema and bone marrow suppression and that sirolimus and everolimus may be associated with an increased risk of anaemia.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The AG's systematic review found 86 randomised controlled trials, including 11 studies of induction therapies, 73 studies of maintenance therapies and 2 studies examining both induction and maintenance therapies.
The committee noted that the AG's systematic review was comprehensive and concluded that all the relevant clinical effectiveness randomised controlled trial evidence had been taken into account.
Relevance to general clinical practice in the NHS
The committee noted that the AG considered that only 11 trials adequately matched the population and current practice in the NHS in England.
Uncertainties generated by the evidence
The committee understood that there was substantial heterogeneity in the AG's network meta-analysis, and none of the maintenance regimens performed consistently well across all 4 outcomes. The committee considered that limited conclusions on differences between these options can be drawn from the AG's network meta-analysis.
The committee understood that there is limited evidence on the effect of once-daily dosing on adherence or clinical outcomes, and that it would be difficult to identify people who would benefit. It concluded that the effect on clinical outcomes was uncertain.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee noted that there were very little subgroup data for any of the interventions. It considered that there are likely to be some subgroups of people for whom individual treatment options may be particularly beneficial, but it had not seen sufficient evidence of clinical or cost effectiveness in specific subgroups.
The committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. This may be because of intolerance or complications requiring withdrawal, for example. The committee heard that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review, and the limited analysis it had seen on treatment switching was highly uncertain. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment around the time of kidney transplant.
The committee understood that about 30% of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The AG's network meta-analysis showed that basiliximab and r‑ATG were significantly more effective than treatment without induction for acute rejection. The committee concluded that basiliximab and r‑ATG are effective induction therapies, but there was no evidence of a difference in clinical effectiveness between them.
The AG's network meta-analysis showed a number of statistically significant differences between regimens, although none of the maintenance regimens performed consistently well across all 4 outcomes assessed. The committee saw that all regimens except belatacept plus mycophenolate mofetil showed evidence of improvement in acute rejection compared with ciclosporin plus azathioprine, although belatacept plus mycophenolate mofetil statistically significantly increased graft function. The committee concluded that the maintenance therapies are effective options.
How has the new clinical evidence that has emerged since the original appraisal (TA85) influenced the current (preliminary) recommendations?
The AG's systematic review found 86 randomised controlled trials, of which 23 were included in NICE's original technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults, and 63 were identified in the updated systematic review for the current appraisal. The committee noted that the AG's systematic review was comprehensive and included all relevant clinical effectiveness randomised controlled trial evidence.
Since the NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults was published in 2004, the marketing authorisation for daclizumab has been withdrawn and new technologies have received marketing authorisations.
Evidence for cost effectiveness
Availability and nature of evidence
Economic analyses were presented by the AG, Astellas, Bristol-Myers Squibb and Novartis.
The AG presented an economic model based on a discrete-time state transition structure.
Astellas submitted a Markov model and presented results for each immunosuppressive drug compared with immediate-release tacrolimus.
Bristol-Myers Squibb presented an analysis of the cost effectiveness of belatacept compared with tacrolimus and ciclosporin, based on a 36-month initial phase followed by a longer-term Markov model.
Novartis presented a patient-level simulation model to capture the cost effectiveness of everolimus plus reduced-dose ciclosporin and mycophenolate sodium plus standard-dose ciclosporin, compared with mycophenolate mofetil plus standard-dose ciclosporin or tacrolimus.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee noted that the AG and Novartis modelled quality of life differently. It understood that the Novartis model suggested that the cost-effectiveness results were very sensitive to the utility assumptions.
The committee concluded that the AG's model was the most informative model for decision-making.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee noted that the AG modelled quality of life using fixed utility decrements for each health state.
The committee noted that Novartis assumed that quality of life would decrease as graft function decreased. It considered that Novartis's analyses implied that the benefits had been underestimated for all treatments, and would be most underestimated for treatments with the largest beneficial effect on graft function.
Are there specific groups of people for whom the technology is particularly cost effective?
The committee noted that there were very little subgroup data for any of the interventions. It considered that there are likely to be some subgroups of people for whom individual treatment options may be particularly beneficial, but it had not seen sufficient evidence of clinical or cost effectiveness in specific subgroups.
The committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. The committee recalled that the limited analysis it had seen on treatment switching was highly uncertain, and was aware that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable.
The committee understood that the systematic review was not restricted to people having their first kidney transplant, but there was insufficient evidence for subgroup analysis. The committee heard from the AG the that economic model gives the same results whether it considers the first or second transplant, but was aware that the conclusions might change if individual interventions were removed because, at the time of the second transplant, they had previously been found to be clinically inappropriate. However, it had not seen evidence for this situation, and considered that it was unlikely that sufficient evidence to inform a robust analysis could be obtained. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants, in people for whom particular therapies had previously been found to be inappropriate.
What are the key drivers of cost effectiveness?
The committee understood that the cost-effectiveness results were very sensitive to the utility assumptions.
Most likely cost-effectiveness estimate (given as an ICER)
Basiliximab dominated (provided more QALYs at a lower cost) treatment without induction and r‑ATG.
r‑ATG was dominated by basiliximab and was associated with ICERs of £63,200 to £333,000 per QALY gained compared with treatment without induction.
Immediate-release tacrolimus was cost effective in all comparisons presented by the AG.
Prolonged-release tacrolimus was dominated by both immediate-release tacrolimus and ciclosporin.
Belatacept was associated with ICERs of £241,000 to £424,000 per QALY gained, compared with immediate-release tacrolimus, sirolimus and ciclosporin.
Mycophenolate mofetil dominated both sirolimus and azathioprine, and was less costly and less effective than mycophenolate sodium and everolimus with ICERs of £144,000 and £1,530,000 per QALY lost respectively.
Mycophenolate sodium was associated with an ICER of £56,600 per QALY gained compared with azathioprine, and £144,000 per QALY gained compared with mycophenolate mofetil.
Sirolimus was dominated by mycophenolate mofetil and immediate-release tacrolimus.
Everolimus was associated with ICERs of £1,530,000 and £383,000 per QALY gained, compared with mycophenolate mofetil and azathioprine respectively.
How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA85) influenced the current (preliminary) recommendations?
Economic analyses were presented by the AG, Astellas, Bristol-Myers Squibb and Novartis. The AG's model was independent of that built for NICE's technology appraisal guidance on immunosuppressive therapy for renal transplantation in adults. The AG highlighted that the previous analysis had not fully accounted for uncertainty and had not taken into account the effect of kidney function on clinical and economic outcomes. Since the original appraisal, some of the technologies have become available as generics.
The committee concluded that the AG's model was the most informative model for decision-making.
Additional factors taken into account
Patient access schemes (PPRS)
None. Astellas advised that there are nationally available discounted contract prices for Modigraf (tacrolimus granules for oral suspension) and Advagraf (prolonged-release tacrolimus).
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee understood that some Jehovah's Witnesses are unwilling to have human blood products, that effective immunosuppression may be particularly beneficial for people from black, Asian and minority ethnic groups, and that mycophenolate mofetil cannot be taken by women who are pregnant.
The committee understood that some adults may not be able to swallow capsules as a result of a disability, or cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin. It recognised that, given its recommendations covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might be discriminatory. The committee noted that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product. However, treatment could be started with an alternative dosage form if the least expensive product is not suitable.
|
{'Recommendations': "This guidance makes recommendations on using basiliximab, rabbit anti-human thymocyte immunoglobulin, tacrolimus (immediate-release and prolonged-release), mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept after kidney transplant in adults. The recommendations apply only to the initial immunosuppressive therapy (induction and maintenance therapy) started around the time of kidney transplant.\n\nIt was outside the scope of the appraisal to make recommendations on using the standard triple therapy regimen of ciclosporin, azathioprine and a corticosteroid after kidney transplant in adults.\n\nUnder an exceptional directive from the Department of Health, the appraisal committee was allowed to make recommendations about using drugs outside the terms of their marketing authorisations if there was compelling evidence of their safety and effectiveness.\n\nBasiliximab, when used as part of an immunosuppressive regimen that includes a calcineurin inhibitor, is recommended as an initial option to prevent organ rejection in adults having a kidney transplant.,\n\nImmediate-release tacrolimus, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in adults having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the person is not able to swallow capsules as a result of a disability or they are unable to have a particular ingredient because of allergy or religious reasons). Tacrolimus granules for oral suspension (Modigraf) should be used only if the company provides it at the same price or lower than that agreed with the Commercial Medicines Unit.\n\nMycophenolate mofetil, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in adults having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the person is not able to swallow capsules as a result of a disability or they are unable to have a particular ingredient because of allergy or religious reasons).,\n\nRabbit anti-human thymocyte immunoglobulin, prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in adults having a kidney transplant.\n\nThe committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in adults who are, or become, unable to have the technologies recommended in sections\xa01.1 to\xa01.3 or standard triple therapy with ciclosporin, azathioprine and a corticosteroid (for example, because of treatment failure, contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes adults who:\n\nare unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or\n\nhave a second or subsequent transplant, having previously found that 1\xa0or more of the recommended initial treatments or standard treatments are clinically unsuitable for example, because of treatment failure, contraindications or intolerance.\n\nThese recommendations are not intended to affect treatment with any of the technologies in this appraisal that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations, or for whom the committee were unable to make a recommendation, may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\n August 2017: the use of basiliximab (with tacrolimus) and mycophenolate mofetil (with tacrolimus) is outside the terms of the marketing authorisations for basiliximab and for mycophenolate mofetil. If these combinations are prescribed, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. For further information, see the General Medical Council's guidance on Good practice in prescribing and managing medicines and devices.\n\n The Department of Health has stated that the statutory funding requirement does not apply to drugs that are used outside the terms of their marketing authorisation.\n\n The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that to maintain therapeutic response when a patient is stabilised on a particular brand, oral tacrolimus products should be prescribed and dispensed by brand name only. If a prescriber considers that switching to a different brand of oral tacrolimus would be of benefit, the change requires careful supervision and therapeutic monitoring by an appropriate specialist. See the MHRA's advice on oral tacrolimus products.", 'Clinical need and practice': "Kidney transplant is used to treat established kidney failure, which is severe and irreversible impairment of kidney function. After a kidney transplant, immunosuppressive therapy is used to reduce the risk of rejection of the transplanted kidney (or 'graft') and prolong its survival.\n\nBetween April 2016 and March 2017, 3,042\xa0kidney transplants were done in adults in the UK; 2,682 of these were in England. At the end of 2014, approximately 31,150\xa0people in the UK were having immunosuppressive therapy after a kidney transplant, including 26,100\xa0people in England.\n\nImmunosuppressive therapy aims to prevent acute rejection and optimise the function of the transplanted kidney, while minimising the adverse effects of immunosuppression (such as increased risk of infection, cancer, diabetes and cardiovascular disease). Immunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2\xa0weeks around the time of transplant and may include polyclonal or monoclonal antibodies. Maintenance therapy starts immediately after transplant and continues for life.\n\nNICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults was published in 2004. It recommended basiliximab, daclizumab, tacrolimus, mycophenolate mofetil and sirolimus, in certain circumstances, as options for immunosuppressive therapy for kidney transplant in adults. Since that appraisal, the marketing authorisation for daclizumab has been withdrawn, new technologies (rabbit anti-human thymocyte immunoglobulin, mycophenolate sodium, belatacept, a prolonged-release formulation of tacrolimus, and everolimus) have received marketing authorisations, and some of the technologies are available as generics.", 'The technologies': "# Induction therapy\n\n## Basiliximab\n\nBasiliximab (Simulect, Novartis Pharmaceuticals) is a monoclonal antibody that acts as an interleukin‑2 receptor antagonist. It has a marketing authorisation in the UK for the prophylaxis of acute organ rejection in adults having a kidney transplant. The summary of product characteristics states that basiliximab is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression, in patients with panel-reactive antibodies less than 80%, or in a triple maintenance immunosuppressive regimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine or mycophenolate mofetil.\n\nBasiliximab is administered intravenously, in 2\xa0doses of 20\xa0mg each (one 2\xa0hours before the surgery and the second 4\xa0days after).\n\nBasiliximab is available in 10‑mg and 20‑mg vials, at a price of £758.69 and £842.38 respectively (excluding VAT; British national formulary [BNF] online [accessed August 2017]), equating to £1,685 per course of treatment (2\xa0doses of 20\xa0mg).\n\n## Rabbit anti-human thymocyte immunoglobulin\n\nRabbit anti-human thymocyte immunoglobulin (r‑ATG; Thymoglobuline, Sanofi) is made by injecting human thymus cells into rabbits. The drug contains immunoglobulins (antibodies) that attach to and destroy some of the cells of the immune system. It has a marketing authorisation in the UK for the prevention of graft rejection in kidney transplant. The summary of product characteristics states that it is usually used with other immunosuppressive drugs.\n\nr‑ATG is administered intravenously, at a dose of 1\xa0to 1.5\xa0mg/kg/day for 3\xa0to 9\xa0days after a kidney transplant (a cumulative dose of 3\xa0to 13.5\xa0mg/kg).\n\nr‑ATG is available in 25\xa0mg vials, at a price of £158.77 (excluding VAT; BNF online [accessed August 2017]), equating to £1,428.93 to £7,144.65 per course for a 70‑kg person.\n\n# Maintenance therapy\n\nSome drugs in this appraisal contain the same active ingredient but in different formulations. Tacrolimus is a calcineurin inhibitor and is available in an immediate-release formulation and a prolonged-release formulation. Mycophenolic acid is an antiproliferative agent. It is available as a prodrug called mycophenolate mofetil and a sodium salt called mycophenolate sodium.\n\n## Immediate-release tacrolimus\n\nBrands of immediate-release tacrolimus include Adoport (Sandoz), Capexion (Mylan), Modigraf (Astellas Pharma), Perixis (Accord Healthcare), Prograf (Astellas Pharma), Tacni (Teva) and Vivadex (Dexcel Pharma). All of these formulations have marketing authorisations in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. Adoport, Capexion, Perixis, Prograf, Tacni and Vivadex are administered orally as capsules, twice a day. Prograf can also be administered intravenously. Modigraf consists of granules for oral suspension.\n\nFor all brands of immediate-release tacrolimus, the summary of product characteristics recommends an initial dose of 0.2 to 0.3\xa0mg/kg/day orally or 0.05 to 0.1\xa0mg/kg/day intravenously, and states that the dosage is usually reduced in the period after the transplant.\n\nModigraf (tacrolimus granules for oral suspension) is available in sachets of 0.2\xa0mg and 1\xa0mg at a price of £7.13\xa0per\xa0mg (excluding VAT; BNF online [accessed August 2017]). The company has agreed a nationally available price reduction for Modigraf with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. Tacrolimus immediate-release capsules are available as 0.5‑mg, 0.75‑mg, 1‑mg, 2‑mg and 5‑mg capsules (depending on the brand), the price of which varies by brand. The assessment group (AG) calculated that the average cost paid by the NHS for immediate-release tacrolimus capsules is £0.52 per\xa0mg (excluding VAT; data from the Electronic Market Information Tool [eMIT], Commercial Medicines Unit). This equates to £50.96 to £76.44 per week for an initial dose of 0.2 to 0.3\xa0mg/kg/day in a 70‑kg person. Adoport is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\n## Prolonged-release tacrolimus\n\nProlonged-release tacrolimus (Advagraf, Astellas Pharma) is administered orally as a capsule, once a day. It has a marketing authorisation in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. The summary of product characteristics recommends an initial dose for adults of 0.2 to 0.3\xa0mg/kg/day. The dosage is usually reduced in the period after the transplant.\n\nProlonged-release tacrolimus (Advagraf) is available as 0.5‑mg, 1‑mg, 3‑mg and 5‑mg capsules, at a price of £1.07 to £1.43 per\xa0mg (excluding VAT; BNF online [accessed August 2017]). This equates to £112.11 to £210.47 per week for an initial dose of 0.2 to 0.3\xa0mg/kg/day in a 70‑kg person. Advagraf is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\nAnother brand of prolonged-release tacrolimus, Envarsus (Chiesi), obtained a marketing authorisation after the scope for this appraisal was finalised. The brand name Envarsus was not included in the AG's search for evidence and Chiesi was not asked to submit evidence for the appraisal.\n\n## Belatacept\n\nBelatacept (Nulojix, Bristol-Myers Squibb) is a soluble fusion protein designed to selectively inhibit CD28-mediated co-stimulation of T‑cells. Belatacept, in combination with corticosteroids and a mycophenolic acid, has a marketing authorisation in the UK for prophylaxis of graft rejection in adults having a kidney transplant. The summary of product characteristics recommends that an interleukin‑2 receptor antagonist is added to this belatacept-based regimen.\n\nBelatacept is administered intravenously. The recommended dose is 10\xa0mg/kg on the day of the transplant, followed by 10\xa0mg/kg on days\xa05, 14, 28, 56 and\xa084 and then 5\xa0mg/kg every 4\xa0weeks from then on.\n\nBelatacept is available in 250‑mg vials at a price of £354.52 (excluding VAT; BNF online [accessed August 2017]). For a 70‑kg person, this equates to £6,381.36 for the first 12\xa0weeks and £709.04 every 4\xa0weeks from week\xa016 onwards.\n\n## Mycophenolate mofetil\n\nMycophenolate mofetil (generic) has a marketing authorisation in the UK, in combination with ciclosporin and corticosteroids, for the prophylaxis of acute transplant rejection in people having a kidney transplant. It can be administered orally (capsules or an oral suspension) or intravenously, at a recommended dose of 2\xa0g/day.\n\nThe price of mycophenolate mofetil varies by brand. The oral suspension (CellCept) is available in 175‑ml containers of 1\xa0g/5\xa0ml suspension at a price of £3.29\xa0per\xa0g (excluding VAT; BNF online [accessed August 2017]). At the time of the initial committee discussion (July 2015), the average cost paid by the NHS for mycophenolate mofetil capsules was £0.38\xa0per\xa0g (excluding VAT; data from eMIT, Commercial Medicines Unit), equating to £5.28 per week.\n\n## Mycophenolate sodium\n\nMycophenolate sodium (Myfortic, Novartis Pharmaceuticals), in combination with ciclosporin and corticosteroids, has a marketing authorisation in the UK for the prophylaxis of acute transplant rejection in adults having a kidney transplant. It is administered orally, at a recommended dose of 1.44\xa0g\xa0per\xa0day.\n\nMycophenolate sodium is available in 180‑mg and 360‑mg tablets, at a price of £4.48\xa0per\xa0g (excluding VAT; BNF online [accessed August 2017]), equating to £45.13 per week.\n\n## Sirolimus\n\nSirolimus (Rapamune, Pfizer) is an antiproliferative that blocks a protein called mammalian target of rapamycin (mTOR). It has a marketing authorisation in the UK for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. It is recommended to be used initially with ciclosporin and corticosteroids for 2 to 3\xa0months, and may be continued only if ciclosporin can be progressively discontinued.\n\nSirolimus is administered orally as a tablet or solution. The recommended dose is 6\xa0mg initially, followed by 2\xa0mg per day for 2\xa0to 3\xa0months, then adjusted to obtain blood trough levels of 4\xa0to\xa012\xa0nanograms/ml.\n\nSirolimus is available as 0.5‑mg, 1‑mg and 2‑mg tablets and a 1\xa0mg/ml oral solution, at a net price of £2.71 to £4.60\xa0per\xa0mg (excluding VAT; BNF online [accessed August 2017]), equating to £16.24 to £27.60 initially, followed by £37.90 to £64.40 per week.\n\n## Everolimus\n\nEverolimus (Certican, Novartis Pharmaceuticals) is an antiproliferative that blocks mTOR. It has a marketing authorisation for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. The summary of product characteristics states that everolimus should be used with ciclosporin and corticosteroids. Everolimus is administered orally at an initial dose of 1.5\xa0mg/day.\n\nEverolimus is available in 0.25‑mg, 0.5‑mg and 0.75‑mg tablets, at a net price of £9.90 per\xa0mg (excluding VAT; BNF online [accessed August 2017]). This equates to £103.95 per week.\n\nCosts for all of the technologies may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence from a number of sources. See the committee papers for full details of the evidence. The appraisal included 9\xa0drugs for immunosuppression after kidney transplant in adults. Basiliximab and rabbit anti-human thymocyte immunoglobulin (r‑ATG) are both induction therapies. The other drugs are maintenance therapies: immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept.\n\nThe appraisal committee reviewed the data available on the clinical and cost effectiveness of the technologies, having considered evidence on the nature of kidney transplant and organ rejection and the value placed on the benefits of immunosuppressive therapy by people with a kidney transplant, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee heard from the clinical experts that the key priority for clinicians is to prolong graft survival for as long as possible, while minimising adverse effects, with the ultimate goal of allowing people to return to normal life. The clinical experts considered that both quality of life and survival are better with a functioning kidney transplant than with dialysis. The patient experts described their experiences of kidney transplants and immunosuppressive regimens, and emphasised the value of maintaining a functioning kidney transplant. The committee understood that effective immunosuppressive therapies are important to prevent organ rejection in adults having kidney transplants.\n\nThe committee heard from the clinical experts that the choice of immunosuppressive therapy is affected by a number of factors, including the characteristics and preferences of the person having treatment. The committee heard that the side-effect profiles of each drug and the risk profile of the kidney donor and recipient are important considerations. In particular, the risks of new-onset diabetes, delayed graft function and nephrotoxicity may be key priorities for some people (for example, people of African-Caribbean and Asian family origins have a higher risk of developing diabetes), whereas the level of immunological risk may be a priority for others. The clinical and patient experts therefore emphasised the importance of having access to a choice of treatment options to meet the needs of different people. The committee acknowledged that immunosuppressive therapies are chosen based on a number of factors, and that some treatments may be particularly beneficial for individual people or groups of people.\n\nThe committee discussed the technologies included in the assessment report. It noted that the final guidance would apply to the interventions listed in the scope and would not affect the current use in the NHS of ciclosporin, azathioprine and prednisolone (the standard triple therapy regimen), which were included as comparators only. A clinical expert suggested that the appraisal should consider alemtuzumab as an induction therapy. The committee was aware that alemtuzumab does not have a marketing authorisation in the UK for immunosuppression after kidney transplant and is not routinely available for transplant patients (it is available on a 'named patient' basis). It was therefore not included in the scope for this appraisal.\n\n# Clinical effectiveness\n\nThe committee considered the clinical effectiveness evidence presented by the AG and companies. The AG's systematic review found 86\xa0randomised controlled trials, of which 23\xa0were included in NICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults, and 63\xa0were identified in the updated systematic review for the current appraisal. The systematic review included 11\xa0studies of induction therapies, 73\xa0studies of maintenance therapies and 2\xa0studies examining both induction and maintenance therapies. The AG considered that only 11\xa0trials adequately matched the population and current practice in the NHS in England. The committee accepted that the AG's systematic review was comprehensive and concluded that all the relevant clinical effectiveness randomised controlled trials had been taken into account. The committee heard from the clinical experts that additional observational evidence is available from the UK Transplant Registry. The AG stated that this evidence had been used in its economic model to inform the natural history of the condition. However, the committee heard from the AG that there were some challenges with the recording of immunosuppressive regimens in the registry. Also there were relatively fewer people having the newer drugs in the registry than in the clinical trials, and so the clinical effectiveness evidence available from this source was limited. The committee understood that the clinical experts were not aware of any additional evidence, and concluded that all the relevant randomised controlled trial evidence had been taken into account.\n\nThe committee discussed the findings of the pooled head-to-head analyses and network meta-analyses for the induction therapies. It understood that both basiliximab and r‑ATG were associated with statistically significant reductions in the incidence of acute rejection compared with placebo or treatment without induction. The committee saw no evidence of a statistically significant difference between basiliximab and r‑ATG, either in head-to-head comparisons or in the network meta-analysis. The committee concluded that basiliximab and r‑ATG are effective induction therapies, but there was no evidence of a difference in clinical effectiveness between them.\n\nThe committee discussed the findings of the clinical effectiveness analyses for the maintenance therapies. It noted that head-to-head comparisons suggested that calcineurin inhibitors (tacrolimus and ciclosporin) were associated with statistically significant reductions in the incidence of acute rejection compared with belatacept, everolimus and sirolimus. It also noted that tacrolimus reduced the incidence of acute rejection compared with ciclosporin. The committee noted that both belatacept and mycophenolate mofetil were associated with improved graft function compared with calcineurin inhibitors. The committee noted that there were no consistent differences between immediate- and prolonged-release tacrolimus, or between mycophenolate mofetil and mycophenolate sodium. The committee noted that the AG's network meta-analysis presented a systematic comparison of maintenance regimens across 4\xa0outcomes (mortality, graft loss, acute rejection and graft function). It noted that all regimens except belatacept plus mycophenolate mofetil showed evidence of improvement in acute rejection compared with ciclosporin plus azathioprine. However, belatacept plus mycophenolate mofetil statistically significantly increased graft function compared with ciclosporin plus azathioprine. The committee understood that there was substantial heterogeneity in the AG's network meta-analysis, and none of the maintenance regimens performed consistently well across all 4\xa0outcomes. The committee concluded that the maintenance therapies included in this appraisal are effective options for immunosuppression in adults having a kidney transplant, although limited conclusions on differences between these options can be drawn from the AG's network meta-analysis.\n\n# Cost effectiveness\n\nThe committee reviewed the economic models presented by the AG and 3\xa0companies, Astellas, Bristol-Myers Squibb and Novartis. The AG presented an economic model based on a discrete-time state transition structure. The model was independent of that built for NICE's technology appraisal guidance on immunosuppressive therapy for renal transplantation in adults. The AG highlighted that the previous analysis had not fully accounted for uncertainty and had not taken into account the effect of kidney function on clinical and economic outcomes. Since the original appraisal, some of the technologies have become available as generics. Astellas submitted a Markov model and presented results for each immunosuppressive drug compared with immediate-release tacrolimus. Bristol-Myers Squibb presented an analysis of the cost effectiveness of belatacept compared with tacrolimus and ciclosporin, based on a 36-month initial phase followed by a longer-term Markov model. Novartis presented a patient-level simulation model to capture the cost effectiveness of everolimus plus reduced-dose ciclosporin and mycophenolate sodium plus standard-dose ciclosporin, compared with mycophenolate mofetil plus standard-dose ciclosporin or tacrolimus. The committee heard from the clinical experts that they considered the AG's model to represent current practice. The committee considered in particular the modelling of quality of life, kidney donor types and maintenance therapy dosing.\n\nThe committee noted that the AG modelled quality of life using fixed utility decrements for each health state, whereas Novartis assumed that quality of life would decrease as graft function decreased. The committee heard from the clinical experts that people with kidney disease often have few symptoms until their kidney function (estimated glomerular filtration rate; eGFR) reaches about 25\xa0ml/min/1.73\xa0m2. Similarly, the patient experts reported good quality of life until they approached the end stages of kidney disease. The committee understood that the Novartis model suggested that the cost-effectiveness results were very sensitive to the utility assumptions. It considered that Novartis's analyses implied that the benefits had been underestimated for all treatments, and would be most underestimated for treatments with the largest beneficial effect on eGFR (such as belatacept plus mycophenolate mofetil and tacrolimus plus azathioprine).\n\nThe committee heard from the clinical experts that a major factor influencing graft survival is the type of organ donor and their age. The experts stated that kidney transplants from living donors have become more common in recent years, and are associated with longer graft survival than kidneys from donors who have died. The AG confirmed that its model included a mix of kidney donor types, and the committee heard that the patterns of graft survival predicted by the model were consistent with the clinical experts' expectations.\n\nThe committee noted comments from consultees stating that the dosage of maintenance therapies used in clinical practice is often lower than is recommended in their marketing authorisations, and often decreases over time. It heard from the clinical experts that the lower doses may be associated with a decrease in the incidence of new-onset diabetes. The AG stated that the model included a reduction in maintenance dosing over time, with the dosage stabilising after 1\xa0to 3\xa0years. The committee accepted that the maintenance therapy dosages and the clinical outcomes associated with them in the AG's model were based on clinical trials.\n\nThe committee discussed the drug costs used in the AG's model and agreed that it was appropriate to use prices from the Electronic Market Information Tool (eMIT), if available, because these reflect the prices paid by the NHS (see NICE's guide to the methods of technology appraisal, section\xa05.5.2). The committee agreed that it was appropriate to consider the prices agreed with the Commercial Medicines Unit for Advagraf (prolonged-release tacrolimus capsules), Modigraf (tacrolimus granules for oral suspension) and Adoport (immediate-release tacrolimus) when making its recommendations, because these prices are nationally available to the NHS. The committee concluded that its preferred analysis used eMIT prices when available and the prices agreed with the Commercial Medicines Unit for Advagraf, Modigraf and Adoport.The committee concluded that the AG's model was the most informative model for decision-making.\n\nThe committee understood that in clinical practice, some treatments may be considered particularly valuable for certain groups of people (see section\xa04.2). It therefore considered whether there was any clinical and cost-effectiveness evidence for specific subgroups. The committee noted that there were very little subgroup data for any of the interventions, and highlighted that the AG had not found enough evidence in its systematic review to inform robust subgroup analyses. The clinical experts acknowledged that there is limited evidence in this area. The committee considered that there are likely to be some subgroups of people for whom individual treatment options may be particularly beneficial, but it had not seen sufficient evidence of clinical or cost effectiveness in specific subgroups. Therefore the committee concluded that it was unable to make recommendations for any of the interventions in specific subgroups (see sections\xa04.20 and 4.21).\n\nThe committee considered the effect of adherence on the clinical and cost effectiveness of immunosuppressive regimens. The committee heard from patient experts that, although it took some adjustment, taking the medicines could be fitted into a daily routine. The patient experts described some people who may find adherence more difficult, such as people at university and those who need to take a lot of medicines for other conditions. The clinical experts also noted that it is the evening dose of tacrolimus that is most often missed. The clinical experts stated that once-daily dosing of tacrolimus (using the prolonged-release formulation) is likely to be helpful for some people, although there are others for whom it makes little difference. The committee understood that there is limited evidence on the effect of once-daily dosing on adherence or clinical outcomes, and that it would be difficult to identify people who would benefit. The committee noted that improved adherence associated with prolonged-release tacrolimus had been modelled by Astellas. It noted that this model was based on a single trial demonstrating the effect of once-daily tacrolimus on adherence, combined with a meta-analysis showing the effect of improved adherence on clinical outcomes. The committee considered that the quality of the evidence informing this meta-analysis varied. The committee also highlighted that it was unclear whether the company had captured the different effects of missing a dose of a once-daily or a twice-daily therapy, and that Astellas's approach assumed the effectiveness of the whole regimen would be increased by improving adherence to tacrolimus. Therefore, the committee considered that there were limitations in Astellas's analysis. The committee noted the additional evidence received from Astellas during consultation. The company highlighted a randomised controlled study by Kuypers et al. (2013) that had been included in its original submission, which compared adherence between tacrolimus once-daily and twice-daily regimens. The company stated that non-randomised evidence was also available, which suggested that prolonged-release tacrolimus improved adherence and reduced within-patient variation in blood levels of tacrolimus. The company stated that these outcomes were associated with graft survival. The AG highlighted that the study by Kuypers et al. (2013) had a number of strengths, but also weaknesses, which limited its generalisability. The committee noted that the study did not report patient-related outcomes such as graft survival. It also noted the AG's view that people had more contact with clinicians when they were transferred from immediate-release tacrolimus to prolonged-release tacrolimus, which could be a potential reason for better adherence. The committee considered that there may be some people for whom once-daily prolonged-release tacrolimus could improve adherence. However considering all the evidence, the committee concluded that it would be difficult to identify the people who would benefit from prolonged-release tacrolimus, and that the effect on clinical outcomes was uncertain.\n\n## Basiliximab\n\nThe committee considered that basiliximab is a clinically effective treatment option. It noted that the AG's economic model showed that basiliximab dominated (that is, provides more quality-adjusted life years [QALYs] at a lower cost) both treatment without induction and r‑ATG, when used with either tacrolimus-based or ciclosporin-based maintenance regimens. Therefore the committee concluded that basiliximab was cost effective and could be recommended as part of a calcineurin-inhibitor-based immunosuppressive regimen, as an option to prevent organ rejection in adults having a kidney transplant. The committee was aware that treatment with basiliximab plus tacrolimus was outside the terms of the marketing authorisation, and noted the exceptional directive from the Department of Health for this appraisal that covers this situation. The committee was convinced that there was sufficient evidence to support this recommendation.\n\n## Rabbit anti-human thymocyte immunoglobulin\n\nThe committee considered r‑ATG to be a clinically effective induction therapy. It noted that in the AG's economic model, r‑ATG was dominated by basiliximab and was associated with incremental cost-effectiveness ratios (ICERs) of £63,200 to £333,000 per QALY gained compared with treatment without induction. The committee understood that the AG's model had assumed vials of r‑ATG would be shared and there was no wastage of partially used vials. It heard from the clinical experts that this was unlikely, so considered that the costs of r‑ATG could have been underestimated. The committee also heard from the clinical experts that r‑ATG causes short-term side effects and so can be unpleasant to take. The committee acknowledged that there may be some subgroups of people, such as people with high immunological risk or delayed graft function, for whom r‑ATG may provide additional benefits. The committee noted comments received during consultation about evidence demonstrating r‑ATG's efficacy in people with high immunological risk and its effect on the incidence of antibody-treated acute rejection. The committee noted the Brennan (2006) study in which the mean peak panel-reactive antibody was approximately 14% in both groups, with a mean value of about 6% at the time of transplant. The committee recognised that immunological risk is influenced by a number of factors as well as panel-reactive antibody levels, but questioned whether the study had included a high immunological risk group and considered that there was not enough evidence to support recommendations in people with high immunological risk. The committee concluded that the evidence it had seen showed that r‑ATG is not cost effective for preventing organ rejection in adults having a kidney transplant.\n\n## Tacrolimus\n\nThe committee heard from the clinical experts that tacrolimus is a potent immunosuppressive therapy, and noted that the immediate-release formulation was cost effective in all comparisons presented by the AG. Therefore the committee concluded that immediate-release tacrolimus could be recommended as an option as part of an immunosuppressive regimen for preventing organ rejection in adults having a kidney transplant.\n\nThe committee heard that there were no consistent statistically significant differences in clinical effectiveness between prolonged-release and immediate-release tacrolimus. It noted that prolonged-release tacrolimus was dominated by both immediate-release tacrolimus and ciclosporin in the AG's economic analyses. Therefore the committee did not consider prolonged-release tacrolimus to be cost effective, based on the evidence it had seen. The committee noted that Astellas's submission stated that its formulation of prolonged-release tacrolimus (Advagraf) is available at a discount through an agreement with the Commercial Medicines Unit, and discussed a scenario analysis presented by the AG using this discount. The discount and the results of the scenario analysis are commercial in confidence and so cannot be reported here. The committee considered that this scenario analysis did not affect its conclusion about the cost effectiveness of prolonged-release tacrolimus.\n\n## Belatacept\n\nThe committee acknowledged that belatacept was likely to be a clinically effective treatment, based on the evidence it had seen. In particular, it noted that belatacept plus mycophenolate mofetil increased graft function compared with ciclosporin plus azathioprine in the AG's network meta-analysis. The committee accepted that belatacept was associated with ICERs ranging from £241,000 to £424,000 per QALY gained, compared with immediate-release tacrolimus, sirolimus and ciclosporin, and that these ICERs were substantially higher than the range normally considered cost effective. The committee acknowledged that there may be some subgroups of people for whom belatacept may provide additional benefits, for example, people with nephrotoxicity or microangiopathy resulting from previous immunosuppressive treatment. However, it considered that there was limited evidence to support recommendations in specific subgroups (see sections\xa04.20 and 4.21).\n\n## Mycophenolic acid\n\nThe committee noted that in the AG's economic analysis, mycophenolate mofetil dominated both sirolimus and azathioprine, and was less costly and less effective than mycophenolate sodium and everolimus; it noted that the ICERs for these comparisons were £144,000 and £1,530,000 per QALY lost respectively. The committee considered that mycophenolate mofetil was a clinically effective option, and was cost effective in all the comparisons presented. The committee concluded that mycophenolate mofetil was a cost-effective use of NHS resources and could be recommended as an option as part of a calcineurin-inhibitor-based immunosuppressive regimen to prevent organ rejection in adults having a kidney transplant.\n\nThe committee heard that there were no noticeable differences in clinical effectiveness between mycophenolate mofetil and mycophenolate sodium. It noted that mycophenolate sodium was associated with an ICER of £56,600 per QALY gained compared with azathioprine, and £144,000 per QALY gained compared with mycophenolate mofetil. The committee concluded that mycophenolate sodium was not cost effective, based on the evidence it had seen.\n\n## Sirolimus\n\nThe committee heard from the clinical experts that treatment with sirolimus can be difficult to manage in clinical practice, and may be associated with a range of adverse effects including peripheral oedema and bone marrow suppression. It also heard that anaemia may be more common with sirolimus and everolimus than with other immunosuppressive therapies (although the AG had assumed the rate would be equal across all regimens). The committee noted that in the AG's base-case economic analyses, sirolimus was dominated by immediate-release tacrolimus and mycophenolate mofetil. The committee considered that this evidence suggested that sirolimus was not cost effective, and noted that the cost effectiveness of sirolimus would worsen if the incidence of anaemia increased.\n\n## Everolimus\n\nThe committee noted that the AG's economic model suggested that everolimus may be more effective than mycophenolate mofetil and azathioprine, although it was also associated with higher costs. The committee noted that the ICERs were £1,530,000 and £383,000 per QALY gained respectively, and were well above the range normally considered cost effective. The committee was also aware that anaemia may be more common with sirolimus and everolimus than with other immunosuppressive therapies, and that this would worsen the cost effectiveness of everolimus in these comparisons.\n\n# Additional considerations\n\nFollowing an appeal, the committee considered in detail the scope of the appraisal and the populations and clinical situations to which its recommendations would apply. It noted that its intention at the time of the first final appraisal determination was that the recommendations would apply to the initial treatments for people having kidney transplants, and explained that this was based on its interpretation of the scope at that time and the evidence available from the systematic review and economic modelling. However, on further review the committee recognised that the scope included immunosuppressive treatments given immediately after transplant and at subsequent stages, in people having a kidney transplant and in people who have had a re-transplant in the last 2\xa0years. The committee therefore acknowledged that the scope for this appraisal includes, in addition to initial treatments, subsequent therapies during the life of a graft and treatments for people having second and subsequent transplants. The committee concluded that the scope was broader than its original recommendations, and discussed the recommendations it could make for these additional clinical scenarios.\n\nThe committee noted that the protocol and systematic review did not include the use of subsequent treatments during the life of the graft and only included studies in which randomisation took place at the time of the transplant. As a result, none of the studies considered during the appraisal investigated the effect of switching regimens during the life of a functioning graft. It also noted that the AG's economic model did not provide estimates of the cost effectiveness of switching to alternative interventions during the life of a graft. The committee considered that the systematic review and economic modelling were suitable to provide evidence on the initial treatments started around the time of transplant. The committee heard from the clinical experts that between 10% and 20% of people cannot continue on their initial immunosuppressive treatments. This may result from intolerance because of nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy associated with ciclosporin, tacrolimus, sirolimus or everolimus, for example. The clinical and patient experts highlighted the need for other treatments to be available to ensure continued immunosuppressive therapy for people unable to continue taking their initial treatment. They also highlighted recent studies which showed that tacrolimus withdrawal should be avoided. They therefore emphasised the need for alternative immunosuppressants if tacrolimus has to be stopped. The committee was aware that returning to dialysis if a transplant fails can have a significant effect on quality of life as well as incurring costs to the NHS. It noted that sirolimus could be a cost-effective option for people with calcineurin inhibitor nephrotoxicity because the only alternative would be dialysis, although it understood that sirolimus is currently routinely commissioned by NHS England for nephrotoxicity. The committee also heard that although thrombotic microangiopathy is rare, it results in graft loss and the person needing dialysis. The clinical experts noted that belatacept is the only immunosuppressant that can be given in these circumstances. The committee recognised the need for urgency in this situation and that individual funding requests might not be suitable or approved quickly enough. It also recognised that belatacept could potentially be a cost-effective use of NHS resources when thrombotic microangiopathy develops because the only alternative would be dialysis. The committee heard from the clinical experts and the AG that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review. The committee recalled that the limited analysis it had seen on treatment switching, submitted by Novartis, was highly uncertain. In addition, it heard that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the clinical and cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee considered that any outstanding clinical and commissioning issues would be better addressed through other routes, such as other NICE programmes or clinical commissioning policies. They noted that the consultees agreed with this approach. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment started around the time of kidney transplant.\n\nThe committee understood that the systematic review was not restricted to people having their first kidney transplant, and heard from the AG that about 30% of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee also heard from the AG that the economic model gives the same results whether it considers the first or second transplant. It was aware that the conclusions from the economic model might change if individual interventions were removed because, at the time of the second transplant, they had previously been found to be clinically inappropriate. However, it had not seen evidence for this situation, and considered that it was unlikely that sufficient evidence to inform a robust analysis could be obtained. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.\n\nThe committee considered the bioequivalence of generic immunosuppressive therapies. It noted that calcineurin inhibitors have a narrow therapeutic index. It understood that the Commission on Human Medicines recommends that oral tacrolimus should be prescribed by brand name, and that care is needed when switching between drugs with a narrow therapeutic index (see the Medicines and Healthcare products Regulatory Agency's drug safety update on oral tacrolimus products). The committee heard from the clinical experts that this primarily applies to the drugs that are dosed based on plasma levels, such as tacrolimus, and that clinicians are aware of the risks associated with generic prescribing and switching formulations. The committee understood that guidance on good practice in prescribing generic immunosuppressive therapies is routinely followed in clinical practice. The committee also heard that clinicians are aware of cost differences between the different brands of immunosuppressive therapies, and take into account local costs in their prescribing decisions. The committee concluded that it did not need to make additional recommendations about the bioequivalence of generic immunosuppressive therapies, and considered that if different preparations are equally suitable, it would be reasonable to recommend using the least expensive product when starting treatment.\n\nThe committee noted the potential equality issue raised by consultees during scoping, in submissions and during the committee meeting. It understood that some Jehovah's Witnesses are unwilling to have human blood products, but noted that none of the recommended technologies are based on human blood products. The committee understood that effective immunosuppression may be particularly beneficial for people from black, Asian and minority ethnic groups, and noted that a number of effective treatment options are available. The committee also heard that mycophenolate mofetil cannot be taken by women who are pregnant and noted that alternative effective treatment options are available.\n\nThe committee discussed providing immunosuppressive therapy for adults who cannot swallow capsules as a result of a disability, or who cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin. The committee noted that these people might need alternative formulations (such as oral suspensions or gelatine-free formulations) instead. The committee noted that oral suspensions and gelatine-free formulations are available for both immediate-release tacrolimus and mycophenolate mofetil, and that these products have marketing authorisations in the UK. The suspensions are more expensive than the capsules, although there is a nationally available price agreed with the Commercial Medicines Unit for Modigraf (see section\xa03.10 and section 3.18). The committee recognised that, given its recommendations (see section\xa04.12 and section\xa04.15) covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might discriminate against adults with protected characteristics. The committee reiterated that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product (see section\xa04.22), but concluded that it could be started with an alternative dosage form if the least expensive product is not suitable. The committee agreed that Modigraf should be used only if the company provides Modigraf at the price agreed with the Commercial Medicines Unit.\n\n# Summary of appraisal committee's key conclusions\n\nTA481\n\nAppraisal title: Immunosuppressive therapy for kidney transplant in adults\n\nSection\n\nKey conclusion\n\nBasiliximab, immediate-release tacrolimus and mycophenolate mofetil are recommended as initial options to prevent organ rejection in adults having a kidney transplant.\n\nThe committee considered that basiliximab is a clinically effective treatment option, and provided more quality-adjusted life years (QALYs) at a lower cost than treatment without induction and rabbit anti-human thymocyte immunoglobulin (r‑ATG).\n\nThe committee heard that tacrolimus is a potent immunosuppressive therapy, and considered that immediate-release tacrolimus was cost effective.\n\nThe committee considered that mycophenolate mofetil was a clinically effective option, and was cost effective in all the comparisons presented.\n\nr‑ATG, prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in adults having a kidney transplant.\n\nThe committee considered that r‑ATG was clinically effective, but concluded that it was not cost effective.\n\nThe committee noted that there were no consistent differences in clinical effectiveness between immediate- and prolonged-release tacrolimus. It considered that prolonged-release tacrolimus was not cost effective.\n\nThe committee noted that belatacept was likely to be clinically effective, but was associated with incremental cost-effectiveness ratios (ICERs) substantially higher than the range normally considered cost effective.\n\nThe committee heard that there were no noticeable differences in clinical effectiveness between mycophenolate mofetil and mycophenolate sodium, and concluded that mycophenolate sodium was not cost effective.\n\nThe committee noted that sirolimus was not a cost-effective treatment option.\n\nThe committee noted the economic modelling suggested that everolimus may be more effective than mycophenolate mofetil and azathioprine, although it was not cost effective.\n\nThe committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in adults who are, or become, unable to have the technologies recommended in sections 1.1 to 1.3 or the standard triple therapy regimen of ciclosporin, azathioprine and a corticosteroid (for example, because of treatment failure, contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes adults who:\n\nare unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or\n\nhave a second or subsequent transplant, having previously found that 1 or more of the recommended initial treatments or standard treatments are clinically unsuitable for example, because of treatment failure, contraindications or intolerance.\n\n–1.3, 4.10, 4.12, 4.15, 1.4, 4.11, 4.13, 4.14, 4.16– 4.18, 1.5\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee understood that effective immunosuppressive therapies are important to prevent organ rejection in adults having kidney transplants.\n\nThe committee heard that the choice of immunosuppressive therapy is affected by a number of factors, including the characteristics and preferences of the person having treatment. The committee understood the value of having a choice of immunosuppressive therapies.\n\n, 4.2\n\nThe technologies\n\nProposed benefits of the technologies\n\nHow innovative are the technologies in their potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard that the key priority for immunosuppressive therapy is to prolong graft survival for as long as possible, while minimising adverse effects. The clinical experts considered that both quality of life and survival are better with a functioning kidney transplant than with dialysis, and the patient experts emphasised the value of maintaining a functioning kidney transplant.\n\n\n\nWhat are the positions of the treatments in the pathway of care for the condition?\n\nImmunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2\xa0weeks around the time of transplant and may include polyclonal or monoclonal antibodies. Maintenance therapy starts immediately after transplant and continues for life.\n\nBasiliximab and r‑ATG are options for induction therapy. Tacrolimus, belatacept, mycophenolate mofetil, mycophenolate sodium, sirolimus and everolimus are options for maintenance therapy.\n\nThe committee understood that in clinical practice, some treatments may be considered particularly valuable for certain groups of people.\n\n, 4.8\n\nAdverse reactions\n\nThe committee heard that sirolimus may be associated with a range of adverse effects including peripheral oedema and bone marrow suppression and that sirolimus and everolimus may be associated with an increased risk of anaemia.\n\n, 4.18\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe AG's systematic review found 86\xa0randomised controlled trials, including 11\xa0studies of induction therapies, 73\xa0studies of maintenance therapies and 2\xa0studies examining both induction and maintenance therapies.\n\nThe committee noted that the AG's systematic review was comprehensive and concluded that all the relevant clinical effectiveness randomised controlled trial evidence had been taken into account.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee noted that the AG considered that only 11\xa0trials adequately matched the population and current practice in the NHS in England.\n\n\n\nUncertainties generated by the evidence\n\nThe committee understood that there was substantial heterogeneity in the AG's network meta-analysis, and none of the maintenance regimens performed consistently well across all 4\xa0outcomes. The committee considered that limited conclusions on differences between these options can be drawn from the AG's network meta-analysis.\n\nThe committee understood that there is limited evidence on the effect of once-daily dosing on adherence or clinical outcomes, and that it would be difficult to identify people who would benefit. It concluded that the effect on clinical outcomes was uncertain.\n\n, 4.9\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee noted that there were very little subgroup data for any of the interventions. It considered that there are likely to be some subgroups of people for whom individual treatment options may be particularly beneficial, but it had not seen sufficient evidence of clinical or cost effectiveness in specific subgroups.\n\nThe committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. This may be because of intolerance or complications requiring withdrawal, for example. The committee heard that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review, and the limited analysis it had seen on treatment switching was highly uncertain. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment around the time of kidney transplant.\n\nThe committee understood that about 30% of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.\n\n, 4.20, 4.21\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe AG's network meta-analysis showed that basiliximab and r‑ATG were significantly more effective than treatment without induction for acute rejection. The committee concluded that basiliximab and r‑ATG are effective induction therapies, but there was no evidence of a difference in clinical effectiveness between them.\n\nThe AG's network meta-analysis showed a number of statistically significant differences between regimens, although none of the maintenance regimens performed consistently well across all 4\xa0outcomes assessed. The committee saw that all regimens except belatacept plus mycophenolate mofetil showed evidence of improvement in acute rejection compared with ciclosporin plus azathioprine, although belatacept plus mycophenolate mofetil statistically significantly increased graft function. The committee concluded that the maintenance therapies are effective options.\n\n, 4.6\n\nHow has the new clinical evidence that has emerged since the original appraisal (TA85) influenced the current (preliminary) recommendations?\n\nThe AG's systematic review found 86\xa0randomised controlled trials, of which 23 were included in NICE's original technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults, and 63 were identified in the updated systematic review for the current appraisal. The committee noted that the AG's systematic review was comprehensive and included all relevant clinical effectiveness randomised controlled trial evidence.\n\nSince the NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in adults was published in 2004, the marketing authorisation for daclizumab has been withdrawn and new technologies have received marketing authorisations.\n\n–4.6, 2.4\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nEconomic analyses were presented by the AG, Astellas, Bristol-Myers Squibb and Novartis.\n\nThe AG presented an economic model based on a discrete-time state transition structure.\n\nAstellas submitted a Markov model and presented results for each immunosuppressive drug compared with immediate-release tacrolimus.\n\nBristol-Myers Squibb presented an analysis of the cost effectiveness of belatacept compared with tacrolimus and ciclosporin, based on a 36-month initial phase followed by a longer-term Markov model.\n\nNovartis presented a patient-level simulation model to capture the cost effectiveness of everolimus plus reduced-dose ciclosporin and mycophenolate sodium plus standard-dose ciclosporin, compared with mycophenolate mofetil plus standard-dose ciclosporin or tacrolimus.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee noted that the AG and Novartis modelled quality of life differently. It understood that the Novartis model suggested that the cost-effectiveness results were very sensitive to the utility assumptions.\n\nThe committee concluded that the AG's model was the most informative model for decision-making.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that the AG modelled quality of life using fixed utility decrements for each health state.\n\nThe committee noted that Novartis assumed that quality of life would decrease as graft function decreased. It considered that Novartis's analyses implied that the benefits had been underestimated for all treatments, and would be most underestimated for treatments with the largest beneficial effect on graft function.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee noted that there were very little subgroup data for any of the interventions. It considered that there are likely to be some subgroups of people for whom individual treatment options may be particularly beneficial, but it had not seen sufficient evidence of clinical or cost effectiveness in specific subgroups.\n\nThe committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. The committee recalled that the limited analysis it had seen on treatment switching was highly uncertain, and was aware that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable.\n\nThe committee understood that the systematic review was not restricted to people having their first kidney transplant, but there was insufficient evidence for subgroup analysis. The committee heard from the AG the that economic model gives the same results whether it considers the first or second transplant, but was aware that the conclusions might change if individual interventions were removed because, at the time of the second transplant, they had previously been found to be clinically inappropriate. However, it had not seen evidence for this situation, and considered that it was unlikely that sufficient evidence to inform a robust analysis could be obtained. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants, in people for whom particular therapies had previously been found to be inappropriate.\n\n, 4.20, 4.21\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee understood that the cost-effectiveness results were very sensitive to the utility assumptions.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nBasiliximab dominated (provided more QALYs at a lower cost) treatment without induction and r‑ATG.\n\nr‑ATG was dominated by basiliximab and was associated with ICERs of £63,200 to £333,000 per QALY gained compared with treatment without induction.\n\nImmediate-release tacrolimus was cost effective in all comparisons presented by the AG.\n\nProlonged-release tacrolimus was dominated by both immediate-release tacrolimus and ciclosporin.\n\nBelatacept was associated with ICERs of £241,000 to £424,000 per QALY gained, compared with immediate-release tacrolimus, sirolimus and ciclosporin.\n\nMycophenolate mofetil dominated both sirolimus and azathioprine, and was less costly and less effective than mycophenolate sodium and everolimus with ICERs of £144,000 and £1,530,000 per QALY lost respectively.\n\nMycophenolate sodium was associated with an ICER of £56,600 per QALY gained compared with azathioprine, and £144,000 per QALY gained compared with mycophenolate mofetil.\n\nSirolimus was dominated by mycophenolate mofetil and immediate-release tacrolimus.\n\nEverolimus was associated with ICERs of £1,530,000 and £383,000 per QALY gained, compared with mycophenolate mofetil and azathioprine respectively.\n\n–4.18\n\nHow has the new cost-effectiveness evidence that has emerged since the original appraisal (TA85) influenced the current (preliminary) recommendations?\n\nEconomic analyses were presented by the AG, Astellas, Bristol-Myers Squibb and Novartis. The AG's model was independent of that built for NICE's technology appraisal guidance on immunosuppressive therapy for renal transplantation in adults. The AG highlighted that the previous analysis had not fully accounted for uncertainty and had not taken into account the effect of kidney function on clinical and economic outcomes. Since the original appraisal, some of the technologies have become available as generics.\n\nThe committee concluded that the AG's model was the most informative model for decision-making.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNone. Astellas advised that there are nationally available discounted contract prices for Modigraf (tacrolimus granules for oral suspension) and Advagraf (prolonged-release tacrolimus).\n\n, 3.12\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee understood that some Jehovah's Witnesses are unwilling to have human blood products, that effective immunosuppression may be particularly beneficial for people from black, Asian and minority ethnic groups, and that mycophenolate mofetil cannot be taken by women who are pregnant.\n\nThe committee understood that some adults may not be able to swallow capsules as a result of a disability, or cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin. It recognised that, given its recommendations covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might be discriminatory. The committee noted that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product. However, treatment could be started with an alternative dosage form if the least expensive product is not suitable.\n\n, 1.2, 4.24"}
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https://www.nice.org.uk/guidance/ta481
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Evidence-based recommendations on immunosuppressive therapies for preventing kidney rejection in adults. The therapies are basiliximab (Simulect), immediate-release tacrolimus (Adoport, Capexion, Modigraf, Prograf, Tacni, Vivadex), mycophenolate mofetil (Cellcept and non-branded versions), rabbit anti-human thymocyte immunoglobulin (Thymoglobuline), prolonged-release tacrolimus (Advagraf, Envarsus), mycophenolate sodium (Myfortic, Ceptava), sirolimus (Rapamune), everolimus (Certican) and belatacept (Nulojix).
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3d45888e5e7c358d4dbf6173cb3ae32246bb49a9
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nice
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Immunosuppressive therapy for kidney transplant in children and young people
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Immunosuppressive therapy for kidney transplant in children and young people
Evidence-based recommendations on immunosuppressive therapies for preventing kidney rejection in children and young people. The therapies are basiliximab (Simulect), immediate-release tacrolimus (Adoport, Capexion, Modigraf, Prograf, Tacni, Vivadex), mycophenolate mofetil (Cellcept and non-branded versions), rabbit anti-human thymocyte immunoglobulin (Thymoglobuline), prolonged-release tacrolimus (Advagraf, Envarsus), mycophenolate sodium (Myfortic, Ceptava), sirolimus (Rapamune), everolimus (Certican) and belatacept (Nulojix).
# Recommendations
This guidance makes recommendations on using basiliximab, rabbit anti-human thymocyte immunoglobulin, tacrolimus (immediate-release and prolonged-release), mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept after kidney transplant in children and young people. The recommendations apply only to the initial immunosuppressive therapy (induction and maintenance therapy) started around the time of kidney transplant.
It was outside the scope of the appraisal to make recommendations on using azathioprine or corticosteroids after kidney transplant in children and young people.
Under an exceptional directive from the Department of Health, the appraisal committee was allowed to make recommendations about using drugs outside the terms of their marketing authorisations if there was compelling evidence of their safety and effectiveness.
Basiliximab, when used as part of an immunosuppressive regimen that includes a calcineurin inhibitor, is recommended as an initial option to prevent organ rejection in children and young people having a kidney transplant.,
Immediate-release tacrolimus, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in children and young people having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the child or young person is not able to swallow capsules or they are unable to have a particular ingredient because of allergy or religious reasons). Tacrolimus granules for oral suspension (Modigraf) should be used only if the company provides it at the same price or lower than that agreed with the Commercial Medicines Unit.
Mycophenolate mofetil, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in children and young people having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the child or young person is not able to swallow capsules or they are unable to have a particular ingredient because of allergy or religious reasons).,
Rabbit anti-human thymocyte immunoglobulin, prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in children and young people having a kidney transplant.
The committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in children or young people who are, or become, unable to have the technologies recommended in sections 1.1 to 1.3 or azathioprine and corticosteroids (for example, because of treatment failure, contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes children and young people who:
are unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or
have a second or subsequent transplant, having previously found that 1 or more of the recommended initial treatments or standard treatments are clinically unsuitable, for example because of treatment failure, contraindications or intolerance.
These recommendations are not intended to affect treatment with any of the technologies in this appraisal that was started in the NHS before this guidance was published. Children and young people having treatment outside these recommendations, or for whom the committee were unable to make a recommendation, may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician and the child or young person or their parents or carers.
August 2017: the use of basiliximab (with tacrolimus) and mycophenolate mofetil (with tacrolimus) is outside the terms of the marketing authorisations for basiliximab and for mycophenolate mofetil. If these combinations are prescribed, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. For further information, see the General Medical Council's guidance on Good practice in prescribing and managing medicines and devices.
The Department of Health has stated that the statutory funding requirement does not apply to drugs that are used outside the terms of their marketing authorisation.
The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that to maintain therapeutic response when a patient is stabilised on a particular brand, oral tacrolimus products should be prescribed and dispensed by brand name only. If a prescriber considers that switching to a different brand of oral tacrolimus would be of benefit, the change requires careful supervision and therapeutic monitoring by an appropriate specialist. See the MHRA's advice on oral tacrolimus products.# Clinical need and practice
Kidney transplant is used to treat established kidney failure, which is severe and irreversible impairment of kidney function. After a kidney transplant, immunosuppressive therapy is used to reduce the risk of rejection of the transplanted kidney (or 'graft') and prolong its survival. Between April 2016 and March 2017, 127 kidney transplants were done in the UK for children and young people under 18 years; 116 of these were in England.
Kidney transplant in children and young people can differ from adults in several important aspects including the cause of kidney failure, the pharmacokinetic properties of immunosuppressive therapies and how they are metabolised, the immune response after transplant, the measures of success of the transplant procedure, the susceptibility to post-transplant complications, and the degree of adherence to treatment.
Immunosuppressive therapy aims to prevent acute rejection and optimise the function of the transplanted kidney, while minimising the adverse effects of immunosuppression (such as increased risk of infection, cancer, diabetes and cardiovascular disease). Immunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2 weeks around the time of transplant and may include polyclonal or monoclonal antibodies. Maintenance therapy starts immediately after transplant and continues for life.
NICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents was published in 2006. It recommended basiliximab, daclizumab, tacrolimus, mycophenolate mofetil and sirolimus, in certain circumstances, as options for immunosuppressive therapy for kidney transplant in children and young people. Since that appraisal, the marketing authorisation for daclizumab has been withdrawn, new technologies (rabbit anti-human thymocyte immunoglobulin, mycophenolate sodium, belatacept, a prolonged-release formulation of tacrolimus, and everolimus) have received marketing authorisations, but some of the marketing authorisations exclude children and young people. In addition, some of the technologies are available as generics.# The technologies
# Induction therapy
## Basiliximab
Basiliximab (Simulect, Novartis Pharmaceuticals) is a monoclonal antibody that acts as an interleukin‑2 receptor antagonist. It has a marketing authorisation in the UK for the prophylaxis of acute organ rejection in people having a kidney transplant. The indication includes children and young people aged 1 to 17 years. The summary of product characteristics states that basiliximab is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression, in patients with panel-reactive antibodies less than 80%, or in a triple maintenance immunosuppressive regimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine or mycophenolate mofetil.
Basiliximab is administered intravenously. In children and young people weighing less than 35 kg, the recommended total dose is 20 mg given in 2 doses of 10 mg each. In children and young people weighing 35 kg or more, the recommended dose is 40 mg given in 2 doses of 20 mg each.
Basiliximab is available in 10‑mg and 20‑mg vials at a price of £758.69 and £842.38 respectively (excluding VAT; British national formulary online ), equating to £1,517 per course of treatment for a patient weighing under 35 kg and £1,685 for a patient weighing 35 kg or more.
## Rabbit anti-human thymocyte immunoglobulin
Rabbit anti-human thymocyte immunoglobulin (r‑ATG; Thymoglobuline, Sanofi) is made by injecting human thymus cells into rabbits. The drug contains immunoglobulins (antibodies) that attach to and destroy some of the cells of the immune system. It has a marketing authorisation in the UK for the prevention of graft rejection in kidney transplant. The summary of product characteristics states that it is usually used with other immunosuppressive drugs, but does not state whether the indication includes children and young people. It also advises that no recommendation about dosage for children and young people can be made, but that available information indicates that they do not need a different dosage to adults.
r‑ATG is administered intravenously, at a dose of 1 to 1.5 mg/kg/day for 3 to 9 days after a kidney transplant (a cumulative dose of 3 to 13.5 mg/kg).
r‑ATG is available in 25‑mg vials at a price of £158.77 (excluding VAT; BNF online ). The assessment group (AG) estimated that the cost of induction therapy with r‑ATG for a 10‑year‑old boy is £2,101 (assuming vials are shared so that there is no wastage).
# Maintenance therapy
Some drugs in this appraisal contain the same active ingredient but in different formulations. Tacrolimus is a calcineurin inhibitor and is available in an immediate-release formulation and a prolonged-release formulation. Mycophenolic acid is an antiproliferative agent. It is available as a prodrug called mycophenolate mofetil and a sodium salt called mycophenolate sodium.
## Immediate-release tacrolimus
Brands of immediate-release tacrolimus include Adoport (Sandoz), Capexion (Mylan), Modigraf (Astellas Pharma), Perixis (Accord Healthcare), Prograf (Astellas Pharma), Tacni (Teva) and Vivadex (Dexcel Pharma). All of these formulations have marketing authorisations in the UK for the prophylaxis of transplant rejection in people having a kidney transplant. Adoport, Capexion, Perixis, Prograf, Tacni and Vivadex are administered orally as capsules, twice a day. Prograf can also be administered intravenously. Modigraf consists of granules for oral suspension.
For all brands of immediate-release tacrolimus, the summary of product characteristics recommends an initial dose for children (age range not specified) of 0.3 mg/kg/day orally or 0.075 to 0.100 mg/kg/day intravenously and states that the dosage is usually reduced in the period after the transplant.
Modigraf (tacrolimus granules for oral suspension) is available in sachets of 0.2 mg and 1 mg at a price of £7.13 per mg (excluding VAT; BNF online ). The company has agreed a nationally available price reduction for Modigraf with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. Tacrolimus immediate-release capsules are available as 0.5 mg, 0.75 mg, 1 mg, 2 mg and 5 mg capsules (depending on the brand), the price of which varies by brand. The AG calculated that the average cost paid by the NHS for immediate-release tacrolimus capsules is £0.52 per mg (excluding VAT; data from the Electronic Market Information Tool , Commercial Medicines Unit). The AG estimated that the weekly cost of maintenance therapy with immediate-release tacrolimus capsules for a 10‑year‑old boy is £34. Adoport is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
## Prolonged-release tacrolimus
Prolonged-release tacrolimus (Advagraf, Astellas Pharma) is administered orally as a capsule, once a day. It has a marketing authorisation in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. The summary of product characteristics recommends an initial dose for adults of 0.2 to 0.3 mg/kg/day. The dosage is usually reduced in the period after the transplant. It also states that the safety and efficacy of prolonged-release tacrolimus in children under 18 years have not yet been established and that limited data are available but no recommendation on dosage can be made.
Prolonged-release tacrolimus (Advagraf) is available as 0.5‑mg, 1‑mg, 3‑mg and 5‑mg capsules at a price of £1.07 to £1.43 per mg (excluding VAT; BNF online ). The AG estimated that the weekly cost of maintenance therapy with prolonged-release tacrolimus for a 10‑year‑old boy is £47 (using the list price and the dosage for adults). Advagraf is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
Another brand of prolonged-release tacrolimus, Envarsus (Chiesi) obtained a marketing authorisation for adults after the scope for this appraisal was finalised. The brand name Envarsus was not included in the AG's search for evidence and Chiesi was not asked to submit evidence for the appraisal.
## Belatacept
Belatacept (Nulojix, Bristol-Myers Squibb) is a soluble fusion protein designed to selectively inhibit CD28-mediated co‑stimulation of T‑cells. Belatacept, in combination with corticosteroids and a mycophenolic acid, has a marketing authorisation in the UK for prophylaxis of graft rejection in adults having a kidney transplant. The summary of product characteristics recommends that an interleukin‑2 receptor antagonist is added to this belatacept-based regimen. It also states that the safety and efficacy of belatacept in children and adolescents under 18 years have not yet been established and that no data are available.
Belatacept is administered intravenously. The recommended dose for adults is 10 mg/kg on the day of the transplant, followed by 10 mg/kg on days 5, 14, 28, 56 and 84 and then 5 mg/kg every 4 weeks from then on.
Belatacept is available in 250‑mg vials at a price of £354.52 (excluding VAT; BNF online ). The AG estimated that the weekly cost of maintenance therapy with belatacept for a 10‑year‑old boy is £56 (using the dosage for adults and assuming vials are shared so that there is no wastage).
## Mycophenolate mofetil
Mycophenolate mofetil (generic) has a marketing authorisation in the UK, in combination with ciclosporin and corticosteroids, for the prophylaxis of acute transplant rejection in people having a kidney transplant. Mycophenolate mofetil can be administered orally (capsules or an oral suspension) or intravenously. The summary of product characteristics states that the recommended daily dose for children and young people (aged 2 to 18 years) is 1,200 mg/m2 up to a maximum of 2 g per day. See the summary of product characteristics for dosage recommendations for patients with a body surface area below 1.5 m2.
The price of mycophenolate mofetil varies by brand. The oral suspension (CellCept) is available in 175‑ml containers of 1 g/5 ml suspension at a price of £3.29 per g (excluding VAT; BNF online ). At the time of the initial committee discussion (July 2015), the average cost paid by the NHS for mycophenolate mofetil capsules was £0.38 per g (excluding VAT; data from eMIT, Commercial Medicines Unit). The AG estimated that the weekly cost of maintenance therapy with mycophenolate mofetil capsules for a 10‑year‑old boy is between £1.74 and £3.48.
## Mycophenolate sodium
Mycophenolate sodium (Myfortic, Novartis Pharmaceuticals), in combination with ciclosporin and corticosteroids, has a marketing authorisation in the UK for the prophylaxis of acute transplant rejection in adults having a kidney transplant. The summary of product characteristics states that insufficient data are available to support the efficacy and safety of mycophenolate sodium in children and adolescents. It is administered orally, at a recommended dose for adults of 1.44 g per day.
Mycophenolate sodium is available in 180 mg and 360 mg tablets at a price of £4.48 per g (excluding VAT; BNF online ). The AG estimated that the weekly cost of maintenance therapy with mycophenolate sodium for a 10‑year‑old boy is £50 (using the dosage for adults).
## Sirolimus
Sirolimus (Rapamune, Pfizer) is an antiproliferative that blocks a protein called mammalian target of rapamycin (mTOR). It has a marketing authorisation in the UK for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. It is recommended to be used initially with ciclosporin and corticosteroids for 2 to 3 months, and may be continued only if ciclosporin can be progressively discontinued. The summary of product characteristics states that the safety and efficacy of sirolimus in children and adolescents under 18 years have not been established.
Sirolimus is administered orally as a tablet or solution. The recommended dose for adults is 6 mg initially, followed by 2 mg per day for 2 to 3 months, then adjusted to obtain blood trough levels of 4 to 12 nanograms/ml.
Sirolimus is available as 0.5 mg, 1 mg and 2 mg tablets and a 1 mg/ml oral solution, at a net price of £2.71 to £4.60 per mg (excluding VAT; BNF online ). The AG estimated that the weekly cost of maintenance therapy with sirolimus for a 10‑year‑old boy is £40 (using the dosage for adults).
## Everolimus
Everolimus (Certican, Novartis Pharmaceuticals) is an antiproliferative that blocks mTOR. It has a marketing authorisation for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. The summary of product characteristics states that everolimus should be used with ciclosporin and corticosteroids. Everolimus is administered orally as a tablet. The recommended initial dose for adults is 1.5 mg/day. The summary of product characteristics states that there is insufficient experience to recommend the use of everolimus in children and adolescents.
Everolimus is available in 0.25‑mg, 0.5‑mg and 0.75‑mg tablets at a net price of £9.90 per mg (excluding VAT; BNF online ). The AG estimated that the weekly cost of maintenance therapy with everolimus for a 10‑year‑old boy is £104 (using the dosage for adults).
Costs for all of the technologies may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 6) considered evidence from a number of sources. See the committee papers for full details of the evidence. The appraisal included 9 drugs for immunosuppression after kidney transplant in children and young people. Basiliximab and rabbit anti-human thymocyte immunoglobulin (r‑ATG) are both induction therapies. The other drugs are maintenance therapies: immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept.
The appraisal committee reviewed the data available on the clinical and cost effectiveness of the technologies, having considered evidence on the nature of kidney transplant and organ rejection and the value placed on the benefits of immunosuppressive therapy by people with a kidney transplant, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee discussed aspects of immunosuppression that are especially important for children and young people. It heard from clinical experts that quality of life is better with a transplant than while having dialysis, so the aim of immunosuppression treatment is to prolong survival of the transplanted kidney (or 'graft'). The committee also heard that it is important to minimise the side effects of immunosuppressive therapies, such as reduced growth and an increased risk of new-onset diabetes. Several submissions from consultees advised that poor adherence (that is, not taking the prescribed medication) is a major cause of graft loss, especially in young people. The committee heard that different people have different preferences for dosing regimens and side-effect profiles, so it is important to tailor treatment to each person. The committee concluded that patients and clinicians prefer to have a choice of immunosuppressive treatments.
The committee discussed the immunosuppressive regimens currently used in the NHS for children and young people with a kidney transplant. The clinical experts advised that most paediatric transplant centres use:
induction without antibodies, then maintenance therapy with tacrolimus and azathioprine (based on Trompeter et al. 2002) or
basiliximab induction, then maintenance therapy with tacrolimus and mycophenolate mofetil (based on the TWIST trial, Grenda et al. 2010).The committee was aware that there are several brands of oral tacrolimus, and that inadvertent switching between products has been associated with toxicity and graft rejection. It heard from clinical experts that, to minimise the risk of accidental switching, UK clinicians follow advice from the Medicines and Healthcare products Regulatory Agency to prescribe and dispense oral tacrolimus products by brand name. It heard from clinical experts that, for the same reason, brand names are used when prescribing ciclosporin (although it was aware that tacrolimus, rather than ciclosporin, is the calcineurin inhibitor of first choice in UK paediatric transplant units). The committee concluded that the immunosuppressive regimens most commonly used by children and young people in the UK were: induction without antibodies then maintenance therapy with tacrolimus and azathioprine; or basiliximab induction then maintenance therapy with tacrolimus and mycophenolate mofetil.
The committee discussed the decision problem addressed by the assessment report. For induction therapy, the committee agreed that it was appropriate to compare the interventions with each other and against treatment without induction. For maintenance therapy, the committee agreed that it was appropriate to compare the interventions with each other and against ciclosporin and azathioprine. The committee noted that the final guidance would apply to the interventions listed in the scope and would not affect the current use in the NHS of azathioprine or corticosteroids, which were included as comparators only. A clinical expert suggested that the appraisal should also consider alemtuzumab as an induction therapy. The committee was aware that alemtuzumab does not have a marketing authorisation in the UK for immunosuppression after kidney transplant and is not routinely available for transplant patients (it is available on a 'named patient' basis). It heard from clinical experts that alemtuzumab is not currently used for children and young people having a kidney transplant in the UK. The committee agreed that alemtuzumab should not be included as either an intervention or a comparator. Regarding the population for the appraisal, the committee agreed with the assessment group (AG) that there were insufficient data to permit analyses of subgroups such as children and young people with different levels of immunological risk. The committee concluded that the assessment report included the appropriate population, interventions and comparators.
# Clinical effectiveness
The AG's systematic review found 3 randomised controlled trials (RCTs) and 10 non-randomised studies of children and young people, of which 1 RCT and 6 non-randomised studies were identified in the updated systemic review for the current appraisal. The committee acknowledged that the number of studies in children and young people was low. It noted that the 3 RCTs were likely to be generalisable to the NHS because the trials were done in Europe, the patient and donor characteristics were largely representative of people using the NHS, and the drug doses were similar to current recommendations. However, the committee acknowledged that the evidence is quite old. The AG did not find any studies of children and young people comparing the following drugs with the comparators in the scope: r-ATG, prolonged-release tacrolimus, mycophenolate sodium, everolimus and belatacept. In addition, only 1 small study of children and young people assessed sirolimus. The clinical experts advised that, given the lack of evidence for children and young people, NHS practice is informed by evidence from adults and by clinical experience. The AG stated that data from the UK Transplant Registry provides useful information on graft and patient survival, but cannot be used to compare the effectiveness of different treatments. The committee concluded that it should consider all of the evidence about the effectiveness of immunosuppressive regimens, including randomised and non-randomised studies in children and young people and RCTs in adults.
The committee discussed whether it had considered all of the relevant evidence. Consultees and clinical experts advised that it was important to consider TWIST, an international RCT that recruited patients of 2 to 18 years having a kidney transplant (Grenda et al. 2010). Patients randomised to the TWIST regimen (daclizumab induction, immediate-release tacrolimus and mycophenolate mofetil maintenance, with corticosteroids that are withdrawn after 4 days) showed greater height gain after 6 months than patients randomised to the comparator regimen (no induction, immediate-release tacrolimus and mycophenolate mofetil with long-term corticosteroids). The committee noted that the UK marketing authorisation for daclizumab has been withdrawn, so daclizumab was not included in this appraisal and as a result TWIST was not included in the assessment report. The committee heard from the clinical experts that basiliximab and daclizumab have the same mechanism of action (both are interleukin‑2 receptor antagonists) and trials in adults show that they have similar effectiveness. The committee acknowledged that, according to patients and clinicians, limiting exposure to corticosteroids is an important aim of treatment. The committee concluded that it was appropriate to consider TWIST when making its recommendations.
The committee discussed the evidence for the clinical effectiveness of basiliximab. Three studies showed that basiliximab reduced acute rejection compared with treatment without induction (Cransberg et al. 2008; Offner et al. 2008 and the network meta-analysis of RCTs in adults). The committee acknowledged that, in 2 RCTs of children and young people, most outcome measures did not differ significantly between basiliximab and treatment without induction (Offner et al. 2008; Grenda et al. 2006). However, it noted that these trials may have been statistically underpowered to detect differences in graft loss and mortality. The committee was aware that TWIST showed increased height gain in children and young people having treatment with a regimen that included an interleukin‑2 receptor antagonist. The committee heard from clinical experts that basiliximab is currently used by several NHS paediatric transplant centres and is well tolerated by patients. The marketing authorisation for basiliximab states that it should be used with ciclosporin. However, the committee noted that UK paediatric transplant centres use basiliximab plus tacrolimus (rather than ciclosporin) and that this combination was used in 2 RCTs in children and young people (TWIST and Grenda at al. 2006). Taking all of the evidence into account, the committee concluded that basiliximab, plus a calcineurin inhibitor, is clinically effective in children and young people.
The committee discussed the evidence for the clinical effectiveness of r‑ATG, noting that the AG did not find any studies in children and young people that compared r‑ATG with the comparators in the scope. Sanofi's response to the assessment report identified 2 non-randomised studies in children and young people that compared r‑ATG with basiliximab or treatment without induction. These studies were excluded from the AG's review because the clinicians chose which maintenance therapy to use for each patient (Baron et al. 2008) and it was not clear what type of anti-human thymocyte immunoglobulin was used (Vilalta et al. 2009). The committee noted that Sanofi did not provide numerical results or detailed information about study design. The committee noted that the network meta-analysis of RCTs in adults showed that r‑ATG reduces acute rejection compared with treatment without induction. It heard from clinical experts that the treatment regimen with r‑ATG is longer and more complex than with basiliximab, and that adults having r‑ATG have more adverse events (including post-transplant lymphoproliferative disorder) than those having basiliximab. The committee noted that it had not been presented with evidence about adverse events in children and young people. It heard from clinical experts that it was very rare for children and young people in the UK to have r‑ATG. Overall, the committee concluded that there was not enough evidence to establish whether r‑ATG is clinically effective in children and young people.
The committee discussed the evidence for the clinical effectiveness of immediate-release tacrolimus. It noted that an RCT in children and young people (Trompeter et al. 2002), and the network meta-analysis of RCTs in adults, showed better graft function and lower incidence of acute rejection with immediate-release tacrolimus than with ciclosporin. The committee was aware that in Trompeter et al. tacrolimus was used with azathioprine, whereas TWIST used tacrolimus with mycophenolate mofetil. It heard from clinical experts that both of these regimens are currently used by NHS paediatric transplant centres and both are usually well tolerated by patients. The committee concluded that immediate-release tacrolimus is clinically effective in children and young people.
The committee discussed the evidence for the clinical effectiveness of prolonged-release tacrolimus, noting that the AG did not find any studies in children and young people that compared prolonged-release tacrolimus with the comparators in the scope. The submission from Astellas referred to non-randomised studies in children and young people, but these studies were excluded from the AG's review. The committee noted that Astellas did not provide numerical results or detailed information about study design. Astellas advised that additional studies were ongoing but it was not known when they would finish. The committee noted that the AG's meta-analysis of RCTs in adults found no significant differences between prolonged-release and immediate-release tacrolimus for mortality, graft loss, graft function and acute rejection. The committee also noted that the summary of product characteristics states that 'the safety and efficacy of Advagraf in children under 18 years of age have not yet been established'. The committee concluded that there was not enough evidence to establish whether prolonged-release tacrolimus is clinically effective in children and young people.
The committee considered whether prolonged-release tacrolimus could improve adherence to treatment. Patient experts advised that taking several tablets at set times each day was challenging, especially for young people who do not have a fixed daily routine, and regimens with fewer tablets may improve adherence. The committee acknowledged the importance of adherence to treatment in children and young people, and it was aware that poor adherence can cause graft loss. The committee referred to the Astellas submission for the related NICE technology appraisal for adults, which included adult studies suggesting that once-daily prolonged-release tacrolimus improves adherence, and may reduce graft loss, compared with twice-daily immediate-release tacrolimus. The committee was concerned that most of these studies measured self-reported adherence, which may be less accurate than electronic monitoring. The committee agreed that there was no robust evidence showing that improved adherence leads to lower rates of mortality, graft loss and acute rejection. It noted that switching from immediate-release to prolonged-release tacrolimus would remove only 1 tablet a day, and it was uncertain whether this would substantially improve adherence to the overall immunosuppressive regimen. The committee heard from a clinical expert that if a person forgot to take their prolonged-release tacrolimus tablet, this would leave them without tacrolimus for 24 hours. The expert advised that, potentially, this could have a greater impact than missing a tablet of immediate-release tacrolimus and being without the drug for 12 hours. The committee concluded that it had not been presented with evidence that prolonged-release tacrolimus improved adherence and clinical outcomes in children and young people.
The committee discussed the evidence for the clinical effectiveness of mycophenolate mofetil. It noted that a non-randomised study in children and young people found lower rates of graft loss with mycophenolate mofetil than with azathioprine (Staskewitz et al. 2001), but 3 other studies did not replicate this result. It noted that the network meta-analysis of RCTs in adults showed a lower incidence of acute rejection with mycophenolate mofetil than with azathioprine. The committee also noted that the TWIST regimen included mycophenolate mofetil. It heard from clinical experts that mycophenolate mofetil is currently used by several NHS paediatric transplant centres and is well tolerated by patients. The marketing authorisation for mycophenolate mofetil states that it should be used with ciclosporin. However, the committee noted that UK paediatric transplant centres use mycophenolate mofetil plus tacrolimus (rather than ciclosporin) and that this combination was used in the TWIST trial. The committee concluded that mycophenolate mofetil is clinically effective in children and young people.
The committee discussed the evidence for the clinical effectiveness of sirolimus. The only evidence in children and young people in the AG's review was a small non-randomised study that did not find any significant differences between sirolimus and immediate-release tacrolimus (Hymes et al. 2011). NICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents published in 2006 did not recommend sirolimus except when proven intolerance to calcineurin inhibitors (including nephrotoxicity) necessitates the complete withdrawal of these treatments. During the present appraisal, none of the submissions and none of the experts provided evidence that sirolimus would be clinically effective for children and young people who cannot tolerate calcineurin inhibitors. Clinical experts advised that some adults taking sirolimus have adverse events, and the committee noted that it had not been presented with data about adverse events in children and young people. The committee referred to the summary of product characteristics, which states that 'the safety and efficacy of Rapamune (sirolimus) in children and adolescents less than 18 years of age has not been established'. The committee heard from a clinical expert that, by adjusting the dose of mycophenolate mofetil, it may be possible to reduce or even stop calcineurin inhibitors for patients who cannot tolerate them. The committee considered that this strategy provided a treatment option for children and young people who cannot tolerate calcineurin inhibitors. Overall, the committee concluded that there was not enough evidence to establish whether sirolimus is clinically effective in children and young people.
The committee discussed the evidence for the clinical effectiveness of mycophenolate sodium, everolimus and belatacept, noting that the AG's review did not identify any studies of these technologies in children and young people. For all 3 drugs, the summary of product characteristics states that safety and efficacy in children and young people has not been established. The committee concluded that there was not enough evidence to establish whether mycophenolate sodium, everolimus and belatacept were clinically effective in children and young people.
# Cost effectiveness
The AG's systematic review did not find any published cost-effectiveness evidence that had emerged since the NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents. The AG developed a new model informed by the systematic review of clinical evidence. The committee noted that the AG's model included 2 types of analysis: using effectiveness estimates from RCTs in children and young people and using effectiveness estimates from a network meta-analysis of RCTs in adults. Given the limited number of clinical trials in children and young people, the committee agreed that it was reasonable to consider the results of both analyses. Similarly, given the lack of data on the health-related quality of life of children and young people with a kidney transplant, the committee agreed that it was reasonable to use utility values estimated from adults. The committee concluded that the AG's model provided a suitable basis for decision-making.
The committee discussed the economic model submitted by Astellas. It noted that the analysis did not follow the NICE scope (because it excluded ciclosporin as a comparator) and did not follow the NICE reference case (because it did not present incremental analyses and it used list prices for drugs that are in the Electronic Market Information Tool ). The Astellas analysis also did not include effectiveness estimates from studies in children and young people. The Astellas model assumed that prolonged-release tacrolimus improved adherence to treatment, which the committee had decided was not an appropriate assumption (see section 4.10). The committee concluded that it preferred to use the AG's model as the basis for its recommendations.
The committee noted Novartis' comments on the assessment report, advising that quality of life decreases as graft function declines. Novartis asked the AG to amend its model so that quality of life depends on graft function. The committee had discussed this issue in the related appraisal for adults. It agreed that the AG's model may underestimate total quality-adjusted life years (QALYs) for all treatments, because in the model quality of life is independent of graft function. The committee considered that the QALY underestimate would be greatest for treatments with the largest beneficial effect on graft function (such as belatacept with mycophenolate mofetil and tacrolimus with azathioprine), but that amending the model in the way suggested by Novartis was unlikely to substantially alter the incremental cost-effectiveness ratios (ICERs). The committee concluded that it was not necessary to amend the AG's model.
The committee discussed the drug costs used in the AG's model and agreed that it was appropriate to use prices from eMIT, if available, because these reflect the prices paid by the NHS (see NICE's guide to the methods of technology appraisal, section 5.5.2). The committee agreed that it was appropriate to consider the prices agreed with the Commercial Medicines Unit for Advagraf (prolonged-release tacrolimus capsules), Modigraf (tacrolimus granules for oral suspension) and Adoport (immediate-release tacrolimus) when making its recommendations, because these prices are nationally available to the NHS. The committee concluded that its preferred analysis used eMIT prices when available and the prices agreed with the Commercial Medicines Unit for Advagraf, Modigraf and Adoport.
## Basiliximab
The committee discussed the cost-effectiveness evidence for basiliximab, noting that all analyses assessed basiliximab plus a calcineurin inhibitor. The AG's model based on Grenda et al. (2006), and the model using data from adults, showed that treatment with basiliximab was cheaper and more effective than treatment without induction. For these 2 analyses, the incremental costs were between −£5,700 and −£11,100 and the incremental QALYs were between 0.12 and 0.18. However, the analysis based on Offner et al. (2008) gave the opposite result (treatment without induction cost £8,530 less and gained 0.55 more QALYs than basiliximab). The committee noted that the discrepancy may have arisen because the odds ratio for graft loss was more favourable to basiliximab in Grenda et al. than in Offner et al. The committee accepted that the Offner et al. trial was probably underpowered to detect differences in mortality and graft loss, meaning that the estimates of treatment effect were uncertain. It also recalled that the TWIST trial demonstrated the effectiveness of a regimen including an interleukin‑2 receptor antagonist, but the TWIST data were not included in the modelling. On balance, the committee accepted the results of the AG's analyses using Grenda et al. (2006) and the adult data, and concluded that basiliximab, when used as part of an initial immunosuppressive regimen that includes a calcineurin inhibitor, was a cost-effective option for preventing organ rejection in children and young people having a kidney transplant.
## Rabbit anti-human thymocyte immunoglobulin
The committee discussed the cost-effectiveness evidence for r‑ATG. The AG's model using data from adults showed that treatment with r‑ATG was dominated by treatment without induction (that is, r-ATG was more expensive and less effective; incremental costs between £6,020 and £9,920; incremental QALYs between −0.03 and −0.06). The model assumed that vials were shared so that there was no wastage, but the committee heard from clinical experts that vial sharing was unlikely to happen in practice. The committee noted that the modelled costs of r‑ATG would increase if wastage was included. Based on the evidence presented, the committee concluded that r‑ATG could not be considered to be a cost-effective option for preventing organ rejection in children and young people having a kidney transplant.
## Tacrolimus
The committee discussed the cost-effectiveness evidence for immediate-release tacrolimus. The AG's model using data from Trompeter et al. (2002), and the model using data from adults, showed that treatment with immediate-release tacrolimus was cheaper and more effective than treatment with ciclosporin. For these 2 analyses, the incremental costs were between −£19,500 and −£44,500; the incremental QALYs were between 0.11 and 0.55. The AG's model using data from adults also showed that treatment with immediate-release tacrolimus was cheaper and more effective than prolonged-release tacrolimus and sirolimus. The committee concluded that immediate-release tacrolimus was a cost-effective option for preventing organ rejection in children and young people having a kidney transplant and that treatment should normally be started with the least expensive product.
The committee discussed the cost-effectiveness evidence for prolonged-release tacrolimus. The AG's model using data from adults showed that treatment with prolonged-release tacrolimus was dominated by treatment with immediate-release tacrolimus (the incremental costs are confidential, the incremental QALYs were −0.05). Astellas' response to the assessment report consultation stated that adherence to treatment was better with prolonged-release tacrolimus and that this benefit was not included in the AG's model. The committee accepted that adherence to treatment was important for children and young people, and it was plausible that a regimen with fewer tablets could improve adherence. However, the committee agreed that it had not been presented with robust data to show better adherence with prolonged-release tacrolimus (see section 4.10) and, given the uncertainty in the evidence, it would not be appropriate to include better adherence in the model. Even taking into account the price agreed with the Commercial Medicines Unit, the committee did not consider prolonged-release tacrolimus to be cost effective, based on the evidence it had seen.
## Mycophenolic acid, everolimus, sirolimus and belatacept
The committee discussed the cost-effectiveness evidence for mycophenolate mofetil. The AG's model using data from adults showed that, in regimens that included ciclosporin, treatment with mycophenolate mofetil was cheaper and more effective than treatment with azathioprine (incremental costs between −£7,020 and −£10,200; incremental QALYs between 0.10 and 0.12). However, in regimens that included immediate-release tacrolimus, treatment with azathioprine was cheaper and more effective than treatment with mycophenolate mofetil (incremental costs between £4,730 and £6,450; incremental QALYs between −0.06 and −0.07). The committee noted that, in the regimens that included tacrolimus, there was only a small difference in QALYs gained between mycophenolate mofetil and azathioprine. It also noted that TWIST demonstrated the effectiveness of mycophenolate mofetil plus tacrolimus, but these data were not included in the model. The committee accepted that patients and clinicians preferred to have a choice of treatments, and the use of mycophenolate mofetil with tacrolimus was well established in the NHS. Taking all of the evidence into account, the committee concluded that mycophenolate mofetil was a cost-effective use of NHS resources for preventing organ rejection in children and young people having a kidney transplant and that treatment should normally be started with the least expensive product.
The committee discussed the cost-effectiveness evidence for mycophenolate sodium, everolimus, sirolimus and belatacept, noting that the AG's analyses used data from adults because no data from children and young people were available. It noted that, compared with mycophenolate mofetil, the ICER for mycophenolate sodium was £51,800 per QALY gained and the ICER for everolimus was £632,000 per QALY gained. Sirolimus was dominated by ciclosporin, immediate-release tacrolimus, azathioprine and mycophenolate mofetil. Belatacept had an ICER of £533,000 per QALY gained compared with immediate-release tacrolimus. The committee considered that, based on the evidence it had seen, mycophenolate sodium, everolimus, sirolimus and belatacept were not cost-effective options for preventing organ rejection in children and young people having a kidney transplant.
# Additional considerations
Following an appeal, the committee considered in detail the scope of the appraisal and the populations and clinical situations to which its recommendations would apply. It noted that its intention at the time of the first final appraisal determination was that the recommendations would apply to the initial treatments for children and young people having kidney transplants, and explained that this was based on its interpretation of the scope at that time and the evidence available from the systematic review and economic modelling. However, on further review the committee recognised that the scope included immunosuppressive treatments given immediately after transplant and at subsequent stages, in children and young people having a kidney transplant and in children and young people who have had a re-transplant in the last 2 years. The committee therefore acknowledged that the scope for this appraisal includes, in addition to initial treatments, subsequent therapies during the life of a graft and treatments for children and young people having second and subsequent transplants. The committee concluded that the scope was broader than its original recommendations, and discussed the recommendations it could make for these additional clinical scenarios.
The committee noted that the protocol and systematic review did not include the use of subsequent treatments during the life of the graft and only included studies in which randomisation took place at the time of the transplant. As a result, none of the studies considered during the appraisal investigated the effect of switching regimens during the life of a functioning graft. It also noted that the AG's economic model did not provide estimates of the cost effectiveness of switching to alternative interventions during the life of a graft. The committee considered that the systematic review and economic modelling were suitable to provide evidence on the initial treatments started around the time of transplant. The committee heard from the clinical experts that between 10% and 20% of people cannot continue on their initial immunosuppressive treatments. This may result from intolerance because of nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy associated with ciclosporin, tacrolimus, sirolimus or everolimus, for example. The clinical and patient experts highlighted the need for other treatments to be available to ensure continued immunosuppressive therapy for children and young people unable to continue taking their initial treatment. They also highlighted recent studies in adults, which showed that tacrolimus withdrawal should be avoided. They therefore emphasised the need for alternative immunosuppressants if tacrolimus has to be stopped. The committee was aware that returning to dialysis if a transplant fails can have a significant effect on quality of life as well as incurring costs to the NHS. It noted that sirolimus could be a cost-effective option for children and young people with calcineurin inhibitor nephrotoxicity because the only alternative would be dialysis, although it understood that sirolimus is currently routinely commissioned by NHS England for nephrotoxicity. The committee also heard that although thrombotic microangiopathy is rare, it results in graft loss and the person needing dialysis. The clinical experts noted that belatacept is the only immunosuppressant that can be given in these circumstances. The committee recognised the need for urgency in this situation and that individual funding requests might not be suitable or approved quickly enough. It also recognised that belatacept could potentially be a cost-effective use of NHS resources when thrombotic microangiopathy develops because the only alternative would be dialysis. The committee heard from the clinical experts and the AG that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review. The committee recalled that the limited analysis it had seen on treatment switching, submitted by Novartis, was highly uncertain. In addition, it heard that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the clinical and cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee considered that any outstanding clinical and commissioning issues would be better addressed through other routes, such as other NICE programmes or clinical commissioning policies. They noted that the consultees agreed with this approach. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment started around the time of kidney transplant.
The committee understood that the systematic review was not restricted to children and young people having their first kidney transplant, and heard from the AG that some of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.
The committee discussed providing immunosuppressive therapy for children and young people who cannot swallow capsules, or who cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin, as a potential equality issue. It heard from clinical experts that young children, and some children and young people with disabilities, cannot swallow capsules and need oral suspensions instead, and noted that people from some religious groups may need a gelatine-free formulation. The committee noted that oral suspensions and gelatine-free formulations are available for both immediate-release tacrolimus and mycophenolate mofetil, and that these products have marketing authorisations in the UK. The suspensions are more expensive than the capsules although there is a nationally available price agreed with the Commercial Medicines Unit for Modigraf (see section 3.10 and section 3.18). The committee recognised that, given its recommendations (see section 4.20 and section 4.22) covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might discriminate against young children, or against children and young people with protected characteristics. The committee reiterated that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product (see sections 4.20 and 4.22), but concluded that it could be started with an alternative dosage form if the least expensive product is not suitable. The committee agreed that Modigraf should be used only if the company provides Modigraf at the price agreed with the Commercial Medicines Unit.
# Summary of appraisal committee's key conclusions
TA482
Appraisal title: Immunosuppressive therapy for kidney transplant in children and young people
Section
Key conclusion
Basiliximab, immediate-release tacrolimus and mycophenolate mofetil are recommended as initial options to prevent organ rejection in children and young people having a kidney transplant.
The committee concluded that basiliximab is clinically effective, and provided more quality-adjusted life years (QALYs) at a lower cost than treatment without induction.
The committee concluded that immediate-release tacrolimus is clinically effective and provided more QALYs at a lower cost than ciclosporin.
The committee concluded that mycophenolate mofetil is clinically effective and it is cost effective in regimens that include ciclosporin. Although there was uncertainty about cost effectiveness in regimens that included tacrolimus, the committee was prepared to accept that mycophenolate mofetil was cost effective in both regimens.
Rabbit anti-human thymocyte immunoglobulin (r‑ATG), prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in children and young people having a kidney transplant.
The committee concluded that there was not enough evidence to establish whether these drugs are clinically effective in children and young people.
Using effectiveness estimates from adults, these drugs were either dominated (more expensive and less effective) or had an incremental cost-effectiveness ratio (ICER) above £50,000 per QALY gained.
The committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in children or young people who are, or become, unable to have the technologies recommended in sections 1.1 to 1.3 or azathioprine or corticosteroids (for example, because of contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes children and young people who:
are unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or
have a second or subsequent transplant, having previously found that 1 or more of the recommended initial treatments or standard treatments are clinically unsuitable, for example because of contraindications or intolerance.
Current practice
Clinical need of patients, including the availability of alternative treatments
People have different preferences for dosing regimens and side-effect profiles, so it is important to tailor treatment to each person. The committee concluded that patients and clinicians prefer to have a choice of immunosuppressive treatments.
The immunosuppressive regimens most commonly used by children and young people in the UK are: induction without antibodies, then maintenance therapy with tacrolimus and azathioprine; or basiliximab induction, then maintenance therapy using tacrolimus and mycophenolate mofetil.
The technologies
Proposed benefits of the technologies
How innovative are the technologies in their potential to make a significant and substantial impact on health-related benefits?
Quality of life is better with a transplant than while having dialysis, so the aim of treatment is to prolong survival of the transplanted kidney.
There were no specific committee considerations about innovation, because many of these technologies have been available for some time.
The committee considered whether prolonged-release tacrolimus could improve adherence to treatment. It concluded that it had not been presented with evidence that prolonged-release tacrolimus improved adherence and clinical outcomes.
What are the positions of the treatments in the pathway of care for the condition?
Immunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2 weeks around the time of transplant. Maintenance therapy starts immediately after transplant and continues for life. Basiliximab and r-ATG are induction therapies. The remaining 7 drugs in the appraisal are maintenance therapies.
Adverse reactions
Clinical experts advised that adults having r-ATG have more adverse events than those having basiliximab. The committee was not presented with evidence about adverse events associated with r-ATG in children and young people.
Clinical experts advised that some adults taking sirolimus have adverse events. The committee was not presented with data about adverse events associated with sirolimus in children and young people.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The assessment group (AG)'s systematic review found few studies in children and young people. The committee concluded that it should consider all of the evidence, including randomised and non-randomised studies in children and young people, and randomised controlled trials (RCTs) in adults.
Consultees and clinical experts advised that it was important to consider TWIST, an RCT that assessed the effectiveness of daclizumab induction then maintenance with immediate-release tacrolimus and mycophenolate mofetil, with corticosteroids that are withdrawn after 4 days. TWIST was not in the AG's review because daclizumab is not part of this appraisal (its marketing authorisation has been withdrawn). The committee heard from the clinical experts that basiliximab and daclizumab have the same mechanism of action and have similar effectiveness. The committee concluded that it was appropriate to consider TWIST when making its recommendations.
Relevance to general clinical practice in the NHS
The 3 RCTs in children and young people were likely to be generalisable to the NHS because the trials were done in Europe, the patient and donor characteristics were largely representative of people using the NHS, and the drug doses were similar to current recommendations. However, the evidence is quite old.
Uncertainties generated by the evidence
The AG did not find any studies of children and young people comparing the following drugs with the comparators in the scope: r‑ATG, prolonged-release tacrolimus, mycophenolate sodium, everolimus and belatacept. Only 1 small study of children and young people assessed sirolimus. Consequently, the committee was uncertain whether these drugs were clinically effective in children and young people.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
There were insufficient data to permit analyses of subgroups.
The committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. This may be because of intolerance or complications requiring withdrawal, for example. The committee heard that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review, and the limited analysis it had seen on treatment switching was highly uncertain. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment around the time of kidney transplant.
The committee understood that some of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
Three studies showed that basiliximab reduced acute rejection compared with no induction. Also, TWIST showed increased height gain in children and young people who had a regimen that included an interleukin‑2 receptor antagonist.
Immediate-release tacrolimus improved graft function and reduced the incidence of acute rejection compared with ciclosporin.
A non-randomised study in children and young people found lower rates of graft loss with mycophenolate mofetil than with azathioprine. The network meta-analysis of adult RCTs showed a lower incidence of acute rejection with mycophenolate mofetil than with azathioprine.
How has the new clinical evidence that has emerged since the original appraisal (TA99) influenced the current (preliminary) recommendations?
For children and young people, the new evidence includes the TWIST RCT, the Offner et al. RCT, and 6 non-randomised studies. There are also several new RCTs in adults.
TWIST and Offner et al. showed that an interleukin‑2 receptor antagonist (such as basiliximab) is clinically effective. The recommendation for basiliximab is consistent with NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents.
A non-randomised study in children and young people, and RCTs in adults, suggest that mycophenolate mofetil is clinically effective. In NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and young people, mycophenolate mofetil is recommended only for certain groups of patients.
Evidence for cost effectiveness
Availability and nature of evidence
The AG's analyses used effectiveness estimates from RCTs in children and young people and, separately, from adult RCTs. The committee agreed that it was reasonable to consider both analyses.
The model submitted by Astellas did not follow the NICE scope and NICE reference case, nor did it include effectiveness estimates from children and young people. The committee preferred to use the AG's model.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Offner et al. trial was probably underpowered to detect differences in mortality and graft loss, meaning that the estimates of treatment effect were uncertain.
Astellas stated that adherence to treatment was better with prolonged-release tacrolimus but this benefit was not included in the AG's model. The committee agreed that it had not been presented with robust data to show better adherence and, given the uncertainty in the evidence, it would not be appropriate to include better adherence in the model.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
Given the lack of data on the health-related quality of life of children and young people with a kidney transplant, the committee agreed that it was reasonable to use utility values from adults.
No significant and substantial health-related benefits have been identified that were not included in the economic model.
Are there specific groups of people for whom the technology is particularly cost effective?
There were insufficient data to permit analyses of subgroups.
The committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. The committee recalled that the limited analysis it had seen on treatment switching was highly uncertain, and was aware that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable.
The committee understood that the systematic review was not restricted to children and young people having their first kidney transplant, but there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.
What are the key drivers of cost effectiveness?
There were no specific committee considerations on the key drivers of cost effectiveness. The committee was aware that, in the AG's model, the differences between treatments in total costs were mainly because of differences in time having dialysis.
Most likely cost-effectiveness estimate (given as an ICER)
Basiliximab was cheaper and more effective than treatment without induction (incremental costs between −£5,700 and −£11,100; incremental QALYs between 0.12 and 0.18).
Immediate-release tacrolimus was cheaper and more effective than ciclosporin (incremental costs between −£19,500 and −£44,500; incremental QALYs between 0.11 and 0.55).
In regimens that included ciclosporin, mycophenolate mofetil was cheaper and more effective than azathioprine (incremental costs between −£7,020 and −£10,200; incremental QALYs between 0.10 and 0.12).
r-ATG was dominated by treatment without induction.
Prolonged-release tacrolimus was dominated by immediate-release tacrolimus.
Compared with mycophenolate mofetil, the ICER for mycophenolate sodium was £51,800 per QALY gained and the ICER for everolimus was £632,000 per QALY gained.
Sirolimus was dominated by all comparators.
Belatacept had an ICER of £533,000 per QALY gained compared with immediate-release tacrolimus.
How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA99) influenced the current (preliminary) recommendations?
The AG's review did not find any published cost-effectiveness evidence that had emerged since the NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and young people. Since that appraisal, some of the technologies have become available as generics. The AG developed a new model informed by the systematic review of clinical evidence.
Additional factors taken into account
Patient access schemes (PPRS)
None. Astellas advised that there are nationally available discounted contract prices for Modigraf (tacrolimus granules for oral suspension) and Advagraf (prolonged-release tacrolimus).
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee understood that young children, and some children and young people with disabilities, cannot swallow capsules. Also some cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin. It recognised that, given its recommendations covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might be discriminatory. The committee noted that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product. However, treatment could be started with an alternative dosage form if the least expensive product is not suitable.
|
{'Recommendations': "This guidance makes recommendations on using basiliximab, rabbit anti-human thymocyte immunoglobulin, tacrolimus (immediate-release and prolonged-release), mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept after kidney transplant in children and young people. The recommendations apply only to the initial immunosuppressive therapy (induction and maintenance therapy) started around the time of kidney transplant.\n\nIt was outside the scope of the appraisal to make recommendations on using azathioprine or corticosteroids after kidney transplant in children and young people.\n\nUnder an exceptional directive from the Department of Health, the appraisal committee was allowed to make recommendations about using drugs outside the terms of their marketing authorisations if there was compelling evidence of their safety and effectiveness.\n\nBasiliximab, when used as part of an immunosuppressive regimen that includes a calcineurin inhibitor, is recommended as an initial option to prevent organ rejection in children and young people having a kidney transplant.,\n\nImmediate-release tacrolimus, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in children and young people having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the child or young person is not able to swallow capsules or they are unable to have a particular ingredient because of allergy or religious reasons). Tacrolimus granules for oral suspension (Modigraf) should be used only if the company provides it at the same price or lower than that agreed with the Commercial Medicines Unit.\n\nMycophenolate mofetil, when used as part of an immunosuppressive regimen, is recommended as an initial option to prevent organ rejection in children and young people having a kidney transplant. Treatment should normally be started with the least expensive product. However, treatment can be started with an alternative dosage form if the least expensive product is not suitable (for example, if the child or young person is not able to swallow capsules or they are unable to have a particular ingredient because of allergy or religious reasons).,\n\nRabbit anti-human thymocyte immunoglobulin, prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in children and young people having a kidney transplant.\n\nThe committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in children or young people who are, or become, unable to have the technologies recommended in sections\xa01.1 to 1.3 or azathioprine and corticosteroids (for example, because of treatment failure, contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes children and young people who:\n\nare unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or\n\nhave a second or subsequent transplant, having previously found that 1\xa0or more of the recommended initial treatments or standard treatments are clinically unsuitable, for example because of treatment failure, contraindications or intolerance.\n\nThese recommendations are not intended to affect treatment with any of the technologies in this appraisal that was started in the NHS before this guidance was published. Children and young people having treatment outside these recommendations, or for whom the committee were unable to make a recommendation, may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician and the child or young person or their parents or carers.\n\n August 2017: the use of basiliximab (with tacrolimus) and mycophenolate mofetil (with tacrolimus) is outside the terms of the marketing authorisations for basiliximab and for mycophenolate mofetil. If these combinations are prescribed, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. For further information, see the General Medical Council's guidance on Good practice in prescribing and managing medicines and devices.\n\n The Department of Health has stated that the statutory funding requirement does not apply to drugs that are used outside the terms of their marketing authorisation.\n\n The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that to maintain therapeutic response when a patient is stabilised on a particular brand, oral tacrolimus products should be prescribed and dispensed by brand name only. If a prescriber considers that switching to a different brand of oral tacrolimus would be of benefit, the change requires careful supervision and therapeutic monitoring by an appropriate specialist. See the MHRA's advice on oral tacrolimus products.", 'Clinical need and practice': "Kidney transplant is used to treat established kidney failure, which is severe and irreversible impairment of kidney function. After a kidney transplant, immunosuppressive therapy is used to reduce the risk of rejection of the transplanted kidney (or 'graft') and prolong its survival. Between April 2016 and March 2017, 127\xa0kidney transplants were done in the UK for children and young people under 18\xa0years; 116 of these were in England.\n\nKidney transplant in children and young people can differ from adults in several important aspects including the cause of kidney failure, the pharmacokinetic properties of immunosuppressive therapies and how they are metabolised, the immune response after transplant, the measures of success of the transplant procedure, the susceptibility to post-transplant complications, and the degree of adherence to treatment.\n\nImmunosuppressive therapy aims to prevent acute rejection and optimise the function of the transplanted kidney, while minimising the adverse effects of immunosuppression (such as increased risk of infection, cancer, diabetes and cardiovascular disease). Immunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2\xa0weeks around the time of transplant and may include polyclonal or monoclonal antibodies. Maintenance therapy starts immediately after transplant and continues for life.\n\nNICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents was published in 2006. It recommended basiliximab, daclizumab, tacrolimus, mycophenolate mofetil and sirolimus, in certain circumstances, as options for immunosuppressive therapy for kidney transplant in children and young people. Since that appraisal, the marketing authorisation for daclizumab has been withdrawn, new technologies (rabbit anti-human thymocyte immunoglobulin, mycophenolate sodium, belatacept, a prolonged-release formulation of tacrolimus, and everolimus) have received marketing authorisations, but some of the marketing authorisations exclude children and young people. In addition, some of the technologies are available as generics.", 'The technologies': "# Induction therapy\n\n## Basiliximab\n\nBasiliximab (Simulect, Novartis Pharmaceuticals) is a monoclonal antibody that acts as an interleukin‑2 receptor antagonist. It has a marketing authorisation in the UK for the prophylaxis of acute organ rejection in people having a kidney transplant. The indication includes children and young people aged 1\xa0to\xa017\xa0years. The summary of product characteristics states that basiliximab is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression, in patients with panel-reactive antibodies less than 80%, or in a triple maintenance immunosuppressive regimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine or mycophenolate mofetil.\n\nBasiliximab is administered intravenously. In children and young people weighing less than 35\xa0kg, the recommended total dose is 20\xa0mg given in 2\xa0doses of 10\xa0mg each. In children and young people weighing 35\xa0kg or more, the recommended dose is 40\xa0mg given in 2\xa0doses of 20\xa0mg each.\n\nBasiliximab is available in 10‑mg and 20‑mg vials at a price of £758.69 and £842.38 respectively (excluding VAT; British national formulary [BNF] online [accessed August 2017]), equating to £1,517 per course of treatment for a patient weighing under 35\xa0kg and £1,685 for a patient weighing 35\xa0kg or more.\n\n## Rabbit anti-human thymocyte immunoglobulin\n\nRabbit anti-human thymocyte immunoglobulin (r‑ATG; Thymoglobuline, Sanofi) is made by injecting human thymus cells into rabbits. The drug contains immunoglobulins (antibodies) that attach to and destroy some of the cells of the immune system. It has a marketing authorisation in the UK for the prevention of graft rejection in kidney transplant. The summary of product characteristics states that it is usually used with other immunosuppressive drugs, but does not state whether the indication includes children and young people. It also advises that no recommendation about dosage for children and young people can be made, but that available information indicates that they do not need a different dosage to adults.\n\nr‑ATG is administered intravenously, at a dose of 1\xa0to 1.5\xa0mg/kg/day for 3\xa0to 9\xa0days after a kidney transplant (a cumulative dose of 3\xa0to 13.5\xa0mg/kg).\n\nr‑ATG is available in 25‑mg vials at a price of £158.77 (excluding VAT; BNF online [accessed August 2017]). The assessment group (AG) estimated that the cost of induction therapy with r‑ATG for a 10‑year‑old boy is £2,101 (assuming vials are shared so that there is no wastage).\n\n# Maintenance therapy\n\nSome drugs in this appraisal contain the same active ingredient but in different formulations. Tacrolimus is a calcineurin inhibitor and is available in an immediate-release formulation and a prolonged-release formulation. Mycophenolic acid is an antiproliferative agent. It is available as a prodrug called mycophenolate mofetil and a sodium salt called mycophenolate sodium.\n\n## Immediate-release tacrolimus\n\nBrands of immediate-release tacrolimus include Adoport (Sandoz), Capexion (Mylan), Modigraf (Astellas Pharma), Perixis (Accord Healthcare), Prograf (Astellas Pharma), Tacni (Teva) and Vivadex (Dexcel Pharma). All of these formulations have marketing authorisations in the UK for the prophylaxis of transplant rejection in people having a kidney transplant. Adoport, Capexion, Perixis, Prograf, Tacni and Vivadex are administered orally as capsules, twice a day. Prograf can also be administered intravenously. Modigraf consists of granules for oral suspension.\n\nFor all brands of immediate-release tacrolimus, the summary of product characteristics recommends an initial dose for children (age range not specified) of 0.3\xa0mg/kg/day orally or 0.075 to 0.100\xa0mg/kg/day intravenously and states that the dosage is usually reduced in the period after the transplant.\n\nModigraf (tacrolimus granules for oral suspension) is available in sachets of 0.2\xa0mg and 1\xa0mg at a price of £7.13\xa0per\xa0mg (excluding VAT; BNF online [accessed August 2017]). The company has agreed a nationally available price reduction for Modigraf with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. Tacrolimus immediate-release capsules are available as 0.5\xa0mg, 0.75\xa0mg, 1\xa0mg, 2\xa0mg and 5\xa0mg capsules (depending on the brand), the price of which varies by brand. The AG calculated that the average cost paid by the NHS for immediate-release tacrolimus capsules is £0.52\xa0per\xa0mg (excluding VAT; data from the Electronic Market Information Tool [eMIT], Commercial Medicines Unit). The AG estimated that the weekly cost of maintenance therapy with immediate-release tacrolimus capsules for a 10‑year‑old boy is £34. Adoport is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\n## Prolonged-release tacrolimus\n\nProlonged-release tacrolimus (Advagraf, Astellas Pharma) is administered orally as a capsule, once a day. It has a marketing authorisation in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. The summary of product characteristics recommends an initial dose for adults of 0.2 to 0.3\xa0mg/kg/day. The dosage is usually reduced in the period after the transplant. It also states that the safety and efficacy of prolonged-release tacrolimus in children under 18\xa0years have not yet been established and that limited data are available but no recommendation on dosage can be made.\n\nProlonged-release tacrolimus (Advagraf) is available as 0.5‑mg, 1‑mg, 3‑mg and 5‑mg capsules at a price of £1.07 to £1.43\xa0per\xa0mg (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with prolonged-release tacrolimus for a 10‑year‑old boy is £47 (using the list price and the dosage for adults). Advagraf is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\nAnother brand of prolonged-release tacrolimus, Envarsus (Chiesi) obtained a marketing authorisation for adults after the scope for this appraisal was finalised. The brand name Envarsus was not included in the AG's search for evidence and Chiesi was not asked to submit evidence for the appraisal.\n\n## Belatacept\n\nBelatacept (Nulojix, Bristol-Myers Squibb) is a soluble fusion protein designed to selectively inhibit CD28-mediated co‑stimulation of T‑cells. Belatacept, in combination with corticosteroids and a mycophenolic acid, has a marketing authorisation in the UK for prophylaxis of graft rejection in adults having a kidney transplant. The summary of product characteristics recommends that an interleukin‑2 receptor antagonist is added to this belatacept-based regimen. It also states that the safety and efficacy of belatacept in children and adolescents under 18\xa0years have not yet been established and that no data are available.\n\nBelatacept is administered intravenously. The recommended dose for adults is 10\xa0mg/kg on the day of the transplant, followed by 10\xa0mg/kg on days\xa05, 14, 28, 56 and\xa084 and then 5\xa0mg/kg every 4\xa0weeks from then on.\n\nBelatacept is available in 250‑mg vials at a price of £354.52 (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with belatacept for a 10‑year‑old boy is £56 (using the dosage for adults and assuming vials are shared so that there is no wastage).\n\n## Mycophenolate mofetil\n\nMycophenolate mofetil (generic) has a marketing authorisation in the UK, in combination with ciclosporin and corticosteroids, for the prophylaxis of acute transplant rejection in people having a kidney transplant. Mycophenolate mofetil can be administered orally (capsules or an oral suspension) or intravenously. The summary of product characteristics states that the recommended daily dose for children and young people (aged 2\xa0to 18\xa0years) is 1,200\xa0mg/m2 up to a maximum of 2\xa0g\xa0per\xa0day. See the summary of product characteristics for dosage recommendations for patients with a body surface area below 1.5\xa0m2.\n\nThe price of mycophenolate mofetil varies by brand. The oral suspension (CellCept) is available in 175‑ml containers of 1\xa0g/5\xa0ml suspension at a price of £3.29\xa0per\xa0g (excluding VAT; BNF online [accessed August 2017]). At the time of the initial committee discussion (July 2015), the average cost paid by the NHS for mycophenolate mofetil capsules was £0.38\xa0per\xa0g (excluding VAT; data from eMIT, Commercial Medicines Unit). The AG estimated that the weekly cost of maintenance therapy with mycophenolate mofetil capsules for a 10‑year‑old boy is between £1.74 and £3.48.\n\n## Mycophenolate sodium\n\nMycophenolate sodium (Myfortic, Novartis Pharmaceuticals), in combination with ciclosporin and corticosteroids, has a marketing authorisation in the UK for the prophylaxis of acute transplant rejection in adults having a kidney transplant. The summary of product characteristics states that insufficient data are available to support the efficacy and safety of mycophenolate sodium in children and adolescents. It is administered orally, at a recommended dose for adults of 1.44\xa0g\xa0per\xa0day.\n\nMycophenolate sodium is available in 180\xa0mg and 360\xa0mg tablets at a price of £4.48 per\xa0g (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with mycophenolate sodium for a 10‑year‑old boy is £50 (using the dosage for adults).\n\n## Sirolimus\n\nSirolimus (Rapamune, Pfizer) is an antiproliferative that blocks a protein called mammalian target of rapamycin (mTOR). It has a marketing authorisation in the UK for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. It is recommended to be used initially with ciclosporin and corticosteroids for 2\xa0to 3\xa0months, and may be continued only if ciclosporin can be progressively discontinued. The summary of product characteristics states that the safety and efficacy of sirolimus in children and adolescents under 18\xa0years have not been established.\n\nSirolimus is administered orally as a tablet or solution. The recommended dose for adults is 6\xa0mg initially, followed by 2\xa0mg\xa0per\xa0day for 2\xa0to 3\xa0months, then adjusted to obtain blood trough levels of 4 to 12\xa0nanograms/ml.\n\nSirolimus is available as 0.5\xa0mg, 1\xa0mg and 2\xa0mg tablets and a 1\xa0mg/ml oral solution, at a net price of £2.71 to £4.60\xa0per\xa0mg (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with sirolimus for a 10‑year‑old boy is £40 (using the dosage for adults).\n\n## Everolimus\n\nEverolimus (Certican, Novartis Pharmaceuticals) is an antiproliferative that blocks mTOR. It has a marketing authorisation for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. The summary of product characteristics states that everolimus should be used with ciclosporin and corticosteroids. Everolimus is administered orally as a tablet. The recommended initial dose for adults is 1.5\xa0mg/day. The summary of product characteristics states that there is insufficient experience to recommend the use of everolimus in children and adolescents.\n\nEverolimus is available in 0.25‑mg, 0.5‑mg and 0.75‑mg tablets at a net price of £9.90\xa0per\xa0mg (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with everolimus for a 10‑year‑old boy is £104 (using the dosage for adults).\n\nCosts for all of the technologies may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence from a number of sources. See the committee papers for full details of the evidence. The appraisal included 9\xa0drugs for immunosuppression after kidney transplant in children and young people. Basiliximab and rabbit anti-human thymocyte immunoglobulin (r‑ATG) are both induction therapies. The other drugs are maintenance therapies: immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept.\n\nThe appraisal committee reviewed the data available on the clinical and cost effectiveness of the technologies, having considered evidence on the nature of kidney transplant and organ rejection and the value placed on the benefits of immunosuppressive therapy by people with a kidney transplant, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee discussed aspects of immunosuppression that are especially important for children and young people. It heard from clinical experts that quality of life is better with a transplant than while having dialysis, so the aim of immunosuppression treatment is to prolong survival of the transplanted kidney (or 'graft'). The committee also heard that it is important to minimise the side effects of immunosuppressive therapies, such as reduced growth and an increased risk of new-onset diabetes. Several submissions from consultees advised that poor adherence (that is, not taking the prescribed medication) is a major cause of graft loss, especially in young people. The committee heard that different people have different preferences for dosing regimens and side-effect profiles, so it is important to tailor treatment to each person. The committee concluded that patients and clinicians prefer to have a choice of immunosuppressive treatments.\n\nThe committee discussed the immunosuppressive regimens currently used in the NHS for children and young people with a kidney transplant. The clinical experts advised that most paediatric transplant centres use:\n\ninduction without antibodies, then maintenance therapy with tacrolimus and azathioprine (based on Trompeter et al. 2002) or\n\nbasiliximab induction, then maintenance therapy with tacrolimus and mycophenolate mofetil (based on the TWIST trial, Grenda et al. 2010).The committee was aware that there are several brands of oral tacrolimus, and that inadvertent switching between products has been associated with toxicity and graft rejection. It heard from clinical experts that, to minimise the risk of accidental switching, UK clinicians follow advice from the Medicines and Healthcare products Regulatory Agency to prescribe and dispense oral tacrolimus products by brand name. It heard from clinical experts that, for the same reason, brand names are used when prescribing ciclosporin (although it was aware that tacrolimus, rather than ciclosporin, is the calcineurin inhibitor of first choice in UK paediatric transplant units). The committee concluded that the immunosuppressive regimens most commonly used by children and young people in the UK were: induction without antibodies then maintenance therapy with tacrolimus and azathioprine; or basiliximab induction then maintenance therapy with tacrolimus and mycophenolate mofetil.\n\nThe committee discussed the decision problem addressed by the assessment report. For induction therapy, the committee agreed that it was appropriate to compare the interventions with each other and against treatment without induction. For maintenance therapy, the committee agreed that it was appropriate to compare the interventions with each other and against ciclosporin and azathioprine. The committee noted that the final guidance would apply to the interventions listed in the scope and would not affect the current use in the NHS of azathioprine or corticosteroids, which were included as comparators only. A clinical expert suggested that the appraisal should also consider alemtuzumab as an induction therapy. The committee was aware that alemtuzumab does not have a marketing authorisation in the UK for immunosuppression after kidney transplant and is not routinely available for transplant patients (it is available on a 'named patient' basis). It heard from clinical experts that alemtuzumab is not currently used for children and young people having a kidney transplant in the UK. The committee agreed that alemtuzumab should not be included as either an intervention or a comparator. Regarding the population for the appraisal, the committee agreed with the assessment group (AG) that there were insufficient data to permit analyses of subgroups such as children and young people with different levels of immunological risk. The committee concluded that the assessment report included the appropriate population, interventions and comparators.\n\n# Clinical effectiveness\n\nThe AG's systematic review found 3\xa0randomised controlled trials (RCTs) and 10\xa0non-randomised studies of children and young people, of which 1\xa0RCT and 6\xa0non-randomised studies were identified in the updated systemic review for the current appraisal. The committee acknowledged that the number of studies in children and young people was low. It noted that the 3\xa0RCTs were likely to be generalisable to the NHS because the trials were done in Europe, the patient and donor characteristics were largely representative of people using the NHS, and the drug doses were similar to current recommendations. However, the committee acknowledged that the evidence is quite old. The AG did not find any studies of children and young people comparing the following drugs with the comparators in the scope: r-ATG, prolonged-release tacrolimus, mycophenolate sodium, everolimus and belatacept. In addition, only 1\xa0small study of children and young people assessed sirolimus. The clinical experts advised that, given the lack of evidence for children and young people, NHS practice is informed by evidence from adults and by clinical experience. The AG stated that data from the UK Transplant Registry provides useful information on graft and patient survival, but cannot be used to compare the effectiveness of different treatments. The committee concluded that it should consider all of the evidence about the effectiveness of immunosuppressive regimens, including randomised and non-randomised studies in children and young people and RCTs in adults.\n\nThe committee discussed whether it had considered all of the relevant evidence. Consultees and clinical experts advised that it was important to consider TWIST, an international RCT that recruited patients of 2 to 18\xa0years having a kidney transplant (Grenda et al. 2010). Patients randomised to the TWIST regimen (daclizumab induction, immediate-release tacrolimus and mycophenolate mofetil maintenance, with corticosteroids that are withdrawn after 4\xa0days) showed greater height gain after 6\xa0months than patients randomised to the comparator regimen (no induction, immediate-release tacrolimus and mycophenolate mofetil with long-term corticosteroids). The committee noted that the UK marketing authorisation for daclizumab has been withdrawn, so daclizumab was not included in this appraisal and as a result TWIST was not included in the assessment report. The committee heard from the clinical experts that basiliximab and daclizumab have the same mechanism of action (both are interleukin‑2 receptor antagonists) and trials in adults show that they have similar effectiveness. The committee acknowledged that, according to patients and clinicians, limiting exposure to corticosteroids is an important aim of treatment. The committee concluded that it was appropriate to consider TWIST when making its recommendations.\n\nThe committee discussed the evidence for the clinical effectiveness of basiliximab. Three studies showed that basiliximab reduced acute rejection compared with treatment without induction (Cransberg et al. 2008; Offner et al. 2008 and the network meta-analysis of RCTs in adults). The committee acknowledged that, in 2\xa0RCTs of children and young people, most outcome measures did not differ significantly between basiliximab and treatment without induction (Offner et al. 2008; Grenda et al. 2006). However, it noted that these trials may have been statistically underpowered to detect differences in graft loss and mortality. The committee was aware that TWIST showed increased height gain in children and young people having treatment with a regimen that included an interleukin‑2 receptor antagonist. The committee heard from clinical experts that basiliximab is currently used by several NHS paediatric transplant centres and is well tolerated by patients. The marketing authorisation for basiliximab states that it should be used with ciclosporin. However, the committee noted that UK paediatric transplant centres use basiliximab plus tacrolimus (rather than ciclosporin) and that this combination was used in 2\xa0RCTs in children and young people (TWIST and Grenda at al. 2006). Taking all of the evidence into account, the committee concluded that basiliximab, plus a calcineurin inhibitor, is clinically effective in children and young people.\n\nThe committee discussed the evidence for the clinical effectiveness of r‑ATG, noting that the AG did not find any studies in children and young people that compared r‑ATG with the comparators in the scope. Sanofi's response to the assessment report identified 2\xa0non-randomised studies in children and young people that compared r‑ATG with basiliximab or treatment without induction. These studies were excluded from the AG's review because the clinicians chose which maintenance therapy to use for each patient (Baron et al. 2008) and it was not clear what type of anti-human thymocyte immunoglobulin was used (Vilalta et al. 2009). The committee noted that Sanofi did not provide numerical results or detailed information about study design. The committee noted that the network meta-analysis of RCTs in adults showed that r‑ATG reduces acute rejection compared with treatment without induction. It heard from clinical experts that the treatment regimen with r‑ATG is longer and more complex than with basiliximab, and that adults having r‑ATG have more adverse events (including post-transplant lymphoproliferative disorder) than those having basiliximab. The committee noted that it had not been presented with evidence about adverse events in children and young people. It heard from clinical experts that it was very rare for children and young people in the UK to have r‑ATG. Overall, the committee concluded that there was not enough evidence to establish whether r‑ATG is clinically effective in children and young people.\n\nThe committee discussed the evidence for the clinical effectiveness of immediate-release tacrolimus. It noted that an RCT in children and young people (Trompeter et al. 2002), and the network meta-analysis of RCTs in adults, showed better graft function and lower incidence of acute rejection with immediate-release tacrolimus than with ciclosporin. The committee was aware that in Trompeter et al. tacrolimus was used with azathioprine, whereas TWIST used tacrolimus with mycophenolate mofetil. It heard from clinical experts that both of these regimens are currently used by NHS paediatric transplant centres and both are usually well tolerated by patients. The committee concluded that immediate-release tacrolimus is clinically effective in children and young people.\n\nThe committee discussed the evidence for the clinical effectiveness of prolonged-release tacrolimus, noting that the AG did not find any studies in children and young people that compared prolonged-release tacrolimus with the comparators in the scope. The submission from Astellas referred to non-randomised studies in children and young people, but these studies were excluded from the AG's review. The committee noted that Astellas did not provide numerical results or detailed information about study design. Astellas advised that additional studies were ongoing but it was not known when they would finish. The committee noted that the AG's meta-analysis of RCTs in adults found no significant differences between prolonged-release and immediate-release tacrolimus for mortality, graft loss, graft function and acute rejection. The committee also noted that the summary of product characteristics states that 'the safety and efficacy of Advagraf [prolonged-release tacrolimus] in children under 18\xa0years of age have not yet been established'. The committee concluded that there was not enough evidence to establish whether prolonged-release tacrolimus is clinically effective in children and young people.\n\nThe committee considered whether prolonged-release tacrolimus could improve adherence to treatment. Patient experts advised that taking several tablets at set times each day was challenging, especially for young people who do not have a fixed daily routine, and regimens with fewer tablets may improve adherence. The committee acknowledged the importance of adherence to treatment in children and young people, and it was aware that poor adherence can cause graft loss. The committee referred to the Astellas submission for the related NICE technology appraisal for adults, which included adult studies suggesting that once-daily prolonged-release tacrolimus improves adherence, and may reduce graft loss, compared with twice-daily immediate-release tacrolimus. The committee was concerned that most of these studies measured self-reported adherence, which may be less accurate than electronic monitoring. The committee agreed that there was no robust evidence showing that improved adherence leads to lower rates of mortality, graft loss and acute rejection. It noted that switching from immediate-release to prolonged-release tacrolimus would remove only 1\xa0tablet a day, and it was uncertain whether this would substantially improve adherence to the overall immunosuppressive regimen. The committee heard from a clinical expert that if a person forgot to take their prolonged-release tacrolimus tablet, this would leave them without tacrolimus for 24\xa0hours. The expert advised that, potentially, this could have a greater impact than missing a tablet of immediate-release tacrolimus and being without the drug for 12\xa0hours. The committee concluded that it had not been presented with evidence that prolonged-release tacrolimus improved adherence and clinical outcomes in children and young people.\n\nThe committee discussed the evidence for the clinical effectiveness of mycophenolate mofetil. It noted that a non-randomised study in children and young people found lower rates of graft loss with mycophenolate mofetil than with azathioprine (Staskewitz et al. 2001), but 3\xa0other studies did not replicate this result. It noted that the network meta-analysis of RCTs in adults showed a lower incidence of acute rejection with mycophenolate mofetil than with azathioprine. The committee also noted that the TWIST regimen included mycophenolate mofetil. It heard from clinical experts that mycophenolate mofetil is currently used by several NHS paediatric transplant centres and is well tolerated by patients. The marketing authorisation for mycophenolate mofetil states that it should be used with ciclosporin. However, the committee noted that UK paediatric transplant centres use mycophenolate mofetil plus tacrolimus (rather than ciclosporin) and that this combination was used in the TWIST trial. The committee concluded that mycophenolate mofetil is clinically effective in children and young people.\n\nThe committee discussed the evidence for the clinical effectiveness of sirolimus. The only evidence in children and young people in the AG's review was a small non-randomised study that did not find any significant differences between sirolimus and immediate-release tacrolimus (Hymes et al. 2011). NICE's technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents published in 2006 did not recommend sirolimus except when proven intolerance to calcineurin inhibitors (including nephrotoxicity) necessitates the complete withdrawal of these treatments. During the present appraisal, none of the submissions and none of the experts provided evidence that sirolimus would be clinically effective for children and young people who cannot tolerate calcineurin inhibitors. Clinical experts advised that some adults taking sirolimus have adverse events, and the committee noted that it had not been presented with data about adverse events in children and young people. The committee referred to the summary of product characteristics, which states that 'the safety and efficacy of Rapamune (sirolimus) in children and adolescents less than 18\xa0years of age has not been established'. The committee heard from a clinical expert that, by adjusting the dose of mycophenolate mofetil, it may be possible to reduce or even stop calcineurin inhibitors for patients who cannot tolerate them. The committee considered that this strategy provided a treatment option for children and young people who cannot tolerate calcineurin inhibitors. Overall, the committee concluded that there was not enough evidence to establish whether sirolimus is clinically effective in children and young people.\n\nThe committee discussed the evidence for the clinical effectiveness of mycophenolate sodium, everolimus and belatacept, noting that the AG's review did not identify any studies of these technologies in children and young people. For all 3\xa0drugs, the summary of product characteristics states that safety and efficacy in children and young people has not been established. The committee concluded that there was not enough evidence to establish whether mycophenolate sodium, everolimus and belatacept were clinically effective in children and young people.\n\n# Cost effectiveness\n\nThe AG's systematic review did not find any published cost-effectiveness evidence that had emerged since the NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents. The AG developed a new model informed by the systematic review of clinical evidence. The committee noted that the AG's model included 2\xa0types of analysis: using effectiveness estimates from RCTs in children and young people and using effectiveness estimates from a network meta-analysis of RCTs in adults. Given the limited number of clinical trials in children and young people, the committee agreed that it was reasonable to consider the results of both analyses. Similarly, given the lack of data on the health-related quality of life of children and young people with a kidney transplant, the committee agreed that it was reasonable to use utility values estimated from adults. The committee concluded that the AG's model provided a suitable basis for decision-making.\n\nThe committee discussed the economic model submitted by Astellas. It noted that the analysis did not follow the NICE scope (because it excluded ciclosporin as a comparator) and did not follow the NICE reference case (because it did not present incremental analyses and it used list prices for drugs that are in the Electronic Market Information Tool [eMIT]). The Astellas analysis also did not include effectiveness estimates from studies in children and young people. The Astellas model assumed that prolonged-release tacrolimus improved adherence to treatment, which the committee had decided was not an appropriate assumption (see section\xa04.10). The committee concluded that it preferred to use the AG's model as the basis for its recommendations.\n\nThe committee noted Novartis' comments on the assessment report, advising that quality of life decreases as graft function declines. Novartis asked the AG to amend its model so that quality of life depends on graft function. The committee had discussed this issue in the related appraisal for adults. It agreed that the AG's model may underestimate total quality-adjusted life years (QALYs) for all treatments, because in the model quality of life is independent of graft function. The committee considered that the QALY underestimate would be greatest for treatments with the largest beneficial effect on graft function (such as belatacept with mycophenolate mofetil and tacrolimus with azathioprine), but that amending the model in the way suggested by Novartis was unlikely to substantially alter the incremental cost-effectiveness ratios (ICERs). The committee concluded that it was not necessary to amend the AG's model.\n\nThe committee discussed the drug costs used in the AG's model and agreed that it was appropriate to use prices from eMIT, if available, because these reflect the prices paid by the NHS (see NICE's guide to the methods of technology appraisal, section\xa05.5.2). The committee agreed that it was appropriate to consider the prices agreed with the Commercial Medicines Unit for Advagraf (prolonged-release tacrolimus capsules), Modigraf (tacrolimus granules for oral suspension) and Adoport (immediate-release tacrolimus) when making its recommendations, because these prices are nationally available to the NHS. The committee concluded that its preferred analysis used eMIT prices when available and the prices agreed with the Commercial Medicines Unit for Advagraf, Modigraf and Adoport.\n\n## Basiliximab\n\nThe committee discussed the cost-effectiveness evidence for basiliximab, noting that all analyses assessed basiliximab plus a calcineurin inhibitor. The AG's model based on Grenda et al. (2006), and the model using data from adults, showed that treatment with basiliximab was cheaper and more effective than treatment without induction. For these 2\xa0analyses, the incremental costs were between −£5,700 and −£11,100 and the incremental QALYs were between 0.12 and 0.18. However, the analysis based on Offner et al. (2008) gave the opposite result (treatment without induction cost £8,530 less and gained 0.55 more QALYs than basiliximab). The committee noted that the discrepancy may have arisen because the odds ratio for graft loss was more favourable to basiliximab in Grenda et al. than in Offner et al. The committee accepted that the Offner et al. trial was probably underpowered to detect differences in mortality and graft loss, meaning that the estimates of treatment effect were uncertain. It also recalled that the TWIST trial demonstrated the effectiveness of a regimen including an interleukin‑2 receptor antagonist, but the TWIST data were not included in the modelling. On balance, the committee accepted the results of the AG's analyses using Grenda et al. (2006) and the adult data, and concluded that basiliximab, when used as part of an initial immunosuppressive regimen that includes a calcineurin inhibitor, was a cost-effective option for preventing organ rejection in children and young people having a kidney transplant.\n\n## Rabbit anti-human thymocyte immunoglobulin\n\nThe committee discussed the cost-effectiveness evidence for r‑ATG. The AG's model using data from adults showed that treatment with r‑ATG was dominated by treatment without induction (that is, r-ATG was more expensive and less effective; incremental costs between £6,020 and £9,920; incremental QALYs between −0.03 and −0.06). The model assumed that vials were shared so that there was no wastage, but the committee heard from clinical experts that vial sharing was unlikely to happen in practice. The committee noted that the modelled costs of r‑ATG would increase if wastage was included. Based on the evidence presented, the committee concluded that r‑ATG could not be considered to be a cost-effective option for preventing organ rejection in children and young people having a kidney transplant.\n\n## Tacrolimus\n\nThe committee discussed the cost-effectiveness evidence for immediate-release tacrolimus. The AG's model using data from Trompeter et al. (2002), and the model using data from adults, showed that treatment with immediate-release tacrolimus was cheaper and more effective than treatment with ciclosporin. For these 2\xa0analyses, the incremental costs were between −£19,500 and −£44,500; the incremental QALYs were between 0.11 and 0.55. The AG's model using data from adults also showed that treatment with immediate-release tacrolimus was cheaper and more effective than prolonged-release tacrolimus and sirolimus. The committee concluded that immediate-release tacrolimus was a cost-effective option for preventing organ rejection in children and young people having a kidney transplant and that treatment should normally be started with the least expensive product.\n\nThe committee discussed the cost-effectiveness evidence for prolonged-release tacrolimus. The AG's model using data from adults showed that treatment with prolonged-release tacrolimus was dominated by treatment with immediate-release tacrolimus (the incremental costs are confidential, the incremental QALYs were −0.05). Astellas' response to the assessment report consultation stated that adherence to treatment was better with prolonged-release tacrolimus and that this benefit was not included in the AG's model. The committee accepted that adherence to treatment was important for children and young people, and it was plausible that a regimen with fewer tablets could improve adherence. However, the committee agreed that it had not been presented with robust data to show better adherence with prolonged-release tacrolimus (see section\xa04.10) and, given the uncertainty in the evidence, it would not be appropriate to include better adherence in the model. Even taking into account the price agreed with the Commercial Medicines Unit, the committee did not consider prolonged-release tacrolimus to be cost effective, based on the evidence it had seen.\n\n## Mycophenolic acid, everolimus, sirolimus and belatacept\n\nThe committee discussed the cost-effectiveness evidence for mycophenolate mofetil. The AG's model using data from adults showed that, in regimens that included ciclosporin, treatment with mycophenolate mofetil was cheaper and more effective than treatment with azathioprine (incremental costs between −£7,020 and −£10,200; incremental QALYs between 0.10 and 0.12). However, in regimens that included immediate-release tacrolimus, treatment with azathioprine was cheaper and more effective than treatment with mycophenolate mofetil (incremental costs between £4,730 and £6,450; incremental QALYs between −0.06 and −0.07). The committee noted that, in the regimens that included tacrolimus, there was only a small difference in QALYs gained between mycophenolate mofetil and azathioprine. It also noted that TWIST demonstrated the effectiveness of mycophenolate mofetil plus tacrolimus, but these data were not included in the model. The committee accepted that patients and clinicians preferred to have a choice of treatments, and the use of mycophenolate mofetil with tacrolimus was well established in the NHS. Taking all of the evidence into account, the committee concluded that mycophenolate mofetil was a cost-effective use of NHS resources for preventing organ rejection in children and young people having a kidney transplant and that treatment should normally be started with the least expensive product.\n\nThe committee discussed the cost-effectiveness evidence for mycophenolate sodium, everolimus, sirolimus and belatacept, noting that the AG's analyses used data from adults because no data from children and young people were available. It noted that, compared with mycophenolate mofetil, the ICER for mycophenolate sodium was £51,800 per QALY gained and the ICER for everolimus was £632,000 per QALY gained. Sirolimus was dominated by ciclosporin, immediate-release tacrolimus, azathioprine and mycophenolate mofetil. Belatacept had an ICER of £533,000 per QALY gained compared with immediate-release tacrolimus. The committee considered that, based on the evidence it had seen, mycophenolate sodium, everolimus, sirolimus and belatacept were not cost-effective options for preventing organ rejection in children and young people having a kidney transplant.\n\n# Additional considerations\n\nFollowing an appeal, the committee considered in detail the scope of the appraisal and the populations and clinical situations to which its recommendations would apply. It noted that its intention at the time of the first final appraisal determination was that the recommendations would apply to the initial treatments for children and young people having kidney transplants, and explained that this was based on its interpretation of the scope at that time and the evidence available from the systematic review and economic modelling. However, on further review the committee recognised that the scope included immunosuppressive treatments given immediately after transplant and at subsequent stages, in children and young people having a kidney transplant and in children and young people who have had a re-transplant in the last 2\xa0years. The committee therefore acknowledged that the scope for this appraisal includes, in addition to initial treatments, subsequent therapies during the life of a graft and treatments for children and young people having second and subsequent transplants. The committee concluded that the scope was broader than its original recommendations, and discussed the recommendations it could make for these additional clinical scenarios.\n\nThe committee noted that the protocol and systematic review did not include the use of subsequent treatments during the life of the graft and only included studies in which randomisation took place at the time of the transplant. As a result, none of the studies considered during the appraisal investigated the effect of switching regimens during the life of a functioning graft. It also noted that the AG's economic model did not provide estimates of the cost effectiveness of switching to alternative interventions during the life of a graft. The committee considered that the systematic review and economic modelling were suitable to provide evidence on the initial treatments started around the time of transplant. The committee heard from the clinical experts that between 10% and 20% of people cannot continue on their initial immunosuppressive treatments. This may result from intolerance because of nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy associated with ciclosporin, tacrolimus, sirolimus or everolimus, for example. The clinical and patient experts highlighted the need for other treatments to be available to ensure continued immunosuppressive therapy for children and young people unable to continue taking their initial treatment. They also highlighted recent studies in adults, which showed that tacrolimus withdrawal should be avoided. They therefore emphasised the need for alternative immunosuppressants if tacrolimus has to be stopped. The committee was aware that returning to dialysis if a transplant fails can have a significant effect on quality of life as well as incurring costs to the NHS. It noted that sirolimus could be a cost-effective option for children and young people with calcineurin inhibitor nephrotoxicity because the only alternative would be dialysis, although it understood that sirolimus is currently routinely commissioned by NHS England for nephrotoxicity. The committee also heard that although thrombotic microangiopathy is rare, it results in graft loss and the person needing dialysis. The clinical experts noted that belatacept is the only immunosuppressant that can be given in these circumstances. The committee recognised the need for urgency in this situation and that individual funding requests might not be suitable or approved quickly enough. It also recognised that belatacept could potentially be a cost-effective use of NHS resources when thrombotic microangiopathy develops because the only alternative would be dialysis. The committee heard from the clinical experts and the AG that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review. The committee recalled that the limited analysis it had seen on treatment switching, submitted by Novartis, was highly uncertain. In addition, it heard that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the clinical and cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee considered that any outstanding clinical and commissioning issues would be better addressed through other routes, such as other NICE programmes or clinical commissioning policies. They noted that the consultees agreed with this approach. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment started around the time of kidney transplant.\n\nThe committee understood that the systematic review was not restricted to children and young people having their first kidney transplant, and heard from the AG that some of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.\n\nThe committee discussed providing immunosuppressive therapy for children and young people who cannot swallow capsules, or who cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin, as a potential equality issue. It heard from clinical experts that young children, and some children and young people with disabilities, cannot swallow capsules and need oral suspensions instead, and noted that people from some religious groups may need a gelatine-free formulation. The committee noted that oral suspensions and gelatine-free formulations are available for both immediate-release tacrolimus and mycophenolate mofetil, and that these products have marketing authorisations in the UK. The suspensions are more expensive than the capsules although there is a nationally available price agreed with the Commercial Medicines Unit for Modigraf (see section\xa03.10 and section\xa03.18). The committee recognised that, given its recommendations (see section\xa04.20 and section\xa04.22) covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might discriminate against young children, or against children and young people with protected characteristics. The committee reiterated that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product (see sections\xa04.20 and 4.22), but concluded that it could be started with an alternative dosage form if the least expensive product is not suitable. The committee agreed that Modigraf should be used only if the company provides Modigraf at the price agreed with the Commercial Medicines Unit.\n\n# Summary of appraisal committee's key conclusions\n\nTA482\n\nAppraisal title: Immunosuppressive therapy for kidney transplant in children and young people\n\nSection\n\nKey conclusion\n\nBasiliximab, immediate-release tacrolimus and mycophenolate mofetil are recommended as initial options to prevent organ rejection in children and young people having a kidney transplant.\n\nThe committee concluded that basiliximab is clinically effective, and provided more quality-adjusted life years (QALYs) at a lower cost than treatment without induction.\n\nThe committee concluded that immediate-release tacrolimus is clinically effective and provided more QALYs at a lower cost than ciclosporin.\n\nThe committee concluded that mycophenolate mofetil is clinically effective and it is cost effective in regimens that include ciclosporin. Although there was uncertainty about cost effectiveness in regimens that included tacrolimus, the committee was prepared to accept that mycophenolate mofetil was cost effective in both regimens.\n\n–1.3, 4.6, 4.18, 4.8, 4.20, 4.11, 4.22\n\nRabbit anti-human thymocyte immunoglobulin (r‑ATG), prolonged-release tacrolimus, mycophenolate sodium, sirolimus, everolimus and belatacept are not recommended as initial treatments to prevent organ rejection in children and young people having a kidney transplant.\n\nThe committee concluded that there was not enough evidence to establish whether these drugs are clinically effective in children and young people.\n\nUsing effectiveness estimates from adults, these drugs were either dominated (more expensive and less effective) or had an incremental cost-effectiveness ratio (ICER) above £50,000 per QALY gained.\n\nThe committee was unable to make recommendations on any of the technologies considered in this appraisal as options for preventing organ rejection in children or young people who are, or become, unable to have the technologies recommended in sections\xa01.1 to 1.3 or azathioprine or corticosteroids (for example, because of contraindications, or intolerance such as nephrotoxicity associated with calcineurin inhibitors, or thrombotic microangiopathy). This includes children and young people who:\n\nare unable to continue having their initial therapy and need to switch to another therapy during the life of their graft or\n\nhave a second or subsequent transplant, having previously found that 1 or more of the recommended initial treatments or standard treatments are clinically unsuitable, for example because of contraindications or intolerance.\n\n, 4.7, 4.9, 4.12, 4.13, 4.19, 4.21, 4.23, 1.5\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nPeople have different preferences for dosing regimens and side-effect profiles, so it is important to tailor treatment to each person. The committee concluded that patients and clinicians prefer to have a choice of immunosuppressive treatments.\n\nThe immunosuppressive regimens most commonly used by children and young people in the UK are: induction without antibodies, then maintenance therapy with tacrolimus and azathioprine; or basiliximab induction, then maintenance therapy using tacrolimus and mycophenolate mofetil.\n\n, 4.2\n\nThe technologies\n\nProposed benefits of the technologies\n\nHow innovative are the technologies in their potential to make a significant and substantial impact on health-related benefits?\n\nQuality of life is better with a transplant than while having dialysis, so the aim of treatment is to prolong survival of the transplanted kidney.\n\nThere were no specific committee considerations about innovation, because many of these technologies have been available for some time.\n\nThe committee considered whether prolonged-release tacrolimus could improve adherence to treatment. It concluded that it had not been presented with evidence that prolonged-release tacrolimus improved adherence and clinical outcomes.\n\n, 4.10\n\nWhat are the positions of the treatments in the pathway of care for the condition?\n\nImmunosuppressive therapy can be categorised as induction therapy or maintenance therapy. Induction therapy is an intensive immunosuppression regimen that is used for up to 2\xa0weeks around the time of transplant. Maintenance therapy starts immediately after transplant and continues for life. Basiliximab and r-ATG are induction therapies. The remaining 7\xa0drugs in the appraisal are maintenance therapies.\n\n\n\nAdverse reactions\n\nClinical experts advised that adults having r-ATG have more adverse events than those having basiliximab. The committee was not presented with evidence about adverse events associated with r-ATG in children and young people.\n\nClinical experts advised that some adults taking sirolimus have adverse events. The committee was not presented with data about adverse events associated with sirolimus in children and young people.\n\n, 4.12\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe assessment group (AG)'s systematic review found few studies in children and young people. The committee concluded that it should consider all of the evidence, including randomised and non-randomised studies in children and young people, and randomised controlled trials (RCTs) in adults.\n\nConsultees and clinical experts advised that it was important to consider TWIST, an RCT that assessed the effectiveness of daclizumab induction then maintenance with immediate-release tacrolimus and mycophenolate mofetil, with corticosteroids that are withdrawn after 4\xa0days. TWIST was not in the AG's review because daclizumab is not part of this appraisal (its marketing authorisation has been withdrawn). The committee heard from the clinical experts that basiliximab and daclizumab have the same mechanism of action and have similar effectiveness. The committee concluded that it was appropriate to consider TWIST when making its recommendations.\n\n, 4.5\n\nRelevance to general clinical practice in the NHS\n\nThe 3\xa0RCTs in children and young people were likely to be generalisable to the NHS because the trials were done in Europe, the patient and donor characteristics were largely representative of people using the NHS, and the drug doses were similar to current recommendations. However, the evidence is quite old.\n\n\n\nUncertainties generated by the evidence\n\nThe AG did not find any studies of children and young people comparing the following drugs with the comparators in the scope: r‑ATG, prolonged-release tacrolimus, mycophenolate sodium, everolimus and belatacept. Only 1\xa0small study of children and young people assessed sirolimus. Consequently, the committee was uncertain whether these drugs were clinically effective in children and young people.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThere were insufficient data to permit analyses of subgroups.\n\nThe committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. This may be because of intolerance or complications requiring withdrawal, for example. The committee heard that there is some limited evidence for treatment switching, but was aware that such evidence had not been searched for in a systematic review, and the limited analysis it had seen on treatment switching was highly uncertain. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable, and that the recommendations only apply to the initial treatment around the time of kidney transplant.\n\nThe committee understood that some of the trials included in the clinical and economic evaluation included people who were having a second or subsequent transplant. However, it recalled that there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.\n\n, 4.25, 4.26\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThree studies showed that basiliximab reduced acute rejection compared with no induction. Also, TWIST showed increased height gain in children and young people who had a regimen that included an interleukin‑2 receptor antagonist.\n\nImmediate-release tacrolimus improved graft function and reduced the incidence of acute rejection compared with ciclosporin.\n\nA non-randomised study in children and young people found lower rates of graft loss with mycophenolate mofetil than with azathioprine. The network meta-analysis of adult RCTs showed a lower incidence of acute rejection with mycophenolate mofetil than with azathioprine.\n\n, 4.8, 4.11\n\nHow has the new clinical evidence that has emerged since the original appraisal (TA99) influenced the current (preliminary) recommendations?\n\nFor children and young people, the new evidence includes the TWIST RCT, the Offner et al. RCT, and 6\xa0non-randomised studies. There are also several new RCTs in adults.\n\nTWIST and Offner et al. showed that an interleukin‑2 receptor antagonist (such as basiliximab) is clinically effective. The recommendation for basiliximab is consistent with NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and adolescents.\n\nA non-randomised study in children and young people, and RCTs in adults, suggest that mycophenolate mofetil is clinically effective. In NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and young people, mycophenolate mofetil is recommended only for certain groups of patients.\n\n–4.6, 4.11\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe AG's analyses used effectiveness estimates from RCTs in children and young people and, separately, from adult RCTs. The committee agreed that it was reasonable to consider both analyses.\n\nThe model submitted by Astellas did not follow the NICE scope and NICE reference case, nor did it include effectiveness estimates from children and young people. The committee preferred to use the AG's model.\n\n, 4.15\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Offner et al. trial was probably underpowered to detect differences in mortality and graft loss, meaning that the estimates of treatment effect were uncertain.\n\nAstellas stated that adherence to treatment was better with prolonged-release tacrolimus but this benefit was not included in the AG's model. The committee agreed that it had not been presented with robust data to show better adherence and, given the uncertainty in the evidence, it would not be appropriate to include better adherence in the model.\n\n, 4.21, 4.10\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nGiven the lack of data on the health-related quality of life of children and young people with a kidney transplant, the committee agreed that it was reasonable to use utility values from adults.\n\nNo significant and substantial health-related benefits have been identified that were not included in the economic model.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThere were insufficient data to permit analyses of subgroups.\n\nThe committee heard from the clinical experts that 10 to 20% of people cannot continue on their initial immunosuppressive treatments. The committee recalled that the limited analysis it had seen on treatment switching was highly uncertain, and was aware that it would be difficult to obtain sufficient robust evidence to inform a full consideration of the cost effectiveness of all possible treatment switching scenarios and permutations, within the context of a technology appraisal. The committee concluded that it was unable to make recommendations on the technologies as subsequent treatments during the life of a graft when initial therapies become unsuitable.\n\nThe committee understood that the systematic review was not restricted to children and young people having their first kidney transplant, but there was insufficient evidence for subgroup analysis. The committee concluded that it was unable to make recommendations on these technologies for second or subsequent transplants when particular therapies had previously been found to be inappropriate.\n\n, 4.25, 4.26\n\nWhat are the key drivers of cost effectiveness?\n\nThere were no specific committee considerations on the key drivers of cost effectiveness. The committee was aware that, in the AG's model, the differences between treatments in total costs were mainly because of differences in time having dialysis.\n\n–\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nBasiliximab was cheaper and more effective than treatment without induction (incremental costs between −£5,700 and −£11,100; incremental QALYs between 0.12 and 0.18).\n\nImmediate-release tacrolimus was cheaper and more effective than ciclosporin (incremental costs between −£19,500 and −£44,500; incremental QALYs between 0.11 and 0.55).\n\nIn regimens that included ciclosporin, mycophenolate mofetil was cheaper and more effective than azathioprine (incremental costs between −£7,020 and −£10,200; incremental QALYs between 0.10 and 0.12).\n\nr-ATG was dominated by treatment without induction.\n\nProlonged-release tacrolimus was dominated by immediate-release tacrolimus.\n\nCompared with mycophenolate mofetil, the ICER for mycophenolate sodium was £51,800 per QALY gained and the ICER for everolimus was £632,000 per QALY gained.\n\nSirolimus was dominated by all comparators.\n\nBelatacept had an ICER of £533,000 per QALY gained compared with immediate-release tacrolimus.\n\n, 4.20, 4.22, 4.19, 4.21, 4.23\n\nHow has the new cost-effectiveness evidence that has emerged since the original appraisal (TA99) influenced the current (preliminary) recommendations?\n\nThe AG's review did not find any published cost-effectiveness evidence that had emerged since the NICE technology appraisal guidance on immunosuppressive therapy for kidney transplantation in children and young people. Since that appraisal, some of the technologies have become available as generics. The AG developed a new model informed by the systematic review of clinical evidence.\n\n, 4.14\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNone. Astellas advised that there are nationally available discounted contract prices for Modigraf (tacrolimus granules for oral suspension) and Advagraf (prolonged-release tacrolimus).\n\n, 3.12\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee understood that young children, and some children and young people with disabilities, cannot swallow capsules. Also some cannot take a particular preparation of tacrolimus or mycophenolate mofetil for religious reasons because it contains gelatine of animal origin. It recognised that, given its recommendations covered all formulations of immediate-release tacrolimus and mycophenolate mofetil, it might be considered unfair to allow access to only the least expensive formulations because people who cannot take a particular formulation as a result of a disability or other characteristic protected under equality legislation would then be unable to have the recommended treatments. It noted that restricting access in this way might be discriminatory. The committee noted that, when prescribing immediate-release tacrolimus or mycophenolate mofetil, treatment should normally be started with the least expensive product. However, treatment could be started with an alternative dosage form if the least expensive product is not suitable.\n\n"}
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https://www.nice.org.uk/guidance/ta482
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Evidence-based recommendations on immunosuppressive therapies for preventing kidney rejection in children and young people. The therapies are basiliximab (Simulect), immediate-release tacrolimus (Adoport, Capexion, Modigraf, Prograf, Tacni, Vivadex), mycophenolate mofetil (Cellcept and non-branded versions), rabbit anti-human thymocyte immunoglobulin (Thymoglobuline), prolonged-release tacrolimus (Advagraf, Envarsus), mycophenolate sodium (Myfortic, Ceptava), sirolimus (Rapamune), everolimus (Certican) and belatacept (Nulojix).
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c44f1df10d3b66fa55c2fc0a7b32eafc86a07222
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nice
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Child maltreatment: when to suspect maltreatment in under 18s
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Child maltreatment: when to suspect maltreatment in under 18s
This guideline covers the signs of possible child maltreatment in children and young people aged under 18 years. It aims to raise awareness and help health professionals who are not child protection specialists to identify the features of physical, sexual and emotional abuse, neglect and fabricated or induced illness.
# Introduction
This guidance provides a summary of clinical features associated with child maltreatment (alerting features) that may be observed when a child presents to healthcare professionals. Its purpose is to raise awareness and help healthcare professionals who are not specialists in child protection to identify children who may be being maltreated. It does not give healthcare professionals recommendations on how to diagnose, confirm or disprove child maltreatment.
Children may present with both physical and psychological symptoms and signs that constitute alerting features of one or more types of maltreatment, and maltreatment may be observed in parent– or carer–child interactions.
There is strong evidence of the harmful short- and long-term effects of child maltreatment. All aspects of the child's health, development and wellbeing can be affected. The effects of child maltreatment can last throughout adulthood and include anxiety, depression, substance misuse, and self-destructive, oppositional or antisocial behaviours. In adulthood, there may be difficulties in forming or sustaining close relationships, sustaining employment and parenting capacity. Physical abuse may result in lifelong disability or physical scarring and harmful psychological consequences, and may even be fatal. The National Service Framework (NSF) for Children, Young People and Maternity Services for England states 'The high cost of abuse and neglect both to individuals (and to society) underpins the duty on all agencies to be proactive in safeguarding children.'
# Definitions
## Child maltreatment
Child maltreatment includes neglect, physical, sexual and emotional abuse, and fabricated or induced illness. This guidance uses the definitions of child maltreatment as set out in the Department for Education's statutory guidance on inter-agency working to safeguard and promote the welfare of children. This also includes an appendix of further relevant guidance from the Department for Education, other government departments and agencies, and external organisations.
## Age groups
This guidance uses the following terms to describe children of different ages:
infant (aged under 1 year)
child (aged under 13 years)
young person (aged 13–17 years).
Exclusions from the guideline
The following topics were outside the scope of this guideline and have therefore not been covered:
risk factors for child maltreatment, which are well recognised. Examples include
parental or carer drug or alcohol misuse
parental or carer mental health problems
intra-familial violence or history of violent offending
previous child maltreatment in members of the family
known maltreatment of animals by the parent or carer
vulnerable and unsupported parents or carers
pre-existing disability in the child
protection of the unborn child
children who have died as a result of child maltreatment. It should be noted that there are special procedures that should be followed when a child dies unexpectedly.
diagnostic assessment and investigations (for example, X-rays)
treatment and care of the child if maltreatment is suspected
how healthcare professionals should proceed once they suspect maltreatment
healthcare professionals' competency, training and behaviour
service organisation
child protection procedures
communication of suspicions to parents or carers, or the child or young person
education and information for parents or carers, or the child or young person.
Communicating with and about the child or young person
Good communication between healthcare professionals and the child or young person, as well as with their families and carers, is essential. Communication should take into account additional needs such as physical, sensory or learning disabilities, or the inability to speak or read English. Consideration should be given to cultural needs of children or young people and their families and carers.
If healthcare professionals have concerns about sharing information with others, they should obtain advice from named or designated professionals for safeguarding children. If concerns are based on information given by a child, healthcare professionals should explain to the child when they are unable to maintain confidentiality, explore the child's concerns about sharing this information and reassure the child that they will continue to be kept informed about what is happening. When gathering collateral information from other health disciplines and other agencies, professionals need to use judgement about whether to explain to the family the need to gather this information for the overall assessment of the child.
Potential obstacles to recognising and responding to possible maltreatment
Healthcare professionals may come across many different obstacles in the process of identifying maltreatment but these should not prevent them from following the appropriate course of action to prevent further harm to the child or young person. Examples of potential obstacles include the following:
Concern about missing a treatable disorder.
Healthcare professionals are used to working with parents and carers in the care of children and fear losing a positive relationship with a family already under their care.
Discomfort of disbelieving, thinking ill of, suspecting or wrongly blaming a parent or carer.
Divided duties to adult and child patients and breaching confidentiality.
An understanding of the reasons why the maltreatment might have occurred, and that there was no intention to harm the child.
Losing control over the child protection process and doubts about its benefits.
Stress.
Personal safety.
Fear of complaints.# Recommendations
The following guidance is based on the best available evidence. The full guidance gives details of the methods and the evidence used to develop the guidance.
# Definitions of terms used in this guidance
The alerting features in this guidance have been divided into two, according to the level of concern, with recommendations to either 'consider' or 'suspect' maltreatment.
## Consider
For the purposes of this guidance, to consider child maltreatment means that maltreatment is one possible explanation for the alerting feature or is included in the differential diagnosis.
## Multi-agency safeguarding arrangements
The responsibility for these arrangements is with 3 safeguarding partners: the local authority, clinical commissioning group for an area, and the chief officer of police for a police area. They have a shared and equal duty to work together to safeguard and promote the welfare of all children in a local area.
## Suspect
For the purposes of this guidance, to suspect child maltreatment means a serious level of concern about the possibility of child maltreatment but is not proof of it.
## Unsuitable explanation
For the purposes of this guidance, an unsuitable explanation for an injury or presentation is one that is implausible, inadequate or inconsistent:
with the child or young person's
presentation
normal activities
existing medical condition
age or developmental stage
account compared to that given by parent and carers
between parents or carers
between accounts over time.
An explanation based on cultural practice is also unsuitable because this should not justify hurting a child or young person.
# Using this guidance
If a healthcare professional encounters an alerting feature of possible child maltreatment that prompts them to consider, suspect or exclude child maltreatment as a possible explanation, it is good practice to follow the process outlined in 1–5 below:
## . Listen and observe
Identifying or excluding child maltreatment involves piecing together information from many sources so that the whole picture of the child or young person is taken into account. This information may come from different sources and agencies and includes:
any history that is given
report of maltreatment, or disclosure from a child or young person or third party. It is standard practice to refer to children's social services when a child or young person makes a disclosure of maltreatment (even though it may not be precise in every detail).
child's appearance
child's behaviour or demeanour
symptom
physical sign
result of an investigation
interaction between the parent or carer and child or young person.
## . Seek an explanation
Seek an explanation for any injury or presentation from both the parent or carer and the child or young person in an open and non-judgemental manner.
Alerting features of maltreatment in children with disabilities may also be features of the disability, making identification of maltreatment more difficult.Healthcare professionals may need to seek appropriate expertise if they are concerned about a child or young person with a disability.
## . Record
Record in the child or young person's clinical record exactly what is observed and heard from whom and when.
Record why this is of concern.
At this point the healthcare professional may consider, suspect or exclude child maltreatment from the differential diagnosis.
## . Consider, suspect or exclude maltreatment
At any stage during the process of considering maltreatment the level of concern may change and lead to exclude or suspect maltreatment.
When hearing about or observing an alerting feature in the guidance:
look for other alerting features of maltreatment in the child or young person's history, presentation or parent– or carer–interaction with the child or young person now or in the past. Then do one or more of the following:
Discuss your concerns with a more experienced colleague, a community paediatrician, child and adolescent mental health service colleague, or a named or designated professional for safeguarding children.
Gather collateral information from other agencies and health disciplines, having used professional judgement about whether to explain the need to gather this information for an overall assessment of the child.
Ensure review of the child or young person at a date appropriate to the concern, looking out for repeated presentations of this or any other alerting features.
If an alerting feature or considering child maltreatment prompts a healthcare professional to suspect child maltreatment they should refer the child or young person to children's social care, following local multi-agency safeguarding arrangements.
This may trigger a child protection investigation, supportive services may be offered to the family following an assessment or alternative explanations may be identified.
Exclude maltreatment when a suitable explanation is found for alerting features. This may be the decision following discussion of the case with a more experienced colleague or after gathering collateral information as part of considering child maltreatment.
## . Record
Record all actions taken in 4 and the outcome.
# Physical features
For the purposes of recommendations 1.1.2, 1.1.5, 1.1.6, 1.1.8 to 1.1.10, 1.1.13, 1.1.14, 1.1.16, 1.2.6 and 1.2.8, an unsuitable explanation for an injury or presentation is one that is implausible, inadequate or inconsistent. Also see the definitions of suspect and consider.
## Bruises
Suspect child maltreatment if a child or young person has bruising in the shape of a hand, ligature, stick, teeth mark, grip or implement.
Suspect child maltreatment if there is bruising or petechiae (tiny red or purple spots) that are not caused by a medical condition (for example, a causative coagulation disorder) and if the explanation for the bruising is unsuitable. Examples include:
bruising in a child who is not independently mobile
multiple bruises or bruises in clusters
bruises of a similar shape and size
bruises on any non-bony part of the body or face including the eyes, ears and buttocks
bruises on the neck that look like attempted strangulation
bruises on the ankles and wrists that look like ligature marks.
## Bites
Suspect child maltreatment if there is a report or appearance of a human bite mark that is thought unlikely to have been caused by a young child.
Consider neglect if there is a report or appearance of an animal bite on a child who has been inadequately supervised.
## Lacerations (cuts), abrasions and scars
Suspect child maltreatment if a child has lacerations, abrasions or scars and the explanation is unsuitable. Examples include lacerations, abrasions or scars:
-n a child who is not independently mobile
that are multiple
with a symmetrical distribution
-n areas usually protected by clothing (for example, back, chest, abdomen, axilla, genital area)
-n the eyes, ears and sides of face
-n the neck, ankles and wrists that look like ligature marks.
## Thermal injuries
Suspect child maltreatment if a child has burn or scald injuries:
if the explanation for the injury is absent or unsuitable or
if the child is not independently mobile or
-n any soft tissue area that would not be expected to come into contact with a hot object in an accident (for example, the backs of hands, soles of feet, buttocks, back) or
in the shape of an implement (for example, cigarette, iron) or
that indicate forced immersion, for example:
scalds to buttocks, perineum and lower limbs
scalds to limbs in a glove or stocking distribution
scalds to limbs with symmetrical distribution
scalds with sharply delineated borders.
## Cold injury
Consider child maltreatment if a child has cold injuries (for example, swollen, red hands or feet) with no obvious medical explanation.
Consider child maltreatment if a child presents with hypothermia and the explanation is unsuitable.
## Fractures
Suspect child maltreatment if a child has one or more fractures in the absence of a medical condition that predisposes to fragile bones (for example, osteogenesis imperfecta, osteopenia of prematurity) or if the explanation is absent or unsuitable. Presentations include:
fractures of different ages
X-ray evidence of occult fractures (fractures identified on X-rays that were not clinically evident). For example, rib fractures in infants.
## Intracranial injuries
Suspect child maltreatment if a child has an intracranial injury in the absence of major confirmed accidental trauma or known medical cause, in one or more of the following circumstances:
the explanation is absent or unsuitable
the child is aged under 3 years
there are also:
retinal haemorrhages or
rib or long bone fractures or
-ther associated inflicted injuries
there are multiple subdural haemorrhages with or without subarachnoid haemorrhage with or without hypoxic ischaemic damage (damage due to lack of blood and oxygen supply) to the brain.
## Eye trauma
Suspect child maltreatment if a child has retinal haemorrhages or injury to the eye in the absence of major confirmed accidental trauma or a known medical explanation, including birth-related causes.
## Spinal injuries
Suspect physical abuse if a child presents with signs of a spinal injury (injury to vertebrae or within the spinal canal) in the absence of major confirmed accidental trauma. Spinal injury may present as:
a finding on skeletal survey or magnetic resonance imaging
cervical injury in association with inflicted head injury
thoracolumbar injury in association with focal neurology or unexplained kyphosis (curvature or deformity of the spine).
## Visceral injuries
Suspect child maltreatment if a child has an intra-abdominal or intrathoracic injury in the absence of major confirmed accidental trauma and there is an absent or unsuitable explanation, or a delay in presentation. There may be no external bruising or other injury.
## Oral injury
Consider child maltreatment if a child has an oral injury and the explanation is absent or unsuitable.
## General injuries
Consider child maltreatment if there is no suitable explanation for a serious or unusual injury.
## Ano-genital signs and symptoms
Suspect sexual abuse if a girl or boy has a genital, anal or perianal injury (as evidenced by bruising, laceration, swelling or abrasion) and the explanation is absent or unsuitable.
Suspect sexual abuse if a girl or boy has a persistent or recurrent genital or anal symptom (for example, bleeding or discharge) that is associated with behavioural or emotional change and that has no medical explanation.
Suspect sexual abuse if a girl or boy has an anal laceration, and constipation, Crohn's disease and passing hard stools have been excluded as the cause.
Consider sexual abuse if an anus exhibiting dynamic anal dilation in a girl or boy is observed during an examination and there is no medical explanation (for example, a neurological disorder or severe constipation).
Consider sexual abuse if a girl or boy has a genital or anal symptom (for example, bleeding or discharge) without a medical explanation.
Consider sexual abuse if a girl or boy has dysuria (discomfort on passing urine) or ano-genital discomfort that is persistent or recurrent and does not have a medical explanation (for example, worms, urinary infection, skin conditions, poor hygiene or known allergies).
Consider sexual abuse if there is evidence of one or more foreign bodies in the vagina or anus. Foreign bodies in the vagina may be indicated by offensive vaginal discharge.
## Sexually transmitted infections
Consider sexual abuse if a child younger than 13 years has hepatitis B unless there is clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household or blood contamination.
Consider sexual abuse if a child younger than 13 years has anogenital warts unless there is clear evidence of mother-to-child transmission during birth or non-sexual transmission from a member of the household.
Suspect sexual abuse if a child younger than 13 years has gonorrhoea, chlamydia, syphilis, genital herpes, hepatitis C, HIV or trichomonas infection unless there is clear evidence of mother-to-child transmission during birth or blood contamination.
Consider sexual abuse if a young person aged 13 to 15 years has hepatitis B unless there is clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household, blood contamination or that the infection was acquired from consensual sexual activity with a peer.
Consider sexual abuse if a young person aged 13 to 15 years has anogenital warts unless there is clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household, or that the infection was acquired from consensual sexual activity with a peer.
Consider sexual abuse if a young person aged 13 to 15 years has gonorrhoea, chlamydia, syphilis, genital herpes, hepatitis C, HIV or trichomonas infection unless there is clear evidence of mother-to-child transmission during birth, blood contamination, or that the sexually transmitted infection (STI) was acquired from consensual sexual activity with a peer. In these circumstances, consider should include discussion of your concerns with a named or designated professional for safeguarding children.
Consider sexual abuse if a young person aged 16 or 17 years has hepatitis B and there is:
no clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household, blood contamination or that the infection was acquired from consensual sexual activity and
a clear difference in power or mental capacity between the young person and their sexual partner, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or
concern that the young person is being exploited.
Consider sexual abuse if a young person aged 16 or 17 years has anogenital warts and there is:
no clear evidence of non-sexual transmission from a member of the household or that the infection was acquired from consensual sexual activity and
a clear difference in power or mental capacity between the young person and their sexual partner, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or
concern that the young person is being exploited.
Consider sexual abuse if a young person aged 16 or 17 years has gonorrhoea, chlamydia, syphilis, genital herpes, hepatitis C, HIV or trichomonas infection and there is:
no clear evidence of blood contamination or that the STI was acquired from consensual sexual activity and
a clear difference in power or mental capacity between the young person and their sexual partner, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or
concern that the young person is being exploited.
# Clinical presentations
## Pregnancy
Be aware that sexual intercourse with a child younger than 13 years is unlawful and therefore pregnancy in such a child means the child has been maltreated. Under the Sexual Offences Act 2003, any sexual intercourse with a child younger than 13 years is unlawful. See the Crown Prosecution Service guidance about the act for further information about consent to sexual intercourse in people under 18.
Consider sexual abuse if a young woman aged 13 to 15 years is pregnant. Under the Sexual Offences Act 2003, any sexual intercourse with a child aged 13 to 15 years is unlawful. See the Crown Prosecution Service guidance about the act for further information about consent to sexual intercourse in people under 18.
Consider sexual abuse if a young woman aged 16 or 17 years is pregnant and there is:
a clear difference in power or mental capacity between the young woman and the putative father, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or
concern that the young woman is being exploited or
concern that the sexual activity was not consensual.
## Apparent life-threatening event
Suspect child maltreatment if a child has repeated apparent life-threatening events, the onset is witnessed only by one parent or carer and a medical explanation has not been identified.
Consider child maltreatment if an infant has an apparent life-threatening event with bleeding from the nose or mouth and a medical explanation has not been identified.
## Poisoning
Suspect child maltreatment in cases of poisoning in children if:
there is a report of deliberate administration of inappropriate substances, including prescribed and non-prescribed drugs or
there are unexpected blood levels of drugs not prescribed for the child or
there is reported or biochemical evidence of ingestions of one or more toxic substances or
the child was unable to access the substance independently or
the explanation for the poisoning or how the substance came to be in the child is absent or unsuitable or
there have been repeated presentations of ingestions in the child or other children in the household.
Consider child maltreatment in cases of hypernatraemia (abnormally high levels of sodium in the blood) and a medical explanation has not been identified.
## Non-fatal submersion injury
Suspect child maltreatment if a child has a non-fatal submersion incident (near-drowning) and the explanation is absent or unsuitable or if the child's presentation is inconsistent with the account.
Consider child maltreatment if a non-fatal submersion incident suggests a lack of supervision.
## Attendance at medical services
Consider child maltreatment if there is an unusual pattern of presentation to and contact with healthcare providers, or there are frequent presentations or reports of injuries.
## Fabricated or induced illness
Consider fabricated or induced illness if a child's history, physical or psychological presentations or findings of assessments, examinations or investigations leads to a discrepancy with a recognised clinical picture. Fabricated or induced illness is a possible explanation even if the child has a past or concurrent physical or psychological condition.
Suspect fabricated or induced illness if a child's history, physical or psychological presentations or findings of assessments, examinations or investigations leads to a discrepancy with a recognised clinical picture and one or more of the following is present:
Reported symptoms and signs only appear or reappear when the parent or carer is present.
Reported symptoms are only observed by the parent or carer.
An inexplicably poor response to prescribed medication or other treatment.
New symptoms are reported as soon as previous ones have resolved.
There is a history of events that is biologically unlikely (for example, infants with a history of very large blood losses who do not become unwell or anaemic).
Despite a definitive clinical opinion being reached, multiple opinions from both primary and secondary care are sought and disputed by the parent or carer and the child continues to be presented for investigation and treatment with a range of signs and symptoms.
The child's normal daily activities (for example, school attendance) are being compromised, or the child is using aids to daily living (for example, wheelchairs) more than would be expected for any medical condition that the child has.Fabricated or induced illness is a likely explanation even if the child has a past or concurrent physical or psychological condition.
## Inappropriately explained poor school attendance
Consider child maltreatment if a child has poor school attendance that the parents or carers know about that has no justification on health, including mental health, grounds and home education is not being provided.
# Neglect – failure of provision and failure of supervision
Neglect is a situation involving risk to the child or young person. It is the persistent failure to meet the child or young person's basic physical or psychological needs that is likely to result in the serious impairment of their health or development. This may or may not be deliberate. There are differences in how parents and carers choose to raise their children, including the choices they make about their children's healthcare. However, failure to recognise and respond to the child or young person's needs may amount to neglect.
There is no diagnostic gold standard for neglect and therefore decision-making in situations of apparent neglect can be very difficult and thresholds hard to establish. It is essential to place the child or young person at the centre of the assessment.
## Provision of basic needs
Consider neglect if a child has severe and persistent infestations, such as scabies or head lice.
Consider neglect if a child's clothing or footwear is consistently inappropriate (for example, for the weather or the child's size). Take into account that instances of inadequate clothing that have a suitable explanation (for example, a sudden change in the weather, slippers worn because they were closest to hand when leaving the house in a rush) or resulting from behaviour associated with neurodevelopmental disorders such as autism would not be alerting features for possible neglect.
Suspect neglect if a child is persistently smelly and dirty.Take into account that children often become dirty and smelly during the course of the day. Use judgement to determine if persistent lack of provision or care is a possibility. Examples include:
child seen at times of the day when it is unlikely that they would have had an opportunity to become dirty or smelly (for example, an early morning visit)
if the dirtiness is ingrained.
Suspect neglect if you repeatedly observe or hear reports of any of the following in the home that is in the parents' or carers' control:
a poor standard of hygiene that affects a child's health
inadequate provision of food
a living environment that is unsafe for the child's developmental stage.Be aware that it may be difficult to distinguish between neglect and material poverty. However, care should be taken to balance recognition of the constraints on the parents' or carers' ability to meet their children's needs for food, clothing and shelter with an appreciation of how people in similar circumstances have been able to meet those needs.
Be aware that abandoning a child is a form of maltreatment.
## Malnutrition
Consider neglect if a child displays faltering growth because of lack of provision of an adequate or appropriate diet. See NICE's guideline on faltering growth.
## Supervision
Achieving a balance between an awareness of risk and allowing children freedom to learn by experience can be difficult. However, if parents or carers persistently fail to anticipate dangers and to take precautions to protect their child from harm it may constitute neglect.
Consider neglect if the explanation for an injury (for example, a burn, sunburn or an ingestion of a harmful substance) suggests a lack of appropriate supervision.
Consider neglect if a child or young person is not being cared for by a person who is able to provide adequate care.
## Ensuring access to appropriate medical care or treatment
Consider neglect if parents or carers fail to administer essential prescribed treatment for their child.
Consider neglect if parents or carers repeatedly fail to bring their child to follow-up appointments that are essential for their child's health and wellbeing.
Consider neglect if parents or carers persistently fail to engage with relevant child health promotion programmes, which include:
immunisation
health and development reviews
screening.
Consider neglect if parents or carers have access to but persistently fail to obtain treatment for their child's dental caries (tooth decay).
Suspect neglect if parents or carers fail to seek medical advice for their child to the extent that the child's health and wellbeing is compromised, including if the child is in ongoing pain.
# Emotional, behavioural, interpersonal and social functioning
## Emotional and behavioural states
Consider child maltreatment if a child or young person displays or is reported to display a marked change in behaviour or emotional state (see examples below) that is a departure from what would be expected for their age and developmental stage and is not fully explained by a known stressful situation that is not part of child maltreatment (for example, bereavement or parental separation) or medical cause. Examples include:
recurrent nightmares containing similar themes
extreme distress
markedly oppositional behaviour
withdrawal of communication
becoming withdrawn.
Consider child maltreatment if a child's behaviour or emotional state is not consistent with their age and developmental stage or cannot be fully explained by medical causes, neurodevelopmental disorders (for example, attention deficit hyperactivity disorder , autism spectrum disorders) or other stressful situation that is not part of child maltreatment (for example, bereavement or parental separation). Examples of behaviour or emotional states that may fit this description include:
Emotional states:
fearful, withdrawn, low self-esteem
Behaviour:
aggressive, oppositional
habitual body rocking
Interpersonal behaviours:
indiscriminate contact or affection seeking
-ver-friendliness to strangers including healthcare professionals
excessive clinginess
persistently resorting to gaining attention
demonstrating excessively 'good' behaviour to prevent parental or carer disapproval
failing to seek or accept appropriate comfort or affection from an appropriate person when significantly distressed
coercive controlling behaviour towards parents or carers
lack of ability to understand and recognise emotions
very young children showing excessive comforting behaviours when witnessing parental or carer distress.
Consider child maltreatment if a child shows repeated, extreme or sustained emotional responses that are out of proportion to a situation and are not expected for the child's age or developmental stage or fully explained by a medical cause, neurodevelopmental disorder (for example, ADHD, autism spectrum disorders) or bipolar disorder and the effects of any known past maltreatment have been explored. Examples of these emotional responses include:
anger or frustration expressed as a temper tantrum in a school-aged child
frequent rages at minor provocation
distress expressed as inconsolable crying.
Consider child maltreatment if a child shows dissociation (transient episodes of detachment that are outside the child's control and that are distinguished from daydreaming, seizures or deliberate avoidance of interaction) that is not fully explained by a known traumatic event unrelated to maltreatment.
Consider child maltreatment if a child or young person regularly has responsibilities that interfere with the child's essential normal daily activities (for example, school attendance).
Consider child maltreatment if a child responds to a health examination or assessment in an unusual, unexpected or developmentally inappropriate way (for example, extreme passivity, resistance or refusal).
## Behavioural disorders or abnormalities either seen or heard about
Consider past or current child maltreatment, particularly sexual, physical or emotional abuse, if a child or young person is deliberately self-harming. Self-harm includes cutting, scratching, picking, biting or tearing skin to cause injury, pulling out hair or eyelashes and deliberately taking prescribed or non-prescribed drugs at higher than therapeutic doses.
Suspect child maltreatment if a child repeatedly scavenges, steals, hoards or hides food with no medical explanation (for example Prader–Willi syndrome, a genetic condition leading to a range of symptoms, including over-eating, restricted growth, reduced muscle tone, and learning and behavioural difficulties).
Consider child maltreatment if a child has secondary day- or night-time wetting that persists despite adequate assessment and management unless there is a medical explanation (for example, urinary tract infection) or clearly identified stressful situation that is not part of maltreatment (for example, bereavement, parental separation).
Consider child maltreatment if a child is reported to be deliberately wetting.
Consider child maltreatment if a child shows encopresis (repeatedly defecating a normal stool in an inappropriate place) or repeated, deliberate smearing of faeces.
Suspect child maltreatment, and in particular sexual abuse, if a pre-pubertal child displays or is reported to display repeated or coercive sexualised behaviours or preoccupation (for example, sexual talk associated with knowledge, emulating sexual activity with another child).
Suspect current or past child maltreatment if a child or young person's sexual behaviour is indiscriminate, precocious or coercive.
Suspect sexual abuse if a pre-pubertal child displays or is reported to display unusual sexualised behaviours. Examples include:
-ral–genital contact with another child or a doll
requesting to be touched in the genital area
inserting or attempting to insert an object, finger or penis into another child's vagina or anus.
Consider child maltreatment if a child or young person has run away from home or care, or is living in alternative accommodation without the full agreement of their parents or carers.
# Parent–child interactions
Consider emotional abuse if there is concern that parent– or carer–child interactions may be harmful. Examples include:
Negativity or hostility towards a child or young person.
Rejection or scapegoating of a child or young person.
Developmentally inappropriate expectations of or interactions with a child, including inappropriate threats or methods of disciplining.
Exposure to frightening or traumatic experiences, including domestic abuse.
Using the child for the fulfilment of the adult's needs (for example, in marital disputes).
Failure to promote the child's appropriate socialisation (for example, involving children in unlawful activities, isolation, not providing stimulation or education).
Suspect emotional abuse if the interactions observed in recommendation 1.5.1 are persistent.
Consider child maltreatment if parents or carers are seen or reported to punish a child for wetting or soiling despite professional advice that the symptom is involuntary.
Consider emotional neglect if there is emotional unavailability and unresponsiveness from the parent or carer towards a child or young person and in particular towards an infant.
Suspect emotional neglect if the interaction observed in recommendation 1.5.4 is persistent.
Consider child maltreatment if a parent or carer refuses to allow a child or young person to speak to a healthcare professional on their own when it is necessary for the assessment of the child or young person.# Recommendations for research
The guideline development group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The guideline development group's full set of research recommendations is detailed in the full guideline.
# Fractures
How can abusive fractures be differentiated from those resulting from conditions that lead to bone fragility and those resulting from accidents, particularly in relation to metaphyseal fractures?
## Why this is important
The existing evidence base does not fully account for the features that differentiate fractures from different causes in infants and pre-school age children. A prospective comparative study of fractures in physical abuse, those resulting from conditions that lead to bone fragility and those resulting from accidental trauma would help address this question. Any such study should encompass a study of metaphyseal fractures.
# Anogenital warts
What is the association between anogenital warts and sexual abuse in children of different ages?
## Why this is important
Anogenital warts can be acquired by vertical transmission, sexual contact and by non-sexual transmission within households. A thorough prospective study is needed to investigate the differential causes of anogenital warts in children. Such a study should include full viral typing of the warts in the index case and contacts where possible.
# Fabricated or induced illness
Are the indicators of fabricated or induced illness as described in the recommendations (see recommendations 1.2.11 and 1.2.12) valid for discriminating fabricated or induced illness from other explanations?
## Why this is important
Although the alerting signs have been developed based on clinical experience and are considered clinically useful in detecting fabricated or induced illness, there is a need to establish their discriminant validity. This could be achieved by a prospective longitudinal study.
# Emotional and behavioural states
What aspects of behaviours and emotional states as alerting individual signs discriminate maltreated children from non-maltreated children in the healthcare setting?
## Why this is important
Much of the research in this area uses composite scores from instruments or scenarios to discriminate maltreated from non-maltreated children. To translate these scores into items that are usable for healthcare professionals who are meeting children for the first time, it is necessary to know whether particular behavioural and emotional states can be used to identify maltreated children. A prospective comparative study in the healthcare setting is required.
# Recurrent abdominal pain
What is the association between unexplained recurrent abdominal pain and child maltreatment?
## Why this is important
Recurrent abdominal pain is a common presentation in primary care and is often unexplained. A large observational study on the association between unexplained recurrent abdominal pain and child maltreatment is needed.
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{'Introduction': "This guidance provides a summary of clinical features associated with child maltreatment (alerting features) that may be observed when a child presents to healthcare professionals. Its purpose is to raise awareness and help healthcare professionals who are not specialists in child protection to identify children who may be being maltreated. It does not give healthcare professionals recommendations on how to diagnose, confirm or disprove child maltreatment.\n\nChildren may present with both physical and psychological symptoms and signs that constitute alerting features of one or more types of maltreatment, and maltreatment may be observed in parent– or carer–child interactions.\n\nThere is strong evidence of the harmful short- and long-term effects of child maltreatment. All aspects of the child's health, development and wellbeing can be affected. The effects of child maltreatment can last throughout adulthood and include anxiety, depression, substance misuse, and self-destructive, oppositional or antisocial behaviours. In adulthood, there may be difficulties in forming or sustaining close relationships, sustaining employment and parenting capacity. Physical abuse may result in lifelong disability or physical scarring and harmful psychological consequences, and may even be fatal. The National Service Framework (NSF) for Children, Young People and Maternity Services for England states 'The high cost of abuse and neglect both to individuals (and to society) underpins the duty on all agencies to be proactive in safeguarding children.'\n\n# Definitions\n\n## Child maltreatment\n\nChild maltreatment includes neglect, physical, sexual and emotional abuse, and fabricated or induced illness. This guidance uses the definitions of child maltreatment as set out in the Department for Education's statutory guidance on inter-agency working to safeguard and promote the welfare of children. This also includes an appendix of further relevant guidance from the Department for Education, other government departments and agencies, and external organisations.\n\n## Age groups\n\nThis guidance uses the following terms to describe children of different ages:\n\ninfant (aged under 1\xa0year)\n\nchild (aged under 13\xa0years)\n\nyoung person (aged 13–17\xa0years).\n\nExclusions from the guideline\n\nThe following topics were outside the scope of this guideline and have therefore not been covered:\n\nrisk factors for child maltreatment, which are well recognised. Examples include\n\n\n\nparental or carer drug or alcohol misuse\n\nparental or carer mental health problems\n\nintra-familial violence or history of violent offending\n\nprevious child maltreatment in members of the family\n\nknown maltreatment of animals by the parent or carer\n\nvulnerable and unsupported parents or carers\n\npre-existing disability in the child\n\n\n\nprotection of the unborn child\n\nchildren who have died as a result of child maltreatment. It should be noted that there are special procedures that should be followed when a child dies unexpectedly.\n\ndiagnostic assessment and investigations (for example, X-rays)\n\ntreatment and care of the child if maltreatment is suspected\n\nhow healthcare professionals should proceed once they suspect maltreatment\n\nhealthcare professionals' competency, training and behaviour\n\nservice organisation\n\nchild protection procedures\n\ncommunication of suspicions to parents or carers, or the child or young person\n\neducation and information for parents or carers, or the child or young person.\n\nCommunicating with and about the child or young person\n\nGood communication between healthcare professionals and the child or young person, as well as with their families and carers, is essential. Communication should take into account additional needs such as physical, sensory or learning disabilities, or the inability to speak or read English. Consideration should be given to cultural needs of children or young people and their families and carers.\n\nIf healthcare professionals have concerns about sharing information with others, they should obtain advice from named or designated professionals for safeguarding children. If concerns are based on information given by a child, healthcare professionals should explain to the child when they are unable to maintain confidentiality, explore the child's concerns about sharing this information and reassure the child that they will continue to be kept informed about what is happening. When gathering collateral information from other health disciplines and other agencies, professionals need to use judgement about whether to explain to the family the need to gather this information for the overall assessment of the child.\n\nPotential obstacles to recognising and responding to possible maltreatment\n\nHealthcare professionals may come across many different obstacles in the process of identifying maltreatment but these should not prevent them from following the appropriate course of action to prevent further harm to the child or young person. Examples of potential obstacles include the following:\n\nConcern about missing a treatable disorder.\n\nHealthcare professionals are used to working with parents and carers in the care of children and fear losing a positive relationship with a family already under their care.\n\nDiscomfort of disbelieving, thinking ill of, suspecting or wrongly blaming a parent or carer.\n\nDivided duties to adult and child patients and breaching confidentiality.\n\nAn understanding of the reasons why the maltreatment might have occurred, and that there was no intention to harm the child.\n\nLosing control over the child protection process and doubts about its benefits.\n\nStress.\n\nPersonal safety.\n\nFear of complaints.", 'Recommendations': "The following guidance is based on the best available evidence. The full guidance gives details of the methods and the evidence used to develop the guidance.\n\n# Definitions of terms used in this guidance\n\nThe alerting features in this guidance have been divided into two, according to the level of concern, with recommendations to either 'consider' or 'suspect' maltreatment.\n\n## Consider\n\nFor the purposes of this guidance, to consider child maltreatment means that maltreatment is one possible explanation for the alerting feature or is included in the differential diagnosis.\n\n## Multi-agency safeguarding arrangements\n\nThe responsibility for these arrangements is with 3\xa0safeguarding partners: the local authority, clinical commissioning group for an area, and the chief officer of police for a police area. They have a shared and equal duty to work together to safeguard and promote the welfare of all children in a local area.\n\n## Suspect\n\nFor the purposes of this guidance, to suspect child maltreatment means a serious level of concern about the possibility of child maltreatment but is not proof of it.\n\n## Unsuitable explanation\n\nFor the purposes of this guidance, an unsuitable explanation for an injury or presentation is one that is implausible, inadequate or inconsistent:\n\nwith the child or young person's\n\n\n\npresentation\n\nnormal activities\n\nexisting medical condition\n\nage or developmental stage\n\naccount compared to that given by parent and carers\n\n\n\nbetween parents or carers\n\nbetween accounts over time.\n\nAn explanation based on cultural practice is also unsuitable because this should not justify hurting a child or young person.\n\n# Using this guidance\n\nIf a healthcare professional encounters an alerting feature of possible child maltreatment that prompts them to consider, suspect or exclude child maltreatment as a possible explanation, it is good practice to follow the process outlined in 1–5 below:\n\n## . Listen and observe\n\nIdentifying or excluding child maltreatment involves piecing together information from many sources so that the whole picture of the child or young person is taken into account. This information may come from different sources and agencies and includes:\n\nany history that is given\n\nreport of maltreatment, or disclosure from a child or young person or third party. It is standard practice to refer to children's social services when a child or young person makes a disclosure of maltreatment (even though it may not be precise in every detail).\n\nchild's appearance\n\nchild's behaviour or demeanour\n\nsymptom\n\nphysical sign\n\nresult of an investigation\n\ninteraction between the parent or carer and child or young person.\n\n## . Seek an explanation\n\nSeek an explanation for any injury or presentation from both the parent or carer and the child or young person in an open and non-judgemental manner.\n\nAlerting features of maltreatment in children with disabilities may also be features of the disability, making identification of maltreatment more difficult.Healthcare professionals may need to seek appropriate expertise if they are concerned about a child or young person with a disability.\n\n## . Record\n\nRecord in the child or young person's clinical record exactly what is observed and heard from whom and when.\n\nRecord why this is of concern.\n\nAt this point the healthcare professional may consider, suspect or exclude child maltreatment from the differential diagnosis.\n\n## . Consider, suspect or exclude maltreatment\n\nAt any stage during the process of considering maltreatment the level of concern may change and lead to exclude or suspect maltreatment.\n\nWhen hearing about or observing an alerting feature in the guidance:\n\nlook for other alerting features of maltreatment in the child or young person's history, presentation or parent– or carer–interaction with the child or young person now or in the past. Then do one or more of the following:\n\nDiscuss your concerns with a more experienced colleague, a community paediatrician, child and adolescent mental health service colleague, or a named or designated professional for safeguarding children.\n\nGather collateral information from other agencies and health disciplines, having used professional judgement about whether to explain the need to gather this information for an overall assessment of the child.\n\nEnsure review of the child or young person at a date appropriate to the concern, looking out for repeated presentations of this or any other alerting features.\n\nIf an alerting feature or considering child maltreatment prompts a healthcare professional to suspect child maltreatment they should refer the child or young person to children's social care, following local multi-agency safeguarding arrangements.\n\nThis may trigger a child protection investigation, supportive services may be offered to the family following an assessment or alternative explanations may be identified.\n\nExclude maltreatment when a suitable explanation is found for alerting features. This may be the decision following discussion of the case with a more experienced colleague or after gathering collateral information as part of considering child maltreatment.\n\n## . Record\n\nRecord all actions taken in 4 and the outcome.\n\n# Physical features\n\nFor the purposes of recommendations 1.1.2, 1.1.5, 1.1.6, 1.1.8 to 1.1.10, 1.1.13, 1.1.14, 1.1.16, 1.2.6 and 1.2.8, an unsuitable explanation for an injury or presentation is one that is implausible, inadequate or inconsistent. Also see the definitions of suspect and consider.\n\n## Bruises\n\nSuspect child maltreatment if a child or young person has bruising in the shape of a hand, ligature, stick, teeth mark, grip or implement.\n\nSuspect child maltreatment if there is bruising or petechiae (tiny red or purple spots) that are not caused by a medical condition (for example, a causative coagulation disorder) and if the explanation for the bruising is unsuitable. Examples include:\n\nbruising in a child who is not independently mobile\n\nmultiple bruises or bruises in clusters\n\nbruises of a similar shape and size\n\nbruises on any non-bony part of the body or face including the eyes, ears and buttocks\n\nbruises on the neck that look like attempted strangulation\n\nbruises on the ankles and wrists that look like ligature marks.\n\n## Bites\n\nSuspect child maltreatment if there is a report or appearance of a human bite mark that is thought unlikely to have been caused by a young child.\n\nConsider neglect if there is a report or appearance of an animal bite on a child who has been inadequately supervised.\n\n## Lacerations (cuts), abrasions and scars\n\nSuspect child maltreatment if a child has lacerations, abrasions or scars and the explanation is unsuitable. Examples include lacerations, abrasions or scars:\n\non a child who is not independently mobile\n\nthat are multiple\n\nwith a symmetrical distribution\n\non areas usually protected by clothing (for example, back, chest, abdomen, axilla, genital area)\n\non the eyes, ears and sides of face\n\non the neck, ankles and wrists that look like ligature marks.\n\n## Thermal injuries\n\nSuspect child maltreatment if a child has burn or scald injuries:\n\nif the explanation for the injury is absent or unsuitable or\n\nif the child is not independently mobile or\n\non any soft tissue area that would not be expected to come into contact with a hot object in an accident (for example, the backs of hands, soles of feet, buttocks, back) or\n\nin the shape of an implement (for example, cigarette, iron) or\n\nthat indicate forced immersion, for example:\n\n\n\nscalds to buttocks, perineum and lower limbs\n\nscalds to limbs in a glove or stocking distribution\n\nscalds to limbs with symmetrical distribution\n\nscalds with sharply delineated borders.\n\n\n\n## Cold injury\n\nConsider child maltreatment if a child has cold injuries (for example, swollen, red hands or feet) with no obvious medical explanation.\n\nConsider child maltreatment if a child presents with hypothermia and the explanation is unsuitable.\n\n## Fractures\n\nSuspect child maltreatment if a child has one or more fractures in the absence of a medical condition that predisposes to fragile bones (for example, osteogenesis imperfecta, osteopenia of prematurity) or if the explanation is absent or unsuitable. Presentations include:\n\nfractures of different ages\n\nX-ray evidence of occult fractures (fractures identified on X-rays that were not clinically evident). For example, rib fractures in infants.\n\n## Intracranial injuries\n\nSuspect child maltreatment if a child has an intracranial injury in the absence of major confirmed accidental trauma or known medical cause, in one or more of the following circumstances:\n\nthe explanation is absent or unsuitable\n\nthe child is aged under 3\xa0years\n\nthere are also:\n\n\n\nretinal haemorrhages or\n\nrib or long bone fractures or\n\nother associated inflicted injuries\n\n\n\nthere are multiple subdural haemorrhages with or without subarachnoid haemorrhage with or without hypoxic ischaemic damage (damage due to lack of blood and oxygen supply) to the brain.\n\n## Eye trauma\n\nSuspect child maltreatment if a child has retinal haemorrhages or injury to the eye in the absence of major confirmed accidental trauma or a known medical explanation, including birth-related causes.\n\n## Spinal injuries\n\nSuspect physical abuse if a child presents with signs of a spinal injury (injury to vertebrae or within the spinal canal) in the absence of major confirmed accidental trauma. Spinal injury may present as:\n\na finding on skeletal survey or magnetic resonance imaging\n\ncervical injury in association with inflicted head injury\n\nthoracolumbar injury in association with focal neurology or unexplained kyphosis (curvature or deformity of the spine).\n\n## Visceral injuries\n\nSuspect child maltreatment if a child has an intra-abdominal or intrathoracic injury in the absence of major confirmed accidental trauma and there is an absent or unsuitable explanation, or a delay in presentation. There may be no external bruising or other injury.\n\n## Oral injury\n\nConsider child maltreatment if a child has an oral injury and the explanation is absent or unsuitable.\n\n## General injuries\n\nConsider child maltreatment if there is no suitable explanation for a serious or unusual injury.\n\n## Ano-genital signs and symptoms\n\nSuspect sexual abuse if a girl or boy has a genital, anal or perianal injury (as evidenced by bruising, laceration, swelling or abrasion) and the explanation is absent or unsuitable.\n\nSuspect sexual abuse if a girl or boy has a persistent or recurrent genital or anal symptom (for example, bleeding or discharge) that is associated with behavioural or emotional change and that has no medical explanation.\n\nSuspect sexual abuse if a girl or boy has an anal laceration, and constipation, Crohn's disease and passing hard stools have been excluded as the cause.\n\nConsider sexual abuse if an anus exhibiting dynamic anal dilation in a girl or boy is observed during an examination and there is no medical explanation (for example, a neurological disorder or severe constipation).\n\nConsider sexual abuse if a girl or boy has a genital or anal symptom (for example, bleeding or discharge) without a medical explanation.\n\nConsider sexual abuse if a girl or boy has dysuria (discomfort on passing urine) or ano-genital discomfort that is persistent or recurrent and does not have a medical explanation (for example, worms, urinary infection, skin conditions, poor hygiene or known allergies).\n\nConsider sexual abuse if there is evidence of one or more foreign bodies in the vagina or anus. Foreign bodies in the vagina may be indicated by offensive vaginal discharge.\n\n## Sexually transmitted infections\n\nConsider sexual abuse if a child younger than 13\xa0years has hepatitis B unless there is clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household or blood contamination.\n\nConsider sexual abuse if a child younger than 13\xa0years has anogenital warts unless there is clear evidence of mother-to-child transmission during birth or non-sexual transmission from a member of the household.\n\nSuspect sexual abuse if a child younger than 13\xa0years has gonorrhoea, chlamydia, syphilis, genital herpes, hepatitis C, HIV or trichomonas infection unless there is clear evidence of mother-to-child transmission during birth or blood contamination.\n\nConsider sexual abuse if a young person aged 13 to 15\xa0years has hepatitis B unless there is clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household, blood contamination or that the infection was acquired from consensual sexual activity with a peer.\n\nConsider sexual abuse if a young person aged 13 to 15\xa0years has anogenital warts unless there is clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household, or that the infection was acquired from consensual sexual activity with a peer.\n\nConsider sexual abuse if a young person aged 13 to 15\xa0years has gonorrhoea, chlamydia, syphilis, genital herpes, hepatitis C, HIV or trichomonas infection unless there is clear evidence of mother-to-child transmission during birth, blood contamination, or that the sexually transmitted infection (STI) was acquired from consensual sexual activity with a peer. In these circumstances, consider should include discussion of your concerns with a named or designated professional for safeguarding children.\n\nConsider sexual abuse if a young person aged 16 or 17\xa0years has hepatitis B and there is:\n\nno clear evidence of mother-to-child transmission during birth, non-sexual transmission from a member of the household, blood contamination or that the infection was acquired from consensual sexual activity and\n\na clear difference in power or mental capacity between the young person and their sexual partner, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or\n\nconcern that the young person is being exploited.\n\nConsider sexual abuse if a young person aged 16 or 17\xa0years has anogenital warts and there is:\n\nno clear evidence of non-sexual transmission from a member of the household or that the infection was acquired from consensual sexual activity and\n\na clear difference in power or mental capacity between the young person and their sexual partner, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or\n\nconcern that the young person is being exploited.\n\nConsider sexual abuse if a young person aged 16 or 17\xa0years has gonorrhoea, chlamydia, syphilis, genital herpes, hepatitis C, HIV or trichomonas infection and there is:\n\nno clear evidence of blood contamination or that the STI was acquired from consensual sexual activity and\n\na clear difference in power or mental capacity between the young person and their sexual partner, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or\n\nconcern that the young person is being exploited.\n\n# Clinical presentations\n\n## Pregnancy\n\nBe aware that sexual intercourse with a child younger than 13\xa0years is unlawful and therefore pregnancy in such a child means the child has been maltreated. Under the Sexual Offences Act 2003, any sexual intercourse with a child younger than 13 years is unlawful. See the Crown Prosecution Service guidance about the act for further information about consent to sexual intercourse in people under 18.\n\nConsider sexual abuse if a young woman aged 13 to 15\xa0years is pregnant. Under the Sexual Offences Act 2003, any sexual intercourse with a child aged 13 to 15\xa0years is unlawful. See the Crown Prosecution Service guidance about the act for further information about consent to sexual intercourse in people under 18.\n\nConsider sexual abuse if a young woman aged 16 or 17\xa0years is pregnant and there is:\n\na clear difference in power or mental capacity between the young woman and the putative father, in particular when the relationship is incestuous or is with a person in a position of trust (for example, teacher, sports coach, minister of religion) or\n\nconcern that the young woman is being exploited or\n\nconcern that the sexual activity was not consensual.\n\n## Apparent life-threatening event\n\nSuspect child maltreatment if a child has repeated apparent life-threatening events, the onset is witnessed only by one parent or carer and a medical explanation has not been identified.\n\nConsider child maltreatment if an infant has an apparent life-threatening event with bleeding from the nose or mouth and a medical explanation has not been identified.\n\n## Poisoning\n\nSuspect child maltreatment in cases of poisoning in children if:\n\nthere is a report of deliberate administration of inappropriate substances, including prescribed and non-prescribed drugs or\n\nthere are unexpected blood levels of drugs not prescribed for the child or\n\nthere is reported or biochemical evidence of ingestions of one or more toxic substances or\n\nthe child was unable to access the substance independently or\n\nthe explanation for the poisoning or how the substance came to be in the child is absent or unsuitable or\n\nthere have been repeated presentations of ingestions in the child or other children in the household.\n\nConsider child maltreatment in cases of hypernatraemia (abnormally high levels of sodium in the blood) and a medical explanation has not been identified.\n\n## Non-fatal submersion injury\n\nSuspect child maltreatment if a child has a non-fatal submersion incident (near-drowning) and the explanation is absent or unsuitable or if the child's presentation is inconsistent with the account.\n\nConsider child maltreatment if a non-fatal submersion incident suggests a lack of supervision.\n\n## Attendance at medical services\n\nConsider child maltreatment if there is an unusual pattern of presentation to and contact with healthcare providers, or there are frequent presentations or reports of injuries.\n\n## Fabricated or induced illness\n\nConsider fabricated or induced illness if a child's history, physical or psychological presentations or findings of assessments, examinations or investigations leads to a discrepancy with a recognised clinical picture. Fabricated or induced illness is a possible explanation even if the child has a past or concurrent physical or psychological condition.\n\nSuspect fabricated or induced illness if a child's history, physical or psychological presentations or findings of assessments, examinations or investigations leads to a discrepancy with a recognised clinical picture and one or more of the following is present:\n\nReported symptoms and signs only appear or reappear when the parent or carer is present.\n\nReported symptoms are only observed by the parent or carer.\n\nAn inexplicably poor response to prescribed medication or other treatment.\n\nNew symptoms are reported as soon as previous ones have resolved.\n\nThere is a history of events that is biologically unlikely (for example, infants with a history of very large blood losses who do not become unwell or anaemic).\n\nDespite a definitive clinical opinion being reached, multiple opinions from both primary and secondary care are sought and disputed by the parent or carer and the child continues to be presented for investigation and treatment with a range of signs and symptoms.\n\nThe child's normal daily activities (for example, school attendance) are being compromised, or the child is using aids to daily living (for example, wheelchairs) more than would be expected for any medical condition that the child has.Fabricated or induced illness is a likely explanation even if the child has a past or concurrent physical or psychological condition.\n\n## Inappropriately explained poor school attendance\n\nConsider child maltreatment if a child has poor school attendance that the parents or carers know about that has no justification on health, including mental health, grounds and home education is not being provided.\n\n# Neglect – failure of provision and failure of supervision\n\nNeglect is a situation involving risk to the child or young person. It is the persistent failure to meet the child or young person's basic physical or psychological needs that is likely to result in the serious impairment of their health or development. This may or may not be deliberate. There are differences in how parents and carers choose to raise their children, including the choices they make about their children's healthcare. However, failure to recognise and respond to the child or young person's needs may amount to neglect.\n\nThere is no diagnostic gold standard for neglect and therefore decision-making in situations of apparent neglect can be very difficult and thresholds hard to establish. It is essential to place the child or young person at the centre of the assessment.\n\n## Provision of basic needs\n\nConsider neglect if a child has severe and persistent infestations, such as scabies or head lice.\n\nConsider neglect if a child's clothing or footwear is consistently inappropriate (for example, for the weather or the child's size). Take into account that instances of inadequate clothing that have a suitable explanation (for example, a sudden change in the weather, slippers worn because they were closest to hand when leaving the house in a rush) or resulting from behaviour associated with neurodevelopmental disorders such as autism would not be alerting features for possible neglect.\n\nSuspect neglect if a child is persistently smelly and dirty.Take into account that children often become dirty and smelly during the course of the day. Use judgement to determine if persistent lack of provision or care is a possibility. Examples include:\n\nchild seen at times of the day when it is unlikely that they would have had an opportunity to become dirty or smelly (for example, an early morning visit)\n\nif the dirtiness is ingrained.\n\nSuspect neglect if you repeatedly observe or hear reports of any of the following in the home that is in the parents' or carers' control:\n\na poor standard of hygiene that affects a child's health\n\ninadequate provision of food\n\na living environment that is unsafe for the child's developmental stage.Be aware that it may be difficult to distinguish between neglect and material poverty. However, care should be taken to balance recognition of the constraints on the parents' or carers' ability to meet their children's needs for food, clothing and shelter with an appreciation of how people in similar circumstances have been able to meet those needs.\n\nBe aware that abandoning a child is a form of maltreatment.\n\n## Malnutrition\n\nConsider neglect if a child displays faltering growth because of lack of provision of an adequate or appropriate diet. See NICE's guideline on faltering growth.\n\n## Supervision\n\nAchieving a balance between an awareness of risk and allowing children freedom to learn by experience can be difficult. However, if parents or carers persistently fail to anticipate dangers and to take precautions to protect their child from harm it may constitute neglect.\n\nConsider neglect if the explanation for an injury (for example, a burn, sunburn or an ingestion of a harmful substance) suggests a lack of appropriate supervision.\n\nConsider neglect if a child or young person is not being cared for by a person who is able to provide adequate care.\n\n## Ensuring access to appropriate medical care or treatment\n\nConsider neglect if parents or carers fail to administer essential prescribed treatment for their child.\n\nConsider neglect if parents or carers repeatedly fail to bring their child to follow-up appointments that are essential for their child's health and wellbeing.\n\nConsider neglect if parents or carers persistently fail to engage with relevant child health promotion programmes, which include:\n\nimmunisation\n\nhealth and development reviews\n\nscreening.\n\nConsider neglect if parents or carers have access to but persistently fail to obtain treatment for their child's dental caries (tooth decay).\n\nSuspect neglect if parents or carers fail to seek medical advice for their child to the extent that the child's health and wellbeing is compromised, including if the child is in ongoing pain.\n\n# Emotional, behavioural, interpersonal and social functioning\n\n## Emotional and behavioural states\n\nConsider child maltreatment if a child or young person displays or is reported to display a marked change in behaviour or emotional state (see examples below) that is a departure from what would be expected for their age and developmental stage and is not fully explained by a known stressful situation that is not part of child maltreatment (for example, bereavement or parental separation) or medical cause. Examples include:\n\nrecurrent nightmares containing similar themes\n\nextreme distress\n\nmarkedly oppositional behaviour\n\nwithdrawal of communication\n\nbecoming withdrawn.\n\nConsider child maltreatment if a child's behaviour or emotional state is not consistent with their age and developmental stage or cannot be fully explained by medical causes, neurodevelopmental disorders (for example, attention deficit hyperactivity disorder [ADHD], autism spectrum disorders) or other stressful situation that is not part of child maltreatment (for example, bereavement or parental separation). Examples of behaviour or emotional states that may fit this description include:\n\nEmotional states:\n\n\n\nfearful, withdrawn, low self-esteem\n\n\n\nBehaviour:\n\n\n\naggressive, oppositional\n\nhabitual body rocking\n\n\n\nInterpersonal behaviours:\n\n\n\nindiscriminate contact or affection seeking\n\nover-friendliness to strangers including healthcare professionals\n\nexcessive clinginess\n\npersistently resorting to gaining attention\n\ndemonstrating excessively 'good' behaviour to prevent parental or carer disapproval\n\nfailing to seek or accept appropriate comfort or affection from an appropriate person when significantly distressed\n\ncoercive controlling behaviour towards parents or carers\n\nlack of ability to understand and recognise emotions\n\nvery young children showing excessive comforting behaviours when witnessing parental or carer distress.\n\n\n\nConsider child maltreatment if a child shows repeated, extreme or sustained emotional responses that are out of proportion to a situation and are not expected for the child's age or developmental stage or fully explained by a medical cause, neurodevelopmental disorder (for example, ADHD, autism spectrum disorders) or bipolar disorder and the effects of any known past maltreatment have been explored. Examples of these emotional responses include:\n\nanger or frustration expressed as a temper tantrum in a school-aged child\n\nfrequent rages at minor provocation\n\ndistress expressed as inconsolable crying.\n\nConsider child maltreatment if a child shows dissociation (transient episodes of detachment that are outside the child's control and that are distinguished from daydreaming, seizures or deliberate avoidance of interaction) that is not fully explained by a known traumatic event unrelated to maltreatment.\n\nConsider child maltreatment if a child or young person regularly has responsibilities that interfere with the child's essential normal daily activities (for example, school attendance).\n\nConsider child maltreatment if a child responds to a health examination or assessment in an unusual, unexpected or developmentally inappropriate way (for example, extreme passivity, resistance or refusal).\n\n## Behavioural disorders or abnormalities either seen or heard about\n\nConsider past or current child maltreatment, particularly sexual, physical or emotional abuse, if a child or young person is deliberately self-harming. Self-harm includes cutting, scratching, picking, biting or tearing skin to cause injury, pulling out hair or eyelashes and deliberately taking prescribed or non-prescribed drugs at higher than therapeutic doses.\n\nSuspect child maltreatment if a child repeatedly scavenges, steals, hoards or hides food with no medical explanation (for example Prader–Willi syndrome, a genetic condition leading to a range of symptoms, including over-eating, restricted growth, reduced muscle tone, and learning and behavioural difficulties).\n\nConsider child maltreatment if a child has secondary day- or night-time wetting that persists despite adequate assessment and management unless there is a medical explanation (for example, urinary tract infection) or clearly identified stressful situation that is not part of maltreatment (for example, bereavement, parental separation).\n\nConsider child maltreatment if a child is reported to be deliberately wetting.\n\nConsider child maltreatment if a child shows encopresis (repeatedly defecating a normal stool in an inappropriate place) or repeated, deliberate smearing of faeces.\n\nSuspect child maltreatment, and in particular sexual abuse, if a pre-pubertal child displays or is reported to display repeated or coercive sexualised behaviours or preoccupation (for example, sexual talk associated with knowledge, emulating sexual activity with another child).\n\nSuspect current or past child maltreatment if a child or young person's sexual behaviour is indiscriminate, precocious or coercive.\n\nSuspect sexual abuse if a pre-pubertal child displays or is reported to display unusual sexualised behaviours. Examples include:\n\noral–genital contact with another child or a doll\n\nrequesting to be touched in the genital area\n\ninserting or attempting to insert an object, finger or penis into another child's vagina or anus.\n\nConsider child maltreatment if a child or young person has run away from home or care, or is living in alternative accommodation without the full agreement of their parents or carers.\n\n# Parent–child interactions\n\nConsider emotional abuse if there is concern that parent– or carer–child interactions may be harmful. Examples include:\n\nNegativity or hostility towards a child or young person.\n\nRejection or scapegoating of a child or young person.\n\nDevelopmentally inappropriate expectations of or interactions with a child, including inappropriate threats or methods of disciplining.\n\nExposure to frightening or traumatic experiences, including domestic abuse.\n\nUsing the child for the fulfilment of the adult's needs (for example, in marital disputes).\n\nFailure to promote the child's appropriate socialisation (for example, involving children in unlawful activities, isolation, not providing stimulation or education).\n\nSuspect emotional abuse if the interactions observed in recommendation 1.5.1 are persistent.\n\nConsider child maltreatment if parents or carers are seen or reported to punish a child for wetting or soiling despite professional advice that the symptom is involuntary.\n\nConsider emotional neglect if there is emotional unavailability and unresponsiveness from the parent or carer towards a child or young person and in particular towards an infant.\n\nSuspect emotional neglect if the interaction observed in recommendation 1.5.4 is persistent.\n\nConsider child maltreatment if a parent or carer refuses to allow a child or young person to speak to a healthcare professional on their own when it is necessary for the assessment of the child or young person.", 'Recommendations for research': "The guideline development group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The guideline development group's full set of research recommendations is detailed in the full guideline.\n\n# Fractures\n\nHow can abusive fractures be differentiated from those resulting from conditions that lead to bone fragility and those resulting from accidents, particularly in relation to metaphyseal fractures?\n\n## Why this is important\n\nThe existing evidence base does not fully account for the features that differentiate fractures from different causes in infants and pre-school age children. A prospective comparative study of fractures in physical abuse, those resulting from conditions that lead to bone fragility and those resulting from accidental trauma would help address this question. Any such study should encompass a study of metaphyseal fractures.\n\n# Anogenital warts\n\nWhat is the association between anogenital warts and sexual abuse in children of different ages?\n\n## Why this is important\n\nAnogenital warts can be acquired by vertical transmission, sexual contact and by non-sexual transmission within households. A thorough prospective study is needed to investigate the differential causes of anogenital warts in children. Such a study should include full viral typing of the warts in the index case and contacts where possible.\n\n# Fabricated or induced illness\n\nAre the indicators of fabricated or induced illness as described in the recommendations (see recommendations 1.2.11 and 1.2.12) valid for discriminating fabricated or induced illness from other explanations?\n\n## Why this is important\n\nAlthough the alerting signs have been developed based on clinical experience and are considered clinically useful in detecting fabricated or induced illness, there is a need to establish their discriminant validity. This could be achieved by a prospective longitudinal study.\n\n# Emotional and behavioural states\n\nWhat aspects of behaviours and emotional states as alerting individual signs discriminate maltreated children from non-maltreated children in the healthcare setting?\n\n## Why this is important\n\nMuch of the research in this area uses composite scores from instruments or scenarios to discriminate maltreated from non-maltreated children. To translate these scores into items that are usable for healthcare professionals who are meeting children for the first time, it is necessary to know whether particular behavioural and emotional states can be used to identify maltreated children. A prospective comparative study in the healthcare setting is required.\n\n# Recurrent abdominal pain\n\nWhat is the association between unexplained recurrent abdominal pain and child maltreatment?\n\n## Why this is important\n\nRecurrent abdominal pain is a common presentation in primary care and is often unexplained. A large observational study on the association between unexplained recurrent abdominal pain and child maltreatment is needed."}
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https://www.nice.org.uk/guidance/cg89
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This guideline covers the signs of possible child maltreatment in children and young people aged under 18 years. It aims to raise awareness and help health professionals who are not child protection specialists to identify the features of physical, sexual and emotional abuse, neglect and fabricated or induced illness.
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48decd0886bf24f0e099df5a6301876183d7d111
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nice
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Child abuse and neglect
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Child abuse and neglect
This guideline covers recognising and responding to abuse and neglect in children and young people aged under 18. It covers physical, sexual and emotional abuse, and neglect. The guideline aims to help anyone whose work brings them into contact with children and young people to spot signs of abuse and neglect and to know how to respond. It also supports practitioners who carry out assessments and provide early help and interventions to children, young people, parents and carers.
# About this guideline
# What is the purpose of this guideline?
This guideline provides recommendations based on evidence on how to recognise and respond to child abuse and neglect. It offers a robust and rigorous review of the literature, in addition to lessons from practice, and provides an overview of the research into best practice in child protection. As a result it provides a reliable guide to what works and what is cost effective, as indicated by the best available evidence. It offers practitioners and commissioners a clear guide to the interventions and approaches that are most appropriate, and represent best value for money.
The Department for Education's statutory guidance on working together to safeguard children sets out the statutory responsibilities. This guideline will help practitioners to fulfil those responsibilities by providing recommendations for practice which:
Provide more detail about how to discharge duties set out in existing guidance.
Emphasise areas of practice that have been highlighted by research evidence as:
being of particular importance, or
not always working well in current practice.
# Why do we need this guideline?
Cruelty to children and young people is a criminal offence, and child abuse and neglect can have serious adverse health and social consequences for children and young people. These include:
effects on growth and physical development (NSPCC's The impact of abuse and neglect on the health and mental health of children and young people)
impaired language development and behaviour by age 4
impaired ability to socialise, play and learn (NSPCC's Developing an effective response to neglect and emotional harm to children)
increased likelihood of being involved in antisocial behaviour (NSPCC's Child abuse and neglect in the UK today)
increased likelihood of suicidal thoughts and attempts during adolescence.
These negative consequences can persist into adulthood. Adult survivors of childhood abuse are more likely to misuse substances and to experience mental health problems and physical ill health.
Recognising and responding to child abuse and neglect, or its early signs, is complex. Key challenges practitioners face may include:
Knowing 'when to be worried' that a child or young person is being abused or neglected, and how serious a cause for concern different indicators may be.
Assessing levels of risk and need in relation to child abuse and neglect.
Knowing what early help interventions are effective when there are early signs of child abuse and neglect.
Knowing what interventions are effective in helping children and young people to recover following child abuse and neglect, and to support families in which there has been child abuse and neglect.
This guideline makes evidence-based recommendations aiming to support these areas of practice.
# What does it cover?
The guideline makes recommendations about practice in relation to children and young people (under 18, including unborn babies) at risk of, experiencing, or who have experienced, child abuse or neglect, and their parents and carers. It is not a comprehensive manual for frontline practice with children and families; rather, it focuses on areas where practice needs to improve, and where there is a paucity of guidance in existence.
The guideline does not cover people who are suspected or known to abuse children or young people of whom they are not the parent, step-parent, partner of a parent, family member or carer. Abuse perpetrated by this group is covered, but response (interventions) for this group is not. This is because the principal focus of this guideline is on supporting children and young people, including through supporting their parents and carers. It also does not cover adults (aged 18 or older) who experienced abuse or neglect as children.
# What is the status of this guidance?
The application of the recommendations in this guideline is not mandatory. While there is no legal obligation to implement our guidance, health and social care practitioners are actively encouraged to follow our recommendations to help them deliver the highest quality care. Our recommendations are not intended to replace the professional expertise and judgement of practitioners, as they discuss care and support options with people.
# How does it relate to statutory and non-statutory guidance?
Practitioners must comply with the statutory functions of the agencies they work for under the Children Act 1989 and Children Act 2004, the Children and Families Act 2014 and the Children and Social Work Act 2017 and any other legislation relevant to their profession. They must also comply with the Department for Education's statutory guidance on working together to safeguard children. Practitioners should also follow the Department for Education's non-statutory guidance on what to do if you're worried a child is being abused. Links to 'Working together to safeguard children' are highlighted in each section.
This legislation and guidance describes what individuals and agencies need to do to keep children and young people safe. This guideline provides detail on how they can do this, based on best available evidence about effectiveness and cost effectiveness, and lessons from practice. The guideline will, in turn, be complemented by profession-specific guidance, such as the Department for Education's keeping children safe in education and the General Medical Council's protecting children and young people: doctors' responsibilities.
For more information on the statutory framework and other guidance, see appendices B and C of 'Working together to safeguard children'.
# How has it been developed?
This guideline has been developed by a multidisciplinary guideline committee, using an extensive review of research evidence, expert witnesses and input from a children and young people's expert reference group. See the NICE guidelines manual for more information about how the guideline is developed.
Recommendations about who a particular intervention is for are based on the evidence base. This means that not all interventions are recommended for all groups.
Some recommendations are made with more certainty than others. We word our recommendations to reflect this. In the sections on interventions we use 'offer' to reflect a strong recommendation, usually where there is clear evidence of benefit. We use 'consider' to reflect a recommendation for which the evidence of benefit is less certain. For more information see making decisions using NICE guidelines.
In the section on recognition of child abuse and neglect, we use 'suspect' and 'consider' to indicate the extent to which an alerting feature suggests child abuse and neglect, with 'suspect' indicating stronger evidence of child abuse and neglect.
# What evidence is the guideline based on?
To develop the guideline we looked for evidence about:
The views of children, young people, their parents and carers.
What interventions are effective in working with children and young people at risk of, or who have experienced, child abuse and neglect and their parents and carers (evidence from randomised and quasi-randomised control trials).
What helps and hinders professional practice in working with this group. This included evidence from syntheses of Serious Case Review data.
All the interventions recommended in this guideline are based on at least 1 well-designed study (randomised or quasi-randomised controlled trial). It is important to note that much of the evidence on effective interventions came from the US, but the applicability of this in a UK context was carefully considered by the guideline committee when making the recommendations.
# How does it relate to other NICE guidelines?
This guideline builds on the NICE guideline on child maltreatment, which covers clinical features of maltreatment. This guideline is broader: it extends coverage of alerting features for child abuse and neglect to those which may be observed by other professional groups, and also addresses assessment, early help and response. The committee identified recommendations from the NICE guideline on child maltreatment that are relevant to both health and social care practitioners, and adapted them for this guideline (see section 1.3).
This guideline has also adapted recommendations from the NICE guidelines on children's attachment and domestic abuse. Other relevant NICE guidelines include harmful sexual behaviour among children and young people and looked-after children and young people.
# More information
To find out what NICE has said on topics related to this guideline, see our web pages on safeguarding and children and young people.# Recommendations
Recommendations in sections 1.1 to 1.3 are for anyone whose work brings them into contact with children, young people, parents and carers including those who work in early years, social care, health (including staff in A&E and health drop‑in settings), education (including schools), the police, the voluntary and community sector, youth justice services and adult services.
# Principles for working with children, young people, parents and carers
## Working with children and young people
Take a child-centred approach to all work with children and young people. Involve them in decision-making to the fullest extent possible depending on their age and developmental stage.
Use a range of methods (for example, drawing, books or activities if appropriate) for communicating with children and young people. Tailor communication to:
their age and developmental stage
any disabilities, for example learning disabilities, neurodevelopmental disorders and hearing and visual impairments, seeking assistance from specialists if needed
communication needs, for example by using communication aids or providing an interpreter (ensure the interpreter is not a family member).
In all conversations with children and young people where there are concerns about child abuse and neglect:
explain confidentiality and when you might need to share specific information, and with whom
be sensitive and empathetic
listen actively and use open questions
find out their views and wishes
check your understanding of what the child has told you
be sensitive to any religious or cultural beliefs
use plain language and explain any technical terms
work at the child or young person's pace
give them opportunities to stop the conversation or leave the room, and follow up if this does happen
explain what will happen next and when.
Make sure that conversations take place somewhere private and where the child or young person feels comfortable. Take account of any sensory issues the child or young person may have.
If your interaction with a child or young person involves touching them (for example, a medical examination) explain what you are going to do and ask for consent:
from them if they are over 16 (follow the Mental Capacity Act 2005) or under 16 but Gillick competent or
from their parent or carer if they are under 16 and not Gillick competent.If the child, young person or parent does not agree, respect their wishes unless touching them is essential to their treatment (seek legal advice first unless the need for treatment is immediate). For more guidance on seeking consent for medical examination in children and young people see the General Medical Council's 0-18 years: guidance for all doctors.
Produce a record of conversations with children and young people about child abuse and neglect, and any subsequent interventions as appropriate to their age, developmental stage and language abilities. This could be in writing or another format suitable to meet the child or young person's communication needs. Ensure that you:
Accurately represent their words, using their actual words unless there is a good reason not to, for example if this would include information about another child or young person.
Check that they have understood and agree with what is recorded (this could include both of you signing a written record) and record any disagreements.
Share reports and plans with the child or young person in a way that is appropriate to their age and understanding.
Clearly explain how you will work together with children and young people and do what you have said you will do. If circumstances change and this is no longer possible, explain why as soon as possible, and offer alternative actions.
Agree with the child or young person (if age appropriate) how you will communicate with each other. Give them contact details, including for services available out of hours. When contacting them:
be aware of safety issues such as whether a perpetrator of abuse may have access to a young person's phone
agree what will happen if you contact them and they do not respond, for example following up with their nominated emergency contact.
## Working with parents and carers
Aim to build good working relationships with parents and carers to encourage their engagement and continued participation. This should involve:
actively listening to them, and helping them to deal with any emotional impact of your involvement with their family
being open and honest
seeking to empower them and engaging them in finding solutions
avoiding blame, even if they may be responsible for the child abuse or neglect
inviting, recognising and discussing any worries they have about specific interventions they will be offered
identifying what they are currently doing well, and building on this
making adjustments for any factors which may make it harder for them to get support, such as refugee status, long-term illness, neurodevelopmental disorders, mental health problems, disability or learning disability
being sensitive to religious or cultural beliefs
working in a way that enables trust to develop while maintaining professional boundaries
maintaining professional curiosity and questioning while building good relationships.
When working with parents and carers:
be reliable and available as promised
provide clear information about who to contact, including in an emergency
keep them informed, including explaining what information has been shared, and with whom
support people's communication needs, for example by using communication aids or providing an interpreter
agree records of any conversations, and share relevant documents and plans
be clear about the issues and concerns that have led to your involvement, and inform parents and carers if those concerns are resolved
be clear about the legal context in which your involvement with them is taking place.
## Working with other practitioners
Coordinate your work with practitioners in other agencies so that children, young people, parents and carers do not need to give the same information repeatedly, in line with the Department for Education's advice on information sharing: advice for practitioners providing safeguarding services.
## Critical thinking and analysis
Present information critically and analytically and do not rely solely on protocols, proformas and electronic recording systems to support your professional thinking and planning.
# Factors that increase vulnerability to child abuse and neglect
Vulnerability factors are factors that are known to increase the risk of child abuse and neglect. The presence of these factors does not mean that child abuse or neglect will occur, but practitioners should use their professional judgement to assess their significance in a particular child, young person or family. They should be considered in conjunction with the alerting features in section 1.3.
These recommendations add further detail to the Department for Education's what to do if you're worried a child is being abused about factors that increase vulnerability to child abuse and neglect.
Recognise that vulnerability factors can be interrelated, and that separate factors can combine to increase the risk of harm to a child or young person.
Take into account socioeconomic vulnerability factors for child abuse and neglect, such as poverty and poor housing.
## Family factors
Recognise that the following parental factors increase vulnerability to child abuse and neglect, and that these may be compounded if the parent or carer lacks support from family or friends:
Substance misuse problems.
A history of domestic abuse, including sexual violence or exploitation.
Emotional volatility or having problems managing anger.
Mental health problems which have a significant impact on the tasks of parenting.
Recognise the following as vulnerability factors for recurring or persistent child abuse and neglect:
The parent or carer does not engage with services.
There have been 1 or more previous episodes of child abuse or neglect.
The parent or carer has a mental health or substance misuse problem which has a significant impact on the tasks of parenting.
There is chronic parental stress.
The parent or carer experienced abuse or neglect as a child.
Recognise that neglect and emotional abuse may be more likely to recur or persist than other forms of abuse.
## Child factors
Be aware of the impact of a child or young person's age or gender on their vulnerability to child abuse and neglect, and the likelihood of recognition. For example, boys and young men may be less likely to disclose sexual exploitation (see also the Department for Education's guidance on child sexual exploitation).
Recognise that disabled children and young people are more vulnerable to child abuse or neglect.
# Recognising child abuse and neglect
These recommendations add further detail to the Department for Education's what to do if you're worried a child is being abused on alerting features for child abuse and neglect.
## Children and young people telling others about child abuse or neglect
Recognise that children and young people who are being abused or neglected may find it difficult to tell someone for the first time because:
they may have feelings of confusion, shame, guilt and of being stigmatised
they may not recognise their own experiences as abusive or neglectful
they may be being coerced by (or may be attached to) the person or people abusing or neglecting them
they may fear the consequences of telling someone, for example that no one will believe them, the abuse or neglect might get worse, their family will be split up or excluded by their community, or they will go into care
they may have communication difficulties or may not speak English fluently.
Recognise that children and young people who are being abused or neglected may not acknowledge this when asked, or may not want others to know.
Recognise that children and young people may communicate their abuse or neglect indirectly through their behaviour and appearance (see recommendations 1.3.12 to 1.3.47 and the NICE guideline on child maltreatment).
Take into account that when children and young people communicate their abuse or neglect (either directly or indirectly), it may refer to non-recent abuse or neglect.
Explore your concerns with children and young people in a non-leading way, for example by using open questions, if you are worried that they may be being abused or neglected.
Avoid causing possible prejudice to any formal investigation during early conversations about child abuse and neglect with children and young people by following guidance in the Ministry of Justice's achieving best evidence in criminal proceedings.
If a child or young person tells you they have been abused or neglected, make a referral to children's social care using your local procedures. Explain to the child or young person who you will need to tell, and discuss what will happen next and when.
For people working in regulated professions (healthcare professionals and teachers), if a girl or young woman tells you they have experienced female genital mutilation (FGM), or you observe physical signs of FGM, you must report this to the police, in line with Home Office guidance on mandatory reporting of female genital mutilation.
## Supporting staff to recognise child abuse and neglect
Senior managers should ensure staff working in community settings, including education, can recognise and respond to child abuse and neglect and are aware of child safeguarding guidance relevant to their profession, for example the Department for Education's keeping children safe in education.
Commissioners should ensure all practitioners working in primary care can recognise and respond to child abuse and neglect. Ways to achieve this include:
ensuring that newly qualified practitioners receive training in line with an approved training programme, for example levels 1 to 3 in the Royal College of Paediatrics and Child Health's safeguarding children and young people: roles and competencies for healthcare staff. This should include an understanding of vulnerability factors for child abuse and neglect, such as parental mental health problems, alcohol and substance misuse
giving information to newly qualified practitioners, for example about local resources such as children's centres and parenting groups
giving practitioners advice on how to make a referral to social care.
For guidance on training health and social care practitioners to respond to domestic violence and abuse, follow recommendations 15 and 16 in the NICE guideline on domestic violence and abuse.
## Alerting features for child abuse and neglect
This section describes indicators that should alert practitioners to the possibility of child abuse or neglect. It may be child abuse or neglect occurring now or that has occurred in the past. Note that physical injuries and other clinical indicators are covered in the NICE guideline on child maltreatment.
In this section we use 'consider' and 'suspect' (as defined in the NICE guideline on child maltreatment) to indicate the extent to which an alerting feature suggests child abuse and neglect, with 'suspect' indicating stronger evidence of child abuse and neglect.
If a child is in immediate danger, refer to children's social care and/or the police. Otherwise, in response to any of the alerting features in this section, please follow the steps below in line with the Department for Education's statutory guidance on working together to safeguard children.
For all alerting features:
Seek advice from named or designated colleagues or your organisation's safeguarding lead.
Speak to the child or young person as detailed in recommendations 1.3.5 and 1.3.6, if this is age and developmentally appropriate and it is safe to do so.
For recommendations starting with 'suspect':
Discuss the need for a referral with children's social care using local multi-agency safeguarding procedures.
For recommendations starting with 'consider':
Look for other alerting features in the child or young person's history, presentation or interactions with their parents or carers, now or in the past.
Gather information from other agencies and explain to the family that this information is needed to make an overall assessment of the child or young person. If this is likely to place the child or young person at risk, seek advice from children's social care.
Make sure a review of the child or young person takes place, with the timing depending on your level of concern. Continue to look out for the alerting feature being repeated, or for any other alerting features.
After taking these steps, if your level of concern increases to 'suspect', discuss the need for a referral with children's social care. If you conclude that a referral to children's social care is not required, you may wish to undertake or make a referral for early help assessment in line with local procedures.
As highlighted in the recommendations below, alerting features for child abuse and neglect can be similar to behaviours arising from other causes, such as other stressful life experiences or neurodevelopmental disorders such as autism. However, practitioners should continue to consider the possibility of child abuse or neglect as a cause for behavioural and emotional alerting features, even if they are seemingly explained by another cause.
Practitioners should also recognise that alerting features may be due to non-recent child abuse or neglect. If the alerting features relate to past child abuse or neglect, but the child or young person is now in a place of safety (for example, in an adoptive family), assess the child or young person to see what support they and their parent, carer, foster carer or adoptive parent need to cope with the consequences of the child abuse or neglect.
## Behavioural and emotional alerting features
Consider child abuse and neglect if a child or young person displays or is reported to display a marked change in behaviour or emotional state (see examples below) that is a departure from what would be expected for their age and developmental stage and is not fully explained by a known stressful situation that is not part of child abuse and neglect (for example, bereavement or parental separation) or medical cause. Examples include:
recurrent nightmares containing similar themes
extreme distress
markedly oppositional behaviour
withdrawal of communication
becoming withdrawn.
Consider child abuse and neglect if a child's behaviour or emotional state is not consistent with their age and developmental stage or cannot be fully explained by medical causes, neurodevelopmental disorders (for example, attention deficit hyperactivity disorder , autism spectrum disorders) or other stressful situation that is not part of child abuse or neglect (for example, bereavement or parental separation). Examples of behaviour or emotional states that may fit this description include:
Emotional states:
fearful, withdrawn, low self-esteem
Behaviour:
aggressive, oppositional
habitual body rocking
Interpersonal behaviours:
indiscriminate contact or affection seeking
-ver-friendliness to strangers including healthcare professionals
excessive clinginess
persistently resorting to gaining attention
demonstrating excessively 'good' behaviour to prevent parental or carer disapproval
failing to seek or accept appropriate comfort or affection from an appropriate person when significantly distressed
coercive controlling behaviour towards parents or carers
lack of ability to understand and recognise emotions
very young children showing excessive comforting behaviours when witnessing parental or carer distress.
Consider child abuse and neglect if a child shows repeated, extreme or sustained emotional responses that are out of proportion to a situation and are not expected for the child's age or developmental stage or fully explained by a medical cause, neurodevelopmental disorder (for example, ADHD, autism spectrum disorders) or bipolar disorder and the effects of any known past abuse or neglect have been explored. Examples of these emotional responses include:
anger or frustration expressed as a temper tantrum in a school-aged child
frequent rages at minor provocation
distress expressed as inconsolable crying.
Consider child abuse and neglect if a child shows dissociation (transient episodes of detachment that are outside the child's control and that are distinguished from daydreaming, seizures or deliberate avoidance of interaction) that is not fully explained by a known traumatic event unrelated to maltreatment.
Consider current or past child abuse or neglect if children or young people are showing any of the following behaviours:
substance or alcohol misuse
self-harm
eating disorders
suicidal behaviours
bullying or being bullied.
Consider child abuse and neglect if a child or young person has run away from home or care, or is living in alternative accommodation without the full agreement of their parents or carers.
Consider child abuse and neglect if a child or young person regularly has responsibilities that interfere with the child's essential normal daily activities (for example, school attendance).
Consider child abuse and neglect if a child responds to a health examination or assessment in an unusual, unexpected or developmentally inappropriate way (for example, extreme passivity, resistance or refusal).
For more guidance about responding to potentially harmful sexual behaviours, see the NICE guideline on harmful sexual behaviour among children and young people.
Suspect current or past child abuse and neglect if a child or young person's sexual behaviour is indiscriminate, precocious or coercive.
Suspect child abuse and neglect, and in particular sexual abuse, if a pre‑pubertal child displays or is reported to display repeated or coercive sexualised behaviours or preoccupation (for example, sexual talk associated with knowledge, emulating sexual activity with another child).
Suspect sexual abuse if a pre-pubertal child displays or is reported to display unusual sexualised behaviours. Examples include:
-ral–genital contact with another child or a doll
requesting to be touched in the genital area
inserting or attempting to insert an object, finger or penis into another child's vagina or anus.
Suspect child abuse and neglect if a child repeatedly scavenges, steals, hoards or hides food with no medical explanation (for example Prader–Willi syndrome).
Suspect neglect if you repeatedly observe or hear reports of any of the following in the home that is in the parents' or carers' control:
a poor standard of hygiene that affects a child's health
inadequate provision of food
a living environment that is unsafe for the child's developmental stage. Be aware that it may be difficult to distinguish between neglect and material poverty. However, care should be taken to balance recognition of the constraints on the parents' or carers' ability to meet their children's needs for food, clothing and shelter with an appreciation of how people in similar circumstances have been able to meet those needs.
Suspect neglect if a child is persistently smelly and dirty. Take into account that children often become dirty and smelly during the course of the day. Use judgement to determine if persistent lack of provision or care is a possibility. Examples include:
child seen at times of the day when it is unlikely that they would have had an opportunity to become dirty or smelly (for example, an early morning visit)
if the dirtiness is ingrained.
Consider neglect if a child has severe and persistent infestations, such as scabies or head lice.
Consider neglect if a child's clothing or footwear is consistently inappropriate (for example, for the weather or the child's size). Take into account that instances of inadequate clothing that have a suitable explanation (for example, a sudden change in the weather, slippers worn because they were closest to hand when leaving the house in a rush) or resulting from behaviour associated with neurodevelopmental disorders such as autism would not be alerting features for possible neglect.
Consider neglect if a child displays faltering growth because of lack of provision of an adequate or appropriate diet. NICE has produced a guideline on faltering growth.
Consider current or past physical or emotional child abuse or neglect if a child under 12 shows poorer than expected language abilities for their overall development (particularly in their ability to express their thoughts, wants and needs) that is not explained by other factors, for example neurodevelopmental difficulties or speaking English as a second language.
These recommendations assume that practitioners are seeing a parent or carer and child interacting.
Consider neglect or physical abuse if a child's behaviour towards their parent or carer shows any of the following, particularly if they are not observed in the child's other interactions:
dislike or lack of cooperation
lack of interest or low responsiveness
high levels of anger or annoyance
seeming passive or withdrawn.
Consider emotional abuse if there is concern that parent– or carer–child interactions may be harmful. Examples include:
Negativity or hostility towards a child or young person.
Rejection or scapegoating of a child or young person.
Developmentally inappropriate expectations of or interactions with a child, including inappropriate threats or methods of disciplining.
Exposure to frightening or traumatic experiences.
Using the child for the fulfilment of the adult's needs (for example, in marital disputes).
Failure to promote the child's appropriate socialisation (for example, involving children in unlawful activities, isolation, not providing stimulation or education).
Suspect emotional abuse if the interactions observed in recommendation 1.3.31 are persistent.
Consider emotional neglect if there is emotional unavailability and unresponsiveness from the parent or carer towards a child or young person and in particular towards an infant.
Suspect emotional neglect if the interaction observed in recommendation 1.3.33 is persistent.
Consider child abuse and neglect if parents or carers are seen or reported to punish a child for wetting or soiling despite practitioner advice that the symptom is involuntary.
Consider child abuse and neglect if a parent or carer refuses to allow a child or young person to speak to a practitioner on their own when it is necessary for the assessment of the child or young person.
Consider neglect if parents or carers persistently fail to anticipate dangers and to take precautions to protect their child from harm. However, take into account that achieving a balance between an awareness of risk and allowing children freedom to learn by experience can be difficult.
Consider neglect if the explanation for an injury (for example, a burn, sunburn or an ingestion of a harmful substance) suggests a lack of appropriate supervision.
Consider neglect if parents or carers fail to administer essential prescribed treatment for their child.
Suspect neglect if parents or carers fail to seek medical advice for their child to the extent that the child's health and wellbeing is compromised, including if the child is in ongoing pain.
Consider neglect if parents or carers repeatedly fail to bring their child to follow-up appointments that are essential for their child's health and wellbeing.
Consider neglect if parents or carers persistently fail to engage with relevant child health promotion programmes, which include:
immunisation
health and development reviews
screening.
Consider neglect if parents or carers have access to but persistently fail to obtain treatment for their child's dental caries (tooth decay).
Follow recommendations 1.2.11 and 1.2.12 in the NICE guideline on child maltreatment if you have concerns about fabricated or induced illness.
## Recognising child trafficking
Recognise that children and young people may be trafficked for sexual exploitation and other reasons including:
forced marriage
domestic servitude
working for low or no pay, or in illegal industries
being used for benefit fraud.
Recognise that both girls and boys can be trafficked and that children and young people can be trafficked within and from the UK, as well from other countries.
If you suspect a child or young person may have been trafficked:
make a referral to children's social care and the police
a designated first responder should make a referral to the government's National Referral Mechanism
ensure that concerns about their age and immigration status do not override child protection considerations
recognise that choosing an interpreter from the child's community may represent to them the community that has exploited them
aim to ensure continuity with the same independent interpreter, keyworker or independent advocate.
# Assessing risk and need in relation to child abuse and neglect
These recommendations are for practitioners undertaking:
early help assessment (undertaken by a lead professional)
assessment under Section 17 of the Children Act 1989 (led by a social worker) or
enquiry under Section 47 of the Children Act 1989 (led by a social worker, sometimes jointly with police).
Refer to guidance on early help and statutory assessment in the Department for Education's statutory guidance on working together to safeguard children as well as local protocols for assessment. The following recommendations highlight areas or practice which have been shown by evidence as being of particular importance, or as not always working well in practice.
## Carrying out assessments
During assessment:
-bserve the child or young person, including their relationships with parents or carers
communicate directly with the child or young person without their parent or carer being present, with the parent or carer's consent
explore in a non-leading way any presenting signs or possible history of child abuse and neglect. Do not rely solely on information from the parent or carer in an assessment. See also recommendations 1.1.1 to 1.1.11 about working with children, young people, parents and carers.
When assessing a child or young person follow the principles in recommendations 1.1.2 and 1.1.3.
During assessment, focus primarily on the child or young person's needs but also remember to:
address both the strengths and weaknesses of parents, carers and the wider family network
acknowledge that parenting can change over time, meaning that strengths and weaknesses are not fixed and should be reviewed
focus attention equally on male and female parents and carers.
As part of assessment or enquiry into child abuse and neglect under the Children Act 1989, collect and analyse information about all significant people (including siblings) in the child or young person's care environment, unless it is not safe to do so (for example in cases of domestic abuse or forced marriage) or it could affect the nature of a criminal investigation. Use professional judgement to determine the risks and benefits of including people in assessment in these instances. Gather the following information about each person:
Their personal, social and health history.
Their family history, including experiences of being parented.
Any adverse childhood experiences.
The quality of their relationship with the child or young person.
As part of assessment or enquiry into child abuse and neglect under the Children Act 1989, communicate your concerns honestly to families about child abuse and neglect. Take into account what information should be shared, and with whom, to avoid increasing the risk of harm to the child or young person (and adult victims in cases of domestic abuse).
Organisations should ensure that practitioners conducting assessment in relation to abuse or neglect of disabled children or young people, or those with neurodevelopmental disorders, can access a specialist with knowledge about those children and young people's specific needs and impairments.
Analyse the information collected during assessment and use it to develop a plan describing what services and support will be provided. Make sure the plan is agreed with the child or young person and their family (also see recommendations 1.1.7 and 1.1.11). Analysis should include evaluating the impact of any vulnerability factors and considering their implications for the child or young person.
Review assessments and plans regularly.
# Early help for families showing possible signs of child abuse or neglect
These recommendations are for:
Practitioners involved in early help for families showing possible signs of child abuse and neglect. This could include those undertaking the lead professional role (including a GP, family support worker, teacher, health visitor or special educational needs coordinator) or those providing early help interventions, such as family support workers.
Commissioners of early help services for children, young people and families.
These recommendations support the Department for Education's statutory guidance on working together to safeguard children by highlighting evidence-based programmes that could be offered as part of early help support based on the evidence.
## Supporting families at the early help stage
Provide early help in line with local protocols and 'Working together to safeguard children', and based on an assessment of the needs of children, young people and families.
Discuss early help support and interventions with children, young people and families as part of building close working relationships with them and gaining their consent (see section 1.1 for principles for working with children, young people, parents and carers). Explain what the support will involve and how you think it may help.
Give children, young people and their families a choice of proposed interventions if possible. Recognise that some interventions may not suit that person or family.
Early help should include:
practical support, for example help to attend appointments and details of other agencies that can provide food, clothes and toys
emotional support, including empathy and active listening, and help to develop strategies for coping.
Give families information about local services and resources, including advocacy, that they may find useful.
## Knowledge and skills of practitioners who provide early help
Commissioners and managers should ensure that all practitioners working at the early help stage:
have an understanding of typical and atypical child development
are able to tailor interventions to the needs of the child or young person, parents and carers including any disability or learning disability
understand the parental vulnerability factors for child abuse and neglect (see recommendations 1.2.3 to 1.2.5)
are aware of the possibility of escalation of risk, particularly if family circumstances change
understand how to work with families as a whole in order to better support children and young people.
## Parenting programmes
Consider a parenting programme lasting at least 12 weeks for parents or carers at risk of abusing or neglecting their child or children. Tailor parenting programmes to the specific needs of parents or carers and children (see recommendations 1.5.9 to 1.5.12).
When selecting parenting programmes think about whether parents or carers would benefit from help to:
develop skills in positive behaviour management
address negative beliefs about the child and their own parenting
manage difficult emotions, including anger.
Consider the Triple P – Positive Parenting Program (attributional retraining and anger management) for mothers of young children (up to age 7), who are experiencing anger management difficulties.
Consider a parenting programme for vulnerable mothers (for example, those with a low level of education or income or aged under 18) of preschool children. It should be based on a planned activities training model and focus on equipping parents or carers to prevent challenging behaviour by:
planning and explaining activities
establishing rules and consequences
ignoring minor misbehaviour and using positive interaction skills. This can be provided with or without support provided by text message between training sessions.
Consider the Parents Under Pressure programme for mothers taking part in methadone maintenance programmes.
For parents or carers who have substance misuse problems, include content in the parenting programme to help them address their substance misuse in the context of parenting. For example, help them to address parenting stress which may be a trigger for substance misuse.
## Home visiting programmes
For parents or carers at risk of abusing or neglecting their child or children, consider a weekly home visiting programme lasting at least 6 months, for example the Healthy Families model. This should be in addition to universal health visiting services available through the Department of Health's healthy child programme.
Identify parents and carers who could be supported by a home visiting programme during pregnancy or shortly after birth, wherever possible.
Ensure that the home visiting programme is agreed with families and includes:
support to develop positive parent–child relationships, including:
helping parents to understand children's behaviour more positively
modelling positive parenting behaviours
-bserving and giving feedback on parent–child interactions
helping parents to develop problem-solving skills
support for parents to address the impact of any substance use, previous domestic abuse and mental health problems on their parenting
support to access other relevant services, including health and mental health services, substance misuse services, early years, educational services and other community services
referral to children's social care where necessary, for example if current domestic abuse is discovered.
Ensure that the programme of home visits is delivered by a practitioner who has been trained in delivering that particular home visiting programme.
# Multi-agency response to child abuse and neglect
These recommendations are for practitioners working with children, young people and parents or carers where a child or young person has been abused or neglected, including those assessed as 'in need', likely to suffer significant harm or suffering significant harm.
Practitioners must follow the 'Processes for managing individual cases' in the Department for Education's statutory guidance on working together to safeguard children. These recommendations complement the statutory guidance by adding or emphasising detail which has been shown by evidence to be of particular importance, or not currently happening in practice.
## Multi-agency working
Practitioners supporting children and young people who have been assessed as being 'in need', or suffering (or likely to suffer) significant harm in relation to child abuse or neglect should:
build relationships with other practitioners working with that family
-rganise handovers if new staff members from their agency become involved
ensure actions set out in the 'child in need' or child protection plan are completed.
## Supporting children and young people
Practitioners supporting children and young people who have been assessed as being 'in need' or suffering (or likely to suffer) significant harm in relation to child abuse or neglect should, with leadership and coordination by the social worker, do the following as a minimum:
protect them from further abuse or neglect
support them to explore aspects of their experience and express their feelings
provide early emotional support, including building emotional resilience and strategies for coping with symptoms such as nightmares, flashbacks and self-harm
assess their physical health needs
assess the need for further mental health support
support them to reduce the risk of future abuse if appropriate, for example if a young person is at risk of sexual exploitation.
## Children and young people affected by domestic abuse
For guidance on domestic abuse, see recommendations 10 and 11 in the NICE guideline on domestic violence and abuse.
## Child trafficking
When working with children and young people who have been trafficked, follow the government's guidance on safeguarding children who may have been trafficked.
# Therapeutic interventions for children, young people and families after child abuse and neglect
These recommendations are for:
Social workers and others coordinating support for children and young people, to help them decide what services to refer children and young people to.
Child and adolescent mental health practitioners (psychologists, psychotherapists, psychiatrists), practitioners in specialist family intervention teams (for example social workers) and voluntary sector agencies.
Strategic commissioners of services for children and young people who have been abused or neglected.
Where interventions are recommended for particular groups, this reflects the evidence base for this intervention.
Discuss in detail with children, young people, parents and carers any interventions you offer them, explaining what the intervention will involve and how you think it may help (see section 1.1 for principles for working with children, young people, parents and carers).
Give children, young people, parents and carers a choice of proposed interventions if possible. Recognise that some interventions, although effective, may not suit that person or family.
The choice of intervention should be based on a detailed assessment of the child or young person.
## Therapeutic interventions following child physical abuse, emotional abuse or neglect
This section provides a range of options for therapeutic interventions for children and young people who have experienced physical abuse, emotional abuse or neglect. Some interventions involve the parent or carer who abused or neglected the child, and others involve alternative carers such as foster carers or adoptive parents. An overview of interventions is shown below.
For more recommendations about looked-after children, including children in residential care, see the NICE guideline on looked-after children and young people.
Offer an attachment-based intervention, for example Attachment and Biobehavioural Catch-up, to parents or carers who have neglected or physically abused a child under 5.
Deliver the attachment-based intervention in the parent or carer's home, if possible, and provide at least 10 sessions. Aim to:
improve how they nurture their child, including when the child is distressed
improve their understanding of what their child's behaviour means
help them respond positively to cues and expressions of the child's feelings
improve how they manage their feelings when caring for their child.
Consider child–parent psychotherapy for parents or carers and their children under 5 if the parent or carer has physically or emotionally abused or neglected the child, or the child has been exposed to domestic violence.
Ensure that child–parent psychotherapy:
is based on the Cicchetti and Toth model
consists of weekly sessions (lasting 45–60 minutes) over 1 year
is delivered in the parents' home, if possible, by a therapist trained in the intervention
involves directly observing the child and the parent–child interaction
explores the parents' understanding of the child's behaviour
explores the relationship between the emotional reactions of the parents and their perceptions of the child on the one hand, and the parents' own childhood experiences on the other hand.
Offer an attachment-based intervention in the home to foster carers looking after children under 5 who have been abused or neglected. Aim to help foster carers to:
improve how they nurture their foster child, including when the child is distressed
improve their understanding of what the child's behaviour means
respond positively to cues and expressions of the child's feelings
behave in ways that are not frightening to the child
improve how they manage their feelings when caring for their child.
Consider the attachment-based intervention in recommendation 1.7.8 for adoptive parents and those providing permanence (including special guardians, foster carers or kinship carers) for children under 5 who have been abused or neglected.
Consider a comprehensive parenting intervention, for example SafeCare, for parents and children under 12 if the parent or carer has physically or emotionally abused or neglected the child. This should be delivered by a professional trained in the intervention and comprise weekly home visits for at least 6 months that address:
parent–child interactions
caregiving structures and parenting routines
parental stress
home safety
any other issues that caused the family to come to the attention of services. As part of the intervention, help the family to access other services they might find useful.
Consider parent–child interaction therapy for parents or carers and children under 12 if the parent or carer has physically abused or neglected the child. Combine group sessions for these parents with individual child–parent sessions focusing on developing child-centred interaction and effective discipline skills.
Offer a group-based parent training intervention, for example KEEP, to foster carers of children aged 5 to 12 who have been abused or neglected and are showing problematic behaviours. Include strategies to manage behaviour and discipline positively. Provide group sessions over at least 16 weeks with groups of 8 to 10 foster carers, including video, role play and homework practice.
Consider the intervention in recommendation 1.7.12 for foster carers of children aged 5 to 12 who have been abused or neglected and are not currently showing problematic behaviours.
Consider multi-systemic therapy for child abuse and neglect (MST‑CAN) for parents or carers of children and young people aged 10 to 17 if the parent or carer has abused or neglected their child. This should last 4 to 6 months and:
involve the whole family
address multiple factors contributing to the problem
be delivered in the home or in another convenient location
include a round-the-clock on-call service to support families to manage crises.
For foster carers of children and young people aged 5 to 17 who have been abused or neglected, consider a trauma-informed group parenting intervention, using a trust-based relational intervention as an example. It should last for at least 4 day‑long sessions and help foster carers to:
develop the child or young person's capacity for self-regulation
build trusting relationships
develop proactive and reactive strategies for managing behaviour.
Consider the trauma-informed group parenting intervention in recommendation 1.7.15 for adoptive parents and those providing permanence (including special guardians, foster carers or kinship carers) for children aged 5 to 17 who have been abused or neglected.
## Therapeutic interventions for children, young people and families after sexual abuse
This section provides a range of options for therapeutic interventions for children and young people who have experienced sexual abuse. An overview of interventions is shown below.
Offer group or individual trauma-focused cognitive behavioural therapy over 12 to 16 sessions (more if needed) to children and young people (boys or girls) who have been sexually abused and show symptoms of anxiety, sexualised behaviour or post-traumatic stress disorder. When offering this therapy:
discuss it fully with the child or young person before providing it and make clear that there are other options available if they would prefer
provide separate trauma-focused cognitive behavioural therapy sessions for the non-abusing parent or carer.
For children and young people (boys or girls) aged 8 to 17 who have been sexually abused, consider an intervention, for example 'Letting the future in', that:
emphasises the importance of the therapeutic relationship between the child or young person and therapist
-ffers support tailored to the child or young person's needs, drawing on a range of approaches including counselling, socio-educative and creative (such as drama or art)
includes individual work with the child or young person (up to 20 sessions, extending to 30 as needed) and parallel work with non-abusing parents or carers (up to 8 sessions).
For girls aged 6 to 14 who have been sexually abused and who are showing symptoms of emotional or behavioural disturbance, consider one of the following, after assessing carefully and discussing which option would suit her best:
individual focused psychoanalytic therapy (up to 30 sessions) or
group psychotherapeutic and psychoeducational sessions (up to 18 sessions). Provide separate supportive sessions for the non-abusing parent or carer, helping them to support the child's attendance at therapy, as well as addressing issues within the family.
# Planning and delivering services
These recommendations are for senior managers in agencies responsible for planning and delivering services to children and young people. They provide additional detail to the Department for Education's statutory guidance on working together to safeguard children on strategic arrangements for multi-agency working.
Plan services in a way that enables children, young people, parents and carers to work with the same practitioners over time where possible.
Agencies responsible for planning and delivering services for children and young people should agree terminology across agencies relating to child protection roles and processes, and ensure these are well publicised.
Ensure that local threshold documents set out responses to other forms of abuse including child sexual exploitation, female genital mutilation, honour-based abuse (including forced marriage), child trafficking, serious youth violence and gang-related abuse. Ensure that these are communicated to local agencies, including those providing universal services, so that they are aware of these forms of abuse.
To address the risks posed by sexual exploitation and gang-related abuse, agencies responsible for planning and delivering services for children and young people should put in place:
effective leadership within agencies
a local lead who will coordinate planning and information sharing between agencies.
## Supervision and support for staff
Organisations should support staff working with children and families at risk of or experiencing child abuse and neglect, and provide good quality supervision, tailored to their level of involvement in safeguarding work. This should include:
case management
reflective practice
emotional support
continuing professional development.# Terms used in this guideline
# Alerting feature
Symptoms and signs that may indicate that child abuse or neglect is taking place, and which should prompt practitioners to take action.
# Analysis
Analysis involves organising the information collected during assessment, judging its significance and exploring different perspectives, to identify themes and reach conclusions on what these mean for the child or young person and their family. It should draw on knowledge from research and practice combined with an understanding of the child's needs.
# Attachment-based intervention
Interventions which are based on attachment theory. Attachment-based interventions focus on improving the relationships between children and young people and their key attachment figures (often, parents or carers), for example by helping the parent or carer to respond more sensitively to the child or young person.
# Bullying
Persistent behaviour by a person or group of people that intentionally hurts a child or young person either physically or emotionally.
# Child abuse and neglect
In this guideline child abuse and neglect includes inflicting harm on a child or young person and also failing to protect them from harm. Children and young people may be abused by someone they know in a family or in an institutional or community setting or, more rarely, by someone they don't know (for example through the internet). Some indicators of abuse and neglect may be indicators of current or past abuse and neglect.
# Child sexual exploitation
Child sexual exploitation is a form of child sexual abuse. It occurs where an individual or group takes advantage of an imbalance of power to coerce, manipulate or deceive a child or young person under the age of 18 into sexual activity (a) in exchange for something the victim needs or wants, and/or (b) for the financial advantage or increased status of the perpetrator or facilitator. The victim may have been sexually exploited even if the sexual activity appears consensual. Child sexual exploitation does not always involve physical contact; it can also occur through the use of technology.
# Child trafficking
Recruiting and transporting children and young people for the purposes of exploitation, for example, sexual exploitation, forced labour or services, benefit fraud, domestic servitude or the removal of organs.
# Children and young people
In this guideline 'infant' means aged under 1 year, 'child' means under 13 years and 'young person' means 13 to 17 years.
# Disabled children and young people
Children and young people who meet the Equality Act 2010 definition of disability, namely those who have a physical or mental impairment that has a substantial and long-term negative effect on their ability to do normal daily activities.
# Domestic abuse
Any incident or pattern of incidents of controlling, coercive, threatening behaviour, violence or abuse between those aged 16 or over who are, or have been, intimate partners or family members regardless of gender or sexuality.
# Early help
Support provided early as soon as a problem emerges. Early help can prevent a problem from worsening or further problems from arising.
# Emotional abuse
Persistently treating a child or young person in a way that can cause severe adverse effects on their emotional development. For example, conveying to them that they are worthless or unloved; not giving them opportunities to express their views; deliberately silencing them or making fun of them; imposing inappropriate expectations on them for their age or developmental stage; and serious bullying (including cyber bullying).
# Faltering growth
This term is used in relation to infants and young children whose weight gain occurs more slowly than expected for their age and sex. In the past this was often described as a 'failure to thrive' but this is no longer the preferred term.
# Female genital mutilation
A practice involving removal of or injury to any part of a girl's external genitalia for non-medical purposes. Female genital mutilation is illegal in England and Wales according to the Female Genital Mutilation 2003 Act.
# Forced marriage
A marriage in which one or both partners have not consented (or cannot consent because of a learning disability) to be married and pressure or abuse has been used.
# Foster carer
Foster carers care for children and young people who are 'looked after' in the public care system. They must go through a process of assessment and approval, before providing care for the child or young person as a member of their household. Some are 'kinship foster carers', which means they are relatives or friends who are fostering a child or young person who has entered the public care system.
# Honour-based abuse
Honour-based abuse includes forced marriage and female genital mutilation (FGM). It can be described as a collection of practices used to control behaviour within families or other social groups to protect perceived cultural and religious beliefs and/or honour. Such abuse can occur when perpetrators perceive that a relative has shamed the family or community by breaking their honour code.
# Lead professional
A professional who leads the provision of early help support to children, young people, parents and carers by acting as their advocate and coordinating their support. The lead professional role could be undertaken by a GP, family support worker, teacher, health visitor or a special educational needs coordinator.
# Maltreatment
In line with the NICE guideline on child maltreatment this includes neglect; physical, sexual and emotional abuse; and fabricated or induced illness. It is also used as an 'umbrella' term for all categories of child abuse and neglect, including witnessing domestic violence, forced marriage, child trafficking, female genital mutilation and child sexual exploitation.
# Neglect
The persistent failure to meet a child's basic physical and/or psychological needs, likely to result in the serious impairment of the child's health or development. Neglect may occur during pregnancy as a result of maternal substance abuse. Once a child is born, neglect may involve a parent or carer failing to:
provide adequate food, clothing and shelter (including exclusion from home or abandonment)
protect a child from physical and emotional harm or danger
ensure adequate supervision (including the use of inadequate caregivers)
ensure access to appropriate medical care or treatment.
It may also include neglect of, or unresponsiveness to, a child's basic emotional needs.
# Parent or carer
This guideline uses 'parent or carer' to acknowledge that people other than a child or young person's parent may be caring for them. We have defined 'parent' as the person with parental responsibility for a child, including an adoptive parent, and 'carer' as someone other than a parent who is caring for a child. This could include family members, such as the partner of a parent. Where we are referring specifically to paid carers we use the term 'foster carer'.
# Parenting intervention
A psycho-educational intervention focusing on improving parenting skills.
# Past child abuse or neglect
Abuse or neglect that a child or young person may have experienced but which is no longer occurring. For example, abuse which occurred in a previous family environment before the child or young person was placed in care or with an adoptive family.
# Physical abuse
A form of abuse which may involve hitting, shaking, throwing, poisoning, burning or scalding, drowning, suffocating or otherwise causing physical harm to a child. Physical harm may also be caused when a parent or carer fabricates the symptoms of, or deliberately induces, illness in a child.
# Practitioner
A person working with children and young people who may have a role in safeguarding them.
# Prader-Willi syndrome
A genetic condition leading to a range of symptoms, including over-eating, restricted growth, reduced muscle tone, and learning and behavioural difficulties.
# Regulated profession
Regulated professions as defined in section 5B(2)(a), (11) and (12) of the Female Genital Mutilation Act 2003. A person works in a regulated profession if they are a healthcare professional, a teacher, or (in Wales) if they are a social care worker.
# Sexual abuse
Involves forcing or enticing a child or young person to take part in sexual activities, not necessarily involving a high level of violence, whether or not the child is aware of what is happening. The activities may involve physical contact, including assault by penetration (for example, rape or oral sex) or non-penetrative acts such as masturbation, kissing, rubbing and touching outside of clothing. They may also include non-contact activities, such as involving children in looking at, or in the production of, sexual images, watching sexual activities, encouraging children to behave in sexually inappropriate ways, or grooming a child in preparation for abuse (including through the internet). Sexual abuse is not solely perpetrated by adult males. Women can also commit acts of sexual abuse, as can other children.
# Special guardian
A person who has been granted a special guardianship order (SGO), a private law order which grants someone parental responsibility for a named child or young person. While parents do not lose parental responsibility when an SGO is granted, the special guardian has the exclusive right to exercise it, and make important decisions about the child or young person. Special guardians may also in some circumstances be provided with local authority financial and other support.
# Vulnerability factor
Situations, behaviours or underlying characteristics of children, young people and their parents or carers and their social environment that increase the child or young person's vulnerability to child abuse or neglect.
For other social care terms see the Think Local, Act Personal Care and Support Jargon Buster.# Putting this guideline into practice
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Offering effective therapeutic interventions for children and their parents or carers. Although families who have children on child protection plans usually receive interventions from a social worker, there is a lack of provision of evidence-based therapeutic interventions to support parents, carers, foster carers and adoptive parents to meet the needs of children who have been abused or neglected.
Providing more training and education for all staff who work with children and young people who have experienced abuse and neglect. Training in recognising the signs of child abuse and neglect and when to act on them is a priority, particularly as new forms of abuse emerge. However, increasing training is likely to prove challenging for many organisations because of cuts in resources.
Making multi-agency responses effective across the country. It should begin at the early help stage. Adopting common language and terms, leadership at all levels, agreeing protocols for information sharing and co-locating staff from different agencies who are working on the same, or related, cases or issues all contribute to effective multi-agency working.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for practice that can be done quickly – such as conducting a baseline assessment (see 3 below) – should be shared quickly. This is because health and social care professionals should use guidelines to guide their work and keep their skills and knowledge up to date – as is required by professional regulating bodies such as the Health and Care Professions Council, General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Involve children, young people, parents and carers, foster carers and adoptive parents in identifying how practice needs to change.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Recognition of child sexual abuse
What approaches to practice enable children (both boys and girls) who have been sexually abused to begin to tell practitioners about their experiences earlier, and in a way that does not contaminate the reliability of subsequent court proceedings?
## Why this is important
Research shows that many children and young people who are sexually abused do not tell anyone about their abuse. Among those who do, many delay telling someone for a long time, sometimes until adulthood. We found little research identifying the approaches or techniques that would make it more likely for a child being sexually abused to tell a practitioner about it. Although there is an evidence base on Achieving Best Evidence interviewing as part of a formal investigation, there is less evidence about approaches that can be used at an earlier stage. Studies are needed that would identify effective approaches to enable children to talk about sexual abuse, while ensuring that these early conversations do not contaminate evidence at a later stage in an investigation.
# Recognition of risk and prevention of female genital mutilation
What interventions are effective and cost effective in:
improving practitioners' recognition of children who are at risk of female genital mutilation (FGM) in the UK or overseas?
improving recognition of co-occurring forms of abuse where relevant?
preventing FGM in this group?
## Why this is important
There is a lack of evidence from the UK about how practitioners can be supported to recognise girls and young women who are at risk of FGM and effective interventions to prevent FGM. This is despite evidence that many practitioners are likely to encounter young women at risk of FGM. There is also a lack of evidence about the extent to which FGM is a risk factor or indicator of other forms of abuse, and therefore whether the identification of FGM should be accompanied by other types of assessment and support. The Home Office has developed an FGM recognition and prevention e-learning resource; however, the effectiveness of this resource does not appear to have been evaluated.
# Recognition of risk and prevention of 'honour-based' violence and forced marriage
What interventions are effective and cost effective in:
improving practitioners' recognition of children who are at risk of or experiencing 'honour-based' violence and forced marriage?
preventing 'honour-based' violence and forced marriage?
## Why this is important
There is a lack of evidence from the UK about how practitioners can be supported to recognise children and young people who are at risk of or experiencing 'honour-based' violence, and how to prevent it. There is also little evidence showing which interventions are most effective for recognising young people at risk of forced marriage and for preventing such marriages from taking place. The government's guidance on forced marriage explains the issues around forced marriage, provides a clear definition and distinction from arranged marriage, lists some of the potential warning signs or indicators, and recommends organisational approaches to dealing with forced marriage. However, the effectiveness of these approaches has not been evaluated.
# Early help home visiting
What are the components of effective home visiting programmes for preventing child abuse and neglect in families of children and young people at risk of child abuse and neglect in the UK?
## Why this is important
There are numerous studies, based mostly in the US, involving home visiting programmes for families at risk of child abuse and neglect. The findings of these studies are mixed, with some programmes proving effective but not others. The descriptions of the programmes and their theoretical basis are often poorly reported. It is therefore difficult to ascertain the key 'active ingredients' in a successful home visiting programme. A meta-analytic study seeking to obtain additional information from study authors on the features of home visiting programmes and their effectiveness, for example using statistical modelling, would help in understanding these programmes.
# Effective prevention of child abuse and neglect in the UK
What interventions are effective and cost effective in the UK to prevent abuse and neglect of children and young people in families at risk of, or showing early signs of, abuse and neglect?
## Why this is important
The evidence reviewed for this guideline on the effectiveness of interventions to prevent abuse and neglect of children and young people was predominantly from outside the UK, and focused on home visiting programmes and parenting programmes. High-quality studies (ideally randomised controlled trials) are needed that:
look specifically at the effectiveness of interventions to prevent child abuse and neglect in the UK
focus on interventions already being provided in the UK that may have no or low-quality evidence to support them at present.
# Reducing social isolation and associated child abuse and neglect
What is the impact of social isolation on children, young people and families at risk of abuse and neglect in the UK? What interventions are effective and cost effective in a UK context in reducing social isolation and any associated child abuse and neglect?
## Why this is important
Evidence presented in the NSPCC's how safe are our children? suggests a link between social isolation and child abuse and neglect. However, there is a lack of evidence about what interventions are effective in reducing social isolation and any associated child abuse and neglect. The aim of research should be to inform practitioners and policy-makers of the impact of social isolation, and the methods that lead to successful engagement with socially isolated children, young people and families, and reduction of associated child abuse and neglect.
# Effective interventions for young people who have been abused or neglected
What interventions are effective and cost effective in improving the wellbeing of young people aged 12 to 17 who have experienced abuse or neglect, including those who are now in temporary or permanent alternative care placements or living independently?
## Why this is important
There is little evidence on effective interventions to improve the wellbeing of young people who have experienced abuse and neglect, except for those who have been sexually abused. Studies are needed that evaluate interventions for young people aged 12 and over who have been abused or neglected in the past, but are now in temporary or permanent alternative care placements. These include foster care, kinship care, residential care, special guardianship and adoption.
# Effective interventions for children and young people who have experienced online-facilitated abuse, including online grooming
What interventions are effective and cost effective in improving the wellbeing of children and young people who have experienced online-facilitated abuse, including grooming online?
## Why this is important
There is little evidence on what interventions are effective in helping children and young people recover from trauma following online abuse, including online grooming. In particular, whether existing interventions may be suitable, or whether different kinds of therapeutic support are needed to address the particular features of online abuse.
# Effective interventions for addressing child abuse and neglect in the UK
What interventions, approaches and methodologies provided by social care and voluntary sector services are effective and cost effective in the UK to prevent the recurrence of child abuse and neglect, and to improve the wellbeing of children, young people and families?
## Why this is important
The evidence reviewed for this guideline on the effectiveness of interventions to address abuse and neglect of children and young people was predominantly from outside the UK, and within the health sector (therapeutic interventions). We identified interventions, approaches and methodologies being used by social care and voluntary sector organisations in the UK but many of these could not be included because they have not been evaluated using high-quality research designs. High-quality studies are needed to show policy-makers and practitioners which ones are effective in the UK and in what circumstances.
# Interventions with fathers and male carers
What interventions are effective and cost effective when working with fathers and male carers to improve their parenting in families where children are being, or have been, abused or neglected?
## Why this is important
There is a lack of research evidence from the UK showing what interventions are effective to improve fathers' and male carers' parenting in families where children are being, or have been, abused or neglected. Most studies reviewed for this guideline, both from the UK and elsewhere, focused on female carers. Studies are needed to show what interventions and practices are effective in engaging fathers and male carers, and improving their parenting if needed.
# Interventions with male foster carers and adoptive parents
What interventions are effective and cost effective when working with male foster carers and adoptive parents who are caring for children and young people who have been abused in the past?
## Why this is important
There is a lack of research evidence from the UK on what interventions are effective in working with male foster carers and adoptive parents – much of the existing literature is in relation to female foster carers and adoptive parents.
# Effectiveness of home visiting following child abuse or neglect
Are home visiting interventions effective and cost effective in improving parenting and preventing recurrence of child abuse and neglect in families in which abuse or neglect is occurring or has occurred?
## Why this is important
There is a lack of evidence from the UK on the impact of home visiting on families in which abuse or neglect is occurring or has occurred (as opposed to its impact on prevention). For children who are subject to a child protection plan, home visiting is one of the tools that may be used for monitoring their welfare and their interaction with their parents or carers. It is also used for engaging with parents or carers to address abusive or neglectful behaviours or ensure children are protected. There is a need for studies which identify what practices are effective in ensuring the safety and wellbeing of children and young people.
# Effective interventions for parents or carers with substance misuse problems
What interventions, including family behaviour therapy, are effective and cost effective in improving parenting and preventing recurrence of neglect by parents or carers with substance misuse problems and whose children are on a child protection plan under the category of neglect in the UK?
## Why this is important
There is a lack of evidence from the UK about the impact of family behaviour therapy and other interventions on parents and carers with substance misuse problems who show neglectful parenting. Studies are needed to examine the effectiveness of family behaviour and other interventions, and the timescales for delivering such interventions. In some cases, it may take longer than the 26-week timescale of care proceedings to address parents' substance misuse problems. This research could inform court decisions about whether to extend the time limit if there was a realistic possibility of reunification at the end of the intervention.
# Effectiveness of web-based parenting programmes
Are web-based parenting programmes effective and cost effective for improving parenting and preventing recurrence of child abuse and neglect in families where child abuse or neglect has occurred?
## Why this is important
There is a lack of research data about the impact of web-based parenting programmes on families where child abuse or neglect has occurred. Our review for this guideline identified 1 small-scale US study of a web-based parenting programme for parents of children with abusive head injury. Research would inform practitioners whether this type of parenting programme could be effective for families where child abuse or neglect has occurred, and if so which families would be most likely to benefit.
# Relative effectiveness of interventions to support foster carers
What is the relative effectiveness and cost effectiveness of the KEEP intervention for foster carers of abused or neglected children compared to other interventions?
## Why this is important
There has been no independent UK study of the relative effectiveness of the KEEP intervention for foster carers and abused or neglected children when compared head to head with other interventions for foster carers. (There are effectiveness studies, but these are with a waitlist or service as usual comparator, rather than comparing different forms of support 'head to head'.) Data about outcomes in fostering services which use the KEEP model are kept by the National Implementation Service, which has responsibility for ensuring that model fidelity is maintained, but does not make comparisons with outcomes of other intervention models. A comparison study would help service providers identify the most appropriate model for supporting foster carers and abused or neglected children.
# Peer support for children and young people who have been abused or neglected
What peer support programmes are effective and cost effective in improving the wellbeing of children and young people who have been abused or neglected?
## Why this is important
There is a small amount of research into peer support interventions for children who have been abused or neglected. There is also anecdotal evidence that children who have experienced abuse or neglect would appreciate formally organised peer support in addition to the informal peer support that children often provide each other. A research study, where careful consideration was given to issues like helping peer supporters to manage confidential information about abuse or neglect, could test the success of a formally organised peer support programme.
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{'About this guideline': "# What is the purpose of this guideline?\n\nThis guideline provides recommendations based on evidence on how to recognise and respond to child abuse and neglect. It offers a robust and rigorous review of the literature, in addition to lessons from practice, and provides an overview of the research into best practice in child protection. As a result it provides a reliable guide to what works and what is cost effective, as indicated by the best available evidence. It offers practitioners and commissioners a clear guide to the interventions and approaches that are most appropriate, and represent best value for money.\n\nThe Department for Education's statutory guidance on working together to safeguard children sets out the statutory responsibilities. This guideline will help practitioners to fulfil those responsibilities by providing recommendations for practice which:\n\nProvide more detail about how to discharge duties set out in existing guidance.\n\nEmphasise areas of practice that have been highlighted by research evidence as:\n\n\n\nbeing of particular importance, or\n\nnot always working well in current practice.\n\n\n\n# Why do we need this guideline?\n\nCruelty to children and young people is a criminal offence, and child abuse and neglect can have serious adverse health and social consequences for children and young people. These include:\n\neffects on growth and physical development (NSPCC's The impact of abuse and neglect on the health and mental health of children and young people)\n\nimpaired language development and behaviour by age 4\n\nimpaired ability to socialise, play and learn (NSPCC's Developing an effective response to neglect and emotional harm to children)\n\nincreased likelihood of being involved in antisocial behaviour (NSPCC's Child abuse and neglect in the UK today)\n\nincreased likelihood of suicidal thoughts and attempts during adolescence.\n\nThese negative consequences can persist into adulthood. Adult survivors of childhood abuse are more likely to misuse substances and to experience mental health problems and physical ill health.\n\nRecognising and responding to child abuse and neglect, or its early signs, is complex. Key challenges practitioners face may include:\n\nKnowing 'when to be worried' that a child or young person is being abused or neglected, and how serious a cause for concern different indicators may be.\n\nAssessing levels of risk and need in relation to child abuse and neglect.\n\nKnowing what early help interventions are effective when there are early signs of child abuse and neglect.\n\nKnowing what interventions are effective in helping children and young people to recover following child abuse and neglect, and to support families in which there has been child abuse and neglect.\n\nThis guideline makes evidence-based recommendations aiming to support these areas of practice.\n\n# What does it cover?\n\nThe guideline makes recommendations about practice in relation to children and young people (under 18, including unborn babies) at risk of, experiencing, or who have experienced, child abuse or neglect, and their parents and carers. It is not a comprehensive manual for frontline practice with children and families; rather, it focuses on areas where practice needs to improve, and where there is a paucity of guidance in existence.\n\nThe guideline does not cover people who are suspected or known to abuse children or young people of whom they are not the parent, step-parent, partner of a parent, family member or carer. Abuse perpetrated by this group is covered, but response (interventions) for this group is not. This is because the principal focus of this guideline is on supporting children and young people, including through supporting their parents and carers. It also does not cover adults (aged 18 or older) who experienced abuse or neglect as children.\n\n# What is the status of this guidance?\n\nThe application of the recommendations in this guideline is not mandatory. While there is no legal obligation to implement our guidance, health and social care practitioners are actively encouraged to follow our recommendations to help them deliver the highest quality care. Our recommendations are not intended to replace the professional expertise and judgement of practitioners, as they discuss care and support options with people.\n\n# How does it relate to statutory and non-statutory guidance?\n\nPractitioners must comply with the statutory functions of the agencies they work for under the Children Act 1989 and Children Act 2004, the Children and Families Act 2014 and the Children and Social Work Act 2017 and any other legislation relevant to their profession. They must also comply with the Department for Education's statutory guidance on working together to safeguard children. Practitioners should also follow the Department for Education's non-statutory guidance on what to do if you're worried a child is being abused. Links to 'Working together to safeguard children' are highlighted in each section.\n\nThis legislation and guidance describes what individuals and agencies need to do to keep children and young people safe. This guideline provides detail on how they can do this, based on best available evidence about effectiveness and cost effectiveness, and lessons from practice. The guideline will, in turn, be complemented by profession-specific guidance, such as the Department for Education's keeping children safe in education and the General Medical Council's protecting children and young people: doctors' responsibilities.\n\nFor more information on the statutory framework and other guidance, see appendices B and C of 'Working together to safeguard children'.\n\n# How has it been developed?\n\nThis guideline has been developed by a multidisciplinary guideline committee, using an extensive review of research evidence, expert witnesses and input from a children and young people's expert reference group. See the NICE guidelines manual for more information about how the guideline is developed.\n\nRecommendations about who a particular intervention is for are based on the evidence base. This means that not all interventions are recommended for all groups.\n\nSome recommendations are made with more certainty than others. We word our recommendations to reflect this. In the sections on interventions we use 'offer' to reflect a strong recommendation, usually where there is clear evidence of benefit. We use 'consider' to reflect a recommendation for which the evidence of benefit is less certain. For more information see making decisions using NICE guidelines.\n\nIn the section on recognition of child abuse and neglect, we use 'suspect' and 'consider' to indicate the extent to which an alerting feature suggests child abuse and neglect, with 'suspect' indicating stronger evidence of child abuse and neglect.\n\n# What evidence is the guideline based on?\n\nTo develop the guideline we looked for evidence about:\n\nThe views of children, young people, their parents and carers.\n\nWhat interventions are effective in working with children and young people at risk of, or who have experienced, child abuse and neglect and their parents and carers (evidence from randomised and quasi-randomised control trials).\n\nWhat helps and hinders professional practice in working with this group. This included evidence from syntheses of Serious Case Review data.\n\nAll the interventions recommended in this guideline are based on at least 1 well-designed study (randomised or quasi-randomised controlled trial). It is important to note that much of the evidence on effective interventions came from the US, but the applicability of this in a UK context was carefully considered by the guideline committee when making the recommendations.\n\n# How does it relate to other NICE guidelines?\n\nThis guideline builds on the NICE guideline on child maltreatment, which covers clinical features of maltreatment. This guideline is broader: it extends coverage of alerting features for child abuse and neglect to those which may be observed by other professional groups, and also addresses assessment, early help and response. The committee identified recommendations from the NICE guideline on child maltreatment that are relevant to both health and social care practitioners, and adapted them for this guideline (see section 1.3).\n\nThis guideline has also adapted recommendations from the NICE guidelines on children's attachment and domestic abuse. Other relevant NICE guidelines include harmful sexual behaviour among children and young people and looked-after children and young people.\n\n# More information\n\nTo find out what NICE has said on topics related to this guideline, see our web pages on safeguarding and children and young people.", 'Recommendations': "Recommendations in sections 1.1 to 1.3 are for anyone whose work brings them into contact with children, young people, parents and carers including those who work in early years, social care, health (including staff in A&E and health drop‑in settings), education (including schools), the police, the voluntary and community sector, youth justice services and adult services.\n\n# Principles for working with children, young people, parents and carers\n\n## Working with children and young people\n\nTake a child-centred approach to all work with children and young people. Involve them in decision-making to the fullest extent possible depending on their age and developmental stage.\n\nUse a range of methods (for example, drawing, books or activities if appropriate) for communicating with children and young people. Tailor communication to:\n\ntheir age and developmental stage\n\nany disabilities, for example learning disabilities, neurodevelopmental disorders and hearing and visual impairments, seeking assistance from specialists if needed\n\ncommunication needs, for example by using communication aids or providing an interpreter (ensure the interpreter is not a family member).\n\nIn all conversations with children and young people where there are concerns about child abuse and neglect:\n\nexplain confidentiality and when you might need to share specific information, and with whom\n\nbe sensitive and empathetic\n\nlisten actively and use open questions\n\nfind out their views and wishes\n\ncheck your understanding of what the child has told you\n\nbe sensitive to any religious or cultural beliefs\n\nuse plain language and explain any technical terms\n\nwork at the child or young person's pace\n\ngive them opportunities to stop the conversation or leave the room, and follow up if this does happen\n\nexplain what will happen next and when.\n\nMake sure that conversations take place somewhere private and where the child or young person feels comfortable. Take account of any sensory issues the child or young person may have.\n\nIf your interaction with a child or young person involves touching them (for example, a medical examination) explain what you are going to do and ask for consent:\n\nfrom them if they are over 16 (follow the Mental Capacity Act 2005) or under 16 but Gillick competent\xa0or\n\nfrom their parent or carer if they are under 16 and not Gillick competent.If the child, young person or parent does not agree, respect their wishes unless touching them is essential to their treatment (seek legal advice first unless the need for treatment is immediate). For more guidance on seeking consent for medical examination in children and young people see the General Medical Council's 0-18 years: guidance for all doctors.\n\nProduce a record of conversations with children and young people about child abuse and neglect, and any subsequent interventions as appropriate to their age, developmental stage and language abilities. This could be in writing or another format suitable to meet the child or young person's communication needs. Ensure that you:\n\nAccurately represent their words, using their actual words unless there is a good reason not to, for example if this would include information about another child or young person.\n\nCheck that they have understood and agree with what is recorded (this could include both of you signing a written record) and record any disagreements.\n\nShare reports and plans with the child or young person in a way that is appropriate to their age and understanding.\n\nClearly explain how you will work together with children and young people and do what you have said you will do. If circumstances change and this is no longer possible, explain why as soon as possible, and offer alternative actions.\n\nAgree with the child or young person (if age appropriate) how you will communicate with each other. Give them contact details, including for services available out of hours. When contacting them:\n\nbe aware of safety issues such as whether a perpetrator of abuse may have access to a young person's phone\n\nagree what will happen if you contact them and they do not respond, for example following up with their nominated emergency contact.\n\n## Working with parents and carers\n\nAim to build good working relationships with parents and carers to encourage their engagement and continued participation. This should involve:\n\nactively listening to them, and helping them to deal with any emotional impact of your involvement with their family\n\nbeing open and honest\n\nseeking to empower them and engaging them in finding solutions\n\navoiding blame, even if they may be responsible for the child abuse or neglect\n\ninviting, recognising and discussing any worries they have about specific interventions they will be offered\n\nidentifying what they are currently doing well, and building on this\n\nmaking adjustments for any factors which may make it harder for them to get support, such as refugee status, long-term illness, neurodevelopmental disorders, mental health problems, disability or learning disability\n\nbeing sensitive to religious or cultural beliefs\n\nworking in a way that enables trust to develop while maintaining professional boundaries\n\nmaintaining professional curiosity and questioning while building good relationships.\n\nWhen working with parents and carers:\n\nbe reliable and available as promised\n\nprovide clear information about who to contact, including in an emergency\n\nkeep them informed, including explaining what information has been shared, and with whom\n\nsupport people's communication needs, for example by using communication aids or providing an interpreter\n\nagree records of any conversations, and share relevant documents and plans\n\nbe clear about the issues and concerns that have led to your involvement, and inform parents and carers if those concerns are resolved\n\nbe clear about the legal context in which your involvement with them is taking place.\n\n## Working with other practitioners\n\nCoordinate your work with practitioners in other agencies so that children, young people, parents and carers do not need to give the same information repeatedly, in line with the Department for Education's advice on information sharing: advice for practitioners providing safeguarding services.\n\n## Critical thinking and analysis\n\nPresent information critically and analytically and do not rely solely on protocols, proformas and electronic recording systems to support your professional thinking and planning.\n\n# Factors that increase vulnerability to child abuse and neglect\n\nVulnerability factors are factors that are known to increase the risk of child abuse and neglect. The presence of these factors does not mean that child abuse or neglect will occur, but practitioners should use their professional judgement to assess their significance in a particular child, young person or family. They should be considered in conjunction with the alerting features in section 1.3.\n\nThese recommendations add further detail to the Department for Education's what to do if you're worried a child is being abused about factors that increase vulnerability to child abuse and neglect.\n\nRecognise that vulnerability factors can be interrelated, and that separate factors can combine to increase the risk of harm to a child or young person.\n\nTake into account socioeconomic vulnerability factors for child abuse and neglect, such as poverty and poor housing.\n\n## Family factors\n\nRecognise that the following parental factors increase vulnerability to child abuse and neglect, and that these may be compounded if the parent or carer lacks support from family or friends:\n\nSubstance misuse problems.\n\nA history of domestic abuse, including sexual violence or exploitation.\n\nEmotional volatility or having problems managing anger.\n\nMental health problems which have a significant impact on the tasks of parenting.\n\nRecognise the following as vulnerability factors for recurring or persistent child abuse and neglect:\n\nThe parent or carer does not engage with services.\n\nThere have been 1 or more previous episodes of child abuse or neglect.\n\nThe parent or carer has a mental health or substance misuse problem which has a significant impact on the tasks of parenting.\n\nThere is chronic parental stress.\n\nThe parent or carer experienced abuse or neglect as a child.\n\nRecognise that neglect and emotional abuse may be more likely to recur or persist than other forms of abuse.\n\n## Child factors\n\nBe aware of the impact of a child or young person's age or gender on their vulnerability to child abuse and neglect, and the likelihood of recognition. For example, boys and young men may be less likely to disclose sexual exploitation (see also the Department for Education's guidance on child sexual exploitation).\n\nRecognise that disabled children and young people are more vulnerable to child abuse or neglect.\n\n# Recognising child abuse and neglect\n\nThese recommendations add further detail to the Department for Education's what to do if you're worried a child is being abused on alerting features for child abuse and neglect.\n\n## Children and young people telling others about child abuse or neglect\n\nRecognise that children and young people who are being abused or neglected may find it difficult to tell someone for the first time because:\n\nthey may have feelings of confusion, shame, guilt and of being stigmatised\n\nthey may not recognise their own experiences as abusive or neglectful\n\nthey may be being coerced by (or may be attached to) the person or people abusing or neglecting them\n\nthey may fear the consequences of telling someone, for example that no one will believe them, the abuse or neglect might get worse, their family will be split up or excluded by their community, or they will go into care\n\nthey may have communication difficulties or may not speak English fluently.\n\nRecognise that children and young people who are being abused or neglected may not acknowledge this when asked, or may not want others to know.\n\nRecognise that children and young people may communicate their abuse or neglect indirectly through their behaviour and appearance (see recommendations 1.3.12 to 1.3.47 and the NICE guideline on child maltreatment).\n\nTake into account that when children and young people communicate their abuse or neglect (either directly or indirectly), it may refer to non-recent abuse or neglect.\n\nExplore your concerns with children and young people in a non-leading way, for example by using open questions, if you are worried that they may be being abused or neglected.\n\nAvoid causing possible prejudice to any formal investigation during early conversations about child abuse and neglect with children and young people by following guidance in the Ministry of Justice's achieving best evidence in criminal proceedings.\n\nIf a child or young person tells you they have been abused or neglected, make a referral to children's social care using your local procedures. Explain to the child or young person who you will need to tell, and discuss what will happen next and when.\n\nFor people working in regulated professions (healthcare professionals and teachers), if a girl or young woman tells you they have experienced female genital mutilation (FGM), or you observe physical signs of FGM, you must report this to the police, in line with Home Office guidance on mandatory reporting of female genital mutilation.\n\n## Supporting staff to recognise child abuse and neglect\n\nSenior managers should ensure staff working in community settings, including education, can recognise and respond to child abuse and neglect and are aware of child safeguarding guidance relevant to their profession, for example the Department for Education's keeping children safe in education.\n\nCommissioners should ensure all practitioners working in primary care can recognise and respond to child abuse and neglect. Ways to achieve this include:\n\nensuring that newly qualified practitioners receive training in line with an approved training programme, for example levels 1 to 3 in the Royal College of Paediatrics and Child Health's safeguarding children and young people: roles and competencies for healthcare staff. This should include an understanding of vulnerability factors for child abuse and neglect, such as parental mental health problems, alcohol and substance misuse\n\ngiving information to newly qualified practitioners, for example about local resources such as children's centres and parenting groups\n\ngiving practitioners advice on how to make a referral to social care.\n\nFor guidance on training health and social care practitioners to respond to domestic violence and abuse, follow recommendations 15 and 16 in the NICE guideline on domestic violence and abuse.\n\n## Alerting features for child abuse and neglect\n\nThis section describes indicators that should alert practitioners to the possibility of child abuse or neglect. It may be child abuse or neglect occurring now or that has occurred in the past. Note that physical injuries and other clinical indicators are covered in the NICE guideline on child maltreatment.\n\nIn this section we use 'consider' and 'suspect' (as defined in the NICE guideline on child maltreatment) to indicate the extent to which an alerting feature suggests child abuse and neglect, with 'suspect' indicating stronger evidence of child abuse and neglect.\n\nIf a child is in immediate danger, refer to children's social care and/or the police. Otherwise, in response to any of the alerting features in this section, please follow the steps below in line with the Department for Education's statutory guidance on working together to safeguard children.\n\nFor all alerting features:\n\nSeek advice from named or designated colleagues or your organisation's safeguarding lead.\n\nSpeak to the child or young person as detailed in recommendations 1.3.5 and 1.3.6, if this is age and developmentally appropriate and it is safe to do so.\n\nFor recommendations starting with 'suspect':\n\nDiscuss the need for a referral with children's social care using local multi-agency safeguarding procedures.\n\nFor recommendations starting with 'consider':\n\nLook for other alerting features in the child or young person's history, presentation or interactions with their parents or carers, now or in the past.\n\nGather information from other agencies and explain to the family that this information is needed to make an overall assessment of the child or young person. If this is likely to place the child or young person at risk, seek advice from children's social care.\n\nMake sure a review of the child or young person takes place, with the timing depending on your level of concern. Continue to look out for the alerting feature being repeated, or for any other alerting features.\n\nAfter taking these steps, if your level of concern increases to 'suspect', discuss the need for a referral with children's social care. If you conclude that a referral to children's social care is not required, you may wish to undertake or make a referral for early help assessment in line with local procedures.\n\nAs highlighted in the recommendations below, alerting features for child abuse and neglect can be similar to behaviours arising from other causes, such as other stressful life experiences or neurodevelopmental disorders such as autism. However, practitioners should continue to consider the possibility of child abuse or neglect as a cause for behavioural and emotional alerting features, even if they are seemingly explained by another cause.\n\nPractitioners should also recognise that alerting features may be due to non-recent child abuse or neglect. If the alerting features relate to past child abuse or neglect, but the child or young person is now in a place of safety (for example, in an adoptive family), assess the child or young person to see what support they and their parent, carer, foster carer or adoptive parent need to cope with the consequences of the child abuse or neglect.\n\n## Behavioural and emotional alerting features\n\nConsider child abuse and neglect if a child or young person displays or is reported to display a marked change in behaviour or emotional state (see examples below) that is a departure from what would be expected for their age and developmental stage and is not fully explained by a known stressful situation that is not part of child abuse and neglect (for example, bereavement or parental separation) or medical cause. Examples include:\n\nrecurrent nightmares containing similar themes\n\nextreme distress\n\nmarkedly oppositional behaviour\n\nwithdrawal of communication\n\nbecoming withdrawn.\n\nConsider child abuse and neglect if a child's behaviour or emotional state is not consistent with their age and developmental stage or cannot be fully explained by medical causes, neurodevelopmental disorders (for example, attention deficit hyperactivity disorder [ADHD], autism spectrum disorders) or other stressful situation that is not part of child abuse or neglect (for example, bereavement or parental separation). Examples of behaviour or emotional states that may fit this description include:\n\nEmotional states:\n\n\n\nfearful, withdrawn, low self-esteem\n\n\n\nBehaviour:\n\n\n\naggressive, oppositional\n\nhabitual body rocking\n\n\n\nInterpersonal behaviours:\n\n\n\nindiscriminate contact or affection seeking\n\nover-friendliness to strangers including healthcare professionals\n\nexcessive clinginess\n\npersistently resorting to gaining attention\n\ndemonstrating excessively 'good' behaviour to prevent parental or carer disapproval\n\nfailing to seek or accept appropriate comfort or affection from an appropriate person when significantly distressed\n\ncoercive controlling behaviour towards parents or carers\n\nlack of ability to understand and recognise emotions\n\nvery young children showing excessive comforting behaviours when witnessing parental or carer distress.\n\n\n\nConsider child abuse and neglect if a child shows repeated, extreme or sustained emotional responses that are out of proportion to a situation and are not expected for the child's age or developmental stage or fully explained by a medical cause, neurodevelopmental disorder (for example, ADHD, autism spectrum disorders) or bipolar disorder and the effects of any known past abuse or neglect have been explored. Examples of these emotional responses include:\n\nanger or frustration expressed as a temper tantrum in a school-aged child\n\nfrequent rages at minor provocation\n\ndistress expressed as inconsolable crying.\n\nConsider child abuse and neglect if a child shows dissociation (transient episodes of detachment that are outside the child's control and that are distinguished from daydreaming, seizures or deliberate avoidance of interaction) that is not fully explained by a known traumatic event unrelated to maltreatment.\n\nConsider current or past child abuse or neglect if children or young people are showing any of the following behaviours:\n\nsubstance or alcohol misuse\n\nself-harm\n\neating disorders\n\nsuicidal behaviours\n\nbullying or being bullied.\n\nConsider child abuse and neglect if a child or young person has run away from home or care, or is living in alternative accommodation without the full agreement of their parents or carers.\n\nConsider child abuse and neglect if a child or young person regularly has responsibilities that interfere with the child's essential normal daily activities (for example, school attendance).\n\nConsider child abuse and neglect if a child responds to a health examination or assessment in an unusual, unexpected or developmentally inappropriate way (for example, extreme passivity, resistance or refusal).\n\nFor more guidance about responding to potentially harmful sexual behaviours, see the NICE guideline on harmful sexual behaviour among children and young people.\n\nSuspect current or past child abuse and neglect if a child or young person's sexual behaviour is indiscriminate, precocious or coercive.\n\nSuspect child abuse and neglect, and in particular sexual abuse, if a pre‑pubertal child displays or is reported to display repeated or coercive sexualised behaviours or preoccupation (for example, sexual talk associated with knowledge, emulating sexual activity with another child).\n\nSuspect sexual abuse if a pre-pubertal child displays or is reported to display unusual sexualised behaviours. Examples include:\n\noral–genital contact with another child or a doll\n\nrequesting to be touched in the genital area\n\ninserting or attempting to insert an object, finger or penis into another child's vagina or anus.\n\nSuspect child abuse and neglect if a child repeatedly scavenges, steals, hoards or hides food with no medical explanation (for example Prader–Willi syndrome).\n\nSuspect neglect if you repeatedly observe or hear reports of any of the following in the home that is in the parents' or carers' control:\n\na poor standard of hygiene that affects a child's health\n\ninadequate provision of food\n\na living environment that is unsafe for the child's developmental stage. Be aware that it may be difficult to distinguish between neglect and material poverty. However, care should be taken to balance recognition of the constraints on the parents' or carers' ability to meet their children's needs for food, clothing and shelter with an appreciation of how people in similar circumstances have been able to meet those needs.\n\nSuspect neglect if a child is persistently smelly and dirty. Take into account that children often become dirty and smelly during the course of the day. Use judgement to determine if persistent lack of provision or care is a possibility. Examples include:\n\nchild seen at times of the day when it is unlikely that they would have had an opportunity to become dirty or smelly (for example, an early morning visit)\n\nif the dirtiness is ingrained.\n\nConsider neglect if a child has severe and persistent infestations, such as scabies or head lice.\n\nConsider neglect if a child's clothing or footwear is consistently inappropriate (for example, for the weather or the child's size). Take into account that instances of inadequate clothing that have a suitable explanation (for example, a sudden change in the weather, slippers worn because they were closest to hand when leaving the house in a rush) or resulting from behaviour associated with neurodevelopmental disorders such as autism would not be alerting features for possible neglect.\n\nConsider neglect if a child displays faltering growth because of lack of provision of an adequate or appropriate diet. NICE has produced a guideline on faltering growth.\n\nConsider current or past physical or emotional child abuse or neglect if a child under 12 shows poorer than expected language abilities for their overall development (particularly in their ability to express their thoughts, wants and needs) that is not explained by other factors, for example neurodevelopmental difficulties or speaking English as a second language.\n\nThese recommendations assume that practitioners are seeing a parent or carer and child interacting.\n\nConsider neglect or physical abuse if a child's behaviour towards their parent or carer shows any of the following, particularly if they are not observed in the child's other interactions:\n\ndislike or lack of cooperation\n\nlack of interest or low responsiveness\n\nhigh levels of anger or annoyance\n\nseeming passive or withdrawn.\n\nConsider emotional abuse if there is concern that parent– or carer–child interactions may be harmful. Examples include:\n\nNegativity or hostility towards a child or young person.\n\nRejection or scapegoating of a child or young person.\n\nDevelopmentally inappropriate expectations of or interactions with a child, including inappropriate threats or methods of disciplining.\n\nExposure to frightening or traumatic experiences.\n\nUsing the child for the fulfilment of the adult's needs (for example, in marital disputes).\n\nFailure to promote the child's appropriate socialisation (for example, involving children in unlawful activities, isolation, not providing stimulation or education).\n\nSuspect emotional abuse if the interactions observed in recommendation 1.3.31 are persistent.\n\nConsider emotional neglect if there is emotional unavailability and unresponsiveness from the parent or carer towards a child or young person and in particular towards an infant.\n\nSuspect emotional neglect if the interaction observed in recommendation 1.3.33 is persistent.\n\nConsider child abuse and neglect if parents or carers are seen or reported to punish a child for wetting or soiling despite practitioner advice that the symptom is involuntary.\n\nConsider child abuse and neglect if a parent or carer refuses to allow a child or young person to speak to a practitioner on their own when it is necessary for the assessment of the child or young person.\n\nConsider neglect if parents or carers persistently fail to anticipate dangers and to take precautions to protect their child from harm. However, take into account that achieving a balance between an awareness of risk and allowing children freedom to learn by experience can be difficult.\n\nConsider neglect if the explanation for an injury (for example, a burn, sunburn or an ingestion of a harmful substance) suggests a lack of appropriate supervision.\n\nConsider neglect if parents or carers fail to administer essential prescribed treatment for their child.\n\nSuspect neglect if parents or carers fail to seek medical advice for their child to the extent that the child's health and wellbeing is compromised, including if the child is in ongoing pain.\n\nConsider neglect if parents or carers repeatedly fail to bring their child to follow-up appointments that are essential for their child's health and wellbeing.\n\nConsider neglect if parents or carers persistently fail to engage with relevant child health promotion programmes, which include:\n\nimmunisation\n\nhealth and development reviews\n\nscreening.\n\nConsider neglect if parents or carers have access to but persistently fail to obtain treatment for their child's dental caries (tooth decay).\n\nFollow recommendations 1.2.11 and 1.2.12 in the NICE guideline on child maltreatment if you have concerns about fabricated or induced illness.\n\n## Recognising child trafficking\n\nRecognise that children and young people may be trafficked for sexual exploitation and other reasons including:\n\nforced marriage\n\ndomestic servitude\n\nworking for low or no pay, or in illegal industries\n\nbeing used for benefit fraud.\n\nRecognise that both girls and boys can be trafficked and that children and young people can be trafficked within and from the UK, as well from other countries.\n\nIf you suspect a child or young person may have been trafficked:\n\nmake a referral to children's social care and the police\n\na designated first responder should make a referral to the government's National Referral Mechanism\n\nensure that concerns about their age and immigration status do not override child protection considerations\n\nrecognise that choosing an interpreter from the child's community may represent to them the community that has exploited them\n\naim to ensure continuity with the same independent interpreter, keyworker or independent advocate.\n\n# Assessing risk and need in relation to child abuse and neglect\n\nThese recommendations are for practitioners undertaking:\n\nearly help assessment (undertaken by a lead professional)\n\nassessment under Section 17 of the Children Act 1989 (led by a social worker) or\n\nenquiry under Section 47 of the Children Act 1989 (led by a social worker, sometimes jointly with police).\n\nRefer to guidance on early help and statutory assessment in the Department for Education's statutory guidance on working together to safeguard children as well as local protocols for assessment. The following recommendations highlight areas or practice which have been shown by evidence as being of particular importance, or as not always working well in practice.\n\n## Carrying out assessments\n\nDuring assessment:\n\nobserve the child or young person, including their relationships with parents or carers\n\ncommunicate directly with the child or young person without their parent or carer being present, with the parent or carer's consent\n\nexplore in a non-leading way any presenting signs or possible history of child abuse and neglect. Do not rely solely on information from the parent or carer in an assessment. See also recommendations 1.1.1 to 1.1.11 about working with children, young people, parents and carers.\n\nWhen assessing a child or young person follow the principles in recommendations 1.1.2 and 1.1.3.\n\nDuring assessment, focus primarily on the child or young person's needs but also remember to:\n\naddress both the strengths and weaknesses of parents, carers and the wider family network\n\nacknowledge that parenting can change over time, meaning that strengths and weaknesses are not fixed and should be reviewed\n\nfocus attention equally on male and female parents and carers.\n\nAs part of assessment or enquiry into child abuse and neglect under the Children Act 1989, collect and analyse information about all significant people (including siblings) in the child or young person's care environment, unless it is not safe to do so (for example in cases of domestic abuse or forced marriage) or it could affect the nature of a criminal investigation. Use professional judgement to determine the risks and benefits of including people in assessment in these instances. Gather the following information about each person:\n\nTheir personal, social and health history.\n\nTheir family history, including experiences of being parented.\n\nAny adverse childhood experiences.\n\nThe quality of their relationship with the child or young person.\n\nAs part of assessment or enquiry into child abuse and neglect under the Children Act 1989, communicate your concerns honestly to families about child abuse and neglect. Take into account what information should be shared, and with whom, to avoid increasing the risk of harm to the child or young person (and adult victims in cases of domestic abuse).\n\nOrganisations should ensure that practitioners conducting assessment in relation to abuse or neglect of disabled children or young people, or those with neurodevelopmental disorders, can access a specialist with knowledge about those children and young people's specific needs and impairments.\n\nAnalyse the information collected during assessment and use it to develop a plan describing what services and support will be provided. Make sure the plan is agreed with the child or young person and their family (also see recommendations 1.1.7 and 1.1.11). Analysis should include evaluating the impact of any vulnerability factors and considering their implications for the child or young person.\n\nReview assessments and plans regularly.\n\n# Early help for families showing possible signs of child abuse or neglect\n\nThese recommendations are for:\n\nPractitioners involved in early help for families showing possible signs of child abuse and neglect. This could include those undertaking the lead professional role (including a GP, family support worker, teacher, health visitor or special educational needs coordinator) or those providing early help interventions, such as family support workers.\n\nCommissioners of early help services for children, young people and families.\n\nThese recommendations support the Department for Education's statutory guidance on working together to safeguard children by highlighting evidence-based programmes that could be offered as part of early help support based on the evidence.\n\n## Supporting families at the early help stage\n\nProvide early help in line with local protocols and 'Working together to safeguard children', and based on an assessment of the needs of children, young people and families.\n\nDiscuss early help support and interventions with children, young people and families as part of building close working relationships with them and gaining their consent (see section 1.1 for principles for working with children, young people, parents and carers). Explain what the support will involve and how you think it may help.\n\nGive children, young people and their families a choice of proposed interventions if possible. Recognise that some interventions may not suit that person or family.\n\nEarly help should include:\n\npractical support, for example help to attend appointments and details of other agencies that can provide food, clothes and toys\n\nemotional support, including empathy and active listening, and help to develop strategies for coping.\n\nGive families information about local services and resources, including advocacy, that they may find useful.\n\n## Knowledge and skills of practitioners who provide early help\n\nCommissioners and managers should ensure that all practitioners working at the early help stage:\n\nhave an understanding of typical and atypical child development\n\nare able to tailor interventions to the needs of the child or young person, parents and carers including any disability or learning disability\n\nunderstand the parental vulnerability factors for child abuse and neglect (see recommendations 1.2.3 to 1.2.5)\n\nare aware of the possibility of escalation of risk, particularly if family circumstances change\n\nunderstand how to work with families as a whole in order to better support children and young people.\n\n## Parenting programmes\n\nConsider a parenting programme lasting at least 12\xa0weeks for parents or carers at risk of abusing or neglecting their child or children. Tailor parenting programmes to the specific needs of parents or carers and children (see recommendations 1.5.9 to 1.5.12).\n\nWhen selecting parenting programmes think about whether parents or carers would benefit from help to:\n\ndevelop skills in positive behaviour management\n\naddress negative beliefs about the child and their own parenting\n\nmanage difficult emotions, including anger.\n\nConsider the Triple P – Positive Parenting Program (attributional retraining and anger management) for mothers of young children (up to age\xa07), who are experiencing anger management difficulties.\n\nConsider a parenting programme for vulnerable mothers (for example, those with a low level of education or income or aged under\xa018) of preschool children. It should be based on a planned activities training model and focus on equipping parents or carers to prevent challenging behaviour by:\n\nplanning and explaining activities\n\nestablishing rules and consequences\n\nignoring minor misbehaviour and using positive interaction skills. This can be provided with or without support provided by text message between training sessions.\n\nConsider the Parents Under Pressure programme for mothers taking part in methadone maintenance programmes.\n\nFor parents or carers who have substance misuse problems, include content in the parenting programme to help them address their substance misuse in the context of parenting. For example, help them to address parenting stress which may be a trigger for substance misuse.\n\n## Home visiting programmes\n\nFor parents or carers at risk of abusing or neglecting their child or children, consider a weekly home visiting programme lasting at least 6\xa0months, for example the Healthy Families model. This should be in addition to universal health visiting services available through the Department of Health's healthy child programme.\n\nIdentify parents and carers who could be supported by a home visiting programme during pregnancy or shortly after birth, wherever possible.\n\nEnsure that the home visiting programme is agreed with families and includes:\n\nsupport to develop positive parent–child relationships, including:\n\n\n\nhelping parents to understand children's behaviour more positively\n\nmodelling positive parenting behaviours\n\nobserving and giving feedback on parent–child interactions\n\n\n\nhelping parents to develop problem-solving skills\n\nsupport for parents to address the impact of any substance use, previous domestic abuse and mental health problems on their parenting\n\nsupport to access other relevant services, including health and mental health services, substance misuse services, early years, educational services and other community services\n\nreferral to children's social care where necessary, for example if current domestic abuse is discovered.\n\nEnsure that the programme of home visits is delivered by a practitioner who has been trained in delivering that particular home visiting programme.\n\n# Multi-agency response to child abuse and neglect\n\nThese recommendations are for practitioners working with children, young people and parents or carers where a child or young person has been abused or neglected, including those assessed as 'in need', likely to suffer significant harm or suffering significant harm.\n\nPractitioners must follow the 'Processes for managing individual cases' in the Department for Education's statutory guidance on working together to safeguard children. These recommendations complement the statutory guidance by adding or emphasising detail which has been shown by evidence to be of particular importance, or not currently happening in practice.\n\n## Multi-agency working\n\nPractitioners supporting children and young people who have been assessed as being 'in need', or suffering (or likely to suffer) significant harm in relation to child abuse or neglect should:\n\nbuild relationships with other practitioners working with that family\n\norganise handovers if new staff members from their agency become involved\n\nensure actions set out in the 'child in need' or child protection plan are completed.\n\n## Supporting children and young people\n\nPractitioners supporting children and young people who have been assessed as being 'in need' or suffering (or likely to suffer) significant harm in relation to child abuse or neglect should, with leadership and coordination by the social worker, do the following as a minimum:\n\nprotect them from further abuse or neglect\n\nsupport them to explore aspects of their experience and express their feelings\n\nprovide early emotional support, including building emotional resilience and strategies for coping with symptoms such as nightmares, flashbacks and self-harm\n\nassess their physical health needs\n\nassess the need for further mental health support\n\nsupport them to reduce the risk of future abuse if appropriate, for example if a young person is at risk of sexual exploitation.\n\n## Children and young people affected by domestic abuse\n\nFor guidance on domestic abuse, see recommendations 10 and 11 in the NICE guideline on domestic violence and abuse.\n\n## Child trafficking\n\nWhen working with children and young people who have been trafficked, follow the government's guidance on safeguarding children who may have been trafficked.\n\n# Therapeutic interventions for children, young people and families after child abuse and neglect\n\nThese recommendations are for:\n\nSocial workers and others coordinating support for children and young people, to help them decide what services to refer children and young people to.\n\nChild and adolescent mental health practitioners (psychologists, psychotherapists, psychiatrists), practitioners in specialist family intervention teams (for example social workers) and voluntary sector agencies.\n\nStrategic commissioners of services for children and young people who have been abused or neglected.\n\nWhere interventions are recommended for particular groups, this reflects the evidence base for this intervention.\n\nDiscuss in detail with children, young people, parents and carers any interventions you offer them, explaining what the intervention will involve and how you think it may help (see section 1.1 for principles for working with children, young people, parents and carers).\n\nGive children, young people, parents and carers a choice of proposed interventions if possible. Recognise that some interventions, although effective, may not suit that person or family.\n\nThe choice of intervention should be based on a detailed assessment of the child or young person.\n\n## Therapeutic interventions following child physical abuse, emotional abuse or neglect\n\nThis section provides a range of options for therapeutic interventions for children and young people who have experienced physical abuse, emotional abuse or neglect. Some interventions involve the parent or carer who abused or neglected the child, and others involve alternative carers such as foster carers or adoptive parents. An overview of interventions is shown below.\n\n\n\nFor more recommendations about looked-after children, including children in residential care, see the NICE guideline on looked-after children and young people.\n\nOffer an attachment-based intervention, for example Attachment and Biobehavioural Catch-up, to parents or carers who have neglected or physically abused a child under\xa05.\n\nDeliver the attachment-based intervention in the parent or carer's home, if possible, and provide at least 10 sessions. Aim to:\n\nimprove how they nurture their child, including when the child is distressed\n\nimprove their understanding of what their child's behaviour means\n\nhelp them respond positively to cues and expressions of the child's feelings\n\nimprove how they manage their feelings when caring for their child.\n\nConsider child–parent psychotherapy for parents or carers and their children under\xa05 if the parent or carer has physically or emotionally abused or neglected the child, or the child has been exposed to domestic violence.\n\nEnsure that child–parent psychotherapy:\n\nis based on the Cicchetti and Toth model\n\nconsists of weekly sessions (lasting 45–60\xa0minutes) over 1\xa0year\n\nis delivered in the parents' home, if possible, by a therapist trained in the intervention\n\ninvolves directly observing the child and the parent–child interaction\n\nexplores the parents' understanding of the child's behaviour\n\nexplores the relationship between the emotional reactions of the parents and their perceptions of the child on the one hand, and the parents' own childhood experiences on the other hand.\n\nOffer an attachment-based intervention in the home to foster carers looking after children under 5 who have been abused or neglected. Aim to help foster carers to:\n\nimprove how they nurture their foster child, including when the child is distressed\n\nimprove their understanding of what the child's behaviour means\n\nrespond positively to cues and expressions of the child's feelings\n\nbehave in ways that are not frightening to the child\n\nimprove how they manage their feelings when caring for their child.\n\nConsider the attachment-based intervention in recommendation 1.7.8 for adoptive parents and those providing permanence (including special guardians, foster carers or kinship carers) for children under 5 who have been abused or neglected.\n\nConsider a comprehensive parenting intervention, for example SafeCare, for parents and children under\xa012 if the parent or carer has physically or emotionally abused or neglected the child. This should be delivered by a professional trained in the intervention and comprise weekly home visits for at least 6\xa0months that address:\n\nparent–child interactions\n\ncaregiving structures and parenting routines\n\nparental stress\n\nhome safety\n\nany other issues that caused the family to come to the attention of services. As part of the intervention, help the family to access other services they might find useful.\n\nConsider parent–child interaction therapy for parents or carers and children under\xa012 if the parent or carer has physically abused or neglected the child. Combine group sessions for these parents with individual child–parent sessions focusing on developing child-centred interaction and effective discipline skills.\n\nOffer a group-based parent training intervention, for example KEEP, to foster carers of children aged 5 to 12 who have been abused or neglected and are showing problematic behaviours. Include strategies to manage behaviour and discipline positively. Provide group sessions over at least 16\xa0weeks with groups of 8 to 10 foster carers, including video, role play and homework practice.\n\nConsider the intervention in recommendation 1.7.12 for foster carers of children aged 5 to 12 who have been abused or neglected and are not currently showing problematic behaviours.\n\nConsider multi-systemic therapy for child abuse and neglect (MST‑CAN) for parents or carers of children and young people aged 10 to 17 if the parent or carer has abused or neglected their child. This should last 4 to 6\xa0months and:\n\ninvolve the whole family\n\naddress multiple factors contributing to the problem\n\nbe delivered in the home or in another convenient location\n\ninclude a round-the-clock on-call service to support families to manage crises.\n\nFor foster carers of children and young people aged 5 to 17 who have been abused or neglected, consider a trauma-informed group parenting intervention, using a trust-based relational intervention as an example. It should last for at least 4 day‑long sessions and help foster carers to:\n\ndevelop the child or young person's capacity for self-regulation\n\nbuild trusting relationships\n\ndevelop proactive and reactive strategies for managing behaviour.\n\nConsider the trauma-informed group parenting intervention in recommendation 1.7.15 for adoptive parents and those providing permanence (including special guardians, foster carers or kinship carers) for children aged 5 to 17 who have been abused or neglected.\n\n## Therapeutic interventions for children, young people and families after sexual abuse\n\nThis section provides a range of options for therapeutic interventions for children and young people who have experienced sexual abuse. An overview of interventions is shown below.\n\nOffer group or individual trauma-focused cognitive behavioural therapy over 12 to 16 sessions (more if needed) to children and young people (boys or girls) who have been sexually abused and show symptoms of anxiety, sexualised behaviour or post-traumatic stress disorder. When offering this therapy:\n\ndiscuss it fully with the child or young person before providing it and make clear that there are other options available if they would prefer\n\nprovide separate trauma-focused cognitive behavioural therapy sessions for the non-abusing parent or carer.\n\nFor children and young people (boys or girls) aged 8 to 17 who have been sexually abused, consider an intervention, for example 'Letting the future in', that:\n\nemphasises the importance of the therapeutic relationship between the child or young person and therapist\n\noffers support tailored to the child or young person's needs, drawing on a range of approaches including counselling, socio-educative and creative (such as drama or art)\n\nincludes individual work with the child or young person (up to 20\xa0sessions, extending to 30 as needed) and parallel work with non-abusing parents or carers (up to 8\xa0sessions).\n\nFor girls aged 6 to 14 who have been sexually abused and who are showing symptoms of emotional or behavioural disturbance, consider one of the following, after assessing carefully and discussing which option would suit her best:\n\nindividual focused psychoanalytic therapy (up to 30\xa0sessions) or\n\ngroup psychotherapeutic and psychoeducational sessions (up to 18\xa0sessions). Provide separate supportive sessions for the non-abusing parent or carer, helping them to support the child's attendance at therapy, as well as addressing issues within the family.\n\n# Planning and delivering services\n\nThese recommendations are for senior managers in agencies responsible for planning and delivering services to children and young people. They provide additional detail to the Department for Education's statutory guidance on working together to safeguard children on strategic arrangements for multi-agency working.\n\nPlan services in a way that enables children, young people, parents and carers to work with the same practitioners over time where possible.\n\nAgencies responsible for planning and delivering services for children and young people should agree terminology across agencies relating to child protection roles and processes, and ensure these are well publicised.\n\nEnsure that local threshold documents set out responses to other forms of abuse including child sexual exploitation, female genital mutilation, honour-based abuse (including forced marriage), child trafficking, serious youth violence and gang-related abuse. Ensure that these are communicated to local agencies, including those providing universal services, so that they are aware of these forms of abuse.\n\nTo address the risks posed by sexual exploitation and gang-related abuse, agencies responsible for planning and delivering services for children and young people should put in place:\n\neffective leadership within agencies\n\na local lead who will coordinate planning and information sharing between agencies.\n\n## Supervision and support for staff\n\nOrganisations should support staff working with children and families at risk of or experiencing child abuse and neglect, and provide good quality supervision, tailored to their level of involvement in safeguarding work. This should include:\n\ncase management\n\nreflective practice\n\nemotional support\n\ncontinuing professional development.", 'Terms used in this guideline': "# Alerting feature\n\nSymptoms and signs that may indicate that child abuse or neglect is taking place, and which should prompt practitioners to take action.\n\n# Analysis\n\nAnalysis involves organising the information collected during assessment, judging its significance and exploring different perspectives, to identify themes and reach conclusions on what these mean for the child or young person and their family. It should draw on knowledge from research and practice combined with an understanding of the child's needs.\n\n# Attachment-based intervention\n\nInterventions which are based on attachment theory. Attachment-based interventions focus on improving the relationships between children and young people and their key attachment figures (often, parents or carers), for example by helping the parent or carer to respond more sensitively to the child or young person.\n\n# Bullying\n\nPersistent behaviour by a person or group of people that intentionally hurts a child or young person either physically or emotionally.\n\n# Child abuse and neglect\n\nIn this guideline child abuse and neglect includes inflicting harm on a child or young person and also failing to protect them from harm. Children and young people may be abused by someone they know in a family or in an institutional or community setting or, more rarely, by someone they don't know (for example through the internet). Some indicators of abuse and neglect may be indicators of current or past abuse and neglect.\n\n# Child sexual exploitation\n\nChild sexual exploitation is a form of child sexual abuse. It occurs where an individual or group takes advantage of an imbalance of power to coerce, manipulate or deceive a child or young person under the age of 18 into sexual activity (a) in exchange for something the victim needs or wants, and/or (b) for the financial advantage or increased status of the perpetrator or facilitator. The victim may have been sexually exploited even if the sexual activity appears consensual. Child sexual exploitation does not always involve physical contact; it can also occur through the use of technology.\n\n# Child trafficking\n\nRecruiting and transporting children and young people for the purposes of exploitation, for example, sexual exploitation, forced labour or services, benefit fraud, domestic servitude or the removal of organs.\n\n# Children and young people\n\nIn this guideline 'infant' means aged under 1\xa0year, 'child' means under 13\xa0years and 'young person' means 13 to 17\xa0years.\n\n# Disabled children and young people\n\nChildren and young people who meet the Equality Act 2010 definition of disability, namely those who have a physical or mental impairment that has a substantial and long-term negative effect on their ability to do normal daily activities.\n\n# Domestic abuse\n\nAny incident or pattern of incidents of controlling, coercive, threatening behaviour, violence or abuse between those aged 16 or over who are, or have been, intimate partners or family members regardless of gender or sexuality.\n\n# Early help\n\nSupport provided early as soon as a problem emerges. Early help can prevent a problem from worsening or further problems from arising.\n\n# Emotional abuse\n\nPersistently treating a child or young person in a way that can cause severe adverse effects on their emotional development. For example, conveying to them that they are worthless or unloved; not giving them opportunities to express their views; deliberately silencing them or making fun of them; imposing inappropriate expectations on them for their age or developmental stage; and serious bullying (including cyber bullying).\n\n# Faltering growth\n\nThis term is used in relation to infants and young children whose weight gain occurs more slowly than expected for their age and sex. In the past this was often described as a 'failure to thrive' but this is no longer the preferred term.\n\n# Female genital mutilation\n\nA practice involving removal of or injury to any part of a girl's external genitalia for non-medical purposes. Female genital mutilation is illegal in England and Wales according to the Female Genital Mutilation 2003 Act.\n\n# Forced marriage\n\nA marriage in which one or both partners have not consented (or cannot consent because of a learning disability) to be married and pressure or abuse has been used.\n\n# Foster carer\n\nFoster carers care for children and young people who are 'looked after' in the public care system. They must go through a process of assessment and approval, before providing care for the child or young person as a member of their household. Some are 'kinship foster carers', which means they are relatives or friends who are fostering a child or young person who has entered the public care system.\n\n# Honour-based abuse\n\nHonour-based abuse includes forced marriage and female genital mutilation (FGM). It can be described as a collection of practices used to control behaviour within families or other social groups to protect perceived cultural and religious beliefs and/or honour. Such abuse can occur when perpetrators perceive that a relative has shamed the family or community by breaking their honour code.\n\n# Lead professional\n\nA professional who leads the provision of early help support to children, young people, parents and carers by acting as their advocate and coordinating their support. The lead professional role could be undertaken by a GP, family support worker, teacher, health visitor or a special educational needs coordinator.\n\n# Maltreatment\n\nIn line with the NICE guideline on child maltreatment this includes neglect; physical, sexual and emotional abuse; and fabricated or induced illness. It is also used as an 'umbrella' term for all categories of child abuse and neglect, including witnessing domestic violence, forced marriage, child trafficking, female genital mutilation and child sexual exploitation.\n\n# Neglect\n\nThe persistent failure to meet a child's basic physical and/or psychological needs, likely to result in the serious impairment of the child's health or development. Neglect may occur during pregnancy as a result of maternal substance abuse. Once a child is born, neglect may involve a parent or carer failing to:\n\nprovide adequate food, clothing and shelter (including exclusion from home or abandonment)\n\nprotect a child from physical and emotional harm or danger\n\nensure adequate supervision (including the use of inadequate caregivers)\n\nensure access to appropriate medical care or treatment.\n\nIt may also include neglect of, or unresponsiveness to, a child's basic emotional needs.\n\n# Parent or carer\n\nThis guideline uses 'parent or carer' to acknowledge that people other than a child or young person's parent may be caring for them. We have defined 'parent' as the person with parental responsibility for a child, including an adoptive parent, and 'carer' as someone other than a parent who is caring for a child. This could include family members, such as the partner of a parent. Where we are referring specifically to paid carers we use the term 'foster carer'.\n\n# Parenting intervention\n\nA psycho-educational intervention focusing on improving parenting skills.\n\n# Past child abuse or neglect\n\nAbuse or neglect that a child or young person may have experienced but which is no longer occurring. For example, abuse which occurred in a previous family environment before the child or young person was placed in care or with an adoptive family.\n\n# Physical abuse\n\nA form of abuse which may involve hitting, shaking, throwing, poisoning, burning or scalding, drowning, suffocating or otherwise causing physical harm to a child. Physical harm may also be caused when a parent or carer fabricates the symptoms of, or deliberately induces, illness in a child.\n\n# Practitioner\n\nA person working with children and young people who may have a role in safeguarding them.\n\n# Prader-Willi syndrome\n\nA genetic condition leading to a range of symptoms, including over-eating, restricted growth, reduced muscle tone, and learning and behavioural difficulties.\n\n# Regulated profession\n\nRegulated professions as defined in section 5B(2)(a), (11) and (12) of the Female Genital Mutilation Act 2003. A person works in a regulated profession if they are a healthcare professional, a teacher, or (in Wales) if they are a social care worker.\n\n# Sexual abuse\n\nInvolves forcing or enticing a child or young person to take part in sexual activities, not necessarily involving a high level of violence, whether or not the child is aware of what is happening. The activities may involve physical contact, including assault by penetration (for example, rape or oral sex) or non-penetrative acts such as masturbation, kissing, rubbing and touching outside of clothing. They may also include non-contact activities, such as involving children in looking at, or in the production of, sexual images, watching sexual activities, encouraging children to behave in sexually inappropriate ways, or grooming a child in preparation for abuse (including through the internet). Sexual abuse is not solely perpetrated by adult males. Women can also commit acts of sexual abuse, as can other children.\n\n# Special guardian\n\nA person who has been granted a special guardianship order (SGO), a private law order which grants someone parental responsibility for a named child or young person. While parents do not lose parental responsibility when an SGO is granted, the special guardian has the exclusive right to exercise it, and make important decisions about the child or young person. Special guardians may also in some circumstances be provided with local authority financial and other support.\n\n# Vulnerability factor\n\nSituations, behaviours or underlying characteristics of children, young people and their parents or carers and their social environment that increase the child or young person's vulnerability to child abuse or neglect.\n\nFor other social care terms see the Think Local, Act Personal Care and Support Jargon Buster.", 'Putting this guideline into practice': 'Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nOffering effective therapeutic interventions for children and their parents or carers. Although families who have children on child protection plans usually receive interventions from a social worker, there is a lack of provision of evidence-based therapeutic interventions to support parents, carers, foster carers and adoptive parents to meet the needs of children who have been abused or neglected.\n\nProviding more training and education for all staff who work with children and young people who have experienced abuse and neglect. Training in recognising the signs of child abuse and neglect and when to act on them is a priority, particularly as new forms of abuse emerge. However, increasing training is likely to prove challenging for many organisations because of cuts in resources.\n\nMaking multi-agency responses effective across the country. It should begin at the early help stage. Adopting common language and terms, leadership at all levels, agreeing protocols for information sharing and co-locating staff from different agencies who are working on the same, or related, cases or issues all contribute to effective multi-agency working.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for practice that can be done quickly – such as conducting a baseline assessment (see 3 below) – should be shared quickly. This is because health and social care professionals should use guidelines to guide their work and keep their skills and knowledge up to date – as is required by professional regulating bodies such as the Health and Care Professions Council, General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Involve children, young people, parents and carers, foster carers and adoptive parents in identifying how practice needs to change.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Recommendations for research ': "The guideline committee has made the following recommendations for research.\n\n# Recognition of child sexual abuse\n\nWhat approaches to practice enable children (both boys and girls) who have been sexually abused to begin to tell practitioners about their experiences earlier, and in a way that does not contaminate the reliability of subsequent court proceedings?\n\n## Why this is important\n\nResearch shows that many children and young people who are sexually abused do not tell anyone about their abuse. Among those who do, many delay telling someone for a long time, sometimes until adulthood. We found little research identifying the approaches or techniques that would make it more likely for a child being sexually abused to tell a practitioner about it. Although there is an evidence base on Achieving Best Evidence interviewing as part of a formal investigation, there is less evidence about approaches that can be used at an earlier stage. Studies are needed that would identify effective approaches to enable children to talk about sexual abuse, while ensuring that these early conversations do not contaminate evidence at a later stage in an investigation.\n\n# Recognition of risk and prevention of female genital mutilation\n\nWhat interventions are effective and cost effective in:\n\nimproving practitioners' recognition of children who are at risk of female genital mutilation (FGM) in the UK or overseas?\n\nimproving recognition of co-occurring forms of abuse where relevant?\n\npreventing FGM in this group?\n\n## Why this is important\n\nThere is a lack of evidence from the UK about how practitioners can be supported to recognise girls and young women who are at risk of FGM and effective interventions to prevent FGM. This is despite evidence that many practitioners are likely to encounter young women at risk of FGM. There is also a lack of evidence about the extent to which FGM is a risk factor or indicator of other forms of abuse, and therefore whether the identification of FGM should be accompanied by other types of assessment and support. The Home Office has developed an FGM recognition and prevention e-learning resource; however, the effectiveness of this resource does not appear to have been evaluated.\n\n# Recognition of risk and prevention of 'honour-based' violence and forced marriage\n\nWhat interventions are effective and cost effective in:\n\nimproving practitioners' recognition of children who are at risk of or experiencing 'honour-based' violence and forced marriage?\n\npreventing 'honour-based' violence and forced marriage?\n\n## Why this is important\n\nThere is a lack of evidence from the UK about how practitioners can be supported to recognise children and young people who are at risk of or experiencing 'honour-based' violence, and how to prevent it. There is also little evidence showing which interventions are most effective for recognising young people at risk of forced marriage and for preventing such marriages from taking place. The government's guidance on forced marriage explains the issues around forced marriage, provides a clear definition and distinction from arranged marriage, lists some of the potential warning signs or indicators, and recommends organisational approaches to dealing with forced marriage. However, the effectiveness of these approaches has not been evaluated.\n\n# Early help home visiting\n\nWhat are the components of effective home visiting programmes for preventing child abuse and neglect in families of children and young people at risk of child abuse and neglect in the UK?\n\n## Why this is important\n\nThere are numerous studies, based mostly in the US, involving home visiting programmes for families at risk of child abuse and neglect. The findings of these studies are mixed, with some programmes proving effective but not others. The descriptions of the programmes and their theoretical basis are often poorly reported. It is therefore difficult to ascertain the key 'active ingredients' in a successful home visiting programme. A meta-analytic study seeking to obtain additional information from study authors on the features of home visiting programmes and their effectiveness, for example using statistical modelling, would help in understanding these programmes.\n\n# Effective prevention of child abuse and neglect in the UK\n\nWhat interventions are effective and cost effective in the UK to prevent abuse and neglect of children and young people in families at risk of, or showing early signs of, abuse and neglect?\n\n## Why this is important\n\nThe evidence reviewed for this guideline on the effectiveness of interventions to prevent abuse and neglect of children and young people was predominantly from outside the UK, and focused on home visiting programmes and parenting programmes. High-quality studies (ideally randomised controlled trials) are needed that:\n\nlook specifically at the effectiveness of interventions to prevent child abuse and neglect in the UK\n\nfocus on interventions already being provided in the UK that may have no or low-quality evidence to support them at present.\n\n# Reducing social isolation and associated child abuse and neglect\n\nWhat is the impact of social isolation on children, young people and families at risk of abuse and neglect in the UK? What interventions are effective and cost effective in a UK context in reducing social isolation and any associated child abuse and neglect?\n\n## Why this is important\n\nEvidence presented in the NSPCC's how safe are our children? suggests a link between social isolation and child abuse and neglect. However, there is a lack of evidence about what interventions are effective in reducing social isolation and any associated child abuse and neglect. The aim of research should be to inform practitioners and policy-makers of the impact of social isolation, and the methods that lead to successful engagement with socially isolated children, young people and families, and reduction of associated child abuse and neglect.\n\n# Effective interventions for young people who have been abused or neglected\n\nWhat interventions are effective and cost effective in improving the wellbeing of young people aged 12 to 17 who have experienced abuse or neglect, including those who are now in temporary or permanent alternative care placements or living independently?\n\n## Why this is important\n\nThere is little evidence on effective interventions to improve the wellbeing of young people who have experienced abuse and neglect, except for those who have been sexually abused. Studies are needed that evaluate interventions for young people aged 12 and over who have been abused or neglected in the past, but are now in temporary or permanent alternative care placements. These include foster care, kinship care, residential care, special guardianship and adoption.\n\n# Effective interventions for children and young people who have experienced online-facilitated abuse, including online grooming\n\nWhat interventions are effective and cost effective in improving the wellbeing of children and young people who have experienced online-facilitated abuse, including grooming online?\n\n## Why this is important\n\nThere is little evidence on what interventions are effective in helping children and young people recover from trauma following online abuse, including online grooming. In particular, whether existing interventions may be suitable, or whether different kinds of therapeutic support are needed to address the particular features of online abuse.\n\n# Effective interventions for addressing child abuse and neglect in the UK\n\nWhat interventions, approaches and methodologies provided by social care and voluntary sector services are effective and cost effective in the UK to prevent the recurrence of child abuse and neglect, and to improve the wellbeing of children, young people and families?\n\n## Why this is important\n\nThe evidence reviewed for this guideline on the effectiveness of interventions to address abuse and neglect of children and young people was predominantly from outside the UK, and within the health sector (therapeutic interventions). We identified interventions, approaches and methodologies being used by social care and voluntary sector organisations in the UK but many of these could not be included because they have not been evaluated using high-quality research designs. High-quality studies are needed to show policy-makers and practitioners which ones are effective in the UK and in what circumstances.\n\n# Interventions with fathers and male carers\n\nWhat interventions are effective and cost effective when working with fathers and male carers to improve their parenting in families where children are being, or have been, abused or neglected?\n\n## Why this is important\n\nThere is a lack of research evidence from the UK showing what interventions are effective to improve fathers' and male carers' parenting in families where children are being, or have been, abused or neglected. Most studies reviewed for this guideline, both from the UK and elsewhere, focused on female carers. Studies are needed to show what interventions and practices are effective in engaging fathers and male carers, and improving their parenting if needed.\n\n# Interventions with male foster carers and adoptive parents\n\nWhat interventions are effective and cost effective when working with male foster carers and adoptive parents who are caring for children and young people who have been abused in the past?\n\n## Why this is important\n\nThere is a lack of research evidence from the UK on what interventions are effective in working with male foster carers and adoptive parents – much of the existing literature is in relation to female foster carers and adoptive parents.\n\n# Effectiveness of home visiting following child abuse or neglect\n\nAre home visiting interventions effective and cost effective in improving parenting and preventing recurrence of child abuse and neglect in families in which abuse or neglect is occurring or has occurred?\n\n## Why this is important\n\nThere is a lack of evidence from the UK on the impact of home visiting on families in which abuse or neglect is occurring or has occurred (as opposed to its impact on prevention). For children who are subject to a child protection plan, home visiting is one of the tools that may be used for monitoring their welfare and their interaction with their parents or carers. It is also used for engaging with parents or carers to address abusive or neglectful behaviours or ensure children are protected. There is a need for studies which identify what practices are effective in ensuring the safety and wellbeing of children and young people.\n\n# Effective interventions for parents or carers with substance misuse problems\n\nWhat interventions, including family behaviour therapy, are effective and cost effective in improving parenting and preventing recurrence of neglect by parents or carers with substance misuse problems and whose children are on a child protection plan under the category of neglect in the UK?\n\n## Why this is important\n\nThere is a lack of evidence from the UK about the impact of family behaviour therapy and other interventions on parents and carers with substance misuse problems who show neglectful parenting. Studies are needed to examine the effectiveness of family behaviour and other interventions, and the timescales for delivering such interventions. In some cases, it may take longer than the 26-week timescale of care proceedings to address parents' substance misuse problems. This research could inform court decisions about whether to extend the time limit if there was a realistic possibility of reunification at the end of the intervention.\n\n# Effectiveness of web-based parenting programmes\n\nAre web-based parenting programmes effective and cost effective for improving parenting and preventing recurrence of child abuse and neglect in families where child abuse or neglect has occurred?\n\n## Why this is important\n\nThere is a lack of research data about the impact of web-based parenting programmes on families where child abuse or neglect has occurred. Our review for this guideline identified 1 small-scale US study of a web-based parenting programme for parents of children with abusive head injury. Research would inform practitioners whether this type of parenting programme could be effective for families where child abuse or neglect has occurred, and if so which families would be most likely to benefit.\n\n# Relative effectiveness of interventions to support foster carers\n\nWhat is the relative effectiveness and cost effectiveness of the KEEP intervention for foster carers of abused or neglected children compared to other interventions?\n\n## Why this is important\n\nThere has been no independent UK study of the relative effectiveness of the KEEP intervention for foster carers and abused or neglected children when compared head to head with other interventions for foster carers. (There are effectiveness studies, but these are with a waitlist or service as usual comparator, rather than comparing different forms of support 'head to head'.) Data about outcomes in fostering services which use the KEEP model are kept by the National Implementation Service, which has responsibility for ensuring that model fidelity is maintained, but does not make comparisons with outcomes of other intervention models. A comparison study would help service providers identify the most appropriate model for supporting foster carers and abused or neglected children.\n\n# Peer support for children and young people who have been abused or neglected\n\nWhat peer support programmes are effective and cost effective in improving the wellbeing of children and young people who have been abused or neglected?\n\n## Why this is important\n\nThere is a small amount of research into peer support interventions for children who have been abused or neglected. There is also anecdotal evidence that children who have experienced abuse or neglect would appreciate formally organised peer support in addition to the informal peer support that children often provide each other. A research study, where careful consideration was given to issues like helping peer supporters to manage confidential information about abuse or neglect, could test the success of a formally organised peer support programme."}
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https://www.nice.org.uk/guidance/ng76
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This guideline covers recognising and responding to abuse and neglect in children and young people aged under 18. It covers physical, sexual and emotional abuse, and neglect. The guideline aims to help anyone whose work brings them into contact with children and young people to spot signs of abuse and neglect and to know how to respond. It also supports practitioners who carry out assessments and provide early help and interventions to children, young people, parents and carers.
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6618facc15d78b28880cb447668550a874bac5b8
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nice
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Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee
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Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee
Evidence-based recommendations on autologous chondrocyte implantation in people with symptomatic articular cartilage defects of the knee.
# Recommendations
Autologous chondrocyte implantation (ACI) is recommended as an option for treating symptomatic articular cartilage defects of the knee, only if:
the person has not had previous surgery to repair articular cartilage defects
there is minimal osteoarthritic damage to the knee (as assessed by clinicians experienced in investigating knee cartilage damage using a validated measure for knee osteoarthritis)
the defect is over 2 cm2 and
the procedure is done at a tertiary referral centre.
Why the committee made these recommendations
Clinical trial evidence shows that ACI can improve the symptoms of articular cartilage defects of the knee. There is evidence that it is likely to be more successful in people who haven't had any previous knee repair surgery, and in people who have very little osteoarthritic damage in the knee. But, it is unclear how well ACI works in the long term compared with microfracture, the most commonly used alternative treatment.
The consensus among UK clinicians is that ACI is the only effective treatment option for defects that are over 2 cm2 when symptoms persist after non-surgical management.
The most accurate cost-effectiveness estimate for ACI compared with microfracture is uncertain, and is not likely to be under £20,000 per quality-adjusted life year (QALY) gained for everyone who is eligible to have ACI. But the cost-effectiveness estimate is lower in people in whom ACI has a better chance of success. This includes people who haven't had any previous knee repair surgery, and people who have very little osteoarthritic damage in the knee. In these people, the most accurate cost-effectiveness estimate is likely to be under £20,000 per QALY gained.# The technologies
Autologous chondrocyte implantation (ACI)
Marketing authorisations
The OsCell John Charnley Laboratory has approval from the Medicines and Healthcare products Regulatory Agency to provide traditional ACI services under a hospital exemption from the advanced therapy medicinal products regulation for products prepared on a non-routine basis. It also has approval from the Human Tissues Authority for procuring, testing, storing and importing human tissues and cells for human application, and storing relevant material that has come from a human body for use for a scheduled purpose. The indication for use of traditional ACI in the knee is for the repair of single or multiple symptomatic, full-thickness cartilage defects of the joint with or without bone involvement in adults. Traditional ACI involves implanting a cell suspension under either a periosteal- or collagen-based membrane. Traditional ACI can be considered when the Oswestry Risk of Knee Arthroplasty (ORKA) score is 3 or 4, but only when other factors can be corrected, for example, using meniscal allograft or realignment osteotomy.
Matrix-associated chondrocyte implantation (MACI) had a European marketing authorisation for the repair of symptomatic, full-thickness cartilage defects of the knee (grades III and IV of the Modified Outerbridge Scale) between 3 cm2 and 20 cm2. The marketing authorisation is currently suspended while Vericel validates a new site for culturing cells.
ChondroCelect had a European marketing authorisation for repair of symptomatic cartilage defects of the femoral condyle of the knee (International Cartilage Repair Society grades III or IV), which was withdrawn by TiGenix during the course of this appraisal for commercial reasons.
ACI is contraindicated in people with severe osteoarthritis of the knee.
Price
Costs may vary in different settings because of negotiated procurement discounts.
The recommendations are based on a maximum cell cost of £16,000.# Committee discussion
The appraisal committee (section 5) considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Current treatment
## ACI is an option after best supportive care but before knee replacement
The committee considered the treatment pathway for treating symptomatic cartilage defects of the knee. It understood that people with articular cartilage defects will first be offered best supportive care. This includes exercise, weight loss, physiotherapy, intra-articular corticosteroid injections, analgesia, off-loading, and applying heat/cold or transcutaneous electrical nerve stimulation. The committee heard from clinical experts that people with articular cartilage defects will be considered for surgery (microfracture, mosaicplasty or autologous chondrocyte implantation ) only if symptoms persist after best supportive care. It understood that a patient having ACI would have 2 surgical procedures: 1 to harvest chondrocytes from a non-damaged portion of the knee, and another to implant the cells in the damaged area. Between the 2 procedures, the cells would be cultured in a laboratory. The committee heard that the choice between ACI, microfracture and mosaicplasty depends on the size of the defect, previous surgery, age, BMI and the condition of the cartilage. The committee was aware of the published consensus of 104 UK surgeons with specialist knowledge of surgical repair techniques for articular chondrocyte defects of the knee. It states that microfracture is less effective in articular cartilage defects over 2 cm2 and that ACI is the surgery of choice for articular cartilage defects over 2 cm2. The committee heard that, in current clinical practice, the preferred surgery for defects smaller than this was microfracture. However, because there is variation in access to ACI, microfracture is currently the most common procedure for articular cartilage defects of all sizes. The clinical experts advised that, for people whose symptoms persist after having ACI or microfracture, other interventions such as mosaicplasty, debridement and lavage, osteotomy, further physiotherapy or a second ACI would be considered. The committee heard that, after microfracture, surgeons are unlikely to offer patients a second microfracture procedure. Total and partial knee replacement are options later in the treatment pathway, if the damage to the cartilage leads to advanced osteoarthritis. The committee heard from the clinical experts that, in clinical practice, total knee replacement is considered to be 'salvage treatment' (particularly in people younger than 55 years) to be used when people have exhausted all other options.
# Comparators
## Microfracture is the most relevant comparator for decision-making
The final scope issued by NICE listed a number of comparators:
Microfracture – the committee agreed this was a relevant comparator.
Mosaicplasty – the committee noted differing views on the use of mosaicplasty in current NHS clinical practice. One clinical expert stated that mosaicplasty was generally used as an alternative to microfracture. However, the committee was persuaded by the assessment group's clinical advice that mosaicplasty is rarely used in NHS clinical practice.
Osteotomy – the committee heard from a clinical expert that this would mainly be used to treat osteoarthritis of the knee, but may be used together with ACI in some people. The committee agreed that osteotomy was not a relevant comparator.
Best supportive care – the committee agreed that ACI would only be used when symptoms persist after best supportive care (see section 3.1), and so concluded that it was not a relevant comparator.
Total knee replacement – the committee agreed that this would be offered later in the treatment pathway, and would not be considered for people for whom ACI was an option (see section 3.1). As such, the committee concluded that knee replacement was not a relevant comparator. The committee appreciated that there would be some variation in the use of these procedures in clinical practice because of the clinical experience and preference of the treating clinician and the availability of treatment. However, the committee concluded that microfracture is the most frequently used alternative to ACI in the NHS, and was the most relevant comparator for ACI in this appraisal.
# Marketing authorisations
## The recommendations only apply to technologies with a current marketing authorisation or an MHRA hospital exemption
The committee discussed the technologies listed in the final scope issued by NICE:
TiGenix, which held the marketing authorisation for ChondroCelect, withdrew its marketing authorisation over the course of the appraisal.
The European marketing authorisation for matrix-associated chondrocyte implantation (MACI; held by Vericel) was suspended at the time of the appraisal because Vericel had closed its European laboratory for commercial reasons. Vericel told the committee that it was currently discussing accrediting its US laboratory with the European Medicines Agency, with the aim of reactivating its European marketing authorisation.
OsCell John Charnley Laboratory is affiliated with a tertiary referral NHS orthopaedic hospital. It is permitted by the Medicines and Healthcare products Regulatory Agency (MHRA) to provide its services through the MHRA's hospital exemption from the regulation on advanced therapy medicinal products.The committee heard from OsCell that, if ACI was more widely available in the NHS, it envisaged that more NHS laboratories would be established specialising in selecting and culturing chondrocytes for ACI. The committee heard from NICE that its technology appraisal guidance only applies to technologies with a current marketing authorisation, but that the MHRA's hospital exemption regulation means that ACI provided by the OsCell John Charnley Laboratory meets this criterion. The committee concluded that it was relevant to consider all the data on clinical and cost effectiveness it had received. However, its recommendations would apply only to technologies with a current marketing authorisation or an MHRA hospital exemption from the regulation on advanced therapy medicinal products.
# Patient experience
## Articular cartilage defects are debilitating and patients would welcome ACI
The committee noted that 29 people had submitted statements to NICE describing their experiences of articular cartilage defects and ACI. It heard that the symptoms of knee cartilage damage include pain, swelling, locking and joint instability, and that these symptoms negatively affect quality of life and a person's ability to do daily activities. In particular, many people with articular cartilage defects of the knee were very active before their injuries, so the physical impairment has had a major effect on their lives. The patients commented that recovery time was long with ACI but that the benefits were worth it. The clinical experts commented that some people prefer microfracture because of its shorter recovery time, whereas some people (such as competitive athletes) prefer ACI because the results are likely to last longer. Several people stated that, after having ACI, they had fewer symptoms and were able to resume daily activities. The committee commented that people who had positive experiences with ACI were more likely to provide comments to NICE and, as such, the patient statements may not reflect the full range of people's experiences. But, overall, the committee concluded that some patients were satisfied with the outcomes of ACI, and would welcome it as a treatment option.
# Clinical trial evidence
## The evidence for short-term outcomes came from 4 randomised controlled trials
The committee considered the clinical-effectiveness evidence for ACI in terms of reducing pain and improving functional impairment associated with articular cartilage defects. For the first 2 committee meetings, the assessment group identified 4 randomised controlled trials that were relevant to the final scope issued by NICE:
Basad et al. (2010), comparing MACI with microfracture in 60 patients over 2 years.
SUMMIT, comparing MACI with microfracture in 144 patients over 5 years.
TIG/ACT, comparing ACI using characterised chondrocytes (ChondroCelect) with microfracture in 118 patients over 5 years.
ACTIVE, comparing several forms of ACI with standard treatment (such as microfracture and mosaicplasty) in 390 patients. The trial has an intended follow-up of 10 years. Although OsCell has shared selected results from this trial in its submissions for this appraisal, no results have been published and the final results are yet to be reported.
## There is some evidence that ACI improves symptoms in the short term
The committee discussed these 4 trials at its first and second meetings, and noted that the evidence suggested that:
Over 2 years to 5 years, both MACI and ChondroCelect were more clinically effective than microfracture (improvements in pain and function on the Knee injury and Osteoarthritis Outcome Score ).
At 5 years, the difference in the number of treatment failures and in health-related quality of life between ChondroCelect and microfracture was not statistically significant (p≥0.05). In contrast, provisional results from the ACTIVE trial suggested that ACI was only clinically beneficial compared with standard treatments (which included microfracture) at 5 years. However, this was based on limited data and, when the committee met for the third time, no data had been published. In its first 2 meetings, the committee heard conflicting opinions from the clinical experts about the effectiveness of ACI. However, generally the experts considered that there was evidence to show that ACI is clinically effective, although this evidence was not definitive. The committee concluded that, although uncertain, there was some evidence that ACI improves symptoms (based on the KOOS score).
## It is uncertain how ACI compares with microfracture in the long term
The committee noted that the studies originally identified by the assessment group (see section 3.5) provided limited data on the failure rates of both ACI and microfracture after 5 years. The committee therefore requested that the assessment group review all randomised controlled trials and observational studies that provided outcomes for more than 5 years for ACI and microfracture, including all generations of ACI (that is, ACI available before ChondroCelect, MACI or ACI using cells from OsCell). For the committee's third meeting, the assessment group had broadened its systematic review to include 2 more relevant studies on the failure rates of ACI and microfracture after 5 years in its analyses:
Nawaz et al. (2014), an observational study of patients' experience with ACI only, at a single English site, over 2 years to 12 years (average follow-up 6.2 years; n=827).
Knutsen et al. (2016), a randomised controlled trial (published since the second committee meeting) comparing ACI with microfracture over 15 years (n=80).
## The assessment group's preferred sources of long-term failure data included Kaplan–Meier data showing time to failure
The assessment group's preferred source of data for long-term failure rates of ACI was Nawaz et al. (2014) because the study:
included more patients than all the other sources of long-term ACI data combined
reflected UK practice
provided data on different 'generations' of ACI
provided data on subgroups.The committee noted that the available data for long-term failure rates of microfracture were more limited. The assessment group's preferred sources of data were for microfracture were:
Saris et al. (2009), which reported 3‑year Kaplan–Meier data on failure rates in the microfracture arm (n=61) of the TIG/ACT trial (see section 3.5). The assessment group chose Saris et al. over Vanlauwe et al. (2011), which had 5‑year Kaplan–Meier data from the TIG/ACT trial, because the reported data in Vanlauwe et al. did not allow a full analysis of the Kaplan–Meier plot.
A 15-year follow-up of the microfracture arm (n=40) from Knutsen et al. (2016; see section 3.7).All the assessment group's preferred sources of long-term failure data (that is, Nawaz et al. Saris et al. and Knutsen et al.) included Kaplan–Meier data showing time to failure. The committee concluded that these studies were the best available to estimate long-term failure rates of ACI and microfracture.
## A robust comparison of the long-term effectiveness of ACI and microfracture was not possible with the data available
The committee noted that Nawaz et al. (2014), Saris et al. (2009) and Knutsen et al. (2016) used different definitions of ACI failure. Nawaz et al. defined it as a need for reintervention, graft delamination and symptom scores close to or worse than before ACI. Both Saris et al. and Knutsen et al. defined failure as reintervention only. This meant there were effectively 'more ways to fail' in the Nawaz et al. study than the other 2 studies. As a result, comparing ACI from Nawaz et al. with microfracture from the other 2 studies may have overestimated the failure rate of ACI compared with microfracture. Given this limitation, the committee considered whether it was better to compare the reintervention rates of ACI with microfracture using data from Knutsen et al. However, the committee was concerned that a trial with only 40 people in each arm may have been underpowered to detect a real difference. It also noted that the trial was not done in the UK so may not reflect NHS practice. The assessment group added that the failure rates of microfracture in Knutsen et al. were lower than those in other studies. The committee concluded that a robust comparison of the long-term effectiveness of ACI and microfracture was not possible with the data available.
## The outcomes may have been confounded by differences in characteristics in patient populations in the trials
The committee noted that the characteristics of the patient populations in Nawaz et al. (2014), Saris et al. (2009) and Knutsen et al. (2016) may also have differed, which may have confounded the outcomes. In particular, fewer patients in Nawaz et al. had had previous knee surgeries than patients in Saris et al. and Knutsen et al. (34% compared with 77% and 93% respectively). This reinforced the committee's previous conclusion that a robust comparison of the long-term effectiveness of ACI and microfracture was not possible with the data available (see section 3.9).
## ACI works better when there has been no previous knee repair and there is no osteoarthritic damage; microfracture is not suitable for defects over 2 cm2
The committee discussed whether there were people for whom ACI or microfracture may work particularly well (or poorly). It noted that, for ACI:
Stratified data from Nawaz et al. (2014) showed lower failure rates in patients who had no previous knee repair and in people with minimal evidence of osteoarthritis (using Kellgren–Lawrence scores). Larger defect size was not associated with poorer outcomes in these patients.
A predefined subgroup analysis of the TIG/ACT trial showed lower failure rates in people with symptoms lasting less than 3 years.For microfracture, it was not possible to determine how previous surgery, the presence or not of osteoarthritis, or duration of symptoms affected the failure rate because of a lack of available stratified data. However, the committee acknowledged the UK clinician consensus that microfracture is less effective in articular cartilage defects over 2 cm2, and that ACI should be used in defects of this size (see section 3.1).
## Results from the crude (unadjusted) comparison of ACI with microfracture were not robust
Given the available evidence and the consensus among UK clinicians, the committee concluded that:
ACI is likely to be associated with better outcomes if the person has not had previous knee repair or they have minimal osteoarthritic damage associated with the cartilage defect (see section 3.11).
ACI is an effective option at this point in the treatment pathway for people with articular cartilage defects over 2 cm2 (see section 3.11).
Limitations in the available subgroup and patient characteristic data meant that an adjustment to account for the differences in the populations between the studies used for estimating the long-term effectiveness of ACI and microfracture was not possible. Because of this, the results from the crude (unadjusted) comparison of ACI with microfracture were not robust.
## It is unclear whether there are differences in how well different forms of ACI work.
The committee considered whether any evidence supported differences in the clinical effectiveness of different ACI interventions (including different cap or matrix material, or whether or not the chondrocytes were characterised). The committee was aware that the marketing authorisations of ChondroCelect and MACI (before being withdrawn and suspended respectively) differed in the stated defect size. The clinical experts explained that this was because the inclusion criteria for the trials that informed the marketing authorisations differed and that, in clinical practice, the choice of ACI intervention was usually independent of defect size. The committee noted that the indirect comparisons of different forms of ACI did not show differences, but agreed that the included trials may have been too small to detect differences. The clinical experts explained that there was little evidence to suggest that types of ACI differ in their clinical effectiveness. The committee concluded that, although different experts may prefer different forms of ACI, the available evidence did not show a difference in their effectiveness.
# Cost-effectiveness estimates
## The committee used the assessment group's model in its decision-making
In its first 2 meetings, the committee considered the economic models from TiGenix (for ChondroCelect) and the assessment group, noting that their structures were broadly similar. Both used Markov health states that allowed for ACI or microfracture and temporary or permanent success, which predicted the probability of knee replacement. For the committee's third meeting, NICE asked the assessment group to update its model to include data identified from the updated systematic review (see section 3.7). Because ChondroCelect was no longer being appraised (see section 3.3) after the first 2 meetings, the committee did not consider the model submitted by TiGenix any further.
## The committee questioned the treatment pathway in the assessment group's model
The committee noted that the updated assessment group's model excluded the possibility of having a second microfracture procedure, such that it now compared ACI followed by ACI or microfracture with microfracture followed by ACI. However, the committee was concerned that patients in this model could have ACI in each modelled intervention arm (that is, a situation in which ACI was not available was not modelled). The committee noted that only 12% of patients who first had microfracture went on to have ACI. It acknowledged that this lessened the issue, but it would have preferred to have seen a scenario analysis in which patients had either microfracture or ACI, but not both sequentially. The committee heard from the clinical experts that, in clinical practice, clinicians may additionally do an osteotomy, debridement and lavage, before considering a total knee replacement as a final treatment option (see section 3.1). The committee concluded that the assessment group's model reasonably approximated the treatment pathway in clinical practice, but did not fully reflect it.
## Using longer-term data from separate sources for modelling ACI and microfracture outcomes is still subject to uncertainty
The assessment group's updated model used new sources of data to model failure rates for ACI and microfracture (see section 3.8). These sources provided Kaplan–Meier data from which the assessment group reconstructed individual patient-level data using the Guyot method. It tested several parametric curves to extrapolate the data beyond the study follow-up periods, and chose the best fitting based on statistical tests. The assessment group provided results for the cost effectiveness of ACI compared with microfracture for the whole population, for that stratified by previous surgery and osteoarthritic damage (based on Kellgren–Lawrence grade) and for a scenario in which it used extrapolated data from Knutsen et al. (2016) to model both ACI and microfracture. The committee recalled that there were still considerable uncertainties surrounding the effectiveness of both ACI and microfracture because unadjusted data from different sources were used (see sections 3.8 to 3.12). The committee discussed how these uncertainties may affect the cost-effectiveness estimates:
The differences in the definition of failure in Nawaz et al. (2014), Knutsen et al. and Saris et al. (2009) (see section 3.9) may have resulted in an overestimate of the incremental cost-effectiveness ratio (ICER) for ACI compared with microfracture.
The higher number of patients who had had previous knee surgeries in the studies of microfracture (Saris et al. and Knutsen et al.) than patients in the long-term study of ACI (Nawaz et al.; see section 3.10) may have resulted in an underestimate of the ICER for ACI compared with microfracture.
It was not possible to determine whether other differences between Nawaz et al. and the microfracture arms of the other trials (see section 3.12) would have resulted in an under- or overestimate of the ICER.
In the scenario in which Knutsen et al. data were used to model failure rates, the lower failure rates of microfracture in Knutsen et al. than in the other studies (see section 3.9) may have resulted in an overestimate of the ICER.
## An accurate estimate of the number of people having knee replacements is not possible
The committee heard from the clinical experts that literature-based estimates of the rates of knee replacement surgery vary widely in people with articular cartilage defects. It noted that there was also uncertainty in how well ACI prevents subsequent total knee replacement compared with microfracture. The committee concluded that the large variance in the probability of knee replacement meant that it was not possible to establish the most plausible estimates to use in the model.
# Costs in the model
## Procedure costs informed by Healthcare Resource Group codes were preferred by the committee
The committee discussed the costs associated with ACI in the assessment group's model, specifically the cost of cell harvesting and cell implanting. The assessment group had assumed that both the harvesting and implantation procedures would be done as day cases, and the clinical experts agreed with this assumption. In its updated model, the assessment group derived costs from Healthcare Resource Group (HRG) costings: specifically, £870 for cell harvesting (HRG code HB25F) and £2,396 for cell implantation (HRG code HB22C). The committee concluded that the assessment group's updated model included its preferred procedure costs.
## The committee heard different estimates of cell costs but used £16,000 as the basis for decision-making
The committee considered the most appropriate costs of producing and supplying cells. It noted that both the assessment group's model and the ChondroCelect model had assumed a cost of £16,000, which was based on the approximate list prices of ChondroCelect and MACI (when they were available in the UK). However, the committee was aware that companies sometimes provide confidential discounts to the NHS, making the real cost of cells difficult to ascertain. The committee noted that the OsCell submission had estimated a lower cost of £4,125, but this excluded the costs of overheads, and so underestimated the true cost of cells. In response to consultation on the updated assessment report, OsCell had revised the cost of the full procedure including the cells and overheads to £9,266. Although OsCell indicated that start-up costs, including setting up a laboratory for growing cells, were accounted for in its estimate of £9,266, the committee felt that current start-up costs were uncertain and may be higher than what OsCell had estimated. The committee concluded that, although the cost to the NHS of providing the cells for ACI was uncertain, the estimate of £16,000 used by the assessment group and in the ChondroCelect model was reasonable for the purposes of decision-making.
# Utility values
## Utility values in the model for people who had articular cartilage defects appear very low and may not represent the experience of patients in the NHS
The committee understood that, because of the short trial follow-up, there were limited long-term data on the utility of ACI and microfracture. The assessment group had sourced utility values from a study published by Gerlier et al. (2010), which compared ACI with microfracture using 5‑year data from the TIG/ACT trial. The committee noted that Gerlier et al. lacked information on sample size, missing values and how the authors had mapped the SF‑36 data to a health utility index. The committee commented that the utility value before surgery (0.65) seemed low, particularly compared with other similar conditions. The utility values before surgery were even lower in the ACTIVE trial, although the relative changes in utility values were similar to those from TIG/ACT. Over the course of this appraisal, utility data from the SUMMIT trial (measured using the EQ‑5D) were published, and reported a utility value before surgery of 0.484. The committee queried why these utilities were so low and heard from a clinical expert that highly active people may perceive cartilage injuries to be particularly disabling. The clinical expert explained that the patients in the trials were young and many were competitive athletes, so would not in general reflect the population considered for ACI in clinical practice. The committee noted that the utility data from SUMMIT showed higher utility values with ACI than with microfracture between week 52 and week 156. Applying these utility values in a scenario analysis rather than the data from Gerlier et al. (which were used in the assessment group's base case) decreased the ICER for ACI compared with microfracture. The committee concluded that there was uncertainty about the modelled utility values and how well they reflected the population considered for ACI in clinical practice. However, it agreed that the most plausible utility values for decision-making were those from Gerlier et al. because these were a less extreme estimate of the impact of cartilage damage on quality of life.
## Assuming that the utility value of a successful microfracture decreases over time is arbitrary and may favour ACI
The committee noted that, in its updated model, the assessment group had lowered the utility of microfracture success at year 5 and beyond from 0.82 to 0.65, to reflect evidence that the benefit of microfracture declines after 5 years. The committee noted that this was equivalent to assuming that microfracture had failed in all people at year 5. The committee considered that it would have been preferable to adjust for the reduced efficacy of microfracture more explicitly, by adjusting the transition probabilities instead of the utility of the success health state. The committee agreed that reducing the utility value for microfracture after 5 years was arbitrary and biased the results in favour of ACI. It noted a sensitivity analysis in which the assessment group set the utility of microfracture success at year 5 and beyond to 0.817 (the same as ACI). This increased the ICER. The committee therefore concluded that removing the assumption that utility decreased over time following a microfracture would likely increase the assessment group's base-case ICER.
## Utility values for people whose ACI or microfracture is not successful is uncertain, but modelled values are likely to favour ACI
The committee noted that the assessment group used a utility value for patients who moved to the 'no further repair' health state of 0.69 (that is, patients whose ACI or microfracture had not been successful, but who did not go on to have subsequent surgery). The committee understood that this utility value reflected some benefit from the first procedure, despite it not being successful, and so was not as low as the utility before the procedure (0.65). The committee noted a scenario analysis using utility values, which reflected more benefit after the first procedure than before increased the ICER. The committee concluded that there was uncertainty in estimating utility values for people who did not have subsequent surgery, and that the assessment group's approach favoured ACI.
# Conclusion
## Taking into account the uncertainty surrounding the estimates, the ICER for the whole eligible population may exceed £20,000 per QALY gained
The assessment group presented the committee with a range of ICERs for ACI compared with microfracture:
Original and updated base case: £14,000 per quality-adjusted life year (QALY) gained.
Scenarios in which different data sources were used to model failure rates: £6,000 to £17,000 per QALY gained.
Only in people who have had previous knee repair surgery: £22,000 per QALY gained.
Only in people who have not had previous knee repair surgery: £8,000 per QALY gained.
The ICER was lower than the base case for people who had minimal osteoarthritis in the knee (Kellgren–Lawrence grade 0 or 1) but was higher than the base case for people who had more severe osteoarthritis (Kellgren–Lawrence grade 2 or 3). The committee noted the numerous uncertainties surrounding the long-term relative effectiveness and utility estimates, and that it was impossible to determine the full effect of all these uncertainties to decide whether any of the ICERs presented by the assessment group were plausible. Additionally, the committee considered that there was a chance that the true ICER may exceed £20,000 per QALY gained for the whole population eligible for ACI in clinical practice. The committee concluded that it was not convinced that the ICER for ACI compared with microfracture was below £20,000 per QALY gained for the whole population eligible for ACI in clinical practice.
## ACI is recommended for use only in certain subgroups and subject to specific criteria
The committee agreed that there was merit in exploring subgroups of patients in whom ACI would be both clinically and cost effective. Based on the evidence presented by the assessment group, and the views of the clinical experts given to the committee, it identified the following subgroups (see section 3.11):
people who have not had previous knee repair
people who have minimal osteoarthritic damage to the knee
people with articular cartilage defects of over 2 cm2.Because the ICER for the subgroup of people who have not had previous knee repair was almost half of that of the entire patient group, the committee agreed that ACI could be cost effective in this subgroup. The committee noted that ACI is generally contraindicated in people with severe osteoarthritis, but the marketing authorisations for traditional ACI and the former marketing authorisations for ChondroCelect and MACI did not define the clinical measure for osteoarthritis (see section 2). The committee noted that Nawaz et al. (2014) had stratified patients in terms of osteoarthritic damage using Kellgren–Lawrence grades. It understood that this grading system was partly subjective, and so decided it was inappropriate to define a cut-off for minimal osteoarthritis using a particular grading system in its final recommendations. Rather, it was appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for ACI using a validated measure for osteoarthritis of the knee. The committee also noted that its recommendations for use in people with articular cartilage defects of over 2 cm2 was in line with the published consensus of 104 UK surgeons. It agreed that it is likely that the true ICER for ACI in the population that fulfils all these 3 criteria is likely to be under £20,000 per QALY gained. Finally, the committee noted that, at the time of making these recommendations, the OsCell John Charnley Laboratory was the only provider of ACI in England and that this laboratory is affiliated with a tertiary referral NHS orthopaedic hospital. It considered it appropriate that ACI should only be recommended in the same setting (that is, a tertiary referral centre with specialist expertise) because the evidence for its use in other settings had not been appraised. The committee concluded that it could recommend ACI as a cost-effective use of NHS resources, subject to the criteria in section 1.1.
# Innovation
## Additional consideration of innovation is not warranted
The committee noted that the companies all considered ACI to be innovative, mainly for reasons related to the technical detail of the procedures. The committee agreed that ACI, despite not being new, is technically innovative. However, in the context of a technology appraisal, innovation needs to be judged in terms of the benefit for patients not captured within the modelling. The committee concluded that it was not possible to surmise that these technologies are innovative in this sense.
# Equality issues
## The recommendations do not exclude access to ACI for people who are eligible to have it
The committee considered its recommendations in the context of the equality legislation. It was aware that one of its criteria for treatment, that is minimal osteoarthritic damage to the knee, excludes people with advanced or severe osteoarthritis, which can be disabling. However, one of the contraindications in the marketing authorisation for the technology is advanced osteoarthritis. In addition, the committee did not stipulate any specific threshold for the level of osteoarthritis, but instead stated in the guidance that it was appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for ACI using a validated measure for osteoarthritis of the knee. The committee was therefore satisfied that it had mitigated as far as it could any potential unfairness.
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{'Recommendations': "Autologous chondrocyte implantation (ACI) is recommended as an option for treating symptomatic articular cartilage defects of the knee, only if:\n\nthe person has not had previous surgery to repair articular cartilage defects\n\nthere is minimal osteoarthritic damage to the knee (as assessed by clinicians experienced in investigating knee cartilage damage using a validated measure for knee osteoarthritis)\n\nthe defect is over 2\xa0cm2 and\n\nthe procedure is done at a tertiary referral centre.\n\nWhy the committee made these recommendations\n\nClinical trial evidence shows that ACI can improve the symptoms of articular cartilage defects of the knee. There is evidence that it is likely to be more successful in people who haven't had any previous knee repair surgery, and in people who have very little osteoarthritic damage in the knee. But, it is unclear how well ACI works in the long term compared with microfracture, the most commonly used alternative treatment.\n\nThe consensus among UK clinicians is that ACI is the only effective treatment option for defects that are over 2\xa0cm2 when symptoms persist after non-surgical management.\n\nThe most accurate cost-effectiveness estimate for ACI compared with microfracture is uncertain, and is not likely to be under £20,000 per quality-adjusted life year (QALY) gained for everyone who is eligible to have ACI. But the cost-effectiveness estimate is lower in people in whom ACI has a better chance of success. This includes people who haven't had any previous knee repair surgery, and people who have very little osteoarthritic damage in the knee. In these people, the most accurate cost-effectiveness estimate is likely to be under £20,000 per QALY gained.", 'The technologies': 'Autologous chondrocyte implantation (ACI)\n\nMarketing authorisations\n\nThe OsCell John Charnley Laboratory has approval from the Medicines and Healthcare products Regulatory Agency to provide traditional ACI services under a hospital exemption from the advanced therapy medicinal products regulation for products prepared on a non-routine basis. It also has approval from the Human Tissues Authority for procuring, testing, storing and importing human tissues and cells for human application, and storing relevant material that has come from a human body for use for a scheduled purpose. The indication for use of traditional ACI in the knee is for the repair of single or multiple symptomatic, full-thickness cartilage defects of the joint with or without bone involvement in adults. Traditional ACI involves implanting a cell suspension under either a periosteal- or collagen-based membrane. Traditional ACI can be considered when the Oswestry Risk of Knee Arthroplasty (ORKA) score is 3\xa0or\xa04, but only when other factors can be corrected, for example, using meniscal allograft or realignment osteotomy.\n\n\n\nMatrix-associated chondrocyte implantation (MACI) had a European marketing authorisation for the repair of symptomatic, full-thickness cartilage defects of the knee (grades\xa0III and\xa0IV of the Modified Outerbridge Scale) between 3\xa0cm2 and 20\xa0cm2. The marketing authorisation is currently suspended while Vericel validates a new site for culturing cells.\n\n\n\nChondroCelect had a European marketing authorisation for repair of symptomatic cartilage defects of the femoral condyle of the knee (International Cartilage Repair Society grades\xa0III or\xa0IV), which was withdrawn by TiGenix during the course of this appraisal for commercial reasons.\n\n\n\nACI is contraindicated in people with severe osteoarthritis of the knee.\n\nPrice\n\nCosts may vary in different settings because of negotiated procurement discounts.\n\nThe recommendations are based on a maximum cell cost of £16,000.', 'Committee discussion': "The appraisal committee (section\xa05) considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Current treatment\n\n## ACI is an option after best supportive care but before knee replacement\n\nThe committee considered the treatment pathway for treating symptomatic cartilage defects of the knee. It understood that people with articular cartilage defects will first be offered best supportive care. This includes exercise, weight loss, physiotherapy, intra-articular corticosteroid injections, analgesia, off-loading, and applying heat/cold or transcutaneous electrical nerve stimulation. The committee heard from clinical experts that people with articular cartilage defects will be considered for surgery (microfracture, mosaicplasty or autologous chondrocyte implantation [ACI]) only if symptoms persist after best supportive care. It understood that a patient having ACI would have 2\xa0surgical procedures: 1\xa0to harvest chondrocytes from a non-damaged portion of the knee, and another to implant the cells in the damaged area. Between the 2\xa0procedures, the cells would be cultured in a laboratory. The committee heard that the choice between ACI, microfracture and mosaicplasty depends on the size of the defect, previous surgery, age, BMI and the condition of the cartilage. The committee was aware of the published consensus of 104\xa0UK surgeons with specialist knowledge of surgical repair techniques for articular chondrocyte defects of the knee. It states that microfracture is less effective in articular cartilage defects over 2\xa0cm2 and that ACI is the surgery of choice for articular cartilage defects over 2\xa0cm2. The committee heard that, in current clinical practice, the preferred surgery for defects smaller than this was microfracture. However, because there is variation in access to ACI, microfracture is currently the most common procedure for articular cartilage defects of all sizes. The clinical experts advised that, for people whose symptoms persist after having ACI or microfracture, other interventions such as mosaicplasty, debridement and lavage, osteotomy, further physiotherapy or a second ACI would be considered. The committee heard that, after microfracture, surgeons are unlikely to offer patients a second microfracture procedure. Total and partial knee replacement are options later in the treatment pathway, if the damage to the cartilage leads to advanced osteoarthritis. The committee heard from the clinical experts that, in clinical practice, total knee replacement is considered to be 'salvage treatment' (particularly in people younger than 55\xa0years) to be used when people have exhausted all other options.\n\n# Comparators\n\n## Microfracture is the most relevant comparator for decision-making\n\nThe final scope issued by NICE listed a number of comparators:\n\nMicrofracture – the committee agreed this was a relevant comparator.\n\nMosaicplasty – the committee noted differing views on the use of mosaicplasty in current NHS clinical practice. One clinical expert stated that mosaicplasty was generally used as an alternative to microfracture. However, the committee was persuaded by the assessment group's clinical advice that mosaicplasty is rarely used in NHS clinical practice.\n\nOsteotomy – the committee heard from a clinical expert that this would mainly be used to treat osteoarthritis of the knee, but may be used together with ACI in some people. The committee agreed that osteotomy was not a relevant comparator.\n\nBest supportive care – the committee agreed that ACI would only be used when symptoms persist after best supportive care (see section\xa03.1), and so concluded that it was not a relevant comparator.\n\nTotal knee replacement – the committee agreed that this would be offered later in the treatment pathway, and would not be considered for people for whom ACI was an option (see section\xa03.1). As such, the committee concluded that knee replacement was not a relevant comparator. The committee appreciated that there would be some variation in the use of these procedures in clinical practice because of the clinical experience and preference of the treating clinician and the availability of treatment. However, the committee concluded that microfracture is the most frequently used alternative to ACI in the NHS, and was the most relevant comparator for ACI in this appraisal.\n\n# Marketing authorisations\n\n## The recommendations only apply to technologies with a current marketing authorisation or an MHRA hospital exemption\n\nThe committee discussed the technologies listed in the final scope issued by NICE:\n\nTiGenix, which held the marketing authorisation for ChondroCelect, withdrew its marketing authorisation over the course of the appraisal.\n\nThe European marketing authorisation for matrix-associated chondrocyte implantation (MACI; held by Vericel) was suspended at the time of the appraisal because Vericel had closed its European laboratory for commercial reasons. Vericel told the committee that it was currently discussing accrediting its US laboratory with the European Medicines Agency, with the aim of reactivating its European marketing authorisation.\n\nOsCell John Charnley Laboratory is affiliated with a tertiary referral NHS orthopaedic hospital. It is permitted by the Medicines and Healthcare products Regulatory Agency (MHRA) to provide its services through the MHRA's hospital exemption from the regulation on advanced therapy medicinal products.The committee heard from OsCell that, if ACI was more widely available in the NHS, it envisaged that more NHS laboratories would be established specialising in selecting and culturing chondrocytes for ACI. The committee heard from NICE that its technology appraisal guidance only applies to technologies with a current marketing authorisation, but that the MHRA's hospital exemption regulation means that ACI provided by the OsCell John Charnley Laboratory meets this criterion. The committee concluded that it was relevant to consider all the data on clinical and cost effectiveness it had received. However, its recommendations would apply only to technologies with a current marketing authorisation or an MHRA hospital exemption from the regulation on advanced therapy medicinal products.\n\n# Patient experience\n\n## Articular cartilage defects are debilitating and patients would welcome ACI\n\nThe committee noted that 29\xa0people had submitted statements to NICE describing their experiences of articular cartilage defects and ACI. It heard that the symptoms of knee cartilage damage include pain, swelling, locking and joint instability, and that these symptoms negatively affect quality of life and a person's ability to do daily activities. In particular, many people with articular cartilage defects of the knee were very active before their injuries, so the physical impairment has had a major effect on their lives. The patients commented that recovery time was long with ACI but that the benefits were worth it. The clinical experts commented that some people prefer microfracture because of its shorter recovery time, whereas some people (such as competitive athletes) prefer ACI because the results are likely to last longer. Several people stated that, after having ACI, they had fewer symptoms and were able to resume daily activities. The committee commented that people who had positive experiences with ACI were more likely to provide comments to NICE and, as such, the patient statements may not reflect the full range of people's experiences. But, overall, the committee concluded that some patients were satisfied with the outcomes of ACI, and would welcome it as a treatment option.\n\n# Clinical trial evidence\n\n## The evidence for short-term outcomes came from 4\xa0randomised controlled trials\n\nThe committee considered the clinical-effectiveness evidence for ACI in terms of reducing pain and improving functional impairment associated with articular cartilage defects. For the first 2\xa0committee meetings, the assessment group identified 4\xa0randomised controlled trials that were relevant to the final scope issued by NICE:\n\nBasad et al. (2010), comparing MACI with microfracture in 60\xa0patients over 2\xa0years.\n\nSUMMIT, comparing MACI with microfracture in 144\xa0patients over 5\xa0years.\n\nTIG/ACT, comparing ACI using characterised chondrocytes (ChondroCelect) with microfracture in 118\xa0patients over 5\xa0years.\n\nACTIVE, comparing several forms of ACI with standard treatment (such as microfracture and mosaicplasty) in 390\xa0patients. The trial has an intended follow-up of 10\xa0years. Although OsCell has shared selected results from this trial in its submissions for this appraisal, no results have been published and the final results are yet to be reported.\n\n## There is some evidence that ACI improves symptoms in the short term\n\nThe committee discussed these 4\xa0trials at its first and second meetings, and noted that the evidence suggested that:\n\nOver 2\xa0years to 5\xa0years, both MACI and ChondroCelect were more clinically effective than microfracture (improvements in pain and function on the Knee injury and Osteoarthritis Outcome Score [KOOS]).\n\nAt 5\xa0years, the difference in the number of treatment failures and in health-related quality of life between ChondroCelect and microfracture was not statistically significant (p≥0.05). In contrast, provisional results from the ACTIVE trial suggested that ACI was only clinically beneficial compared with standard treatments (which included microfracture) at 5\xa0years. However, this was based on limited data and, when the committee met for the third time, no data had been published. In its first 2\xa0meetings, the committee heard conflicting opinions from the clinical experts about the effectiveness of ACI. However, generally the experts considered that there was evidence to show that ACI is clinically effective, although this evidence was not definitive. The committee concluded that, although uncertain, there was some evidence that ACI improves symptoms (based on the KOOS score).\n\n## It is uncertain how ACI compares with microfracture in the long term\n\nThe committee noted that the studies originally identified by the assessment group (see section\xa03.5) provided limited data on the failure rates of both ACI and microfracture after 5\xa0years. The committee therefore requested that the assessment group review all randomised controlled trials and observational studies that provided outcomes for more than 5\xa0years for ACI and microfracture, including all generations of ACI (that is, ACI available before ChondroCelect, MACI or ACI using cells from OsCell). For the committee's third meeting, the assessment group had broadened its systematic review to include 2\xa0more relevant studies on the failure rates of ACI and microfracture after 5\xa0years in its analyses:\n\nNawaz et al. (2014), an observational study of patients' experience with ACI only, at a single English site, over 2\xa0years to 12\xa0years (average follow-up 6.2\xa0years; n=827).\n\nKnutsen et al. (2016), a randomised controlled trial (published since the second committee meeting) comparing ACI with microfracture over 15\xa0years (n=80).\n\n## The assessment group's preferred sources of long-term failure data included Kaplan–Meier data showing time to failure\n\nThe assessment group's preferred source of data for long-term failure rates of ACI was Nawaz et al. (2014) because the study:\n\nincluded more patients than all the other sources of long-term ACI data combined\n\nreflected UK practice\n\nprovided data on different 'generations' of ACI\n\nprovided data on subgroups.The committee noted that the available data for long-term failure rates of microfracture were more limited. The assessment group's preferred sources of data were for microfracture were:\n\nSaris et al. (2009), which reported 3‑year Kaplan–Meier data on failure rates in the microfracture arm (n=61) of the TIG/ACT trial (see section\xa03.5). The assessment group chose Saris et al. over Vanlauwe et al. (2011), which had 5‑year Kaplan–Meier data from the TIG/ACT trial, because the reported data in Vanlauwe et al. did not allow a full analysis of the Kaplan–Meier plot.\n\nA 15-year follow-up of the microfracture arm (n=40) from Knutsen et al. (2016; see section\xa03.7).All the assessment group's preferred sources of long-term failure data (that is, Nawaz et al. Saris et al. and Knutsen et al.) included Kaplan–Meier data showing time to failure. The committee concluded that these studies were the best available to estimate long-term failure rates of ACI and microfracture.\n\n## A robust comparison of the long-term effectiveness of ACI and microfracture was not possible with the data available\n\nThe committee noted that Nawaz et al. (2014), Saris et al. (2009) and Knutsen et al. (2016) used different definitions of ACI failure. Nawaz et al. defined it as a need for reintervention, graft delamination and symptom scores close to or worse than before ACI. Both Saris et al. and Knutsen et al. defined failure as reintervention only. This meant there were effectively 'more ways to fail' in the Nawaz et al. study than the other 2\xa0studies. As a result, comparing ACI from Nawaz et al. with microfracture from the other 2\xa0studies may have overestimated the failure rate of ACI compared with microfracture. Given this limitation, the committee considered whether it was better to compare the reintervention rates of ACI with microfracture using data from Knutsen et al. However, the committee was concerned that a trial with only 40\xa0people in each arm may have been underpowered to detect a real difference. It also noted that the trial was not done in the UK so may not reflect NHS practice. The assessment group added that the failure rates of microfracture in Knutsen et al. were lower than those in other studies. The committee concluded that a robust comparison of the long-term effectiveness of ACI and microfracture was not possible with the data available.\n\n## The outcomes may have been confounded by differences in characteristics in patient populations in the trials\n\nThe committee noted that the characteristics of the patient populations in Nawaz et al. (2014), Saris et al. (2009) and Knutsen et al. (2016) may also have differed, which may have confounded the outcomes. In particular, fewer patients in Nawaz et al. had had previous knee surgeries than patients in Saris et al. and Knutsen et al. (34% compared with 77% and 93% respectively). This reinforced the committee's previous conclusion that a robust comparison of the long-term effectiveness of ACI and microfracture was not possible with the data available (see section\xa03.9).\n\n## ACI works better when there has been no previous knee repair and there is no osteoarthritic damage; microfracture is not suitable for defects over 2\xa0cm2\n\nThe committee discussed whether there were people for whom ACI or microfracture may work particularly well (or poorly). It noted that, for ACI:\n\nStratified data from Nawaz et al. (2014) showed lower failure rates in patients who had no previous knee repair and in people with minimal evidence of osteoarthritis (using Kellgren–Lawrence scores). Larger defect size was not associated with poorer outcomes in these patients.\n\nA predefined subgroup analysis of the TIG/ACT trial showed lower failure rates in people with symptoms lasting less than 3\xa0years.For microfracture, it was not possible to determine how previous surgery, the presence or not of osteoarthritis, or duration of symptoms affected the failure rate because of a lack of available stratified data. However, the committee acknowledged the UK clinician consensus that microfracture is less effective in articular cartilage defects over 2\xa0cm2, and that ACI should be used in defects of this size (see section\xa03.1).\n\n## Results from the crude (unadjusted) comparison of ACI with microfracture were not robust\n\nGiven the available evidence and the consensus among UK clinicians, the committee concluded that:\n\nACI is likely to be associated with better outcomes if the person has not had previous knee repair or they have minimal osteoarthritic damage associated with the cartilage defect (see section\xa03.11).\n\nACI is an effective option at this point in the treatment pathway for people with articular cartilage defects over 2\xa0cm2 (see section\xa03.11).\n\nLimitations in the available subgroup and patient characteristic data meant that an adjustment to account for the differences in the populations between the studies used for estimating the long-term effectiveness of ACI and microfracture was not possible. Because of this, the results from the crude (unadjusted) comparison of ACI with microfracture were not robust.\n\n## It is unclear whether there are differences in how well different forms of ACI work.\n\nThe committee considered whether any evidence supported differences in the clinical effectiveness of different ACI interventions (including different cap or matrix material, or whether or not the chondrocytes were characterised). The committee was aware that the marketing authorisations of ChondroCelect and MACI (before being withdrawn and suspended respectively) differed in the stated defect size. The clinical experts explained that this was because the inclusion criteria for the trials that informed the marketing authorisations differed and that, in clinical practice, the choice of ACI intervention was usually independent of defect size. The committee noted that the indirect comparisons of different forms of ACI did not show differences, but agreed that the included trials may have been too small to detect differences. The clinical experts explained that there was little evidence to suggest that types of ACI differ in their clinical effectiveness. The committee concluded that, although different experts may prefer different forms of ACI, the available evidence did not show a difference in their effectiveness.\n\n# Cost-effectiveness estimates\n\n## The committee used the assessment group's model in its decision-making\n\nIn its first 2\xa0meetings, the committee considered the economic models from TiGenix (for ChondroCelect) and the assessment group, noting that their structures were broadly similar. Both used Markov health states that allowed for ACI or microfracture and temporary or permanent success, which predicted the probability of knee replacement. For the committee's third meeting, NICE asked the assessment group to update its model to include data identified from the updated systematic review (see section\xa03.7). Because ChondroCelect was no longer being appraised (see section\xa03.3) after the first 2\xa0meetings, the committee did not consider the model submitted by TiGenix any further.\n\n## The committee questioned the treatment pathway in the assessment group's model\n\nThe committee noted that the updated assessment group's model excluded the possibility of having a second microfracture procedure, such that it now compared ACI followed by ACI or microfracture with microfracture followed by ACI. However, the committee was concerned that patients in this model could have ACI in each modelled intervention arm (that is, a situation in which ACI was not available was not modelled). The committee noted that only 12% of patients who first had microfracture went on to have ACI. It acknowledged that this lessened the issue, but it would have preferred to have seen a scenario analysis in which patients had either microfracture or ACI, but not both sequentially. The committee heard from the clinical experts that, in clinical practice, clinicians may additionally do an osteotomy, debridement and lavage, before considering a total knee replacement as a final treatment option (see section\xa03.1). The committee concluded that the assessment group's model reasonably approximated the treatment pathway in clinical practice, but did not fully reflect it.\n\n## Using longer-term data from separate sources for modelling ACI and microfracture outcomes is still subject to uncertainty\n\nThe assessment group's updated model used new sources of data to model failure rates for ACI and microfracture (see section\xa03.8). These sources provided Kaplan–Meier data from which the assessment group reconstructed individual patient-level data using the Guyot method. It tested several parametric curves to extrapolate the data beyond the study follow-up periods, and chose the best fitting based on statistical tests. The assessment group provided results for the cost effectiveness of ACI compared with microfracture for the whole population, for that stratified by previous surgery and osteoarthritic damage (based on Kellgren–Lawrence grade) and for a scenario in which it used extrapolated data from Knutsen et al. (2016) to model both ACI and microfracture. The committee recalled that there were still considerable uncertainties surrounding the effectiveness of both ACI and microfracture because unadjusted data from different sources were used (see sections 3.8 to 3.12). The committee discussed how these uncertainties may affect the cost-effectiveness estimates:\n\nThe differences in the definition of failure in Nawaz et al. (2014), Knutsen et al. and Saris et al. (2009) (see section\xa03.9) may have resulted in an overestimate of the incremental cost-effectiveness ratio (ICER) for ACI compared with microfracture.\n\nThe higher number of patients who had had previous knee surgeries in the studies of microfracture (Saris et al. and Knutsen et al.) than patients in the long-term study of ACI (Nawaz et al.; see section 3.10) may have resulted in an underestimate of the ICER for ACI compared with microfracture.\n\nIt was not possible to determine whether other differences between Nawaz et al. and the microfracture arms of the other trials (see section\xa03.12) would have resulted in an under- or overestimate of the ICER.\n\nIn the scenario in which Knutsen et al. data were used to model failure rates, the lower failure rates of microfracture in Knutsen et al. than in the other studies (see section\xa03.9) may have resulted in an overestimate of the ICER.\n\n## An accurate estimate of the number of people having knee replacements is not possible\n\nThe committee heard from the clinical experts that literature-based estimates of the rates of knee replacement surgery vary widely in people with articular cartilage defects. It noted that there was also uncertainty in how well ACI prevents subsequent total knee replacement compared with microfracture. The committee concluded that the large variance in the probability of knee replacement meant that it was not possible to establish the most plausible estimates to use in the model.\n\n# Costs in the model\n\n## Procedure costs informed by Healthcare Resource Group codes were preferred by the committee\n\nThe committee discussed the costs associated with ACI in the assessment group's model, specifically the cost of cell harvesting and cell implanting. The assessment group had assumed that both the harvesting and implantation procedures would be done as day cases, and the clinical experts agreed with this assumption. In its updated model, the assessment group derived costs from Healthcare Resource Group (HRG) costings: specifically, £870 for cell harvesting (HRG code HB25F) and £2,396 for cell implantation (HRG code HB22C). The committee concluded that the assessment group's updated model included its preferred procedure costs.\n\n## The committee heard different estimates of cell costs but used £16,000 as the basis for decision-making\n\nThe committee considered the most appropriate costs of producing and supplying cells. It noted that both the assessment group's model and the ChondroCelect model had assumed a cost of £16,000, which was based on the approximate list prices of ChondroCelect and MACI (when they were available in the UK). However, the committee was aware that companies sometimes provide confidential discounts to the NHS, making the real cost of cells difficult to ascertain. The committee noted that the OsCell submission had estimated a lower cost of £4,125, but this excluded the costs of overheads, and so underestimated the true cost of cells. In response to consultation on the updated assessment report, OsCell had revised the cost of the full procedure including the cells and overheads to £9,266. Although OsCell indicated that start-up costs, including setting up a laboratory for growing cells, were accounted for in its estimate of £9,266, the committee felt that current start-up costs were uncertain and may be higher than what OsCell had estimated. The committee concluded that, although the cost to the NHS of providing the cells for ACI was uncertain, the estimate of £16,000 used by the assessment group and in the ChondroCelect model was reasonable for the purposes of decision-making.\n\n# Utility values\n\n## Utility values in the model for people who had articular cartilage defects appear very low and may not represent the experience of patients in the NHS\n\nThe committee understood that, because of the short trial follow-up, there were limited long-term data on the utility of ACI and microfracture. The assessment group had sourced utility values from a study published by Gerlier et al. (2010), which compared ACI with microfracture using 5‑year data from the TIG/ACT trial. The committee noted that Gerlier et al. lacked information on sample size, missing values and how the authors had mapped the SF‑36 data to a health utility index. The committee commented that the utility value before surgery (0.65) seemed low, particularly compared with other similar conditions. The utility values before surgery were even lower in the ACTIVE trial, although the relative changes in utility values were similar to those from TIG/ACT. Over the course of this appraisal, utility data from the SUMMIT trial (measured using the EQ‑5D) were published, and reported a utility value before surgery of 0.484. The committee queried why these utilities were so low and heard from a clinical expert that highly active people may perceive cartilage injuries to be particularly disabling. The clinical expert explained that the patients in the trials were young and many were competitive athletes, so would not in general reflect the population considered for ACI in clinical practice. The committee noted that the utility data from SUMMIT showed higher utility values with ACI than with microfracture between week\xa052 and week\xa0156. Applying these utility values in a scenario analysis rather than the data from Gerlier et al. (which were used in the assessment group's base case) decreased the ICER for ACI compared with microfracture. The committee concluded that there was uncertainty about the modelled utility values and how well they reflected the population considered for ACI in clinical practice. However, it agreed that the most plausible utility values for decision-making were those from Gerlier et al. because these were a less extreme estimate of the impact of cartilage damage on quality of life.\n\n## Assuming that the utility value of a successful microfracture decreases over time is arbitrary and may favour ACI\n\nThe committee noted that, in its updated model, the assessment group had lowered the utility of microfracture success at year\xa05 and beyond from 0.82 to 0.65, to reflect evidence that the benefit of microfracture declines after 5\xa0years. The committee noted that this was equivalent to assuming that microfracture had failed in all people at year\xa05. The committee considered that it would have been preferable to adjust for the reduced efficacy of microfracture more explicitly, by adjusting the transition probabilities instead of the utility of the success health state. The committee agreed that reducing the utility value for microfracture after 5\xa0years was arbitrary and biased the results in favour of ACI. It noted a sensitivity analysis in which the assessment group set the utility of microfracture success at year\xa05 and beyond to 0.817 (the same as ACI). This increased the ICER. The committee therefore concluded that removing the assumption that utility decreased over time following a microfracture would likely increase the assessment group's base-case ICER.\n\n## Utility values for people whose ACI or microfracture is not successful is uncertain, but modelled values are likely to favour ACI\n\nThe committee noted that the assessment group used a utility value for patients who moved to the 'no further repair' health state of 0.69 (that is, patients whose ACI or microfracture had not been successful, but who did not go on to have subsequent surgery). The committee understood that this utility value reflected some benefit from the first procedure, despite it not being successful, and so was not as low as the utility before the procedure (0.65). The committee noted a scenario analysis using utility values, which reflected more benefit after the first procedure than before increased the ICER. The committee concluded that there was uncertainty in estimating utility values for people who did not have subsequent surgery, and that the assessment group's approach favoured ACI.\n\n# Conclusion\n\n## Taking into account the uncertainty surrounding the estimates, the ICER for the whole eligible population may exceed £20,000 per QALY gained\n\nThe assessment group presented the committee with a range of ICERs for ACI compared with microfracture:\n\nOriginal and updated base case: £14,000 per quality-adjusted life year (QALY) gained.\n\nScenarios in which different data sources were used to model failure rates: £6,000 to £17,000 per QALY gained.\n\nOnly in people who have had previous knee repair surgery: £22,000 per QALY gained.\n\nOnly in people who have not had previous knee repair surgery: £8,000 per QALY gained.\n\nThe ICER was lower than the base case for people who had minimal osteoarthritis in the knee (Kellgren–Lawrence grade 0\xa0or\xa01) but was higher than the base case for people who had more severe osteoarthritis (Kellgren–Lawrence grade\xa02 or\xa03). The committee noted the numerous uncertainties surrounding the long-term relative effectiveness and utility estimates, and that it was impossible to determine the full effect of all these uncertainties to decide whether any of the ICERs presented by the assessment group were plausible. Additionally, the committee considered that there was a chance that the true ICER may exceed £20,000 per QALY gained for the whole population eligible for ACI in clinical practice. The committee concluded that it was not convinced that the ICER for ACI compared with microfracture was below £20,000 per QALY gained for the whole population eligible for ACI in clinical practice.\n\n## ACI is recommended for use only in certain subgroups and subject to specific criteria\n\nThe committee agreed that there was merit in exploring subgroups of patients in whom ACI would be both clinically and cost effective. Based on the evidence presented by the assessment group, and the views of the clinical experts given to the committee, it identified the following subgroups (see section\xa03.11):\n\npeople who have not had previous knee repair\n\npeople who have minimal osteoarthritic damage to the knee\n\npeople with articular cartilage defects of over 2\xa0cm2.Because the ICER for the subgroup of people who have not had previous knee repair was almost half of that of the entire patient group, the committee agreed that ACI could be cost effective in this subgroup. The committee noted that ACI is generally contraindicated in people with severe osteoarthritis, but the marketing authorisations for traditional ACI and the former marketing authorisations for ChondroCelect and MACI did not define the clinical measure for osteoarthritis (see section\xa02). The committee noted that Nawaz et al. (2014) had stratified patients in terms of osteoarthritic damage using Kellgren–Lawrence grades. It understood that this grading system was partly subjective, and so decided it was inappropriate to define a cut-off for minimal osteoarthritis using a particular grading system in its final recommendations. Rather, it was appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for ACI using a validated measure for osteoarthritis of the knee. The committee also noted that its recommendations for use in people with articular cartilage defects of over 2\xa0cm2 was in line with the published consensus of 104\xa0UK surgeons. It agreed that it is likely that the true ICER for ACI in the population that fulfils all these 3\xa0criteria is likely to be under £20,000 per QALY gained. Finally, the committee noted that, at the time of making these recommendations, the OsCell John Charnley Laboratory was the only provider of ACI in England and that this laboratory is affiliated with a tertiary referral NHS orthopaedic hospital. It considered it appropriate that ACI should only be recommended in the same setting (that is, a tertiary referral centre with specialist expertise) because the evidence for its use in other settings had not been appraised. The committee concluded that it could recommend ACI as a cost-effective use of NHS resources, subject to the criteria in section\xa01.1.\n\n# Innovation\n\n## Additional consideration of innovation is not warranted\n\nThe committee noted that the companies all considered ACI to be innovative, mainly for reasons related to the technical detail of the procedures. The committee agreed that ACI, despite not being new, is technically innovative. However, in the context of a technology appraisal, innovation needs to be judged in terms of the benefit for patients not captured within the modelling. The committee concluded that it was not possible to surmise that these technologies are innovative in this sense.\n\n# Equality issues\n\n## The recommendations do not exclude access to ACI for people who are eligible to have it\n\nThe committee considered its recommendations in the context of the equality legislation. It was aware that one of its criteria for treatment, that is minimal osteoarthritic damage to the knee, excludes people with advanced or severe osteoarthritis, which can be disabling. However, one of the contraindications in the marketing authorisation for the technology is advanced osteoarthritis. In addition, the committee did not stipulate any specific threshold for the level of osteoarthritis, but instead stated in the guidance that it was appropriate for clinicians experienced in investigating knee cartilage damage to assess suitability for ACI using a validated measure for osteoarthritis of the knee. The committee was therefore satisfied that it had mitigated as far as it could any potential unfairness."}
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https://www.nice.org.uk/guidance/ta477
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Evidence-based recommendations on autologous chondrocyte implantation in people with symptomatic articular cartilage defects of the knee.
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1eeb6e51c6e0bf8d1d2a7bf7e8199269f15680d1
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nice
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Brentuximab vedotin for treating relapsed or refractory systemic anaplastic large cell lymphoma
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Brentuximab vedotin for treating relapsed or refractory systemic anaplastic large cell lymphoma
Evidence-based recommendations on brentuximab vedotin (Adcetris) for treating relapsed or refractory systemic anaplastic large cell lymphoma in adults.
# Recommendations
Brentuximab vedotin is recommended as an option for treating relapsed or refractory systemic anaplastic large cell lymphoma in adults, only if:
they have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and
the company provides brentuximab vedotin according to the commercial access agreement with NHS England.
When using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with brentuximab vedotin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Brentuximab vedotin has a marketing authorisation for treating relapsed or refractory systemic anaplastic large cell lymphoma in adults, but it is most likely to be used in the NHS as first-line salvage therapy. At this point in the treatment pathway, the appropriate comparator is chemotherapy.
Evidence from the main clinical trial for brentuximab vedotin shows that it is effective based on response rates. However, the trial is not comparative, and therefore there is uncertainty about the full extent of the survival benefit from treatment with brentuximab vedotin.
The best available evidence comes from an unadjusted indirect comparison of brentuximab vedotin and chemotherapy, although there is still uncertainty about the robustness of the results because of the differences in age, stage of disease, and performance status in the groups compared.
The plausible estimates of cost effectiveness are below £30,000 per quality-adjusted life year gained, and this was considered to be an acceptable use of NHS resources. However, because the clinical- and cost-effectiveness data are based on people with an ECOG performance status of 0 or 1, brentuximab vedotin is only recommended for this group.# The technology
Marketing authorisation
Brentuximab vedotin is indicated for 'the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma'.
Brentuximab vedotin has been available to patients in England through the Cancer Drugs Fund since April 2013 for relapsed or refractory systemic anaplastic large cell lymphoma.
Recommended dose and schedule
The recommended dose is 1.8 mg/kg administered by intravenous infusion over 30 minutes every 3 weeks.
Price
The price of brentuximab vedotin is £2,500 for a 50‑mg vial (excluding VAT; British national formulary accessed August 2017).
Takeda has agreed a commercial access agreement with NHS England in which a discount is applied at the point of purchase or invoice for brentuximab vedotin. The financial terms of the agreement are commercial in confidence.# Committee discussion
The appraisal committee considered evidence submitted by Takeda UK and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Patient experience
## Brentuximab vedotin is well tolerated and could significantly improve quality of life
The patient expert explained that a diagnosis of systemic anaplastic large cell lymphoma can have a big effect on a person's physical and psychological wellbeing. The clinical and patient experts highlighted that brentuximab vedotin is generally better tolerated than existing treatments because it has more manageable and fewer side effects, and that it can significantly improve patients' quality of life. The committee concluded that access to effective treatments and improving quality of life are significant benefits to patients.
# Clinical management
## There is an unmet clinical need for people with relapsed or refractory systemic anaplastic large cell lymphoma
There is no NICE technology appraisal guidance for systemic anaplastic large cell lymphoma. The committee understood that CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine and prednisolone) is a commonly used first-line regimen for people with systemic anaplastic large cell lymphoma. Some people may also have additional first-line treatment with high-dose chemotherapy (most commonly BEAM ) and autologous stem cell transplant. The clinical expert explained that most people with systemic anaplastic large cell lymphoma have relapsed or refractory disease. The committee heard that this group represents a major area of unmet clinical need. People typically have short overall survival after relapse and there is a lack of clear agreement or a strong evidence base to recommend second-line therapies. Salvage therapies are used, followed by either autologous or allogeneic stem cell transplant. The choice of treatment depends on clinician and patient preference, which can be influenced by a number of factors (for example, patient fitness, type of therapy and response to prior therapy, donor availability and clinical trial options). The committee agreed that people with relapsed or refractory systemic anaplastic large cell lymphoma have an unmet clinical need.
## Brentuximab vedotin is likely to be mostly used as a first-line salvage therapy
The committee was aware that brentuximab vedotin is used as an alternative salvage therapy to standard chemotherapy regimens (for example, GDP and ICE ). The committee noted that neither the marketing authorisation for brentuximab vedotin nor its indication in the Cancer Drugs Fund (available in England since April 2013 for relapsed or refractory systemic anaplastic large cell lymphoma) specified a certain number of previous treatments before using brentuximab vedotin. It could therefore potentially be used as second-, third- or fourth-line therapy in the treatment pathway for relapsed or refractory systemic anaplastic large cell lymphoma depending on previous salvage treatments and response to those treatments. It noted that the inclusion criteria for SG035‑0004 (the pivotal trial on which the marketing authorisation is based) specified 'after treatment failure of at least 1 therapy with curative intent'. The clinical expert explained that brentuximab vedotin is usually used with 2 strategies in mind: as a first-line salvage therapy before either autologous or allogeneic stem cell transplant, and as a first salvage therapy without future stem cell transplant. The committee was also aware from the Cancer Drugs Fund's clinical lead that brentuximab vedotin is used in the Cancer Drugs Fund as a second-line therapy. The committee noted that both the clinical expert and the Cancer Drugs Fund clinical lead agreed that brentuximab vedotin would be used as a first-line salvage therapy (that is as second-line therapy after first-line chemotherapy ) instead of salvage chemotherapy. The committee noted that in response to consultation, comments were received that stated brentuximab vedotin would be used for some people later in the pathway.
## People have fewer cycles of brentuximab vedotin in Cancer Drugs Fund clinical practice than in both SG035-0004 and the summary of product characteristics
The committee asked if rules for stopping treatment are used in clinical practice. It noted that the summary of product characteristics for brentuximab vedotin states that it should be used for a minimum of 8 cycles up to a maximum of 16 cycles in patients whose disease is stable. The committee noted that the mean number of cycles of brentuximab vedotin received by the intention-to-treat population in SG035‑0004 was 8.2 cycles. The clinical expert highlighted that real-world evidence from the Cancer Drugs Fund suggests that the median number of cycles for brentuximab vedotin is 5 to 6, and that this estimate includes people who go on to have stem cell transplant, people who do not, and people who stop taking brentuximab vedotin because of a lack of a clinical response or unmanageable side effects. The committee was aware that there are clinical criteria to identify people for whom stem cell transplant is not appropriate before starting first-line salvage therapy, for example people with comorbidities that would compromise fitness for a stem cell transplant, but it may not always be possible to decide whether stem cell transplant is appropriate before starting brentuximab vedotin. The committee heard that when brentuximab vedotin is used as a first-line salvage therapy before either autologous or allogeneic stem cell transplant, assessing the response with PET-CT imaging would typically be done after 3 to 4 cycles of brentuximab vedotin and treatment stopped after 4 to 6 cycles. The committee was aware that for the small minority of people for whom brentuximab vedotin is used as first-line salvage therapy without future stem cell transplant, the median number of cycles of brentuximab vedotin is 6 to 8, but up to 16 cycles of brentuximab can be used if there is evidence of ongoing response and tolerability. The committee accepted that most people in clinical practice would have fewer cycles than specified in the summary of product characteristics and the SG035‑0004 trial, and agreed this should be considered in its decision-making.
# Clinical evidence
## The main evidence for brentuximab vedotin comes from 1 single-arm, phase 2 study
The company's main evidence was based on a multicentre, phase 2, single-arm study (SG035‑0004) in 58 patients with relapsed or refractory systemic anaplastic large cell lymphoma after treatment failure of at least 1 therapy with curative intent and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary outcome of the trial was objective response rate, with secondary outcomes including duration of response, complete remission, progression-free survival and overall survival. These outcomes were assessed by an independent review at a median follow-up time of 16.8 months. The company also presented data for up to 5 years' follow-up (median observation time of 71.8 months) based on investigator assessment.
Best clinical response (n=58)
Objective response rate: 50 (86%), 95% confidence interval (CI) 74.6 to 93.9
Complete remission: 34 (59%), 95% CI 44.9 to 71.4
Partial remission: 16 (28%), 95% CI not applicable
Disease control rate: 52 (90%), 95% CI 78.8 to 96.1
Duration of response, median (95% CI)
Objective response rate: 13.2 (95% CI 5.7 to not estimable). The duration of response was 0.1+ months to 21.7+ months and the median follow-up time from first dose for patients who achieved objective response per independent review was 11.8 months
Complete remission: Not reached (95% CI 13.0 to not estimable)
Overall survival
Not reached (95% CI 21.3 to not estimable). The estimated 36-month overall survival was 63% (the median observation time ) from first dose was 33.4 months
Overall population
Estimated 5-year overall survival rate: 60% (95% confidence interval 47% to 73%)
Median overall survival: Not estimable (95% CI 21.3 to not reached; range 0.8 to 82.4+ months)
Median progression-free survival: 20.0 months (95% CI 9.4 to not reached)
Of 58 enrolled patients, 42 (72%) had anaplastic lymphoma kinase (ALK)-negative disease
Estimated 5-year overall survival: 61% (95% CI 47% to 76%)
Median progression-free survival: 20.0 months (95% CI 6.7 to not reached)
Median overall survival: not reached
Of 58 enrolled patients, 16 (28%) had ALK-positive disease
Estimated 5-year overall survival: 56% (95% CI 32% to 81%)
Median progression-free survival: 25.5 months (95% CI 8.0 to not reached)
Median overall survival: Not reached
## SG035-0004 is the most appropriate source of clinical data for brentuximab vedotin
Two retrospective case series (Gopal et al. 2014 and Chihara et al. 2015) and 3 named patient programmes (Gibb et al. 2013 based in the UK) provided further non-randomised supplementary evidence. Gopal et al. (2014) evaluated brentuximab vedotin as a treatment for older people with systemic anaplastic large cell lymphoma and reported a median progression-free survival of 15.6 months (95% confidence interval 4.2 to not reached; range 0.0+ to 22.4+ months). Data from the UK named patient programme demonstrated that in people with CD30+ lymphoma who had several previous treatments, brentuximab vedotin had an objective response rate of 67% and median progression-free survival of 5.1 months. The committee concluded that the results from the SG035‑0004 trial were the most appropriate for its decision-making, noting that although the Gopal and Gibb studies only included a few patients with systemic anaplastic large cell lymphoma, the results largely supported those from SG035‑0004.
## It is appropriate to reflect the performance status of the SG035-0004 trial population in decision-making
The committee noted that patients in SG035‑0004 had an ECOG performance status of 0 or 1, corresponding to a population whose activities are relatively unrestricted by their disease. This is in contrast to the population specified in brentuximab vedotin's marketing authorisation, in which performance status is not a criterion. The committee considered the disparity between the populations in SG035‑0004 and the marketing authorisation, and noted that people with a worse performance status than 1 may benefit less from brentuximab vedotin. It also considered this group could require more cycles of treatment. The committee concluded that because it is unclear how effective brentuximab vedotin is in people with a performance status of more than 1, its decision-making should reflect the available trial evidence.
## Trial data suggest that brentuximab vedotin is effective but there is uncertainty
The committee was concerned that the single-arm design of the trial meant that the results were potentially biased, but appreciated that it would be difficult to do a randomised controlled trial for brentuximab vedotin because of the rarity of systemic anaplastic large cell lymphoma. It accepted that the results from the data cut-off at a median follow-up of 16.8 months and a median observation time of 71.8 months showed that brentuximab vedotin was clinically effective based on response rates, but there was uncertainty in the clinical evidence about the full extent of progression-free survival and overall survival. The committee concluded that there was a large degree of uncertainty in the clinical evidence, but noted that both comments from clinical and patient experts and the response rates from the trials suggested that brentuximab vedotin was an effective treatment for people with an ECOG performance status of 0 or 1.
# Indirect treatment comparison
## The company indirectly compared overall survival of brentuximab vedotin and chemotherapy, only in people with no stem cell transplant
The committee was aware that there were no data directly comparing overall survival for brentuximab vedotin and chemotherapy. It noted that the company had done an indirect comparison of brentuximab vedotin and chemotherapy. It compared the outcomes from a subgroup of patients from SG035‑0004 who did not go on to have stem cell transplant (n=41, the 'self-control cohort') with those from a subgroup of patients from Mak et al. (2013). Mak et al. reported progression-free survival and overall survival data for a historical cohort of 153 patients on the British Columbia Cancer Agency Lymphoid Cancer database who had peripheral T-cell lymphoma with relapsed or progressive disease. The committee noted that the company focused its analyses on a subset of people reported in Mak et al. who had already had systemic chemotherapy (n=89) but not stem cell transplant. The company considered 2 subgroups from this subset: a subgroup of patients with anaplastic large cell lymphoma (n=17) and a broader subgroup including patients with peripheral T-cell lymphoma and a performance status of less than 2 (n=47).
## The unadjusted indirect comparison is appropriate but the results should be treated with caution
The committee noted the heterogeneity between the self-control cohort from SG035‑0004 (n=41) and the subgroup of patients in Mak et al. who had already had systemic chemotherapy (n=89), particularly for age, stage of disease and performance status. The committee was aware that these issues could to lead to bias in favour of brentuximab vedotin. The committee was also aware that it was not possible for the company to compare the baseline characteristics of the self-control cohort from SG035‑0004 with those from the subset of patients from Mak et al. with anaplastic large cell lymphoma (n=17) and peripheral T-cell lymphoma and a performance status less than 2 (n=47) because the baseline characteristics were not reported. The committee acknowledged the company had considered doing a matched adjusted indirect comparison using data from the self-control cohort from SG035‑0004 and from the subgroup of patients in Mak et al. who had already had systemic chemotherapy (n=89), but had concluded that it was inappropriate to do this because the effective sample size would be 4.8 after adjusting for available variables. The committee agreed with this. The committee concluded that the company's unadjusted indirect comparison of overall survival was the best available evidence for its decision-making, although there was still uncertainty about the robustness of the results because of the potential bias in favour of brentuximab vedotin, resulting from the heterogeneity in age, stage of disease, and performance status.
# The company's economic model
## The company's model is appropriate and represents the treatment pathway
The committee noted that the company had modelled 6 population cohorts: brentuximab vedotin or chemotherapy with no stem cell transplant, brentuximab vedotin or chemotherapy with autologous stem cell transplant, and brentuximab vedotin or chemotherapy with allogeneic stem cell transplant. These reflect the clinical pathway of care for systemic anaplastic large cell lymphoma. Overall, the committee accepted the structure of the model as representing the treatment pathway for patients with relapsed or refractory systemic anaplastic large cell lymphoma. It noted that the company had modelled brentuximab vedotin consistent with its use in clinical practice. The committee considered the model appropriate for its decision-making. It noted that the company's cost-effectiveness analyses included a confidential commercial access agreement between the company and NHS England.
## The company updated its model after consultation to incorporate the committee's preferred assumptions
In response to consultation, the company updated its economic model to include the committee's preferred assumptions and a number of scenario analyses that explored the use of Mak et al. data to model both progression-free survival and overall survival for chemotherapy, parametric models of progression-free and overall survival for both brentuximab vedotin and chemotherapy, and the use of higher excess mortality rates than in the original model.
# Stem cell transplant rates
## The company's model uses appropriate stem cell transplant rates
The committee noted that the modelling of treatment effectiveness and extrapolation of progression-free survival and overall survival was based on a combination of clinical response rates, stem cell transplant by response categories and survival outcomes by transplant status (that is, no stem cell transplant, autologous or allogeneic stem cell transplant). The committee also noted that the company had assumed that for a proportion of patients, brentuximab vedotin or chemotherapy acts as a bridge to stem cell transplant, which is a potentially curative therapy. Data for clinical response rates for brentuximab vedotin were based on the intention-to treat population in SG035‑0004 in the base-case analysis. Response rates for chemotherapy in the base-case analysis were based on responses with the most recent cancer-related therapy before brentuximab vedotin for the subgroup of 39 patients in S035-0004 whose most recent therapy was for relapsed or refractory disease. The committee heard from the clinical expert that the response rates used in the model to obtain the proportions of patients having stem cell transplant reflected those seen in clinical practice. The committee was aware that the National Comprehensive Cancer Network practice guidelines do not indicate how to identify which patients should have allogeneic or autologous stem cell transplant. The committee noted that the company's preferred assumption was to use the ratio of autologous stem cell transplant to allogeneic stem cell transplant from SG035‑0004 (47% for autologous stem cell transplant and 53% for allogeneic stem cell transplant). The committee heard from the clinical expert that the rate of allogeneic stem cell transplant is higher than the rate of autologous stem cell transplant in England, which is consistent with the company's modelling approach.The committee agreed that the company's approach for modelling the rate of stem cell transplant was appropriate for decision-making.
## The modelling of progression-free and overall survival for people having stem cell transplant is appropriate
The committee noted that for people who had a stem cell transplant, progression-free survival and overall survival were modelled on data from Smith et al. 2013 (autologous stem cell transplant, n=115; allogeneic stem cell transplant, n=126) and were assumed to be equivalent irrespective of treatment arm. The committee was aware from the clinical expert that survival after stem cell transplant does not depend on the treatment used as the bridge to stem cell transplant but on the type of stem cell transplant received and the time from transplant. The mortality rate is higher with allogeneic transplant and in the first 100 days after transplant. The committee agreed that the company's approach for modelling progression-free survival and overall survival was appropriate for decision-making.
# Survival data
## Basing brentuximab vedotin progression-free and overall survival on investigator assessment is appropriate
The committee was aware that the data source for progression-free survival and overall survival was SG035‑0004 (n=41) and that the outcomes were based on investigator assessment at a median observation time of 71.8 months (section 3.5). The committee discussed the appropriateness of using investigator-assessed data instead of independent review, given that the primary analysis for the trial was independent review, with investigator assessment as a secondary analysis. The committee was aware that the company had used investigator assessment because it provided longer follow-up data (median observation at 71.4 months) and was more reflective of the assessments used in the self-control cohort. The committee was also aware that the ERG had concerns about using the investigator-assessed data. The ERG considered the independent review to have a lower risk of bias and to be more objective, although it acknowledged that the investigator-assessed data were the best available long-term data. The committee examined the investigator-assessed and independent review Kaplan–Meier curves for progression-free survival from SG035‑0004 and the ERG's comparison of the company's extrapolation of progression-free survival (using a log-logistic model) for both investigator-assessed and independent review data. The committee noted that in both cases, there was a substantial additional progression-free survival gain using the investigator-assessed data compared with the independent review data. The committee heard from the company that agreement between the 2 assessments for best clinical response (but not progression-free survival) had been investigated as an exploratory analysis in SG035‑0004 and that best clinical response was in agreement in 46 of 58 patients. This suggested that investigator assessment of response supported efficacy analyses by independent review. The committee heard from clinical experts and the Cancer Drug's Fund's clinical lead that the investigator-assessed data are more clinically relevant. This is because assessment of response is not based only on CT or PET-CT scans but also includes assessment of symptoms and the findings from clinical examination where the tumours are clinically obvious and there is little scope for bias. Only the assessment of scans is subject to independent review. The clinical expert also highlighted that the data in Mak et al. were based on investigator assessment and therefore it was appropriate to use investigator-assessed data from SG035‑0004 in any comparison of data. The committee concluded that data for progression-free survival and overall survival based on investigator assessment were appropriate for decision-making.
## Parametric models are preferable to mixture cure models for extrapolating brentuximab vedotin progression-free and overall survival
The committee noted that the company's preferred method was to use a log-logistic mixture cure model to extrapolate both progression-free and overall survival. The committee was aware that the company used this model because it assumed that the long plateau in the Kaplan–Meier curves for the investigator-assessed data indicated cure. For progression-free survival, a plateau in the Kaplan–Meier curves based on investigator assessment was seen after about 3 years of follow-up, reflecting a mortality rate equal to that expected in the general population. The company highlighted that this trend was not seen for progression-free survival based on independent review and this was likely to be a result of insufficient follow-up. For overall survival, the company also highlighted a plateau was seen in the Kaplan–Meier curve after about 1.3 years, reflecting a mortality rate equal to that expected in the general population. The committee noted a statement from a clinical expert that the clear tail and plateauing on the progression-free and overall survival curves for brentuximab vedotin were noteworthy, and happened at much higher survival levels than those seen for chemotherapy in Mak et al. The committee considered the company's method for deriving the mixture cure models. The company estimated a mixture cure model in which a proportion of patients (the cure fraction) was assumed to no longer be at risk of progression or death (function tending towards general population mortality) and the remainder (the uncured fraction) had a survival function tending towards zero. The committee had concerns about how the company estimated the mixture cure models because it was not clear how the proportion of patients in the 'better prognosis' group (which is effectively defined on model entry) can be different between progression-free survival and overall survival for the same patients. The company stated that this was an automated part of the fitting algorithm, but the committee considered it implausible because it would be impossible to interpret in a meaningful way, especially because progression-free survival included pre-progression death events. The committee noted that there was clinical justification for assuming that a proportion of people who have brentuximab vedotin have a similar mortality risk as the general population. The committee concluded that because of concerns about estimating the mixture cure models, it was more appropriate that parametric models be used to extrapolate progression-free and overall survival for brentuximab vedotin.
## Both gamma and log-normal curves are plausible for extrapolating brentuximab vedotin progression-free and overall survival when using a parametric model
In response to consultation the company provided analyses in which it used a parametric model rather than a mixture cure model to extrapolate progression-free and overall survival. The company's preferred parametric model extrapolated progression-free and overall survival using a gamma curve, which the committee noted was the most optimistic assumption. The committee also noted that there was a wide variation in long-term survival using the different curves, but that both the gamma and the more conservative log-normal curve appeared to fit the data. The committee concluded that the most appropriate curve to extrapolate the brentuximab vedotin data was uncertain, and therefore agreed that it was appropriate to consider both the gamma and log-normal curves in its decision-making.
## Mak et al. is the most appropriate source of data for chemotherapy progression-free and overall survival in the model
The committee noted that the company's original economic model used different sources of data for progression-free survival and for overall survival. Data for progression-free survival came from the self-control cohort in SG035‑0004 (n=39), data for overall survival came from Mak et al. (subset with peripheral T-cell lymphoma and performance status of less than 2 for the base-case analysis, subset with anaplastic large cell lymphoma in sensitivity analyses; section 3.10). The committee noted the ERG's concerns about the self-control cohort because patients whose disease was in long-term remission will not have been captured (which is likely to create a bias in favour of brentuximab vedotin). Also there were no deaths in the self-control cohort so it could not equate with progression-free survival or time to progression (which would censor patients at time of death). It was also not possible to determine if previous treatments used to estimate response for the self-control cohort were representative of the chemotherapy comparators applied in the model. The committee noted that chemotherapy regimens used in practice are not expected to differ significantly. The clinical expert considered Mak et al. to be a more appropriate source of data than the self-control cohort in SG035‑0004. The committee agreed that Mak et al. was the most appropriate source of data for modelling progression-free survival and overall survival.
## The company's use of a log-normal curve to extrapolate chemotherapy progression-free and overall survival was appropriate
In response to consultation, the company used a log-normal curve to extrapolate both the progression-free and overall survival data from Mak et al. The committee noted that this curve was the best statistical fit for the data, and that there was very little difference visually when fitting other parametric models to the data. It concluded that a log-normal parametric curve was appropriate to extrapolate the chemotherapy data from Mak et al.
## The model estimates that brentuximab vedotin substantially improves progression-free and overall survival
The model suggests that brentuximab vedotin is associated with a mean increase of 4.6 or 2.9 years of progression-free and 8.3 or 6.8 years of overall survival, depending on whether brentuximab vedotin is extrapolated using a gamma or log-normal curve respectively. The committee recalled that there was uncertainty in the clinical evidence used in the model, but concluded that the estimates indicate that treatment with brentuximab vedotin would substantially increase both progression-free and overall survival compared with chemotherapy.
# Costs
## The number of brentuximab vedotin cycles used has a significant effect on its cost effectiveness
The committee noted that in both the company's original and revised models, the acquisition cost for brentuximab vedotin was calculated from the mean number of cycles administered in SG035‑0004. These were calculated separately for each population cohort (8.8 for the stem cell transplant cohorts and 8.0 for the no stem cell transplant cohorts) to enable differences in time-on-treatment to be captured when modelling proportions of patients having stem cell transplant different to those in SG035‑0004. The ERG explored a scenario in which it varied the lower and upper boundaries of brentuximab vedotin cycles, to 5 cycles (the median number used in Cancer Drugs Fund clinical practice ) and 16 cycles (as indicated in the summary of product characteristics) respectively. This scenario showed that the cost-effectiveness results were sensitive to the number of brentuximab vedotin cycles. The committee concluded that the number of cycles used had a substantial effect on brentuximab vedotin's cost effectiveness.
# Post-progression therapies
## Clinical expert distribution of therapies after progression reflects clinical practice
The committee noted that in the company's original model, all patients were assumed to have a further line of treatment after progression, with 80% of people whose disease has progressed after chemotherapy modelled to have brentuximab vedotin. The ERG considered this inappropriate and not in line with NICE's final scope, which included established clinical management without brentuximab vedotin as the comparator. In response to consultation, the company provided a revised economic model incorporating 2 alternative distributions of post-progression therapy. The trial-based distribution was the ERG's preferred approach but the company preferred the 'clinical expert-based distribution' which it used in its base-case analysis. The committee heard from the clinical expert that this distribution reflected clinical practice in England because it included best supportive care (that is, palliative treatments) for people for whom multi-agent chemotherapy regimens are contraindicated or not tolerated. The committee concluded that the clinical expert distribution of therapy after progression was the most appropriate for decision-making.
# Excess mortality rates
## Higher excess mortality rates sourced from published literature are appropriate for decision-making
The committee noted that the company had applied general population mortality (based on UK life tables) to the parametric survival models (mixture cure or standard) to extrapolate progression-free survival and overall survival to ensure that the long-term extrapolations were clinically plausible. The committee also noted that the company had applied the general population mortality because there is uncertainty about how the mortality rate for people who are long-term survivors after treatment for relapsed or refractory anaplastic large cell lymphoma compares with that of the general population. The committee was aware that the company understood that long-term survivors would still be at risk of secondary malignancies as a result of the effects of stem cell transplant or pre-stem cell transplant therapy and therefore faced an excess mortality risk compared with the general population. The committee agreed that it was appropriate to apply an excess mortality risk, but was concerned that the values used in the company's original economic model were based on the advice of 1 clinical expert (excess mortality rates used were: 5% for brentuximab vedotin , 10% for brentuximab vedotin , 7% for chemotherapy and 10% for chemotherapy ). In response to consultation, the company did a targeted literature search to obtain higher excess mortality rates (excess mortality rates used were: 100% for brentuximab vedotin and chemotherapy , 200% for brentuximab vedotin and chemotherapy , and 300% for brentuximab vedotin and chemotherapy ). The committee considered the new evidence and concluded that it was appropriate to use the higher rates sourced from published literature in its decision-making.
# Cost-effectiveness analyses
## The committee only considered 1 ICER for people with systemic anaplastic large cell lymphoma
The committee was aware that neither the company nor the ERG had presented separate incremental cost-effectiveness ratios (ICERs) for the population who had stem cell transplants and the population who had not had stem cell transplant. Both the company and the ERG presented a single ICER which compared all 3 brentuximab vedotin cohorts with all 3 chemotherapy cohorts. However, the committee acknowledged that a small number of people for whom brentuximab vedotin is used as first-line salvage therapy without future stem cell transplant (that is, no stem cell transplant cohorts) may have up to 16 cycles, with the median number of cycles ranging from 6 to 8. The committee understood that in this population, because of the higher number of cycles and poorer prognosis, brentuximab vedotin was likely to be associated with a higher ICER than in the population who had brentuximab vedotin as a 'bridge' to stem cell transplant. However, it noted the small size of this population (that is, people for whom brentuximab vedotin is used as first-line salvage therapy without future stem cell transplant) and was persuaded that merging the no stem cell and stem cell cohorts would not cause significant health loss. The committee therefore concluded that it was appropriate to consider cost-effectiveness analyses based on 1 ICER for people with systemic anaplastic large cell lymphoma in its decision-making.
## The company's updated analyses includes the committee's preferred assumptions but some uncertainty remains
The committee considered the company's deterministic and probabilistic ICERs in its updated model, provided in response to consultation. For brentuximab vedotin compared with chemotherapy, the deterministic ICER was £18,324 per quality-adjusted life year (QALY) gained and the probabilistic ICER was £20,399 per QALY gained. Both of these ICERs included the confidential commercial access agreement between the company and NHS England. The committee acknowledged that the company's updated analyses after consultation included all its preferred assumptions. However, it recalled that uncertainty remained in terms of the most appropriate parametric curve to use for extrapolating long-term survival with brentuximab vedotin data (section 3.17), and that the number of cycles of brentuximab vedotin in the model had a large effect on the cost effectiveness of brentuximab vedotin (section 3.21).
## All plausible extrapolation curves result in ICERs below £30,000 per QALY gained
The committee considered how the company's choice of parametric curve affected the deterministic ICER for brentuximab vedotin. The committee noted that the ICERs ranged from £18,324 per QALY gained using a gamma curve to £32,801 per QALY gained using an exponential curve. The committee also noted that for the gamma and log-normal parametric curves (the committee's preferred choice of curves), the ICERs were £18,324 per QALY gained and £24,064 per QALY gained respectively. The committee was reassured that only the implausible exponential curve produced an ICER above the range usually considered to be a cost-effective use of NHS resources.
## The number of cycles of brentuximab vedotin from the SG35-0004 trial is most appropriate for decision-making
The committee recalled that the number of cycles of brentuximab vedotin had a substantial effect on the ICER. It noted that the ERG's sensitivity analyses produced ICERs from £11,048 per QALY gained with 5 cycles of brentuximab vedotin to £35,848 per QALY gained with the maximum 16 cycles. The committee noted that, assuming the benefit of treatment remained the same, the ICER for brentuximab vedotin in people having 16 cycles was above the range usually considered to be a cost-effective use of NHS resources. It recalled that in practice, people would have fewer cycles than specified in the summary of product characteristics and the SG035‑0004 trial (section 3.4). It concluded that the number of cycles used in SG35-0004 and the company's model was the most appropriate for decision-making, but was reassured that the ICER may plausibly be lower.
## Brentuximab vedotin is a cost-effective use of NHS resources
The committee considered that the most plausible ICER was between £18,324 and £24,064 per QALY gained, depending on whether a gamma or a log-normal curve respectively was used and based on the number of cycles in the SG35-0004 trial. The committee noted that it is plausible that the number of cycles of brentuximab vedotin in clinical practice is fewer than modelled for some people, which would reduce the ICER. The committee concluded that all plausible ICERs were within the range usually considered a cost-effective use of NHS resources.
# End of life
## Brentuximab vedotin only meets 1 of NICE's end-of-life criteria
Having concluded that all plausible ICERs were within the range for brentuximab vedotin to be considered a cost-effective use of NHS resources, the committee discussed the additional evidence provided by the company in response to consultation to support the case for brentuximab vedotin as an end-of-life therapy. It considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. It agreed that it could not make reliable conclusions about life expectancy and survival benefit using the results from the self-control cohort from SG035‑0004, because it had concerns about using this as a source of data for overall survival for chemotherapy (section 3.18). The committee heard from the company that Mak et al. reported a median overall survival of 13.7 months for people with peripheral T-cell lymphoma and a performance status of 0 or 1 (the subgroup used in the company's model), but noted that median overall survival for people with systemic anaplastic large cell lymphoma was 3.0 months. Because the committee's preference is for mean values for overall survival, it instead considered estimates from the economic model. The committee discussed the criterion of short life expectancy with current treatment, which is normally less than 24 months, and noted that the modelled overall survival with chemotherapy in the company's updated model was 3.98 years. In response to consultation, the company provided supplementary evidence from the UK-based Haematological Malignancy Research Network (HMRN), the results of which are academic in confidence and cannot be reported here. In discussing this evidence, the committee noted that the population in the HMRN dataset was broader than the population in the SG035‑00045 trial (that is, it included people of any performance status). It noted that mean overall survival for the population in the HMRN dataset was therefore likely to be lower than that for people in whom brentuximab vedotin would be an option in NHS practice. The committee therefore concluded that brentuximab vedotin did not meet the criterion of short life expectancy. The committee then discussed whether brentuximab vedotin could meet the criterion for extension to life, normally of at least an additional 3 months. Using its preferred assumptions and a gamma curve to extrapolate progression-free and overall survival, the committee noted that mean overall survival with brentuximab vedotin was 12.28 years, representing an extension of 8.3 years. The committee considered that, based on the modelled overall survival benefit, brentuximab vedotin would meet the criterion for extension to life. However, it recalled that brentuximab vedotin did not meet the first end-of-life criterion, and concluded that brentuximab vedotin cannot be considered an end-of-life therapy.
# Equality
## Healthcare professionals should consider ECOG performance status when implementing the recommendations
The committee considered whether its recommendations were associated with any potential issues related to equality. It concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.
# Other factors
## The committee did not identify any other factors that would affect its recommendations
The committee discussed the company's comments about the innovative nature of brentuximab vedotin. It heard from a clinical and patient expert that treatment with brentuximab vedotin produces high complete remission rates and that results are seen quickly, allowing treatment to be stopped early for most people. They considered the benefits of brentuximab vedotin to be a major change in the management of relapsed and refractory systemic anaplastic large cell lymphoma, providing patients with a valuable treatment option instead of toxic current treatment. The committee concluded that brentuximab vedotin was an innovative and promising treatment, but that it had not been presented with any evidence of additional benefits that were not captured in the QALY measure.
# Conclusion
## Brentuximab vedotin is only recommended within its marketing authorisation for people with a performance status of 0 or 1
The committee considered that the most plausible ICERs for brentuximab vedotin (£18,324 to £24,064 per QALY gained) meant that it could be considered a cost-effective use of NHS resources. However, the committee acknowledged that there was limited representation of people with an ECOG performance status of more than 1 in SG035‑0004, the trial on which the cost-effective analyses were based. It therefore considered that its recommendations should closely reflect the population in the SG035‑00045 trial, because it was unclear if the cost-effectiveness results would be reflected in people with an ECOG performance status of more than 1. The committee concluded that it could recommend brentuximab vedotin as an option for treating relapsed or refractory systemic anaplastic clear cell lymphoma in adults, only if they have an ECOG performance status of 0 or 1 and the company provides brentuximab vedotin according to the commercial access agreement with NHS England.
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{'Recommendations': 'Brentuximab vedotin is recommended as an option for treating relapsed or refractory systemic anaplastic large cell lymphoma in adults, only if:\n\nthey have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and\n\nthe company provides brentuximab vedotin according to the commercial access agreement with NHS England.\n\nWhen using ECOG performance status, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with brentuximab vedotin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nBrentuximab vedotin has a marketing authorisation for treating relapsed or refractory systemic anaplastic large cell lymphoma in adults, but it is most likely to be used in the NHS as first-line salvage therapy. At this point in the treatment pathway, the appropriate comparator is chemotherapy.\n\nEvidence from the main clinical trial for brentuximab vedotin shows that it is effective based on response rates. However, the trial is not comparative, and therefore there is uncertainty about the full extent of the survival benefit from treatment with brentuximab vedotin.\n\nThe best available evidence comes from an unadjusted indirect comparison of brentuximab vedotin and chemotherapy, although there is still uncertainty about the robustness of the results because of the differences in age, stage of disease, and performance status in the groups compared.\n\nThe plausible estimates of cost effectiveness are below £30,000 per quality-adjusted life year gained, and this was considered to be an acceptable use of NHS resources. However, because the clinical- and cost-effectiveness data are based on people with an ECOG performance status of 0 or 1, brentuximab vedotin is only recommended for this group.', 'The technology': "Marketing authorisation\n\nBrentuximab vedotin is indicated for 'the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma'.\n\nBrentuximab vedotin has been available to patients in England through the Cancer Drugs Fund since April 2013 for relapsed or refractory systemic anaplastic large cell lymphoma.\n\nRecommended dose and schedule\n\nThe recommended dose is 1.8\xa0mg/kg administered by intravenous infusion over 30\xa0minutes every 3\xa0weeks.\n\nPrice\n\nThe price of brentuximab vedotin is £2,500 for a 50‑mg vial (excluding VAT; British national formulary accessed August 2017).\n\nTakeda has agreed a commercial access agreement with NHS England in which a discount is applied at the point of purchase or invoice for brentuximab vedotin. The financial terms of the agreement are commercial in confidence.", 'Committee discussion': "The appraisal committee considered evidence submitted by Takeda UK and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Patient experience\n\n## Brentuximab vedotin is well tolerated and could significantly improve quality of life\n\nThe patient expert explained that a diagnosis of systemic anaplastic large cell lymphoma can have a big effect on a person's physical and psychological wellbeing. The clinical and patient experts highlighted that brentuximab vedotin is generally better tolerated than existing treatments because it has more manageable and fewer side effects, and that it can significantly improve patients' quality of life. The committee concluded that access to effective treatments and improving quality of life are significant benefits to patients.\n\n# Clinical management\n\n## There is an unmet clinical need for people with relapsed or refractory systemic anaplastic large cell lymphoma\n\nThere is no NICE technology appraisal guidance for systemic anaplastic large cell lymphoma. The committee understood that CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine and prednisolone) is a commonly used first-line regimen for people with systemic anaplastic large cell lymphoma. Some people may also have additional first-line treatment with high-dose chemotherapy (most commonly BEAM [carmustine or lomustine, etoposide, cytarabine, and melphalan]) and autologous stem cell transplant. The clinical expert explained that most people with systemic anaplastic large cell lymphoma have relapsed or refractory disease. The committee heard that this group represents a major area of unmet clinical need. People typically have short overall survival after relapse and there is a lack of clear agreement or a strong evidence base to recommend second-line therapies. Salvage therapies are used, followed by either autologous or allogeneic stem cell transplant. The choice of treatment depends on clinician and patient preference, which can be influenced by a number of factors (for example, patient fitness, type of therapy and response to prior therapy, donor availability and clinical trial options). The committee agreed that people with relapsed or refractory systemic anaplastic large cell lymphoma have an unmet clinical need.\n\n## Brentuximab vedotin is likely to be mostly used as a first-line salvage therapy\n\nThe committee was aware that brentuximab vedotin is used as an alternative salvage therapy to standard chemotherapy regimens (for example, GDP [gemcitabine, dexamethasone and cisplatin] and ICE [ifosfamide, carboplatin and etoposide]). The committee noted that neither the marketing authorisation for brentuximab vedotin nor its indication in the Cancer Drugs Fund (available in England since April 2013 for relapsed or refractory systemic anaplastic large cell lymphoma) specified a certain number of previous treatments before using brentuximab vedotin. It could therefore potentially be used as second-, third- or fourth-line therapy in the treatment pathway for relapsed or refractory systemic anaplastic large cell lymphoma depending on previous salvage treatments and response to those treatments. It noted that the inclusion criteria for SG035‑0004 (the pivotal trial on which the marketing authorisation is based) specified 'after treatment failure of at least 1\xa0therapy with curative intent'. The clinical expert explained that brentuximab vedotin is usually used with 2\xa0strategies in mind: as a first-line salvage therapy before either autologous or allogeneic stem cell transplant, and as a first salvage therapy without future stem cell transplant. The committee was also aware from the Cancer Drugs Fund's clinical lead that brentuximab vedotin is used in the Cancer Drugs Fund as a second-line therapy. The committee noted that both the clinical expert and the Cancer Drugs Fund clinical lead agreed that brentuximab vedotin would be used as a first-line salvage therapy (that is as second-line therapy after first-line chemotherapy [for example, CHOP]) instead of salvage chemotherapy. The committee noted that in response to consultation, comments were received that stated brentuximab vedotin would be used for some people later in the pathway.\n\n## People have fewer\xa0cycles of brentuximab vedotin in Cancer Drugs Fund clinical practice than in both SG035-0004 and the summary of product characteristics\n\nThe committee asked if rules for stopping treatment are used in clinical practice. It noted that the summary of product characteristics for brentuximab vedotin states that it should be used for a minimum of 8\xa0cycles up to a maximum of 16\xa0cycles in patients whose disease is stable. The committee noted that the mean number of\xa0cycles of brentuximab vedotin received by the intention-to-treat population in SG035‑0004 was 8.2\xa0cycles. The clinical expert highlighted that real-world evidence from the Cancer Drugs Fund suggests that the median number of\xa0cycles for brentuximab vedotin is 5 to 6, and that this estimate includes people who go on to have stem cell transplant, people who do not, and people who stop taking brentuximab vedotin because of a lack of a clinical response or unmanageable side effects. The committee was aware that there are clinical criteria to identify people for whom stem cell transplant is not appropriate before starting first-line salvage therapy, for example people with comorbidities that would compromise fitness for a stem cell transplant, but it may not always be possible to decide whether stem cell transplant is appropriate before starting brentuximab vedotin. The committee heard that when brentuximab vedotin is used as a first-line salvage therapy before either autologous or allogeneic stem cell transplant, assessing the response with PET-CT imaging would typically be done after 3 to 4\xa0cycles of brentuximab vedotin and treatment stopped after 4 to 6\xa0cycles. The committee was aware that for the small minority of people for whom brentuximab vedotin is used as first-line salvage therapy without future stem cell transplant, the median number of\xa0cycles of brentuximab vedotin is 6 to 8, but up to 16\xa0cycles of brentuximab can be used if there is evidence of ongoing response and tolerability. The committee accepted that most people in clinical practice would have fewer\xa0cycles than specified in the summary of product characteristics and the SG035‑0004 trial, and agreed this should be considered in its decision-making.\n\n# Clinical evidence\n\n## The main evidence for brentuximab vedotin comes from 1\xa0single-arm, phase\xa02 study\n\nThe company's main evidence was based on a multicentre, phase\xa02, single-arm study (SG035‑0004) in 58\xa0patients with relapsed or refractory systemic anaplastic large cell lymphoma after treatment failure of at least 1\xa0therapy with curative intent and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary outcome of the trial was objective response rate, with secondary outcomes including duration of response, complete remission, progression-free survival and overall survival. These outcomes were assessed by an independent review at a median follow-up time of 16.8\xa0months. The company also presented data for up to 5\xa0years' follow-up (median observation time of 71.8\xa0months) based on investigator assessment.\n\n\n\nBest clinical response (n=58)\n\nObjective response rate: 50 (86%), 95% confidence interval (CI) 74.6 to 93.9\n\nComplete remission: 34 (59%), 95% CI 44.9 to 71.4\n\nPartial remission: 16 (28%), 95% CI not applicable\n\nDisease control rate: 52 (90%), 95% CI 78.8 to 96.1\n\nDuration of response, median (95% CI)\n\nObjective response rate: 13.2 (95% CI 5.7 to not estimable). The duration of response was 0.1+\xa0months to 21.7+\xa0months and the median follow-up time from first dose for patients who achieved objective response per independent review was 11.8\xa0months\n\nComplete remission: Not reached (95% CI 13.0 to not estimable)\n\nOverall survival\n\nNot reached (95% CI 21.3 to not estimable). The estimated 36-month overall survival was 63% (the median observation time [time to death or last contact]) from first dose was 33.4\xa0months\n\n\n\nOverall population\n\nEstimated 5-year overall survival rate: 60% (95% confidence interval [CI] 47% to 73%)\n\nMedian overall survival: Not estimable (95% CI 21.3 to not reached; range 0.8 to 82.4+ months)\n\nMedian progression-free survival: 20.0\xa0months (95% CI 9.4 to not reached)\n\nOf 58 enrolled patients, 42 (72%) had anaplastic lymphoma kinase (ALK)-negative disease\n\nEstimated 5-year overall survival: 61% (95% CI 47% to 76%)\n\nMedian progression-free survival: 20.0\xa0months (95% CI 6.7 to not reached)\n\nMedian overall survival: not reached\n\nOf 58 enrolled patients, 16 (28%) had ALK-positive disease\n\nEstimated 5-year overall survival: 56% (95% CI 32% to 81%)\n\nMedian progression-free survival: 25.5\xa0months (95% CI 8.0 to not reached)\n\nMedian overall survival: Not reached\n\n## SG035-0004 is the most appropriate source of clinical data for brentuximab vedotin\n\nTwo retrospective case series (Gopal\xa0et\xa0al. 2014 and Chihara\xa0et\xa0al. 2015) and 3 named patient programmes (Gibb\xa0et\xa0al. 2013 based in the UK) provided further non-randomised supplementary evidence. Gopal\xa0et\xa0al. (2014) evaluated brentuximab vedotin as a treatment for older people with systemic anaplastic large cell lymphoma and reported a median progression-free survival of 15.6\xa0months (95% confidence interval 4.2 to not reached; range 0.0+ to 22.4+\xa0months). Data from the UK named patient programme demonstrated that in people with CD30+ lymphoma who had several previous treatments, brentuximab vedotin had an objective response rate of 67% and median progression-free survival of 5.1\xa0months. The committee concluded that the results from the SG035‑0004 trial were the most appropriate for its decision-making, noting that although the Gopal and Gibb studies only included a few patients with systemic anaplastic large cell lymphoma, the results largely supported those from SG035‑0004.\n\n## It is appropriate to reflect the performance status of the SG035-0004 trial population in decision-making\n\nThe committee noted that patients in SG035‑0004 had an ECOG performance status of 0 or 1, corresponding to a population whose activities are relatively unrestricted by their disease. This is in contrast to the population specified in brentuximab vedotin's marketing authorisation, in which performance status is not a criterion. The committee considered the disparity between the populations in SG035‑0004 and the marketing authorisation, and noted that people with a worse performance status than 1 may benefit less from brentuximab vedotin. It also considered this group could require more\xa0cycles of treatment. The committee concluded that because it is unclear how effective brentuximab vedotin is in people with a performance status of more than 1, its decision-making should reflect the available trial evidence.\n\n## Trial data suggest that brentuximab vedotin is effective but there is uncertainty\n\nThe committee was concerned that the single-arm design of the trial meant that the results were potentially biased, but appreciated that it would be difficult to do a randomised controlled trial for brentuximab vedotin because of the rarity of systemic anaplastic large cell lymphoma. It accepted that the results from the data cut-off at a median follow-up of 16.8\xa0months and a median observation time of 71.8\xa0months showed that brentuximab vedotin was clinically effective based on response rates, but there was uncertainty in the clinical evidence about the full extent of progression-free survival and overall survival. The committee concluded that there was a large degree of uncertainty in the clinical evidence, but noted that both comments from clinical and patient experts and the response rates from the trials suggested that brentuximab vedotin was an effective treatment for people with an ECOG performance status of 0 or 1.\n\n# Indirect treatment comparison\n\n## The company indirectly compared overall survival of brentuximab vedotin and chemotherapy, only in people with no stem cell transplant\n\nThe committee was aware that there were no data directly comparing overall survival for brentuximab vedotin and chemotherapy. It noted that the company had done an indirect comparison of brentuximab vedotin and chemotherapy. It compared the outcomes from a subgroup of patients from SG035‑0004 who did not go on to have stem cell transplant (n=41, the 'self-control cohort') with those from a subgroup of patients from Mak\xa0et\xa0al. (2013). Mak\xa0et\xa0al. reported progression-free survival and overall survival data for a historical cohort of 153\xa0patients on the British Columbia Cancer Agency Lymphoid Cancer database who had peripheral T-cell lymphoma with relapsed or progressive disease. The committee noted that the company focused its analyses on a subset of people reported in Mak\xa0et\xa0al. who had already had systemic chemotherapy (n=89) but not stem cell transplant. The company considered 2\xa0subgroups from this subset: a subgroup of patients with anaplastic large cell lymphoma (n=17) and a broader subgroup including patients with peripheral T-cell lymphoma and a performance status of less than 2 (n=47).\n\n## The unadjusted indirect comparison is appropriate but the results should be treated with caution\n\nThe committee noted the heterogeneity between the self-control cohort from SG035‑0004 (n=41) and the subgroup of patients in Mak\xa0et\xa0al. who had already had systemic chemotherapy (n=89), particularly for age, stage of disease and performance status. The committee was aware that these issues could to lead to bias in favour of brentuximab vedotin. The committee was also aware that it was not possible for the company to compare the baseline characteristics of the self-control cohort from SG035‑0004 with those from the subset of patients from Mak\xa0et\xa0al. with anaplastic large cell lymphoma (n=17) and peripheral T-cell lymphoma and a performance status less than 2 (n=47) because the baseline characteristics were not reported. The committee acknowledged the company had considered doing a matched adjusted indirect comparison using data from the self-control cohort from SG035‑0004 and from the subgroup of patients in Mak\xa0et\xa0al. who had already had systemic chemotherapy (n=89), but had concluded that it was inappropriate to do this because the effective sample size would be 4.8 after adjusting for available variables. The committee agreed with this. The committee concluded that the company's unadjusted indirect comparison of overall survival was the best available evidence for its decision-making, although there was still uncertainty about the robustness of the results because of the potential bias in favour of brentuximab vedotin, resulting from the heterogeneity in age, stage of disease, and performance status.\n\n# The company's economic model\n\n## The company's model is appropriate and represents the treatment pathway\n\nThe committee noted that the company had modelled 6\xa0population cohorts: brentuximab vedotin or chemotherapy with no stem cell transplant, brentuximab vedotin or chemotherapy with autologous stem cell transplant, and brentuximab vedotin or chemotherapy with allogeneic stem cell transplant. These reflect the clinical pathway of care for systemic anaplastic large cell lymphoma. Overall, the committee accepted the structure of the model as representing the treatment pathway for patients with relapsed or refractory systemic anaplastic large cell lymphoma. It noted that the company had modelled brentuximab vedotin consistent with its use in clinical practice. The committee considered the model appropriate for its decision-making. It noted that the company's cost-effectiveness analyses included a confidential commercial access agreement between the company and NHS England.\n\n## The company updated its model after consultation to incorporate the committee's preferred assumptions\n\nIn response to consultation, the company updated its economic model to include the committee's preferred assumptions and a number of scenario analyses that explored the use of Mak\xa0et\xa0al. data to model both progression-free survival and overall survival for chemotherapy, parametric models of progression-free and overall survival for both brentuximab vedotin and chemotherapy, and the use of higher excess mortality rates than in the original model.\n\n# Stem cell transplant rates\n\n## The company's model uses appropriate stem cell transplant rates\n\nThe committee noted that the modelling of treatment effectiveness and extrapolation of progression-free survival and overall survival was based on a combination of clinical response rates, stem cell transplant by response categories and survival outcomes by transplant status (that is, no stem cell transplant, autologous or allogeneic stem cell transplant). The committee also noted that the company had assumed that for a proportion of patients, brentuximab vedotin or chemotherapy acts as a bridge to stem cell transplant, which is a potentially curative therapy. Data for clinical response rates for brentuximab vedotin were based on the intention-to treat population in SG035‑0004 in the base-case analysis. Response rates for chemotherapy in the base-case analysis were based on responses with the most recent cancer-related therapy before brentuximab vedotin for the subgroup of 39\xa0patients in S035-0004 whose most recent therapy was for relapsed or refractory disease. The committee heard from the clinical expert that the response rates used in the model to obtain the proportions of patients having stem cell transplant reflected those seen in clinical practice. The committee was aware that the National Comprehensive Cancer Network practice guidelines do not indicate how to identify which patients should have allogeneic or autologous stem cell transplant. The committee noted that the company's preferred assumption was to use the ratio of autologous stem cell transplant to allogeneic stem cell transplant from SG035‑0004 (47% for autologous stem cell transplant and 53% for allogeneic stem cell transplant). The committee heard from the clinical expert that the rate of allogeneic stem cell transplant is higher than the rate of autologous stem cell transplant in England, which is consistent with the company's modelling approach.The committee agreed that the company's approach for modelling the rate of stem cell transplant was appropriate for decision-making.\n\n## The modelling of progression-free and overall survival for people having stem cell transplant is appropriate\n\nThe committee noted that for people who had a stem cell transplant, progression-free survival and overall survival were modelled on data from Smith\xa0et\xa0al. 2013 (autologous stem cell transplant, n=115; allogeneic stem cell transplant, n=126) and were assumed to be equivalent irrespective of treatment arm. The committee was aware from the clinical expert that survival after stem cell transplant does not depend on the treatment used as the bridge to stem cell transplant but on the type of stem cell transplant received and the time from transplant. The mortality rate is higher with allogeneic transplant and in the first 100\xa0days after transplant. The committee agreed that the company's approach for modelling progression-free survival and overall survival was appropriate for decision-making.\n\n# Survival data\n\n## Basing brentuximab vedotin progression-free and overall survival on investigator assessment is appropriate\n\nThe committee was aware that the data source for progression-free survival and overall survival was SG035‑0004 (n=41) and that the outcomes were based on investigator assessment at a median observation time of 71.8\xa0months (section\xa03.5). The committee discussed the appropriateness of using investigator-assessed data instead of independent review, given that the primary analysis for the trial was independent review, with investigator assessment as a secondary analysis. The committee was aware that the company had used investigator assessment because it provided longer follow-up data (median observation at 71.4\xa0months) and was more reflective of the assessments used in the self-control cohort. The committee was also aware that the ERG had concerns about using the investigator-assessed data. The ERG considered the independent review to have a lower risk of bias and to be more objective, although it acknowledged that the investigator-assessed data were the best available long-term data. The committee examined the investigator-assessed and independent review Kaplan–Meier curves for progression-free survival from SG035‑0004 and the ERG's comparison of the company's extrapolation of progression-free survival (using a log-logistic model) for both investigator-assessed and independent review data. The committee noted that in both cases, there was a substantial additional progression-free survival gain using the investigator-assessed data compared with the independent review data. The committee heard from the company that agreement between the 2\xa0assessments for best clinical response (but not progression-free survival) had been investigated as an exploratory analysis in SG035‑0004 and that best clinical response was in agreement in 46 of 58\xa0patients. This suggested that investigator assessment of response supported efficacy analyses by independent review. The committee heard from clinical experts and the Cancer Drug's Fund's clinical lead that the investigator-assessed data are more clinically relevant. This is because assessment of response is not based only on CT or PET-CT scans but also includes assessment of symptoms and the findings from clinical examination where the tumours are clinically obvious and there is little scope for bias. Only the assessment of scans is subject to independent review. The clinical expert also highlighted that the data in Mak\xa0et\xa0al. were based on investigator assessment and therefore it was appropriate to use investigator-assessed data from SG035‑0004 in any comparison of data. The committee concluded that data for progression-free survival and overall survival based on investigator assessment were appropriate for decision-making.\n\n## Parametric models are preferable to mixture cure models for extrapolating brentuximab vedotin progression-free and overall survival\n\nThe committee noted that the company's preferred method was to use a log-logistic mixture cure model to extrapolate both progression-free and overall survival. The committee was aware that the company used this model because it assumed that the long plateau in the Kaplan–Meier curves for the investigator-assessed data indicated cure. For progression-free survival, a plateau in the Kaplan–Meier curves based on investigator assessment was seen after about 3\xa0years of follow-up, reflecting a mortality rate equal to that expected in the general population. The company highlighted that this trend was not seen for progression-free survival based on independent review and this was likely to be a result of insufficient follow-up. For overall survival, the company also highlighted a plateau was seen in the Kaplan–Meier curve after about 1.3\xa0years, reflecting a mortality rate equal to that expected in the general population. The committee noted a statement from a clinical expert that the clear tail and plateauing on the progression-free and overall survival curves for brentuximab vedotin were noteworthy, and happened at much higher survival levels than those seen for chemotherapy in Mak\xa0et\xa0al. The committee considered the company's method for deriving the mixture cure models. The company estimated a mixture cure model in which a proportion of patients (the cure fraction) was assumed to no longer be at risk of progression or death (function tending towards general population mortality) and the remainder (the uncured fraction) had a survival function tending towards zero. The committee had concerns about how the company estimated the mixture cure models because it was not clear how the proportion of patients in the 'better prognosis' group (which is effectively defined on model entry) can be different between progression-free survival and overall survival for the same patients. The company stated that this was an automated part of the fitting algorithm, but the committee considered it implausible because it would be impossible to interpret in a meaningful way, especially because progression-free survival included pre-progression death events. The committee noted that there was clinical justification for assuming that a proportion of people who have brentuximab vedotin have a similar mortality risk as the general population. The committee concluded that because of concerns about estimating the mixture cure models, it was more appropriate that parametric models be used to extrapolate progression-free and overall survival for brentuximab vedotin.\n\n## Both gamma and log-normal curves are plausible for extrapolating brentuximab vedotin progression-free and overall survival when using a parametric model\n\nIn response to consultation the company provided analyses in which it used a parametric model rather than a mixture cure model to extrapolate progression-free and overall survival. The company's preferred parametric model extrapolated progression-free and overall survival using a gamma curve, which the committee noted was the most optimistic assumption. The committee also noted that there was a wide variation in long-term survival using the different curves, but that both the gamma and the more conservative log-normal curve appeared to fit the data. The committee concluded that the most appropriate curve to extrapolate the brentuximab vedotin data was uncertain, and therefore agreed that it was appropriate to consider both the gamma and log-normal curves in its decision-making.\n\n## Mak\xa0et\xa0al. is the most appropriate source of data for chemotherapy progression-free and overall survival in the model\n\nThe committee noted that the company's original economic model used different sources of data for progression-free survival and for overall survival. Data for progression-free survival came from the self-control cohort in SG035‑0004 (n=39), data for overall survival came from Mak\xa0et\xa0al. (subset with peripheral T-cell lymphoma and performance status of less than 2 [n=47] for the base-case analysis, subset with anaplastic large cell lymphoma [n=17] in sensitivity analyses; section\xa03.10). The committee noted the ERG's concerns about the self-control cohort because patients whose disease was in long-term remission will not have been captured (which is likely to create a bias in favour of brentuximab vedotin). Also there were no deaths in the self-control cohort so it could not equate with progression-free survival or time to progression (which would censor patients at time of death). It was also not possible to determine if previous treatments used to estimate response for the self-control cohort were representative of the chemotherapy comparators applied in the model. The committee noted that chemotherapy regimens used in practice are not expected to differ significantly. The clinical expert considered Mak\xa0et\xa0al. to be a more appropriate source of data than the self-control cohort in SG035‑0004. The committee agreed that Mak\xa0et\xa0al. was the most appropriate source of data for modelling progression-free survival and overall survival.\n\n## The company's use of a log-normal curve to extrapolate chemotherapy progression-free and overall survival was appropriate\n\nIn response to consultation, the company used a log-normal curve to extrapolate both the progression-free and overall survival data from Mak\xa0et\xa0al. The committee noted that this curve was the best statistical fit for the data, and that there was very little difference visually when fitting other parametric models to the data. It concluded that a log-normal parametric curve was appropriate to extrapolate the chemotherapy data from Mak\xa0et\xa0al.\n\n## The model estimates that brentuximab vedotin substantially improves progression-free and overall survival\n\nThe model suggests that brentuximab vedotin is associated with a mean increase of 4.6 or 2.9\xa0years of progression-free and 8.3 or 6.8\xa0years of overall survival, depending on whether brentuximab vedotin is extrapolated using a gamma or log-normal curve respectively. The committee recalled that there was uncertainty in the clinical evidence used in the model, but concluded that the estimates indicate that treatment with brentuximab vedotin would substantially increase both progression-free and overall survival compared with chemotherapy.\n\n# Costs\n\n## The number of brentuximab vedotin\xa0cycles used has a significant effect on its cost effectiveness\n\nThe committee noted that in both the company's original and revised models, the acquisition cost for brentuximab vedotin was calculated from the mean number of\xa0cycles administered in SG035‑0004. These were calculated separately for each population cohort (8.8 for the stem cell transplant cohorts and 8.0 for the no stem cell transplant cohorts) to enable differences in time-on-treatment to be captured when modelling proportions of patients having stem cell transplant different to those in SG035‑0004. The ERG explored a scenario in which it varied the lower and upper boundaries of brentuximab vedotin\xa0cycles, to 5\xa0cycles (the median number used in Cancer Drugs Fund clinical practice [see section\xa03.3]) and 16\xa0cycles (as indicated in the summary of product characteristics) respectively. This scenario showed that the cost-effectiveness results were sensitive to the number of brentuximab vedotin\xa0cycles. The committee concluded that the number of\xa0cycles used had a substantial effect on brentuximab vedotin's cost effectiveness.\n\n# Post-progression therapies\n\n## Clinical expert distribution of therapies after progression reflects clinical practice\n\nThe committee noted that in the company's original model, all patients were assumed to have a further line of treatment after progression, with 80% of people whose disease has progressed after chemotherapy modelled to have brentuximab vedotin. The ERG considered this inappropriate and not in line with NICE's final scope, which included established clinical management without brentuximab vedotin as the comparator. In response to consultation, the company provided a revised economic model incorporating 2\xa0alternative distributions of post-progression therapy. The trial-based distribution was the ERG's preferred approach but the company preferred the 'clinical expert-based distribution' which it used in its base-case analysis. The committee heard from the clinical expert that this distribution reflected clinical practice in England because it included best supportive care (that is, palliative treatments) for people for whom multi-agent chemotherapy regimens are contraindicated or not tolerated. The committee concluded that the clinical expert distribution of therapy after progression was the most appropriate for decision-making.\n\n# Excess mortality rates\n\n## Higher excess mortality rates sourced from published literature are appropriate for decision-making\n\nThe committee noted that the company had applied general population mortality (based on UK life tables) to the parametric survival models (mixture cure or standard) to extrapolate progression-free survival and overall survival to ensure that the long-term extrapolations were clinically plausible. The committee also noted that the company had applied the general population mortality because there is uncertainty about how the mortality rate for people who are long-term survivors after treatment for relapsed or refractory anaplastic large cell lymphoma compares with that of the general population. The committee was aware that the company understood that long-term survivors would still be at risk of secondary malignancies as a result of the effects of stem cell transplant or pre-stem cell transplant therapy and therefore faced an excess mortality risk compared with the general population. The committee agreed that it was appropriate to apply an excess mortality risk, but was concerned that the values used in the company's original economic model were based on the advice of 1\xa0clinical expert (excess mortality rates used were: 5% for brentuximab vedotin [no stem cell transplant], 10% for brentuximab vedotin [with stem cell transplant], 7% for chemotherapy [no stem cell transplant] and 10% for chemotherapy [with stem cell transplant]). In response to consultation, the company did a targeted literature search to obtain higher excess mortality rates (excess mortality rates used were: 100% for brentuximab vedotin and chemotherapy [no stem cell transplant], 200% for brentuximab vedotin and chemotherapy [with autologous stem cell transplantation], and 300% for brentuximab vedotin and chemotherapy [with allogeneic stem cell transplantation]). The committee considered the new evidence and concluded that it was appropriate to use the higher rates sourced from published literature in its decision-making.\n\n# Cost-effectiveness analyses\n\n## The committee only considered 1 ICER for people with systemic anaplastic large cell lymphoma\n\nThe committee was aware that neither the company nor the ERG had presented separate incremental cost-effectiveness ratios (ICERs) for the population who had stem cell transplants and the population who had not had stem cell transplant. Both the company and the ERG presented a single ICER which compared all 3 brentuximab vedotin cohorts with all 3 chemotherapy cohorts. However, the committee acknowledged that a small number of people for whom brentuximab vedotin is used as first-line salvage therapy without future stem cell transplant (that is, no stem cell transplant cohorts) may have up to 16\xa0cycles, with the median number of\xa0cycles ranging from 6 to 8. The committee understood that in this population, because of the higher number of\xa0cycles and poorer prognosis, brentuximab vedotin was likely to be associated with a higher ICER than in the population who had brentuximab vedotin as a 'bridge' to stem cell transplant. However, it noted the small size of this population (that is, people for whom brentuximab vedotin is used as first-line salvage therapy without future stem cell transplant) and was persuaded that merging the no stem cell and stem cell cohorts would not cause significant health loss. The committee therefore concluded that it was appropriate to consider cost-effectiveness analyses based on 1 ICER for people with systemic anaplastic large cell lymphoma in its decision-making.\n\n## The company's updated analyses includes the committee's preferred assumptions but some uncertainty remains\n\nThe committee considered the company's deterministic and probabilistic ICERs in its updated model, provided in response to consultation. For brentuximab vedotin compared with chemotherapy, the deterministic ICER was £18,324 per quality-adjusted life year (QALY) gained and the probabilistic ICER was £20,399 per QALY gained. Both of these ICERs included the confidential commercial access agreement between the company and NHS England. The committee acknowledged that the company's updated analyses after consultation included all its preferred assumptions. However, it recalled that uncertainty remained in terms of the most appropriate parametric curve to use for extrapolating long-term survival with brentuximab vedotin data (section\xa03.17), and that the number of\xa0cycles of brentuximab vedotin in the model had a large effect on the cost effectiveness of brentuximab vedotin (section\xa03.21).\n\n## All plausible extrapolation curves result in ICERs below £30,000 per QALY gained\n\nThe committee considered how the company's choice of parametric curve affected the deterministic ICER for brentuximab vedotin. The committee noted that the ICERs ranged from £18,324 per QALY gained using a gamma curve to £32,801 per QALY gained using an exponential curve. The committee also noted that for the gamma and log-normal parametric curves (the committee's preferred choice of curves), the ICERs were £18,324 per QALY gained and £24,064 per QALY gained respectively. The committee was reassured that only the implausible exponential curve produced an ICER above the range usually considered to be a cost-effective use of NHS resources.\n\n## The number of\xa0cycles of brentuximab vedotin from the SG35-0004 trial is most appropriate for decision-making\n\nThe committee recalled that the number of\xa0cycles of brentuximab vedotin had a substantial effect on the ICER. It noted that the ERG's sensitivity analyses produced ICERs from £11,048 per QALY gained with 5\xa0cycles of brentuximab vedotin to £35,848 per QALY gained with the maximum 16\xa0cycles. The committee noted that, assuming the benefit of treatment remained the same, the ICER for brentuximab vedotin in people having 16\xa0cycles was above the range usually considered to be a cost-effective use of NHS resources. It recalled that in practice, people would have fewer\xa0cycles than specified in the summary of product characteristics and the SG035‑0004 trial (section\xa03.4). It concluded that the number of\xa0cycles used in SG35-0004 and the company's model was the most appropriate for decision-making, but was reassured that the ICER may plausibly be lower.\n\n## Brentuximab vedotin is a cost-effective use of NHS resources\n\nThe committee considered that the most plausible ICER was between £18,324 and £24,064 per QALY gained, depending on whether a gamma or a log-normal curve respectively was used and based on the number of\xa0cycles in the SG35-0004 trial. The committee noted that it is plausible that the number of\xa0cycles of brentuximab vedotin in clinical practice is fewer than modelled for some people, which would reduce the ICER. The committee concluded that all plausible ICERs were within the range usually considered a cost-effective use of NHS resources.\n\n# End of life\n\n## Brentuximab vedotin only meets 1 of NICE's end-of-life criteria\n\nHaving concluded that all plausible ICERs were within the range for brentuximab vedotin to be considered a cost-effective use of NHS resources, the committee discussed the additional evidence provided by the company in response to consultation to support the case for brentuximab vedotin as an end-of-life therapy. It considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods. It agreed that it could not make reliable conclusions about life expectancy and survival benefit using the results from the self-control cohort from SG035‑0004, because it had concerns about using this as a source of data for overall survival for chemotherapy (section\xa03.18). The committee heard from the company that Mak\xa0et\xa0al. reported a median overall survival of 13.7\xa0months for people with peripheral T-cell lymphoma and a performance status of 0 or 1 (the subgroup used in the company's model), but noted that median overall survival for people with systemic anaplastic large cell lymphoma was 3.0\xa0months. Because the committee's preference is for mean values for overall survival, it instead considered estimates from the economic model. The committee discussed the criterion of short life expectancy with current treatment, which is normally less than 24\xa0months, and noted that the modelled overall survival with chemotherapy in the company's updated model was 3.98\xa0years. In response to consultation, the company provided supplementary evidence from the UK-based Haematological Malignancy Research Network (HMRN), the results of which are academic in confidence and cannot be reported here. In discussing this evidence, the committee noted that the population in the HMRN dataset was broader than the population in the SG035‑00045 trial (that is, it included people of any performance status). It noted that mean overall survival for the population in the HMRN dataset was therefore likely to be lower than that for people in whom brentuximab vedotin would be an option in NHS practice. The committee therefore concluded that brentuximab vedotin did not meet the criterion of short life expectancy. The committee then discussed whether brentuximab vedotin could meet the criterion for extension to life, normally of at least an additional 3\xa0months. Using its preferred assumptions and a gamma curve to extrapolate progression-free and overall survival, the committee noted that mean overall survival with brentuximab vedotin was 12.28\xa0years, representing an extension of 8.3\xa0years. The committee considered that, based on the modelled overall survival benefit, brentuximab vedotin would meet the criterion for extension to life. However, it recalled that brentuximab vedotin did not meet the first end-of-life criterion, and concluded that brentuximab vedotin cannot be considered an end-of-life therapy.\n\n# Equality\n\n## Healthcare professionals should consider ECOG performance status when implementing the recommendations\n\nThe committee considered whether its recommendations were associated with any potential issues related to equality. It concluded that healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect ECOG performance status and make any adjustments they consider appropriate.\n\n# Other factors\n\n## The committee did not identify any other factors that would affect its recommendations\n\nThe committee discussed the company's comments about the innovative nature of brentuximab vedotin. It heard from a clinical and patient expert that treatment with brentuximab vedotin produces high complete remission rates and that results are seen quickly, allowing treatment to be stopped early for most people. They considered the benefits of brentuximab vedotin to be a major change in the management of relapsed and refractory systemic anaplastic large cell lymphoma, providing patients with a valuable treatment option instead of toxic current treatment. The committee concluded that brentuximab vedotin was an innovative and promising treatment, but that it had not been presented with any evidence of additional benefits that were not captured in the QALY measure.\n\n# Conclusion\n\n## Brentuximab vedotin is only recommended within its marketing authorisation for people with a performance status of 0 or 1\n\nThe committee considered that the most plausible ICERs for brentuximab vedotin (£18,324 to £24,064 per QALY gained) meant that it could be considered a cost-effective use of NHS resources. However, the committee acknowledged that there was limited representation of people with an ECOG performance status of more than 1 in SG035‑0004, the trial on which the cost-effective analyses were based. It therefore considered that its recommendations should closely reflect the population in the SG035‑00045 trial, because it was unclear if the cost-effectiveness results would be reflected in people with an ECOG performance status of more than 1. The committee concluded that it could recommend brentuximab vedotin as an option for treating relapsed or refractory systemic anaplastic clear cell lymphoma in adults, only if they have an ECOG performance status of 0 or 1 and the company provides brentuximab vedotin according to the commercial access agreement with NHS England."}
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https://www.nice.org.uk/guidance/ta478
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Evidence-based recommendations on brentuximab vedotin (Adcetris) for treating relapsed or refractory systemic anaplastic large cell lymphoma in adults.
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e2cbebf19fd0877b71cb992296614c88f6d9b77e
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nice
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Reslizumab for treating severe eosinophilic asthma
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Reslizumab for treating severe eosinophilic asthma
Evidence-based recommendations on reslizumab (Cinqaero) for treating severe eosinophilic asthma in adults.
# Recommendations
Reslizumab, as an add-on therapy, is recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if:
the blood eosinophil count has been recorded as 400 cells per microlitre or more
the person has had 3 or more severe asthma exacerbations needing systemic corticosteroids in the past 12 months and
the company provides reslizumab with the discount agreed in the patient access scheme.
At 12 months:
stop reslizumab if the asthma has not responded adequately or
continue reslizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as:
a clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or
a clinically significant reduction in continuous oral corticosteroid use while maintaining or improving asthma control.
These recommendations are not intended to affect treatment with reslizumab that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Reslizumab (Cinqaero, Teva) is an interleukin‑5 inhibitor that reduces eosinophil numbers and activity.
Marketing authorisation
Reslizumab has a marketing authorisation in the UK as 'add-on therapy in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment'.
Adverse reactions
The most common adverse reaction is increased blood creatine phosphokinase, which is transient and asymptomatic. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Intravenous infusion based on body weight once every 4 weeks. For patients between 35 kg and 199 kg the recommended dose is achieved using a vial-based dosing scheme. For patients below 35 kg or above 199 kg the recommended dose is 3 mg/kg body weight.
Price
The list price is £499.99 per 100‑mg vial and £124.99 per 25‑mg vial (excluding VAT). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of reslizumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by Teva and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of reslizumab, having considered evidence on the nature of severe eosinophilic asthma and the value placed on the benefits of reslizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Patient experience
Inadequately controlled severe eosinophilic asthma is a distressing and socially isolating condition. The committee heard from the patient expert that severe asthma has an unpredictable course. People with very severe asthma are often unable to work and may need help with day-to-day activities because of the symptoms. Exacerbations are very frightening and can happen without warning. They can result in frequent hospital visits and in severe cases are life-threatening, which may require intensive care support including intubation. The committee heard from the clinical experts that standard treatment for inadequately controlled severe eosinophilic asthma is corticosteroids. These are often effective, and oral or injected corticosteroids are the mainstay of treatment for exacerbations, but when taken frequently or long term they are associated with some major complications. The patient expert explained that these include diabetes, glaucoma, weight gain, bone density loss, hip replacement, raised blood pressure and mood swings. These can have a significant effect on patients, and can mean that numerous additional medications are needed to counteract the effects of the corticosteroids. The committee heard from the patient expert that she has to attend appointments for these complications, and it takes between 2 and 4 hours daily to administer all of her medicines. The committee understood that people would welcome treatment options that replace the need for, or reduce the dose of, oral corticosteroids. The committee heard that treatments such as reslizumab reduce the number of exacerbations, and are also expected to reduce oral corticosteroid use. It concluded that inadequately controlled severe eosinophilic asthma is associated with substantial morbidity and that there is a need for alternative treatment options.
# Current clinical management of asthma
The clinical experts explained that treatment for asthma in clinical practice follows guidelines from the British Thoracic Society and the Scottish Intercollegiate Guidelines Network. The clinical experts explained that the management of severe eosinophilic asthma lies within what were previously known as step 4 and step 5 of the superseded 2014 version of these guidelines. The current guidelines (2016) suggest that people having high-dose inhaled therapies (previously step 4) or continuous or frequent use of oral corticosteroids (previously step 5) should be referred for specialist care. Additional interventions may include leukotriene receptor antagonists, theophyllines, oral corticosteroids, and help with smoking cessation. The committee understood that oral or injected corticosteroids can be used for short periods, for example to manage an exacerbation, but oral corticosteroids can be used as long-term maintenance. The committee was aware that the marketing authorisation for reslizumab is for 'severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment'. It questioned whether only people who continue to have exacerbations despite treatment with continuous or frequent use of oral corticosteroids (previously step 5 of the guidelines) would be eligible for reslizumab. The clinical experts explained that people who have severe uncontrolled eosinophilic asthma having high-dose therapies (previously step 4) or continuous and frequent use of oral corticosteroids (previously step 5) would have treatment at specialist centres, and that many of these patients have asthma that will respond to optimised treatment. Reslizumab would only be considered for patients who continue to have clinically significant exacerbations despite optimised conventional treatment, and about 50% of these people might be taking maintenance oral corticosteroids. The committee understood that people with severe eosinophilic asthma on optimised treatment described in the high-dose therapies (previously step 4) or continuous and frequent use of oral corticosteroids (previously step 5) stages of the guidelines would be considered eligible for treatment with reslizumab.
# Diagnosing severe eosinophilic asthma
The clinical experts explained that there are no standard diagnostic criteria for severe eosinophilic asthma in clinical practice. The committee heard that clinicians use the patient's phenotype to come to a probable diagnosis, which is confirmed using objective criteria in the form of evidence of eosinophilia (including blood or sputum eosinophil counts, exhaled nitric oxide levels, or biopsy specimens from nasal polyps). A rapid response to oral corticosteroids is also used to diagnose eosinophilic asthma. The committee heard that peripheral blood eosinophil count is a commonly used biomarker but it is suppressed by corticosteroid use, therefore only measurements taken before corticosteroid treatment are reliable. The clinical experts stated that measuring sputum eosinophils gives the most accurate diagnosis of eosinophilic asthma, but this is not widely used in clinical practice. The committee acknowledged the complexity of diagnosing eosinophilic asthma.
# Clinical effectiveness
## Population
The committee discussed the generalisability of the clinical trials to UK clinical practice. The company presented evidence from trials that included people aged 12 to 75 years with asthma and a blood eosinophil count of 400 cells per microlitre or more, inadequately controlled with medium to high-dose inhaled corticosteroids. The committee noted that the key trials, study 3082 and study 3083, included people with a blood eosinophil count of more than 400 cells per microlitre in the previous 12 months. The committee was aware that the marketing authorisation for reslizumab does not give a specific eosinophil count because the European Medicines Agency stated that blood eosinophil levels are not sufficiently predictive to include a cut-off value. The clinical experts stated that the high eosinophil count threshold was a limitation of the clinical trials because reslizumab is more effective the higher the eosinophil count, and therefore it might not be as effective in clinical practice as in the trials. They also explained that some patients in the trials may have had sensitivity to fungal allergens, which would account for the high eosinophil counts seen at baseline. However, the clinical experts clarified that people with lower eosinophil counts than those in the trials may also potentially benefit from treatment with reslizumab. The committee noted that a small proportion of patients in the trials were taking oral corticosteroids, but they were not permitted to reduce their corticosteroid dose during the trial. The committee concluded that the studies are relevant to the UK but that, in clinical practice, patients considered for this treatment may have lower eosinophil counts than in the trials and a higher percentage will be on oral corticosteroids.
## Frequency of exacerbations
The committee noted that study 3082 and study 3083 recruited people with 1 or more exacerbations in the previous year. It was aware that the company proposed, and presented a base-case cost-effectiveness analysis for, a restricted population including people with 3 or more exacerbations per year. The committee heard from the clinical experts that they would particularly like to have this treatment available for patients having maintenance oral corticosteroids who have 3 or more exacerbations per year. The committee also heard that the number of exacerbations in 1 year does not necessarily indicate future exacerbation rates, and that event rates vary in patients from year to year. It considered that this is a limitation of the trials, which looked at only 1 year in what is a variable and lifelong condition. However, the committee noted a comment from a consultee in response to the second consultation that previous exacerbations are a strong predictor of subsequent exacerbations. The committee concluded that a criterion based on the number of exacerbations was not unreasonable, and expressed the view that the more frequent the exacerbations, the greater the clinical need.
The committee discussed whether treatment with reslizumab would be appropriate for people who do not take maintenance oral corticosteroids. The clinical experts highlighted that probably at least 50% of patients on what were previously known as steps 4 or 5 of the British Thoracic Society and Scottish Intercollegiate Guidelines Network guidelines are having treatment with maintenance oral corticosteroids, but still have several exacerbations. The clinical experts explained that these people would be eligible for treatment with reslizumab but there are also other patients, who are not taking maintenance oral corticosteroids, who would benefit from reslizumab treatment. Patients who are not taking maintenance oral corticosteroids may have 1 of the following maintenance treatments in addition to high-dose inhaled corticosteroids: leukotriene receptor antagonists, theophylline, slow-release beta‑2 agonists or tiotropium. The committee considered the clinical experts' statements that maintenance corticosteroids are an effective treatment for people with severe asthma, and that a proportion of people who are taking maintenance corticosteroids will still have uncontrolled severe eosinophilic asthma. The committee noted that there are limited data on the effectiveness of reslizumab in people who are on maintenance corticosteroids, because only 19% and 12% of people respectively in study 3082 and study 3083 fulfilled this criterion. The committee concluded that reslizumab may be considered for people who are not taking maintenance oral corticosteroids, but it would be most beneficial for people who have multiple exacerbations despite maintenance oral corticosteroid use.
## Comparison with mepolizumab
The committee noted that at its first meeting, and in response to the first consultation, comparison with NICE's technology appraisal guidance on mepolizumab was raised as an issue. Several consultees stated the desirability of a recommendation that is the same for reslizumab and mepolizumab in terms of eosinophil count, number of exacerbations and oral corticosteroid usage. The committee noted that mepolizumab was not in the NICE scope as a comparator for this appraisal, and therefore no comparative data had been presented by the company. The committee acknowledged that clinicians might want to use reslizumab and mepolizumab interchangeably in clinical practice. However the company submission was based on the trial data for reslizumab, which differs from the evidence base for mepolizumab. The committee therefore had no information on the clinical and cost effectiveness of reslizumab in a population similar to that in the NICE guidance for mepolizumab; that is, people with an eosinophil count of 300 cells per microlitre, 4 or more exacerbations in a year, or taking continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months. The committee concluded that it could only consider the data presented by the company, and it had no information that allowed it to make a recommendation for reslizumab in line with mepolizumab.
## Direct comparison with best supportive care
The committee considered the results from the trials, including study 3082 and study 3083. It noted that reslizumab, compared with placebo, was associated with lower rates of clinically significant exacerbations. The committee concluded that, compared with placebo, reslizumab is effective in reducing the rate of clinically significant exacerbations.
## Indirect treatment comparison with omalizumab
The committee noted that the NICE scope included omalizumab as a comparator in a small 'overlap' population of people who also had severe persistent allergic IgE‑mediated asthma, and therefore could have either reslizumab or omalizumab. It heard that clinicians would decide which drug is most appropriate based on the person's phenotype. For predominantly eosinophilic symptoms, such as nasal polyps and sinusitis, people would be offered reslizumab. However, the committee noted the comment from a consultee in response to the second consultation that reslizumab may not be more appropriate than omalizumab for this group. People with predominantly IgE-related symptoms, such as eczema and urticaria, would be offered omalizumab. The committee noted that the company had presented an indirect treatment comparison using data from study 3082 and study 3083 for reslizumab and from the INNOVATE and EXTRA trials for omalizumab. It noted that the company based its comparison on the full trial populations, but there are fundamental differences between them. The committee acknowledged that the 2 drugs have different mechanisms of action and different populations. It also considered that adjusting for these differences in the very small overlap population was unlikely to be robust. The committee concluded that the results from the company's indirect comparison of reslizumab with omalizumab were highly uncertain and not suitable for decision-making. The committee therefore did not consider this comparison further.
# Cost effectiveness
The committee considered the company's cost-effectiveness analysis. It noted that the company's original base case was for reslizumab compared with standard care, for people with severe asthma who have had 3 or more exacerbations in the previous year. The committee noted that this is a subgroup of the overall trial population of people with severe asthma who have had 1 or more exacerbations in the previous year. The committee recalled its previous conclusion (see section 4.4) that neither the trials, nor the base-case populations, accurately reflect patients in the UK who might be considered for reslizumab; people with severe disease despite optimised care, often with lower eosinophil counts than in the trials, and with higher rates of maintenance corticosteroid use. The committee noted that the company had also presented cost-effectiveness analyses comparing reslizumab with omalizumab. The committee recalled its previous conclusion (see section 4.9) that the comparison with omalizumab is highly uncertain and not suitable for decision-making. The committee concluded that it would only consider the company's analysis for reslizumab compared with best standard care using the results from study 3082 and study 3083.
## Choice of standard care
The committee discussed the choice of standard care in the company's model. The committee was aware that the model did not incorporate stopping or reducing the dose of oral corticosteroids, because oral corticosteroid dose had been kept constant in the trials. It queried whether standard care with long-term maintenance oral corticosteroids is a more appropriate comparator than standard care with oral corticosteroids taken in short courses. The committee recalled the evidence from the clinical experts that 50% of patients with severe eosinophilic asthma may already be on maintenance oral corticosteroids. The clinical and patient experts stated that the long-term effects of oral corticosteroid treatment are serious and could become as problematic as the asthma itself (see section 4.1). The clinical experts stated that some observational data exist on oral corticosteroid sparing and the costs associated with treating corticosteroid-induced complications. The committee noted that in response to the appraisal consultation documents the company had discussed the issues around oral corticosteroid sparing, but the model structure did not allow the costs and consequences of oral corticosteroid use to be incorporated. The committee agreed it would have liked to have seen some exploratory analysis around this issue to explore the potential benefit of reslizumab in reducing oral corticosteroid use and therefore the adverse effects associated with oral corticosteroids, as suggested by the clinical experts (see section 4.1). The committee also noted a comment received in response to consultation that there was an ongoing corticosteroid reduction trial. The committee heard from the company that a trial of a subcutaneous formulation of reslizumab, that examined the effect of oral corticosteroid sparing, had been requested by the regulators and was underway. The committee concluded that because more patients in UK clinical practice have maintenance oral corticosteroids than those in the trials, this potential benefit of reslizumab had not been taken into account in the cost-effectiveness analysis. It expressed interest in evidence in support of this proposed benefit when further trial data become available.
## Exacerbation transition probabilities
The committee considered the company's approach to estimating transition probabilities between exacerbation states of the economic model. In the original base case the company had noted that patients randomised to placebo, as well as those in the reslizumab arm of the trials, experienced a reduction in exacerbations. The company stated that this reflects a potential placebo effect. To account for this placebo effect, the company adjusted the estimates in both the placebo and the reslizumab arms. The committee heard from the clinical experts that patients in both arms of the trials would be carefully followed and monitored during the trial, so would have had optimised, closely supervised care, which they may not have had before entering the trial. This could account for at least some of the improvement, rather than it being a placebo effect. The committee agreed that improvement could reflect the benefit of optimised care, or regression to the mean. This would be likely to affect both arms, and the adjusted rates were no more likely than the unadjusted rates to reflect the true treatment benefit of reslizumab. The committee agreed that it would have preferred to see results from a model that used the observed (unadjusted) data from the relevant subgroup in the trials to determine the transition probabilities. In response to the second appraisal consultation document, the company provided a revised base-case analysis that did not include an upward adjustment in the exacerbation rate of the standard care arm, so closely reflected the actual baseline exacerbation rate seen in the trials. Transition probabilities used in the model submitted in response to the first appraisal document, but without the placebo adjustment, were incorporated in the company's revised base case. Based on these updated transition probabilities, the model used a mean annual exacerbation rate of 2.68 for standard care (instead of the previous value of 4.85) which the committee accepted was slightly lower than the mean rate of exacerbation of 2.73 reported in the placebo arms in the clinical trials. The committee concluded that this approach was in line with their original request and that the revised analysis was appropriate.
In response to consultation, the company highlighted that using the baseline exacerbation rate seen in the trials was likely to be conservative. It highlighted several UK studies that showed severe asthma patients attending specialised centres have a higher level of exacerbations than in their revised model. In response to the committee's previous concern around whether the higher rate of 4.85 exacerbations would apply to people with severe eosinophilic asthma, the company reported new evidence showing that patients with severe eosinophilic asthma had roughly similar exacerbation rates to patients with non-eosinophilic asthma (although it acknowledged that the results lacked statistical significance). The company further explored this expected higher rate in a scenario analysis. This was based on the approach suggested by the evidence review group (ERG) in their previous report, in which the observed rate of exacerbation in the clinical trial (2.68) was assumed to apply for the duration of the trial (that is 1 year) and was then assumed to increase linearly over the following 9 years until the exacerbation rate of the 'real world' data (that is 4.85 exacerbations per year) was reached at year 10. The committee noted the company's evidence supporting higher exacerbation rates than seen in the clinical trials, but concluded that the most robust estimate of relative effectiveness was derived from the exacerbation rates shown in the clinical trials, and that this was the best available data for decision-making.
## Duration of treatment
The committee discussed the duration of treatment with reslizumab assumed by the company in its model. The committee noted the company's algorithm that calculated the expected response at the end of the year based on an early response at 16 weeks. The clinical experts stated that patients would not routinely be assessed for response to reslizumab at 16 weeks because this is too early to assess the effect on exacerbations, and other measures would not be reliable enough. A more appropriate reassessment period would be 6 months, followed by annual reassessments. The clinical experts stated that if patients continued to benefit from treatment, they would remain on reslizumab indefinitely. In response to consultation the company showed that there is minimal difference in cost effectiveness for reassessment at 16 weeks, 6 months or 52 weeks. The committee also noted other consultation comments that patients on other asthma drugs are reassessed at 16 weeks and therefore it would be helpful to use this same reassessment time point for reslizumab. However, the committee noted a response to the second consultation that suggested 16 weeks was not appropriate for reslizumab and perhaps, given that reslizumab has the same mechanism of action as mepolizumab, a reassessment at 12 months would be more appropriate. The committee heard from the company that no rule for stopping treatment with reslizumab was incorporated in the economic model. But the company clarified that a proportion of patients were modelled to stop treatment at 16 weeks because of early response, and at 52 weeks for lack of clinical response, and that the summary of product characteristics for reslizumab says treatment should be reassessed at 12 months. The committee therefore concluded that reassessment at 12 months was the most appropriate.
## Administration costs and drug wastage
The committee considered the administration costs used by the company in its model. The committee noted that in its response to the first consultation, the company updated the administration costs to reflect clinical practice. The committee concluded that the company had included more appropriate administration costs for reslizumab in its revised model.
The committee noted that reslizumab has a marketing authorisation at a dose of 3 mg/kg given intravenously every 4 weeks, using a 100‑mg vial and a 25‑mg vial. It was aware that the company had submitted a change in the summary of product characteristics to incorporate vial-based dosing by bodyweight, which had been accepted. The committee heard from the company that vial-based dosing would simplify the dose determination process and reduce preparation time, minimise wastage and reduce the total cost of treatment. This is because patients in each dosing group will have a dose slightly lower than the 3 mg/kg weight-based dosing. The company further highlighted that clinical response and efficacy would be maintained compared with weight-based dosing. The ERG considered this to be a reasonable approach and the committee concluded that vial-based dosing was appropriate.
## Utility values
The committee discussed the estimates of utility in the model. The ERG's view was that the company's original base case should have used values mapped from AQLQ to EQ‑5D, because the evidence came from the trials. In response to the first consultation, the company's revised base case used the ERG's preferred utility values. In response to the second consultation, the company updated the mean utility values for the severe exacerbation health state. Post-hoc analyses from the clinical trials showed that patients with severe eosinophilic asthma, with 3 or more exacerbations in the previous year, had a lower mean duration for a severe exacerbation in the reslizumab arm compared with the placebo arm. The committee noted that based on this information, the company changed the utility value of 0.51 for both reslizumab and best supportive care for the duration of the full model cycle (4 weeks) in the severe exacerbation state to 0.54 for reslizumab and 0.50 for best supportive care. The ERG highlighted the uncertainty in these utility value estimates because of the lack of robust health-related quality-of-life data, but considered the calculation to be appropriate. It further noted that the revised utility values had only a minor effect on the cost effectiveness. The committee therefore accepted the revised utility value estimates for severe exacerbations.
## Incremental cost-effectiveness results
The company presented its revised base case, in response to consultation, taking into account the revised patient access scheme discount applied to reslizumab compared with best standard care. The company's base-case deterministic incremental cost-effectiveness ratio (ICER) for people with 3 or more exacerbations in the previous 12 months is £29,870 per quality-adjusted life year (QALY) gained and the probabilistic ICER for people with 3 or more exacerbations in the previous 12 months is £27,509 per QALY gained. The committee again noted comments from consultees which highlighted the need to see the oral corticosteroid sparing effect of reslizumab being captured in the economic model. It was aware that there are limited data supporting the potential benefits of interleukin‑5 inhibitors in reducing oral corticosteroids. The committee concluded that, had the potential benefits of oral corticosteroid sparing been included in the economic analysis, the most plausible ICER for reslizumab could be slightly lower and any future data on this would be welcomed. The committee agreed that reslizumab could be considered a cost-effective use of NHS resources and concluded that reslizumab, as an add-on therapy, could be recommended as an option for treating severe eosinophilic asthma that is inadequately controlled despite maintenance therapy with high-dose inhaled corticosteroids, only if the blood eosinophil count has been 400 cells per microlitre or more and the person has had 3 or more asthma exacerbations in the previous 12 months.
# Pharmaceutical Price Regulation Scheme
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view in this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Innovation
The committee heard from stakeholders that reslizumab is innovative in its potential to make a significant and substantial effect on health-related benefits. The committee heard from the clinical experts that there are few treatments for severe eosinophilic asthma that have the potential to reduce corticosteroid use. It noted that it had not seen any evidence on preventing or delaying the use of maintenance oral corticosteroids but heard from the clinicians that this is an important aim of treatment with reslizumab. The committee agreed that some benefits related to avoiding the significant adverse effects of oral corticosteroid use had not been fully captured in the QALY calculations. The committee also considered that there were benefits to carers, which may not have been captured in the QALY calculation. The committee therefore agreed that reslizumab could be considered innovative.
# Summary of appraisal committee's key conclusions
TA479
Appraisal title: Reslizumab for treating severe eosinophilic asthma
Section
Key conclusion
Reslizumab, as an add-on therapy, is recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if:
the blood eosinophil count has been recorded as 400 cells per microlitre or more
the person has had 3 or more severe asthma exacerbations needing systemic corticosteroids in the past 12 months and
the company provides reslizumab with the discount agreed in the patient access scheme.
At 12 months:
stop reslizumab if the asthma has not responded adequately or
continue reslizumab if the asthma has responded adequately and assess response each year.
Combining all the amendments including no adjustment for clinical rate of exacerbations, updated utility values, vial-based dosing and enhanced patient access scheme, the resulting incremental cost-effectiveness ratio (ICER) is £29,870 per quality-adjusted life year (QALY) gained for people with 3 or more exacerbations in the previous year. The committee concluded that, had the potential benefits of oral corticosteroid sparing been included in the economic analysis, the most plausible ICER for reslizumab could be slightly lower and any future data on this would be very much welcomed.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee understood that people with severe eosinophilic asthma on optimised treatment described in the high-dose inhaled therapies (previously step 4) or continuous and frequent use of oral corticosteroids (previously step 5) stages of the guidelines would be considered eligible for treatment with reslizumab.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee concluded that, compared with placebo, reslizumab is effective in reducing the rate of clinically significant exacerbations.
The committee heard from stakeholders that reslizumab is innovative in its potential to make a significant and substantial effect on health-related benefits. It also heard from the clinical experts that there are few treatments for severe eosinophilic asthma that have the potential to reduce corticosteroid use.
What is the position of the treatment in the pathway of care for the condition?
The committee concluded that treatment with reslizumab may be considered for people who are not taking maintenance oral corticosteroids, but that it would be most beneficial for people who have multiple exacerbations despite maintenance oral corticosteroid use.
Adverse reactions
The most common adverse reaction is increased blood creatine phosphokinase, which is transient and asymptomatic.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that there is limited data on the effectiveness of reslizumab in people who are on maintenance corticosteroids, because only 19% and 12% of people respectively in study 3082 and study 3083 fulfilled this criterion. The committee concluded that treatment with reslizumab may be considered for people who are not taking maintenance oral corticosteroids, but that it would be most beneficial for people who have multiple exacerbations despite maintenance oral corticosteroid use.
Relevance to general clinical practice in the NHS
The committee concluded that study 3082 and study 3083 are relevant to the UK but that, in clinical practice, patients considered for reslizumab may have lower eosinophil counts than in the trials and a higher percentage will be on oral corticosteroids.
Uncertainties generated by the evidence
The committee heard from the clinical experts that they would particularly like to have this treatment available for patients having maintenance oral corticosteroids who have 3 or more exacerbations per year. The committee also heard that the number of exacerbations in 1 year is not necessarily indicative of future exacerbation rates, and that event rates vary in patients from year to year. It considered that this is a limitation of the trials, which looked at only 1 year in what is a variable and lifelong condition. However, the committee noted a comment from a consultee in response to the second consultation that previous exacerbations are a strong predictor of subsequent exacerbations.
The committee concluded that the results from the company's indirect comparison of reslizumab with omalizumab were highly uncertain and not suitable for decision-making. The committee therefore did not consider this comparison further.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee concluded that patients with more exacerbations have a higher clinical need.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee concluded that, compared with placebo, reslizumab is effective in reducing the rate of clinically significant exacerbations.
Evidence for cost effectiveness
Availability and nature of evidence
The committee noted that the company had presented cost-effectiveness analyses comparing reslizumab with omalizumab but that the comparison with omalizumab is highly uncertain and not suitable for decision-making. The committee concluded that it would only consider the company's analysis for reslizumab compared with best standard care using the results from study 3082 and study 3083.
Uncertainties around and plausibility of assumptions and inputs in the economic model
In response to the second appraisal document, and in line with the committee's preference, the company provided a revised base-case analysis that did not include an upward adjustment in the exacerbation rate of the standard care arm. Transition probabilities used in the model submitted in response to the first appraisal document, but without the placebo adjustment, were incorporated in the revised base case. Based on these updated transition probabilities the model used a mean annual exacerbation rate of 2.68 for standard care (instead of the previous value of 4.85), which the committee accepted was slightly lower than the mean rate of exacerbation of 2.73 reported in the placebo arms in the clinical trials. The committee concluded that this approach was in line with their original request and that the revised analyses was appropriate.
The company stated, in its response to consultation, that using the baseline exacerbation rate seen in the trials was likely to be conservative, and it highlighted several UK studies that showed patients with severe asthma were attending specialised centres. The committee noted the evidence supplied by the company in support of higher exacerbation rates than seen in the clinical trials, but concluded that the most robust estimate of relative effectiveness was derived from the exacerbation rates shown in the properly conducted clinical trials, and that this was the best available data for decision-making.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee noted that based on information from post-hoc analyses, the company changed the utility value of 0.51 for both reslizumab and best supportive care for duration of the full model cycle (4 weeks) in the severe exacerbation state to utility values of 0.54 for reslizumab and 0.50 for the best supportive care arm. Because the revision of the utility values for severe exacerbations has only a minor effect on the cost effectiveness, the committee accepted the additional updated utility value estimates for severe exacerbations.
It was aware that the model did not incorporate stopping or reducing the dose of oral corticosteroids, because the dose had been kept constant in the trials. The committee concluded that because more patients in UK clinical practice have maintenance oral corticosteroids than those in the trials, it would have liked to have seen some exploratory analysis around this issue because this is a potential benefit of reslizumab.
Are there specific groups of people for whom the technology is particularly cost effective?
For the specific group of people with more than 3 exacerbations in the previous 12 months, the ICER was in the range considered to be a cost-effective use of NHS resources.
What are the key drivers of cost effectiveness?
The calculation and choice of exacerbation transition probabilities were the key drivers of cost effectiveness for reslizumab compared with best supportive care.
Most likely cost-effectiveness estimate (given as an ICER)
By combining all the amendments including no adjustment for clinical rate of exacerbations, updated utility values, vial-based dosing and enhanced patient access scheme, the resulting ICER is £29,870 per QALY gained for people with 3 or more exacerbations in the previous year. The committee concluded that, had the potential benefits of oral corticosteroid sparing been included in the economic analysis, the most plausible ICER for reslizumab could be slightly lower and any future data on this would be very much welcomed. The committee agreed that reslizumab could be considered a cost-effective use of NHS resources. It concluded that reslizumab, as an add-on therapy, could be recommended as an option for treating severe eosinophilic asthma inadequately controlled despite maintenance therapy with high-dose inhaled corticosteroids, only if the blood eosinophil count has been recorded as 400 cells per microlitre or more and the person has had 3 or more asthma exacerbations in the previous 12 months.
Additional factors taken into account
Patient access schemes (PPRS)
A patient access scheme discount was applied to the ICERs presented by the company and the evidence review group (ERG) for reslizumab compared with best standard care.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
No equalities issues were identified.
|
{'Recommendations': 'Reslizumab, as an add-on therapy, is recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if:\n\nthe blood eosinophil count has been recorded as 400\xa0cells per microlitre or more\n\nthe person has had 3\xa0or more severe asthma exacerbations needing systemic corticosteroids in the past 12\xa0months and\n\nthe company provides reslizumab with the discount agreed in the patient access scheme.\n\nAt 12\xa0months:\n\nstop reslizumab if the asthma has not responded adequately or\n\ncontinue reslizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as:\n\na clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or\n\na clinically significant reduction in continuous oral corticosteroid use while maintaining or improving asthma control.\n\nThese recommendations are not intended to affect treatment with reslizumab that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nReslizumab (Cinqaero, Teva) is an interleukin‑5 inhibitor that reduces eosinophil numbers and activity.\n\nMarketing authorisation\n\nReslizumab has a marketing authorisation in the UK as 'add-on therapy in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment'.\n\nAdverse reactions\n\nThe most common adverse reaction is increased blood creatine phosphokinase, which is transient and asymptomatic. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nIntravenous infusion based on body weight once every 4\xa0weeks. For patients between 35\xa0kg and 199\xa0kg the recommended dose is achieved using a vial-based dosing scheme. For patients below 35\xa0kg or above 199\xa0kg the recommended dose is 3\xa0mg/kg body weight.\n\nPrice\n\nThe list price is £499.99 per 100‑mg vial and £124.99 per 25‑mg vial (excluding VAT). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of reslizumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Teva and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of reslizumab, having considered evidence on the nature of severe eosinophilic asthma and the value placed on the benefits of reslizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Patient experience\n\nInadequately controlled severe eosinophilic asthma is a distressing and socially isolating condition. The committee heard from the patient expert that severe asthma has an unpredictable course. People with very severe asthma are often unable to work and may need help with day-to-day activities because of the symptoms. Exacerbations are very frightening and can happen without warning. They can result in frequent hospital visits and in severe cases are life-threatening, which may require intensive care support including intubation. The committee heard from the clinical experts that standard treatment for inadequately controlled severe eosinophilic asthma is corticosteroids. These are often effective, and oral or injected corticosteroids are the mainstay of treatment for exacerbations, but when taken frequently or long term they are associated with some major complications. The patient expert explained that these include diabetes, glaucoma, weight gain, bone density loss, hip replacement, raised blood pressure and mood swings. These can have a significant effect on patients, and can mean that numerous additional medications are needed to counteract the effects of the corticosteroids. The committee heard from the patient expert that she has to attend appointments for these complications, and it takes between 2 and 4\xa0hours daily to administer all of her medicines. The committee understood that people would welcome treatment options that replace the need for, or reduce the dose of, oral corticosteroids. The committee heard that treatments such as reslizumab reduce the number of exacerbations, and are also expected to reduce oral corticosteroid use. It concluded that inadequately controlled severe eosinophilic asthma is associated with substantial morbidity and that there is a need for alternative treatment options.\n\n# Current clinical management of asthma\n\nThe clinical experts explained that treatment for asthma in clinical practice follows guidelines from the British Thoracic Society and the Scottish Intercollegiate Guidelines Network. The clinical experts explained that the management of severe eosinophilic asthma lies within what were previously known as step\xa04 and step\xa05 of the superseded 2014 version of these guidelines. The current guidelines (2016) suggest that people having high-dose inhaled therapies (previously step\xa04) or continuous or frequent use of oral corticosteroids (previously step\xa05) should be referred for specialist care. Additional interventions may include leukotriene receptor antagonists, theophyllines, oral corticosteroids, and help with smoking cessation. The committee understood that oral or injected corticosteroids can be used for short periods, for example to manage an exacerbation, but oral corticosteroids can be used as long-term maintenance. The committee was aware that the marketing authorisation for reslizumab is for 'severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment'. It questioned whether only people who continue to have exacerbations despite treatment with continuous or frequent use of oral corticosteroids (previously step\xa05 of the guidelines) would be eligible for reslizumab. The clinical experts explained that people who have severe uncontrolled eosinophilic asthma having high-dose therapies (previously step\xa04) or continuous and frequent use of oral corticosteroids (previously step\xa05) would have treatment at specialist centres, and that many of these patients have asthma that will respond to optimised treatment. Reslizumab would only be considered for patients who continue to have clinically significant exacerbations despite optimised conventional treatment, and about 50% of these people might be taking maintenance oral corticosteroids. The committee understood that people with severe eosinophilic asthma on optimised treatment described in the high-dose therapies (previously step\xa04) or continuous and frequent use of oral corticosteroids (previously step\xa05) stages of the guidelines would be considered eligible for treatment with reslizumab.\n\n# Diagnosing severe eosinophilic asthma\n\nThe clinical experts explained that there are no standard diagnostic criteria for severe eosinophilic asthma in clinical practice. The committee heard that clinicians use the patient's phenotype to come to a probable diagnosis, which is confirmed using objective criteria in the form of evidence of eosinophilia (including blood or sputum eosinophil counts, exhaled nitric oxide levels, or biopsy specimens from nasal polyps). A rapid response to oral corticosteroids is also used to diagnose eosinophilic asthma. The committee heard that peripheral blood eosinophil count is a commonly used biomarker but it is suppressed by corticosteroid use, therefore only measurements taken before corticosteroid treatment are reliable. The clinical experts stated that measuring sputum eosinophils gives the most accurate diagnosis of eosinophilic asthma, but this is not widely used in clinical practice. The committee acknowledged the complexity of diagnosing eosinophilic asthma.\n\n# Clinical effectiveness\n\n## Population\n\nThe committee discussed the generalisability of the clinical trials to UK clinical practice. The company presented evidence from trials that included people aged 12\xa0to 75\xa0years with asthma and a blood eosinophil count of 400\xa0cells per microlitre or more, inadequately controlled with medium to high-dose inhaled corticosteroids. The committee noted that the key trials, study\xa03082 and study\xa03083, included people with a blood eosinophil count of more than 400\xa0cells per microlitre in the previous 12\xa0months. The committee was aware that the marketing authorisation for reslizumab does not give a specific eosinophil count because the European Medicines Agency stated that blood eosinophil levels are not sufficiently predictive to include a cut-off value. The clinical experts stated that the high eosinophil count threshold was a limitation of the clinical trials because reslizumab is more effective the higher the eosinophil count, and therefore it might not be as effective in clinical practice as in the trials. They also explained that some patients in the trials may have had sensitivity to fungal allergens, which would account for the high eosinophil counts seen at baseline. However, the clinical experts clarified that people with lower eosinophil counts than those in the trials may also potentially benefit from treatment with reslizumab. The committee noted that a small proportion of patients in the trials were taking oral corticosteroids, but they were not permitted to reduce their corticosteroid dose during the trial. The committee concluded that the studies are relevant to the UK but that, in clinical practice, patients considered for this treatment may have lower eosinophil counts than in the trials and a higher percentage will be on oral corticosteroids.\n\n## Frequency of exacerbations\n\nThe committee noted that study\xa03082 and study\xa03083 recruited people with 1\xa0or more exacerbations in the previous year. It was aware that the company proposed, and presented a base-case cost-effectiveness analysis for, a restricted population including people with 3\xa0or more exacerbations per year. The committee heard from the clinical experts that they would particularly like to have this treatment available for patients having maintenance oral corticosteroids who have 3\xa0or more exacerbations per year. The committee also heard that the number of exacerbations in 1\xa0year does not necessarily indicate future exacerbation rates, and that event rates vary in patients from year to year. It considered that this is a limitation of the trials, which looked at only 1\xa0year in what is a variable and lifelong condition. However, the committee noted a comment from a consultee in response to the second consultation that previous exacerbations are a strong predictor of subsequent exacerbations. The committee concluded that a criterion based on the number of exacerbations was not unreasonable, and expressed the view that the more frequent the exacerbations, the greater the clinical need.\n\nThe committee discussed whether treatment with reslizumab would be appropriate for people who do not take maintenance oral corticosteroids. The clinical experts highlighted that probably at least 50% of patients on what were previously known as steps\xa04 or 5 of the British Thoracic Society and Scottish Intercollegiate Guidelines Network guidelines are having treatment with maintenance oral corticosteroids, but still have several exacerbations. The clinical experts explained that these people would be eligible for treatment with reslizumab but there are also other patients, who are not taking maintenance oral corticosteroids, who would benefit from reslizumab treatment. Patients who are not taking maintenance oral corticosteroids may have 1 of the following maintenance treatments in addition to high-dose inhaled corticosteroids: leukotriene receptor antagonists, theophylline, slow-release beta‑2 agonists or tiotropium. The committee considered the clinical experts' statements that maintenance corticosteroids are an effective treatment for people with severe asthma, and that a proportion of people who are taking maintenance corticosteroids will still have uncontrolled severe eosinophilic asthma. The committee noted that there are limited data on the effectiveness of reslizumab in people who are on maintenance corticosteroids, because only 19% and 12% of people respectively in study\xa03082 and study\xa03083 fulfilled this criterion. The committee concluded that reslizumab may be considered for people who are not taking maintenance oral corticosteroids, but it would be most beneficial for people who have multiple exacerbations despite maintenance oral corticosteroid use.\n\n## Comparison with mepolizumab\n\nThe committee noted that at its first meeting, and in response to the first consultation, comparison with NICE's technology appraisal guidance on mepolizumab was raised as an issue. Several consultees stated the desirability of a recommendation that is the same for reslizumab and mepolizumab in terms of eosinophil count, number of exacerbations and oral corticosteroid usage. The committee noted that mepolizumab was not in the NICE scope as a comparator for this appraisal, and therefore no comparative data had been presented by the company. The committee acknowledged that clinicians might want to use reslizumab and mepolizumab interchangeably in clinical practice. However the company submission was based on the trial data for reslizumab, which differs from the evidence base for mepolizumab. The committee therefore had no information on the clinical and cost effectiveness of reslizumab in a population similar to that in the NICE guidance for mepolizumab; that is, people with an eosinophil count of 300\xa0cells per microlitre, 4\xa0or more exacerbations in a year, or taking continuous oral corticosteroids of at least the equivalent of prednisolone 5\xa0mg per day over the previous 6\xa0months. The committee concluded that it could only consider the data presented by the company, and it had no information that allowed it to make a recommendation for reslizumab in line with mepolizumab.\n\n## Direct comparison with best supportive care\n\nThe committee considered the results from the trials, including study\xa03082 and study\xa03083. It noted that reslizumab, compared with placebo, was associated with lower rates of clinically significant exacerbations. The committee concluded that, compared with placebo, reslizumab is effective in reducing the rate of clinically significant exacerbations.\n\n## Indirect treatment comparison with omalizumab\n\nThe committee noted that the NICE scope included omalizumab as a comparator in a small 'overlap' population of people who also had severe persistent allergic IgE‑mediated asthma, and therefore could have either reslizumab or omalizumab. It heard that clinicians would decide which drug is most appropriate based on the person's phenotype. For predominantly eosinophilic symptoms, such as nasal polyps and sinusitis, people would be offered reslizumab. However, the committee noted the comment from a consultee in response to the second consultation that reslizumab may not be more appropriate than omalizumab for this group. People with predominantly IgE-related symptoms, such as eczema and urticaria, would be offered omalizumab. The committee noted that the company had presented an indirect treatment comparison using data from study\xa03082 and study\xa03083 for reslizumab and from the INNOVATE and EXTRA trials for omalizumab. It noted that the company based its comparison on the full trial populations, but there are fundamental differences between them. The committee acknowledged that the 2\xa0drugs have different mechanisms of action and different populations. It also considered that adjusting for these differences in the very small overlap population was unlikely to be robust. The committee concluded that the results from the company's indirect comparison of reslizumab with omalizumab were highly uncertain and not suitable for decision-making. The committee therefore did not consider this comparison further.\n\n# Cost effectiveness\n\nThe committee considered the company's cost-effectiveness analysis. It noted that the company's original base case was for reslizumab compared with standard care, for people with severe asthma who have had 3\xa0or more exacerbations in the previous year. The committee noted that this is a subgroup of the overall trial population of people with severe asthma who have had 1\xa0or more exacerbations in the previous year. The committee recalled its previous conclusion (see section\xa04.4) that neither the trials, nor the base-case populations, accurately reflect patients in the UK who might be considered for reslizumab; people with severe disease despite optimised care, often with lower eosinophil counts than in the trials, and with higher rates of maintenance corticosteroid use. The committee noted that the company had also presented cost-effectiveness analyses comparing reslizumab with omalizumab. The committee recalled its previous conclusion (see section\xa04.9) that the comparison with omalizumab is highly uncertain and not suitable for decision-making. The committee concluded that it would only consider the company's analysis for reslizumab compared with best standard care using the results from study\xa03082 and study\xa03083.\n\n## Choice of standard care\n\nThe committee discussed the choice of standard care in the company's model. The committee was aware that the model did not incorporate stopping or reducing the dose of oral corticosteroids, because oral corticosteroid dose had been kept constant in the trials. It queried whether standard care with long-term maintenance oral corticosteroids is a more appropriate comparator than standard care with oral corticosteroids taken in short courses. The committee recalled the evidence from the clinical experts that 50% of patients with severe eosinophilic asthma may already be on maintenance oral corticosteroids. The clinical and patient experts stated that the long-term effects of oral corticosteroid treatment are serious and could become as problematic as the asthma itself (see section\xa04.1). The clinical experts stated that some observational data exist on oral corticosteroid sparing and the costs associated with treating corticosteroid-induced complications. The committee noted that in response to the appraisal consultation documents the company had discussed the issues around oral corticosteroid sparing, but the model structure did not allow the costs and consequences of oral corticosteroid use to be incorporated. The committee agreed it would have liked to have seen some exploratory analysis around this issue to explore the potential benefit of reslizumab in reducing oral corticosteroid use and therefore the adverse effects associated with oral corticosteroids, as suggested by the clinical experts (see section\xa04.1). The committee also noted a comment received in response to consultation that there was an ongoing corticosteroid reduction trial. The committee heard from the company that a trial of a subcutaneous formulation of reslizumab, that examined the effect of oral corticosteroid sparing, had been requested by the regulators and was underway. The committee concluded that because more patients in UK clinical practice have maintenance oral corticosteroids than those in the trials, this potential benefit of reslizumab had not been taken into account in the cost-effectiveness analysis. It expressed interest in evidence in support of this proposed benefit when further trial data become available.\n\n## Exacerbation transition probabilities\n\nThe committee considered the company's approach to estimating transition probabilities between exacerbation states of the economic model. In the original base case the company had noted that patients randomised to placebo, as well as those in the reslizumab arm of the trials, experienced a reduction in exacerbations. The company stated that this reflects a potential placebo effect. To account for this placebo effect, the company adjusted the estimates in both the placebo and the reslizumab arms. The committee heard from the clinical experts that patients in both arms of the trials would be carefully followed and monitored during the trial, so would have had optimised, closely supervised care, which they may not have had before entering the trial. This could account for at least some of the improvement, rather than it being a placebo effect. The committee agreed that improvement could reflect the benefit of optimised care, or regression to the mean. This would be likely to affect both arms, and the adjusted rates were no more likely than the unadjusted rates to reflect the true treatment benefit of reslizumab. The committee agreed that it would have preferred to see results from a model that used the observed (unadjusted) data from the relevant subgroup in the trials to determine the transition probabilities. In response to the second appraisal consultation document, the company provided a revised base-case analysis that did not include an upward adjustment in the exacerbation rate of the standard care arm, so closely reflected the actual baseline exacerbation rate seen in the trials. Transition probabilities used in the model submitted in response to the first appraisal document, but without the placebo adjustment, were incorporated in the company's revised base case. Based on these updated transition probabilities, the model used a mean annual exacerbation rate of 2.68 for standard care (instead of the previous value of 4.85) which the committee accepted was slightly lower than the mean rate of exacerbation of 2.73 reported in the placebo arms in the clinical trials. The committee concluded that this approach was in line with their original request and that the revised analysis was appropriate.\n\nIn response to consultation, the company highlighted that using the baseline exacerbation rate seen in the trials was likely to be conservative. It highlighted several UK studies that showed severe asthma patients attending specialised centres have a higher level of exacerbations than in their revised model. In response to the committee's previous concern around whether the higher rate of 4.85\xa0exacerbations would apply to people with severe eosinophilic asthma, the company reported new evidence showing that patients with severe eosinophilic asthma had roughly similar exacerbation rates to patients with non-eosinophilic asthma (although it acknowledged that the results lacked statistical significance). The company further explored this expected higher rate in a scenario analysis. This was based on the approach suggested by the evidence review group (ERG) in their previous report, in which the observed rate of exacerbation in the clinical trial (2.68) was assumed to apply for the duration of the trial (that is 1\xa0year) and was then assumed to increase linearly over the following 9\xa0years until the exacerbation rate of the 'real world' data (that is 4.85\xa0exacerbations per year) was reached at year\xa010. The committee noted the company's evidence supporting higher exacerbation rates than seen in the clinical trials, but concluded that the most robust estimate of relative effectiveness was derived from the exacerbation rates shown in the clinical trials, and that this was the best available data for decision-making.\n\n## Duration of treatment\n\nThe committee discussed the duration of treatment with reslizumab assumed by the company in its model. The committee noted the company's algorithm that calculated the expected response at the end of the year based on an early response at 16\xa0weeks. The clinical experts stated that patients would not routinely be assessed for response to reslizumab at 16\xa0weeks because this is too early to assess the effect on exacerbations, and other measures would not be reliable enough. A more appropriate reassessment period would be 6\xa0months, followed by annual reassessments. The clinical experts stated that if patients continued to benefit from treatment, they would remain on reslizumab indefinitely. In response to consultation the company showed that there is minimal difference in cost effectiveness for reassessment at 16\xa0weeks, 6\xa0months or 52\xa0weeks. The committee also noted other consultation comments that patients on other asthma drugs are reassessed at 16\xa0weeks and therefore it would be helpful to use this same reassessment time point for reslizumab. However, the committee noted a response to the second consultation that suggested 16\xa0weeks was not appropriate for reslizumab and perhaps, given that reslizumab has the same mechanism of action as mepolizumab, a reassessment at 12\xa0months would be more appropriate. The committee heard from the company that no rule for stopping treatment with reslizumab was incorporated in the economic model. But the company clarified that a proportion of patients were modelled to stop treatment at 16\xa0weeks because of early response, and at 52\xa0weeks for lack of clinical response, and that the summary of product characteristics for reslizumab says treatment should be reassessed at 12\xa0months. The committee therefore concluded that reassessment at 12\xa0months was the most appropriate.\n\n## Administration costs and drug wastage\n\nThe committee considered the administration costs used by the company in its model. The committee noted that in its response to the first consultation, the company updated the administration costs to reflect clinical practice. The committee concluded that the company had included more appropriate administration costs for reslizumab in its revised model.\n\nThe committee noted that reslizumab has a marketing authorisation at a dose of 3\xa0mg/kg given intravenously every 4\xa0weeks, using a 100‑mg vial and a 25‑mg vial. It was aware that the company had submitted a change in the summary of product characteristics to incorporate vial-based dosing by bodyweight, which had been accepted. The committee heard from the company that vial-based dosing would simplify the dose determination process and reduce preparation time, minimise wastage and reduce the total cost of treatment. This is because patients in each dosing group will have a dose slightly lower than the 3\xa0mg/kg weight-based dosing. The company further highlighted that clinical response and efficacy would be maintained compared with weight-based dosing. The ERG considered this to be a reasonable approach and the committee concluded that vial-based dosing was appropriate.\n\n## Utility values\n\nThe committee discussed the estimates of utility in the model. The ERG's view was that the company's original base case should have used values mapped from AQLQ to EQ‑5D, because the evidence came from the trials. In response to the first consultation, the company's revised base case used the ERG's preferred utility values. In response to the second consultation, the company updated the mean utility values for the severe exacerbation health state. Post-hoc analyses from the clinical trials showed that patients with severe eosinophilic asthma, with 3\xa0or more exacerbations in the previous year, had a lower mean duration for a severe exacerbation in the reslizumab arm compared with the placebo arm. The committee noted that based on this information, the company changed the utility value of 0.51 for both reslizumab and best supportive care for the duration of the full model cycle (4\xa0weeks) in the severe exacerbation state to 0.54 for reslizumab and 0.50 for best supportive care. The ERG highlighted the uncertainty in these utility value estimates because of the lack of robust health-related quality-of-life data, but considered the calculation to be appropriate. It further noted that the revised utility values had only a minor effect on the cost effectiveness. The committee therefore accepted the revised utility value estimates for severe exacerbations.\n\n## Incremental cost-effectiveness results\n\nThe company presented its revised base case, in response to consultation, taking into account the revised patient access scheme discount applied to reslizumab compared with best standard care. The company's base-case deterministic incremental cost-effectiveness ratio (ICER) for people with 3\xa0or more exacerbations in the previous 12\xa0months is £29,870 per quality-adjusted life year (QALY) gained and the probabilistic ICER for people with 3\xa0or more exacerbations in the previous 12\xa0months is £27,509 per QALY gained. The committee again noted comments from consultees which highlighted the need to see the oral corticosteroid sparing effect of reslizumab being captured in the economic model. It was aware that there are limited data supporting the potential benefits of interleukin‑5 inhibitors in reducing oral corticosteroids. The committee concluded that, had the potential benefits of oral corticosteroid sparing been included in the economic analysis, the most plausible ICER for reslizumab could be slightly lower and any future data on this would be welcomed. The committee agreed that reslizumab could be considered a cost-effective use of NHS resources and concluded that reslizumab, as an add-on therapy, could be recommended as an option for treating severe eosinophilic asthma that is inadequately controlled despite maintenance therapy with high-dose inhaled corticosteroids, only if the blood eosinophil count has been 400\xa0cells per microlitre or more and the person has had 3\xa0or more asthma exacerbations in the previous 12\xa0months.\n\n# Pharmaceutical Price Regulation Scheme\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view in this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Innovation\n\nThe committee heard from stakeholders that reslizumab is innovative in its potential to make a significant and substantial effect on health-related benefits. The committee heard from the clinical experts that there are few treatments for severe eosinophilic asthma that have the potential to reduce corticosteroid use. It noted that it had not seen any evidence on preventing or delaying the use of maintenance oral corticosteroids but heard from the clinicians that this is an important aim of treatment with reslizumab. The committee agreed that some benefits related to avoiding the significant adverse effects of oral corticosteroid use had not been fully captured in the QALY calculations. The committee also considered that there were benefits to carers, which may not have been captured in the QALY calculation. The committee therefore agreed that reslizumab could be considered innovative.\n\n# Summary of appraisal committee's key conclusions\n\nTA479\n\nAppraisal title: Reslizumab for treating severe eosinophilic asthma\n\nSection\n\nKey conclusion\n\nReslizumab, as an add-on therapy, is recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if:\n\nthe blood eosinophil count has been recorded as 400\xa0cells per microlitre or more\n\nthe person has had 3\xa0or more severe asthma exacerbations needing systemic corticosteroids in the past 12\xa0months and\n\nthe company provides reslizumab with the discount agreed in the patient access scheme.\n\nAt 12 months:\n\nstop reslizumab if the asthma has not responded adequately or\n\ncontinue reslizumab if the asthma has responded adequately and assess response each year.\n\nCombining all the amendments including no adjustment for clinical rate of exacerbations, updated utility values, vial-based dosing and enhanced patient access scheme, the resulting incremental cost-effectiveness ratio (ICER) is £29,870 per quality-adjusted life year (QALY) gained for people with 3\xa0or more exacerbations in the previous year. The committee concluded that, had the potential benefits of oral corticosteroid sparing been included in the economic analysis, the most plausible ICER for reslizumab could be slightly lower and any future data on this would be very much welcomed.\n\n, 1.2, 4.18\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee understood that people with severe eosinophilic asthma on optimised treatment described in the high-dose inhaled therapies (previously step\xa04) or continuous and frequent use of oral corticosteroids (previously step\xa05) stages of the guidelines would be considered eligible for treatment with reslizumab.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that, compared with placebo, reslizumab is effective in reducing the rate of clinically significant exacerbations.\n\nThe committee heard from stakeholders that reslizumab is innovative in its potential to make a significant and substantial effect on health-related benefits. It also heard from the clinical experts that there are few treatments for severe eosinophilic asthma that have the potential to reduce corticosteroid use.\n\n, 4.20\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that treatment with reslizumab may be considered for people who are not taking maintenance oral corticosteroids, but that it would be most beneficial for people who have multiple exacerbations despite maintenance oral corticosteroid use.\n\n\n\nAdverse reactions\n\nThe most common adverse reaction is increased blood creatine phosphokinase, which is transient and asymptomatic.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee noted that there is limited data on the effectiveness of reslizumab in people who are on maintenance corticosteroids, because only 19% and 12% of people respectively in study\xa03082 and study\xa03083 fulfilled this criterion. The committee concluded that treatment with reslizumab may be considered for people who are not taking maintenance oral corticosteroids, but that it would be most beneficial for people who have multiple exacerbations despite maintenance oral corticosteroid use.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that study\xa03082 and study\xa03083 are relevant to the UK but that, in clinical practice, patients considered for reslizumab may have lower eosinophil counts than in the trials and a higher percentage will be on oral corticosteroids.\n\n\n\nUncertainties generated by the evidence\n\nThe committee heard from the clinical experts that they would particularly like to have this treatment available for patients having maintenance oral corticosteroids who have 3\xa0or more exacerbations per year. The committee also heard that the number of exacerbations in 1\xa0year is not necessarily indicative of future exacerbation rates, and that event rates vary in patients from year to year. It considered that this is a limitation of the trials, which looked at only 1\xa0year in what is a variable and lifelong condition. However, the committee noted a comment from a consultee in response to the second consultation that previous exacerbations are a strong predictor of subsequent exacerbations.\n\nThe committee concluded that the results from the company's indirect comparison of reslizumab with omalizumab were highly uncertain and not suitable for decision-making. The committee therefore did not consider this comparison further.\n\n, 4.9\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee concluded that patients with more exacerbations have a higher clinical need.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that, compared with placebo, reslizumab is effective in reducing the rate of clinically significant exacerbations.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee noted that the company had presented cost-effectiveness analyses comparing reslizumab with omalizumab but that the comparison with omalizumab is highly uncertain and not suitable for decision-making. The committee concluded that it would only consider the company's analysis for reslizumab compared with best standard care using the results from study\xa03082 and study\xa03083.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nIn response to the second appraisal document, and in line with the committee's preference, the company provided a revised base-case analysis that did not include an upward adjustment in the exacerbation rate of the standard care arm. Transition probabilities used in the model submitted in response to the first appraisal document, but without the placebo adjustment, were incorporated in the revised base case. Based on these updated transition probabilities the model used a mean annual exacerbation rate of 2.68 for standard care (instead of the previous value of 4.85), which the committee accepted was slightly lower than the mean rate of exacerbation of 2.73 reported in the placebo arms in the clinical trials. The committee concluded that this approach was in line with their original request and that the revised analyses was appropriate.\n\nThe company stated, in its response to consultation, that using the baseline exacerbation rate seen in the trials was likely to be conservative, and it highlighted several UK studies that showed patients with severe asthma were attending specialised centres. The committee noted the evidence supplied by the company in support of higher exacerbation rates than seen in the clinical trials, but concluded that the most robust estimate of relative effectiveness was derived from the exacerbation rates shown in the properly conducted clinical trials, and that this was the best available data for decision-making.\n\n, 4.13\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that based on information from post-hoc analyses, the company changed the utility value of 0.51 for both reslizumab and best supportive care for duration of the full model cycle (4\xa0weeks) in the severe exacerbation state to utility values of 0.54 for reslizumab and 0.50 for the best supportive care arm. Because the revision of the utility values for severe exacerbations has only a minor effect on the cost effectiveness, the committee accepted the additional updated utility value estimates for severe exacerbations.\n\nIt was aware that the model did not incorporate stopping or reducing the dose of oral corticosteroids, because the dose had been kept constant in the trials. The committee concluded that because more patients in UK clinical practice have maintenance oral corticosteroids than those in the trials, it would have liked to have seen some exploratory analysis around this issue because this is a potential benefit of reslizumab.\n\n, 4.11\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nFor the specific group of people with more than 3\xa0exacerbations in the previous 12\xa0months, the ICER was in the range considered to be a cost-effective use of NHS resources.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe calculation and choice of exacerbation transition probabilities were the key drivers of cost effectiveness for reslizumab compared with best supportive care.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nBy combining all the amendments including no adjustment for clinical rate of exacerbations, updated utility values, vial-based dosing and enhanced patient access scheme, the resulting ICER is £29,870 per QALY gained for people with 3\xa0or more exacerbations in the previous year. The committee concluded that, had the potential benefits of oral corticosteroid sparing been included in the economic analysis, the most plausible ICER for reslizumab could be slightly lower and any future data on this would be very much welcomed. The committee agreed that reslizumab could be considered a cost-effective use of NHS resources. It concluded that reslizumab, as an add-on therapy, could be recommended as an option for treating severe eosinophilic asthma inadequately controlled despite maintenance therapy with high-dose inhaled corticosteroids, only if the blood eosinophil count has been recorded as 400\xa0cells per microlitre or more and the person has had 3\xa0or more asthma exacerbations in the previous 12\xa0months.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nA patient access scheme discount was applied to the ICERs presented by the company and the evidence review group (ERG) for reslizumab compared with best standard care.\n\n\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified.\n\n–"}
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https://www.nice.org.uk/guidance/ta479
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Evidence-based recommendations on reslizumab (Cinqaero) for treating severe eosinophilic asthma in adults.
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311a259295f0e63ef232da2da1c7942aa3d829ff
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nice
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Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease
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Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease
Evidence-based recommendations on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure in people with motor neurone disease. This involves implanting electrodes into the diaphragm to make it contract. This gradually strengthens the diaphragm and may eventually help the person to breathe without a ventilator.
# Recommendations
Current evidence on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease suggests that there are serious long-term safety concerns. Evidence on efficacy is limited and therefore, this procedure should not be used to treat this condition.# Indications and current treatments
Motor neurone disease is a neurodegenerative condition affecting the brain and spinal cord. The most common type of the disease is amyotrophic lateral sclerosis. Motor neurone disease is characterised by the degeneration of primarily motor neurones, leading to muscle weakness, limb weakness, problems with speech, swallowing and breathing, which ultimately leads to respiratory failure and death.
Current standard care for managing chronic respiratory failure in patients with motor neurone disease includes non-invasive forms of ventilation support (such as Bi-level positive airway pressure ). In advanced stages of respiratory failure mechanical ventilation is done through a permanent tracheostomy.# The procedure
The aim of intramuscular diaphragm stimulation is to make the diaphragm contract, strengthening it and allowing full or partial weaning from mechanical ventilation. This procedure needs intact phrenic nerve function, and avoids the need to access the phrenic nerve through the neck or thorax, as well as reducing the risk of phrenic nerve damage.
The procedure is done laparoscopically with the patient under general anaesthesia. A special probe is used to identify areas of the diaphragm where minimal electrical stimulation causes maximal diaphragm contraction (known as the 'motor points'). Two intramuscular electrodes are implanted on the abdominal surface of each hemi-diaphragm at the motor points. The electrode leads are tunnelled subcutaneously to an exit site in the chest where they are connected to an external battery-powered pulse generator. A reference electrode (anode) is also implanted and the leads tunnelled with the other electrodes. Intraoperative stimulation and voltage calibration tests are carried out to confirm adequate contraction of the diaphragm. After implantation the patient has a diaphragm conditioning programme, which involves progressive use of the system for increasing periods of time with gradual weaning from the ventilator.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a multicentre randomised controlled trial (RCT) of 74 patients with respiratory failure caused by amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) plus diaphragm pacing (n=37) was compared with NIV alone (n=37). Overall survival (defined as the time from randomisation to death from any cause) was statistically significantly shorter in the NIV plus pacing group than in the NIV-alone group (median 11.0 months; 95% confidence interval 8.3 to 13.6, compared with 22.5 months; 95% CI 13.6 to not reached, adjusted hazard ratio 2.27; 95% CI 1.22 to 4.25, p=0.009). Tracheostomy-free survival (defined as the time to death or tracheostomy) was also statistically significantly shorter in the NIV plus pacing group than in the NIV-alone group (median 11.0 months; 95% CI 8.3 to 13.6, compared with 22.5 months; 95% CI 13.6 to not reached, adjusted hazard ratio 2.42; 95% CI 1.28 to 4.59, p=0.007). Median survival from symptom onset was 28 months (95% CI 22 to 45) for NIV plus pacing patients and 45 months (95% CI 32 to not reached) for those having NIV alone.
In another multicentre triple-blind RCT in 74 patients with probable or definite ALS, active stimulation (n=37) was compared with sham stimulation (n=37). The NIV-free survival in the intention-to-treat population was statistically significantly shorter in the active stimulation group than in the sham stimulation group (median 6.0 months; 95% CI 3.6 to 8.7, compared with 8.8 months; 95% CI 4.2 to not reached, adjusted hazard ratio 1.96; 95% CI 1.08 to 3.56, p=0.02). The cumulative incidence of NIV did not differ between the 2 groups (since randomisation: median 6; 95% CI 5.1 to 12, compared with 8.8; 95% CI 4.7 to not reached, p=0.42; since symptom onset: median 40; 95% CI 33.6 to 61.7, compared with 34.1; 95% CI 26.4 to not reached, p=0.81). A statistically significant difference in overall tracheostomy-free survival in favour of the sham survival group was seen in the final analysis (49% of patients died in the active stimulation group compared with 19% in the sham stimulation group; adjusted hazard ratio 3.14; 95% CI 1.31 to 7.53). Overall survival from randomisation was statistically significantly shorter in the active stimulation group than in the sham stimulation group (median 15.6 months; 95% CI 9 to 27, compared with not reached , p=0.007). This was also true for overall survival from symptom onset (median 51 months; 95% CI 39 to 74.1, compared with not reached , p=0.03).
In the multicentre RCT of 74 patients with respiratory failure caused by ALS, there were no statistically significant differences between the NIV plus pacing group and the NIV-alone group in patient or carer pre-planned quality-of-life measures. These included the health questionnaires SF-36 (physical health score p=0.78, mental health score p=0.11), Sleep Apnoea Quality of Life (SAQLI, p=0.11) and Caregiver Burden Inventory (CBI, p=0.55). The patient health utility (measured using the EQ-5D-3L) was slightly lower in the NIV plus pacing group than in the NIV-alone group (p=0.056), and the differences were statistically significant when a score of 0 was assigned to the EQ-5D-3L following death. Differences between groups were modest at any individual time point (at 12 months the mean difference was −0.12; 95% CI −0.24 to −0.00, p=0.056), but longitudinal analysis demonstrated statistically and clinically significant differences on all patient EQ-5D-3L questionnaires (mean difference −0.14; 95% CI −0.24 to 0.04, p=0.001).
The specialist advisers listed key efficacy outcomes as reduction in dependency on external mechanical ventilation, survival and quality of life.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a multicentre randomised controlled trial (RCT) of 74 patients with respiratory failure caused by amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) plus diaphragm pacing (n=37) was compared with NIV alone (n=37). In the NIV plus pacing group 76% (26/37) of patients died and in the NIV-alone group 51% (19/37) of patients died. The causes of death were similar across the groups (mainly respiratory failure, chest infection, ALS and hypothermia). In another multicentre triple-blind RCT in 74 patients with probable or definite ALS, active stimulation (n=37) was compared with sham stimulation (n=37). More patients died in the active stimulation group than in the sham stimulation group (49% compared with 19% ) as a result of chest infection, acute respiratory failure and terminal respiratory insufficiency. Six patients died before NIV in the active stimulation group because of acute respiratory failure in 5 and sudden cardiac death in 1. No deaths were related to treatment.
There were more adverse events reported in the NIV plus pacing group than in the NIV-alone group (162 events in 78% of patients compared with 81 events in 62% of patients) in the RCT of 74 patients with respiratory failure caused by ALS. More patients had serious adverse events in the NIV plus pacing group than in the NIV-alone group (73% compared with 51% ; 46 events compared with 31 events). Respiratory events were the most common in both groups (68% compared with 38% ) followed by gastrointestinal events (27% compared with 24% ), symptoms of motor neurone disease (22% compared with 8% ), gastrostomy (percutaneous endoscopic or per-oral image-guided insertion; 14% compared with 24% ), genitourinary events (8% in each group), cardiovascular events (11% compared with 5% ) and dermatological problems (8% compared with 11% ).
Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure needing mechanical ventilation, venous thromboembolism and gastrostomy tube placement) were reported in 65% of the active stimulation group and in 59% of the sham stimulation group in the triple-blind RCT of 74 patients. Some patients had more than 1 adverse event. Other serious adverse events reported include dyspnoea (3 patients), loss of walking ability (3 patients), oesophagitis (1 patient), admission to hospital for any cause (3 patients), accidental removal of gastrostomy tube (1 patient), and reopening of the laparoscopy insertion point needing repair (1 patient). Capnothorax was reported in 13% (5/38) of patients with ALS in a case series of 88 patients. Capnothorax was managed successfully by aspiration, drainage or observation.
Suture granuloma causing infection at the superficial wire connection site (treated by externalising the electrodes) was reported in 1 patient with ALS in the case series of 88 patients. Infection at the stimulation cable entry point was noted in 22% (8/37) of patients in the active group (3 patients needed antibiotics) and 19% (7/37) of patients in the control group (5 patients needed antibiotics) in the triple-blind RCT of 74 patients. Respiratory infections (needing antibiotics) were reported in 5 patients in a case series of 16 ALS patients with respiratory insufficiency treated by diaphragm pacing. Superficial wound infection (treated with antibiotics) was reported in 1 patient in the same study. Urinary infection (needing admission to hospital) and severe pulmonary infection were reported in 1 patient each in a case series of 11 patients.
External electrode repairs were needed in 7 patients in the case series of 16 patients with ALS. Wire failure was reported in 14% (5/37) of patients in the NIV plus diaphragm pacing group in the RCT of 74 patients with respiratory failure caused by ALS.
Pain (needing analgesics) was commonly reported in the active stimulation and sham stimulation groups (92% compared with 89% ) in the triple-blind RCT of 74 patients. Pain needing a reduction in the intensity of diaphragm pacing was noted on day 2 in 54% (20/37) of patients in the active stimulation group and none in the sham stimulation group in the same study.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: excess mortality. They considered that the following were theoretical adverse events: decompensated respiratory failure, breathlessness related to diaphragm pacing and atrophy and progression of diaphragm weakness.# Further information
For related NICE guidance, see the NICE website.
Patient commentary was sought but none was received.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2683-1
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{'Recommendations': 'Current evidence on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease suggests that there are serious long-term safety concerns. Evidence on efficacy is limited and therefore, this procedure should not be used to treat this condition.', 'Indications and current treatments': 'Motor neurone disease is a neurodegenerative condition affecting the brain and spinal cord. The most common type of the disease is amyotrophic lateral sclerosis. Motor neurone disease is characterised by the degeneration of primarily motor neurones, leading to muscle weakness, limb weakness, problems with speech, swallowing and breathing, which ultimately leads to respiratory failure and death.\n\nCurrent standard care for managing chronic respiratory failure in patients with motor neurone disease includes non-invasive forms of ventilation support (such as Bi-level positive airway pressure [BiPAP]). In advanced stages of respiratory failure mechanical ventilation is done through a permanent tracheostomy.', 'The procedure': "The aim of intramuscular diaphragm stimulation is to make the diaphragm contract, strengthening it and allowing full or partial weaning from mechanical ventilation. This procedure needs intact phrenic nerve function, and avoids the need to access the phrenic nerve through the neck or thorax, as well as reducing the risk of phrenic nerve damage.\n\nThe procedure is done laparoscopically with the patient under general anaesthesia. A special probe is used to identify areas of the diaphragm where minimal electrical stimulation causes maximal diaphragm contraction (known as the 'motor points'). Two intramuscular electrodes are implanted on the abdominal surface of each hemi-diaphragm at the motor points. The electrode leads are tunnelled subcutaneously to an exit site in the chest where they are connected to an external battery-powered pulse generator. A reference electrode (anode) is also implanted and the leads tunnelled with the other electrodes. Intraoperative stimulation and voltage calibration tests are carried out to confirm adequate contraction of the diaphragm. After implantation the patient has a diaphragm conditioning programme, which involves progressive use of the system for increasing periods of time with gradual weaning from the ventilator.", 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a multicentre randomised controlled trial (RCT) of 74\xa0patients with respiratory failure caused by amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) plus diaphragm pacing (n=37) was compared with NIV alone (n=37). Overall survival (defined as the time from randomisation to death from any cause) was statistically significantly shorter in the NIV plus pacing group than in the NIV-alone group (median 11.0\xa0months; 95%\xa0confidence interval [CI] 8.3 to 13.6, compared with 22.5\xa0months; 95%\xa0CI 13.6 to not reached, adjusted hazard ratio 2.27; 95%\xa0CI 1.22 to 4.25, p=0.009). Tracheostomy-free survival (defined as the time to death or tracheostomy) was also statistically significantly shorter in the NIV plus pacing group than in the NIV-alone group (median 11.0\xa0months; 95%\xa0CI 8.3 to 13.6, compared with 22.5\xa0months; 95%\xa0CI 13.6 to not reached, adjusted hazard ratio 2.42; 95%\xa0CI 1.28 to 4.59, p=0.007). Median survival from symptom onset was 28\xa0months (95%\xa0CI 22 to 45) for NIV plus pacing patients and 45\xa0months (95%\xa0CI 32 to not reached) for those having NIV alone.\n\nIn another multicentre triple-blind RCT in 74\xa0patients with probable or definite ALS, active stimulation (n=37) was compared with sham stimulation (n=37). The NIV-free survival in the intention-to-treat population was statistically significantly shorter in the active stimulation group than in the sham stimulation group (median 6.0\xa0months; 95%\xa0CI 3.6 to 8.7, compared with 8.8\xa0months; 95%\xa0CI 4.2 to not reached, adjusted hazard ratio 1.96; 95%\xa0CI 1.08 to 3.56, p=0.02). The cumulative incidence of NIV did not differ between the 2\xa0groups (since randomisation: median 6; 95%\xa0CI 5.1 to 12, compared with 8.8; 95%\xa0CI 4.7 to not reached, p=0.42; since symptom onset: median 40; 95%\xa0CI 33.6 to 61.7, compared with 34.1; 95%\xa0CI 26.4 to not reached, p=0.81). A statistically significant difference in overall tracheostomy-free survival in favour of the sham survival group was seen in the final analysis (49% [18/37] of patients died in the active stimulation group compared with 19% [7/37] in the sham stimulation group; adjusted hazard ratio 3.14; 95%\xa0CI 1.31 to 7.53). Overall survival from randomisation was statistically significantly shorter in the active stimulation group than in the sham stimulation group (median 15.6\xa0months; 95%\xa0CI 9 to 27, compared with not reached [more than 33], p=0.007). This was also true for overall survival from symptom onset (median 51\xa0months; 95%\xa0CI 39 to 74.1, compared with not reached [more than 133], p=0.03).\n\nIn the multicentre RCT of 74\xa0patients with respiratory failure caused by ALS, there were no statistically significant differences between the NIV plus pacing group and the NIV-alone group in patient or carer pre-planned quality-of-life measures. These included the health questionnaires SF-36 (physical health score p=0.78, mental health score p=0.11), Sleep Apnoea Quality of Life (SAQLI, p=0.11) and Caregiver Burden Inventory (CBI, p=0.55). The patient health utility (measured using the EQ-5D-3L) was slightly lower in the NIV plus pacing group than in the NIV-alone group (p=0.056), and the differences were statistically significant when a score of 0 was assigned to the EQ-5D-3L following death. Differences between groups were modest at any individual time point (at 12\xa0months the mean difference was −0.12; 95%\xa0CI −0.24 to −0.00, p=0.056), but longitudinal analysis demonstrated statistically and clinically significant differences on all patient EQ-5D-3L questionnaires (mean difference −0.14; 95%\xa0CI −0.24 to 0.04, p=0.001).\n\nThe specialist advisers listed key efficacy outcomes as reduction in dependency on external mechanical ventilation, survival and quality of life.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a multicentre randomised controlled trial (RCT) of 74\xa0patients with respiratory failure caused by amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) plus diaphragm pacing (n=37) was compared with NIV alone (n=37). In the NIV plus pacing group 76% (26/37) of patients died and in the NIV-alone group 51% (19/37) of patients died. The causes of death were similar across the groups (mainly respiratory failure, chest infection, ALS and hypothermia). In another multicentre triple-blind RCT in 74\xa0patients with probable or definite ALS, active stimulation (n=37) was compared with sham stimulation (n=37). More patients died in the active stimulation group than in the sham stimulation group (49% [18/37] compared with 19% [7/37]) as a result of chest infection, acute respiratory failure and terminal respiratory insufficiency. Six patients died before NIV in the active stimulation group because of acute respiratory failure in 5 and sudden cardiac death in 1. No deaths were related to treatment.\n\nThere were more adverse events reported in the NIV plus pacing group than in the NIV-alone group (162\xa0events [5.9\xa0events per person-year] in 78% [29/37] of patients compared with 81\xa0events [2.5\xa0events per person-year] in 62% [23/37] of patients) in the RCT of 74\xa0patients with respiratory failure caused by ALS. More patients had serious adverse events in the NIV plus pacing group than in the NIV-alone group (73% [27/37] compared with 51% [19/37]; 46\xa0events compared with 31\xa0events). Respiratory events were the most common in both groups (68% [25/37] compared with 38% [14/37]) followed by gastrointestinal events (27% [10/37] compared with 24% [9/37]), symptoms of motor neurone disease (22% [8/37] compared with 8% [3/37]), gastrostomy (percutaneous endoscopic or per-oral image-guided insertion; 14% [5/37] compared with 24% [9/37]), genitourinary events (8% [3/37] in each group), cardiovascular events (11% [4/37] compared with 5% [2/37]) and dermatological problems (8% [3/37] compared with 11% [4/37]).\n\nSerious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure needing mechanical ventilation, venous thromboembolism and gastrostomy tube placement) were reported in 65% [24/37] of the active stimulation group and in 59% [22/37] of the sham stimulation group in the triple-blind RCT of 74\xa0patients. Some patients had more than 1\xa0adverse event. Other serious adverse events reported include dyspnoea (3\xa0patients), loss of walking ability (3\xa0patients), oesophagitis (1\xa0patient), admission to hospital for any cause (3\xa0patients), accidental removal of gastrostomy tube (1\xa0patient), and reopening of the laparoscopy insertion point needing repair (1\xa0patient). Capnothorax was reported in 13% (5/38) of patients with ALS in a case series of 88\xa0patients. Capnothorax was managed successfully by aspiration, drainage or observation.\n\nSuture granuloma causing infection at the superficial wire connection site (treated by externalising the electrodes) was reported in 1\xa0patient with ALS in the case series of 88\xa0patients. Infection at the stimulation cable entry point was noted in 22% (8/37) of patients in the active group (3\xa0patients needed antibiotics) and 19% (7/37) of patients in the control group (5\xa0patients needed antibiotics) in the triple-blind RCT of 74\xa0patients. Respiratory infections (needing antibiotics) were reported in 5\xa0patients in a case series of 16\xa0ALS patients with respiratory insufficiency treated by diaphragm pacing. Superficial wound infection (treated with antibiotics) was reported in 1\xa0patient in the same study. Urinary infection (needing admission to hospital) and severe pulmonary infection were reported in 1\xa0patient each in a case series of 11\xa0patients.\n\nExternal electrode repairs were needed in 7\xa0patients in the case series of 16\xa0patients with ALS. Wire failure was reported in 14% (5/37) of patients in the NIV plus diaphragm pacing group in the RCT of 74\xa0patients with respiratory failure caused by ALS.\n\nPain (needing analgesics) was commonly reported in the active stimulation and sham stimulation groups (92% [34/37] compared with 89% [33/37]) in the triple-blind RCT of 74\xa0patients. Pain needing a reduction in the intensity of diaphragm pacing was noted on day\xa02 in 54% (20/37) of patients in the active stimulation group and none in the sham stimulation group in the same study.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: excess mortality. They considered that the following were theoretical adverse events: decompensated respiratory failure, breathlessness related to diaphragm pacing and atrophy and progression of diaphragm weakness.', 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2683-1'}
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https://www.nice.org.uk/guidance/ipg593
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Evidence-based recommendations on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure in people with motor neurone disease. This involves implanting electrodes into the diaphragm to make it contract. This gradually strengthens the diaphragm and may eventually help the person to breathe without a ventilator.
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9c8e9d607bca9a2f076d0d9783cfd3420f9f5967
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nice
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Faltering growth: recognition and management of faltering growth in children
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Faltering growth: recognition and management of faltering growth in children
This guideline covers recognition, assessment and monitoring of faltering growth in infants and children. It includes a definition of growth thresholds for concern and identifying the risk factors for, and possible causes of, faltering growth. It also covers interventions, when to refer, service design, and information and support.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# .Weight loss in the early days of life
Some weight loss in the first days after birth (referred to in this guideline as the early days of life) is normal and usually relates to body fluid adjustments. Sometimes there may be reason for concern about weight loss in the early days of life, which may need assessment and intervention. For this reason weight loss in the early days of life is dealt with separately in this guideline from concerns about inadequate weight gain in older infants and children, which is often related to nutritional intake.
Be aware that:
it is common for infants to lose some weight during the early days of life
this weight loss usually stops after about 3 or 4 days of life
most infants have returned to their birth weight by 3 weeks of age.
If infants in the early days of life lose more than 10% of their birth weight:
perform a clinical assessment, looking for evidence of dehydration, or of an illness or disorder that might account for the weight loss
take a detailed history to assess feeding (see NICE's guideline on postnatal care up to 8 weeks after birth)
consider direct observation of feeding
ensure observation of feeding is done by a person with appropriate training and expertise (for example, in relation to breastfeeding and bottle feeding)
perform further investigations only if they are indicated based on the clinical assessment.
Provide feeding support (see recommendations in NICE's guideline on postnatal care up to 8 weeks after birth) if there is concern about weight loss in infants in the early days of life, for example if they have lost more than 10% of their birth weight.
If infants lose more than 10% of their birth weight in the early days of life, or they have not returned to their birth weight by 3 weeks of age, consider:
referral to paediatric services if there is evidence of illness, marked weight loss, or failure to respond to feeding support (see recommendations in NICE's guideline on postnatal care up to 8 weeks after birth)
when to reassess if not referred to paediatric services.
If an infant loses more than 10% of their birth weight in the early days of life, measure their weight again at appropriate intervals depending on the level of concern, but no more frequently than daily.
Be aware that supplementary feeding with infant formula in a breastfed infant may help with weight gain, but often results in cessation of breastfeeding.
If supplementation with an infant formula is given to a breastfed infant:
support the mother to continue breastfeeding
advise expressing breast milk to promote milk supply and
feed the infant with any available breast milk before giving any infant formula.
# Faltering growth after the early days of life
## Thresholds
Consider using the following as thresholds for concern about faltering growth in infants and children (a centile space being the space between adjacent centile lines on the UK WHO growth charts):
a fall across 1 or more weight centile spaces, if birthweight was below the 9th centile
a fall across 2 or more weight centile spaces, if birthweight was between the 9th and 91st centiles
a fall across 3 or more weight centile spaces, if birthweight was above the 91st centile
when current weight is below the 2nd centile for age, whatever the birthweight.
## Measurement of weight and height or length
If there is concern about faltering growth (for example, based on the criteria in recommendation 1.2.1):
weigh the infant or child
measure their length (from birth to 2 years old) or height (if aged over 2 years)
plot the above measurements and available previous measurements on the UK WHO growth charts to assess weight change and linear growth over time.
If there are concerns about an infant's length or a child's length or height, if possible obtain the biological parents' heights and work out the mid-parental height centile. If the child's length or height centile is below the range predicted from parental heights (more than 2 centile spaces below the mid-parental centile) be aware this could suggest undernutrition or a primary growth disorder.
If there is concern about faltering growth or linear growth in a child over 2 years of age, determine the BMI centile:
using the UK WHO centiles and the accompanying BMI centile 'look‑up chart' or
by calculating the BMI (weight in kg/height in metres squared) and plotting this on the BMI centile chart.Then:
if the BMI is below the 2nd centile, be aware this may reflect either undernutrition or a small build
if the BMI is below the 0.4th centile, this suggests probable undernutrition that needs assessment and intervention.
Record all growth measurements in the parent- or carer-held Personal Child Health Record.
## Assessment
If there is concern about faltering growth:
perform a clinical, developmental and social assessment
take a detailed feeding or eating history
consider direct observation of feeding or meal times
consider investigating for:
urinary tract infection (follow the principles of assessment in NICE's guideline on urinary tract infection in under 16s)
coeliac disease, if the diet has included gluten-containing foods (follow the principles of assessment in NICE's guideline on coeliac disease)
perform further investigations only if they are indicated based on the clinical assessment.
If observation of eating or feeding is needed because of concern about faltering growth, ensure this is done by a person with appropriate training and expertise.
Be aware that the following factors may be associated with faltering growth:
preterm birth
neurodevelopmental concerns
maternal postnatal depression or anxiety.
Recognise that in faltering growth:
a range of factors may contribute to the problem, and it may not be possible to identify a clear cause
there may be difficulties in the interaction between an infant or child and the parents or carers that may contribute to the problem, but this may not be the primary cause.
Based on the feeding history and any direct observation of feeding, consider whether any of the following are contributing to faltering growth in milk-fed infants:
ineffective suckling in breastfed infants
ineffective bottle feeding
feeding patterns or routines being used
the feeding environment
feeding aversion
parent/carer–infant interactions
how parents or carers respond to the infant's feeding cues
physical disorders that affect feeding.
Based on the feeding history and any direct observation of mealtimes, consider whether any of the following are contributing to faltering growth:
mealtime arrangements and practices
types of foods offered
food aversion and avoidance
parent/carer–child interactions, for example responding to the child's mealtime cues
appetite, for example a lack of interest in eating
physical disorders that affect feeding.
Consider asking the parents or carers of infants and children with faltering growth to keep a diary recording food intake (types and amounts) and mealtime issues (for example, settings, behaviour) to help inform management strategies and assess progress.
Be aware that investigations (other than those recommended in recommendation 1.2.6) are unlikely to reveal an underlying disorder in a child with faltering growth who appears well with no other clinical concerns.
If a child with faltering growth develops new clinical symptoms or signs after the initial assessment, reconsider whether investigations are needed.
## Interventions for faltering growth
Together with parents and carers, establish a management plan with specific goals for every infant or child where there are concerns about faltering growth. This plan could include:
assessments or investigations
interventions
clinical and growth monitoring
when reassessment to review progress and achievement of growth goals should happen.
Provide feeding support (see recommendations in NICE's guideline on postnatal care up to 8 weeks after birth) if there is concern about faltering growth in the first weeks of life. Consider whether such feeding support might be helpful in older milk-fed infants, including those having complementary solid foods.
Be aware that while supplementary feeding with infant formula may increase weight gain in a breastfed infant if there is concern about faltering growth, it often results in cessation of breastfeeding.
If supplementation with an infant formula is given to a breastfed infant because of concern about faltering growth after the early days of life:
support the mother to continue breastfeeding
advise expressing breast milk to promote milk supply and
feed the infant with any available breast milk before giving any infant formula.
When there are concerns about faltering growth, discuss the following, as individually appropriate, with the infant's or child's parents or carers:
encouraging relaxed and enjoyable feeding and mealtimes
eating together as a family or with other children
encouraging young children to feed themselves
allowing young children to be 'messy' with their food
making sure feeds and mealtimes are not too brief or too long
setting reasonable boundaries for mealtime behaviour while avoiding punitive approaches
avoiding coercive feeding
establishing regular eating schedules (for example 3 meals and 2 snacks in a day).
If necessary, based on the assessment, advise on food choices for infants and children that:
are appropriate to the child's developmental stage in terms of quantity, type and food texture
-ptimise energy and nutrient density.
In infants or children who need a further increase in the nutrient density of their diet beyond that achieved through advice on food choices, consider:
short-term dietary fortification using energy-dense foods
referral to a paediatric dietitian.
Advise the parents or carers of infants or children with faltering growth that drinking too many energy-dense drinks, including milk, can reduce a child's appetite for other foods.
Consider a trial of an oral liquid nutritional supplement for infants or children with continuing faltering growth despite other interventions (see recommendations 1.2.16 to 1.2.22).
Regularly reassess infants and children receiving an oral nutritional supplement for faltering growth to decide if it should be continued. Take into account:
weight change
linear growth
intake of other foods
tolerance
adherence
the views of parents or carers.
Only consider enteral tube feeding for infants and children with faltering growth when:
there are serious concerns about weight gain and
an appropriate specialist multidisciplinary assessment for possible causes and contributory factors has been completed and
-ther interventions have been tried without improvement.
If enteral tube feeding is to be used in an infant or child with faltering growth, make a plan with appropriate multidisciplinary involvement for:
the goals of the treatment (for example, reaching a specific weight target)
the strategy for its withdrawal once the goal is reached (for example, progressive reduction together with strategies to promote oral intake).
## Monitoring
If there are concerns about faltering growth (see recommendation 1.2.1), measure the weight at appropriate intervals taking account of factors such as age and the level of concern, but usually no more often than:
daily if less than 1 month old
weekly between 1–6 months old
fortnightly between 6–12 months
monthly from 1 year of age.
Monitor weight if there are concerns about faltering growth (see recommendation 1.2.1), but be aware that weighing children more frequently than is needed (see recommendation 1.2.27) may add to parental anxiety (for example, minor short-term changes may cause unnecessary concern).
Be aware that weight loss is unusual except in the early days of life, and may be a reason for increased concern and more frequent weighing than is recommended (see recommendation 1.2.27).
If there are concerns about faltering growth monitor length or height at intervals, but no more often than every 3 months.
## Referral
If an infant or child with faltering growth has any of the following discuss with, or refer to, an appropriate paediatric specialist care service:
symptoms or signs that may indicate an underlying disorder
a failure to respond to interventions delivered in a primary care setting
slow linear growth or unexplained short stature (see recommendation 1.2.3)
rapid weight loss or severe undernutrition
features that cause safeguarding concerns (see the NICE guideline on child maltreatment).
Do not admit infants or children with faltering growth to hospital unless they are acutely unwell or there is a specific indication requiring inpatient care, such as a plan to begin tube feeding (see recommendation 1.2.25).
# Organisation of care
Ensure there is a pathway of care for infants and children where there are concerns about faltering growth or weight loss in the early days of life that:
clearly sets out the roles of healthcare professionals in primary and secondary care settings
establishes and makes clear the process for referral to and coordination of specialist care in the pathway.
Provide community-based care for infants and children where there are faltering growth concerns or weight loss in the early days of life with a team (the 'primary care team') that includes, for example:
a midwife
a health visitor
a GP.
Ensure that the primary care team has access to the following healthcare professionals with expertise relevant to faltering growth:
infant feeding specialist
consultant paediatrician
paediatric dietitian
speech and language therapist with expertise in feeding and eating difficulties
clinical psychologist
-ccupational therapist.
Consider identifying a lead healthcare professional to coordinate care and to act as the first point of contact for parents of children with faltering growth, for example if several professionals are involved.
# Information and support
Recognise the emotional impact that concerns about faltering growth or weight loss in the early days can have on parents and carers and offer them information about available:
professional support
peer support.
Follow the principles in the NICE guidelines on patient experience in NHS services, babies, children and young people's experience of healthcare and shared decision making in relation to communication (including different formats and languages), information and shared decision making.
Provide information on faltering growth or weight loss in the early days of life, to parents or carers that is:
specific to them and their child
clearly explained and understandable to them
spoken and in writing.
If there is concern about faltering growth in an infant or child or weight loss in the early days of life, discuss with the parents or carers:
the reasons for the concern, and how the growth measurements are interpreted
any worries or issues they may have
any possible or likely causes or factors that may be contributing to the problem
the management plan (see recommendation 1.2.15).
# Terms used in this guideline
## Child
Pre-school children from 1 year of age.
## Food or feeding aversion
Behaviours sometimes observed in infants or children indicating a persistent unwillingness to eat. Such behaviours, depending upon age, might include signs of distress when presented with food, spitting of food or avoidance behaviour.
## Infant
A baby up to 1 year of age.
## Linear growth
This is the increase in length (under 2 years of age) or height (2 years or older) over time in infants and children.
## Oral liquid nutritional supplement
A high-energy liquid feed designed for enteral use, usually selected and prescribed after specialist advice from a paediatric dietitian.
## Undernutrition
This is what happens when nutrition is not sufficient. An infant or child with undernutrition may be abnormally thin, may weigh less than expected for their length or height, and if prolonged, undernutrition can lead to stunting (length or height less than expected for age).# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
The term 'faltering growth' (previously called 'failure to thrive') is widely used to refer to a slower rate of weight gain in childhood than expected for age and sex. The term faltering growth is preferred as periods of slow growth may represent temporary variation from the expected pattern and the word 'failure' may be seen as pejorative. Various definitions of faltering growth have been used in the past, meaning estimates of prevalence in the UK vary widely.
The World Health Organization (WHO) has produced growth standards, based on longitudinal studies of healthy breastfed infants. These standards, along with UK term and preterm infant growth data, have been incorporated into UK WHO growth charts for monitoring growth in UK children. A child's weight, length or height and head circumference can be plotted on these charts to provide a visual representation of growth over time. Epidemiological data suggest that healthy children usually progress relatively consistently along a growth centile.
Newborn infants normally lose weight in the early days of life. Persisting or large weight losses can cause concern in parents, carers and health professionals about ineffective establishment of feeding. In older children, faltering growth can occur when nutritional intake does not meet a child's specific energy requirements. Undernutrition presents as a relatively slow weight gain, demonstrated by downward movement across weight centiles on the growth chart.
Children with faltering growth may be identified by routine growth monitoring or by parental or health professional concern. Standard management is usually community based, with support and advice provided to increase energy intake and manage challenging feeding behaviour. Some children will be referred to paediatric dieticians or paediatricians for further assessment and management.
Certain health conditions predispose children to faltering growth (for example, cystic fibrosis or coeliac disease). Specific treatment for these conditions can improve or restore expected rates of weight gain. In children with no specific cause for faltering growth, simple interventions to increase nutritional intake may be effective in improving weight gain. Faltering growth in early childhood may be associated with persisting problems with appetite and feeding.
The cause of faltering growth in the absence of a specific underlying health condition is likely to be complex and multifactorial. In the past, child neglect or socioeconomic and educational disadvantage were often considered to be likely contributors. While neglected children may be undernourished, neglect is an uncommon explanation for faltering growth. Similarly, significant associations with socioeconomic or educational factors have not been demonstrated.
There is variation across the UK in care provided for infants, children and families where concerns are raised about early weight loss or faltering growth. There is cultural and socioeconomic variation in starting and continuing breastfeeding, the approach to introducing complementary solid food and choice of foods, feeding behaviour and parental acceptance of feeding support and advice.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# High energy liquid feed supplements
Do high energy liquid feed supplements improve growth in children with faltering growth?
## Why this is important
It seems logical to attempt to treat inadequate dietary intake with food of some kind, and high energy liquid dietary supplements appear to be effective when used in older adults. Although they are also widely promoted for use in children, little research on their efficacy has been done. Experimental research suggests that high energy liquid feed supplements may supress appetite and displace normal diet, and one case series found that when high energy liquid feed supplements were withdrawn appetite improved with no impact on weight. Further research is important to establish whether their effectiveness justifies their cost and the suppressant effect on appetite.
# Feeding interventions for the management of neonatal weight loss
What is the effectiveness of feeding interventions compared with usual care/advice for breastfed neonates (up to 28 days old) with weight loss of greater than 10%?
## Why this is important
Weight loss in breastfeeding infants in the first month of life can cause anxiety for parents and healthcare professionals. It can also incur costs to the NHS from admissions of the infant to hospital, with the potential for cessation of exclusive breastfeeding with its associated long-term health benefits.
Practice varies across the UK. Robust evidence about which feeding interventions improve outcomes could inform practice, potentially reducing unnecessary and costly interventions and supporting parent–infant relationships and physical and emotional health.
# Behavioural interventions
What is the effectiveness of behavioural interventions compared with usual care/advice for children with faltering growth?
## Why this is important
Health visitors provide behavioural interventions for faltering growth in community settings. This is carried out with the aim to optimise the Healthy Child Programme and provide support and build relationships with parents and children. Behavioural interventions are time consuming and therefore incur costs. Evidence for the specific components of behavioural interventions are scarce and if found to be effective they could have short-term and longer-term preventative results. A standardised approach to behavioural interventions could both improve clinical practice and save costs.
# Frequency of monitoring
How frequently should children be measured to identify faltering growth?
## Why this is important
It is important to know whether a particular frequency or schedule of measurement of infants and children would identify faltering growth at an earlier age and contribute to an earlier catch‑up in weight. Present practice suggests routine measurements be taken at the time of routine childhood immunisation. Is this schedule of measurement the most likely to confirm whether an infant or child has faltering growth as early as possible? It is unclear whether the present pattern of measurement is most effective for children for whom there are concerns about their growth. If an altered schedule of routine measurement was found to be identifying faltering growth at an earlier age and contribute to an early catch‑up in weight, it would be necessary to consider how best to deliver such a schedule to the entire population of infants and children.
# Support needs of parents
What are the experiences and concerns of parents of children with faltering growth?
## Why this is important
Having a child with faltering growth can be a distressing experience. Parents can feel blamed or unheard. Faltering growth happens when children are young so can have a long-term impact on the child–parent relationship. There are no studies that describe parental experiences or concerns and therefore there is a gap in the evidence. Research on this topic would help to improve understanding of the needs and concerns of parents who have children with faltering growth, which will then enable healthcare professionals to better address them. Understanding the experiences, expectations and needs of parents should inform the design of effective intervention strategies that are tailored to the family.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# .Weight loss in the early days of life\n\nSome weight loss in the first days after birth (referred to in this guideline as the early days of life) is normal and usually relates to body fluid adjustments. Sometimes there may be reason for concern about weight loss in the early days of life, which may need assessment and intervention. For this reason weight loss in the early days of life is dealt with separately in this guideline from concerns about inadequate weight gain in older infants and children, which is often related to nutritional intake.\n\nBe aware that:\n\nit is common for infants to lose some weight during the early days of life\n\nthis weight loss usually stops after about 3\xa0or 4\xa0days of life\n\nmost infants have returned to their birth weight by 3\xa0weeks of age.\n\nIf infants in the early days of life lose more than 10% of their birth weight:\n\nperform a clinical assessment, looking for evidence of dehydration, or of an illness or disorder that might account for the weight loss\n\ntake a detailed history to assess feeding (see NICE's guideline on postnatal care up to 8\xa0weeks after birth)\n\nconsider direct observation of feeding\n\nensure observation of feeding is done by a person with appropriate training and expertise (for example, in relation to breastfeeding and bottle feeding)\n\nperform further investigations only if they are indicated based on the clinical assessment.\n\nProvide feeding support (see recommendations in NICE's guideline on postnatal care up to 8\xa0weeks after birth) if there is concern about weight loss in infants in the early days of life, for example if they have lost more than 10% of their birth weight.\n\nIf infants lose more than 10% of their birth weight in the early days of life, or they have not returned to their birth weight by 3\xa0weeks of age, consider:\n\nreferral to paediatric services if there is evidence of illness, marked weight loss, or failure to respond to feeding support (see recommendations in NICE's guideline on postnatal care up to 8\xa0weeks after birth)\n\nwhen to reassess if not referred to paediatric services.\n\nIf an infant loses more than 10% of their birth weight in the early days of life, measure their weight again at appropriate intervals depending on the level of concern, but no more frequently than daily.\n\nBe aware that supplementary feeding with infant formula in a breastfed infant may help with weight gain, but often results in cessation of breastfeeding.\n\nIf supplementation with an infant formula is given to a breastfed infant:\n\nsupport the mother to continue breastfeeding\n\nadvise expressing breast milk to promote milk supply and\n\nfeed the infant with any available breast milk before giving any infant formula.\n\n# Faltering growth after the early days of life\n\n## Thresholds\n\nConsider using the following as thresholds for concern about faltering growth in infants and children (a centile space being the space between adjacent centile lines on the UK WHO growth charts):\n\na fall across 1\xa0or more weight centile spaces, if birthweight was below the 9th centile\n\na fall across 2\xa0or more weight centile spaces, if birthweight was between the 9th and 91st centiles\n\na fall across 3\xa0or more weight centile spaces, if birthweight was above the 91st centile\n\nwhen current weight is below the 2nd centile for age, whatever the birthweight.\n\n## Measurement of weight and height or length\n\nIf there is concern about faltering growth (for example, based on the criteria in recommendation\xa01.2.1):\n\nweigh the infant or child\n\nmeasure their length (from birth to 2\xa0years old) or height (if aged over 2\xa0years)\n\nplot the above measurements and available previous measurements on the UK WHO growth charts to assess weight change and linear growth over time.\n\nIf there are concerns about an infant's length or a child's length or height, if possible obtain the biological parents' heights and work out the mid-parental height centile. If the child's length or height centile is below the range predicted from parental heights (more than 2\xa0centile spaces below the mid-parental centile) be aware this could suggest undernutrition or a primary growth disorder.\n\nIf there is concern about faltering growth or linear growth in a child over 2\xa0years of age, determine the BMI centile:\n\nusing the UK WHO centiles and the accompanying BMI centile 'look‑up chart' or\n\nby calculating the BMI (weight in kg/height in metres squared) and plotting this on the BMI centile chart.Then:\n\nif the BMI is below the 2nd centile, be aware this may reflect either undernutrition or a small build\n\nif the BMI is below the 0.4th centile, this suggests probable undernutrition that needs assessment and intervention.\n\nRecord all growth measurements in the parent- or carer-held Personal Child Health Record.\n\n## Assessment\n\nIf there is concern about faltering growth:\n\nperform a clinical, developmental and social assessment\n\ntake a detailed feeding or eating history\n\nconsider direct observation of feeding or meal times\n\nconsider investigating for:\n\n\n\nurinary tract infection (follow the principles of assessment in NICE's guideline on urinary tract infection in under\xa016s)\n\ncoeliac disease, if the diet has included gluten-containing foods (follow the principles of assessment in NICE's guideline on coeliac disease)\n\n\n\nperform further investigations only if they are indicated based on the clinical assessment.\n\nIf observation of eating or feeding is needed because of concern about faltering growth, ensure this is done by a person with appropriate training and expertise.\n\nBe aware that the following factors may be associated with faltering growth:\n\npreterm birth\n\nneurodevelopmental concerns\n\nmaternal postnatal depression or anxiety.\n\nRecognise that in faltering growth:\n\na range of factors may contribute to the problem, and it may not be possible to identify a clear cause\n\nthere may be difficulties in the interaction between an infant or child and the parents or carers that may contribute to the problem, but this may not be the primary cause.\n\nBased on the feeding history and any direct observation of feeding, consider whether any of the following are contributing to faltering growth in milk-fed infants:\n\nineffective suckling in breastfed infants\n\nineffective bottle feeding\n\nfeeding patterns or routines being used\n\nthe feeding environment\n\nfeeding aversion\n\nparent/carer–infant interactions\n\nhow parents or carers respond to the infant's feeding cues\n\nphysical disorders that affect feeding.\n\nBased on the feeding history and any direct observation of mealtimes, consider whether any of the following are contributing to faltering growth:\n\nmealtime arrangements and practices\n\ntypes of foods offered\n\nfood aversion and avoidance\n\nparent/carer–child interactions, for example responding to the child's mealtime cues\n\nappetite, for example a lack of interest in eating\n\nphysical disorders that affect feeding.\n\nConsider asking the parents or carers of infants and children with faltering growth to keep a diary recording food intake (types and amounts) and mealtime issues (for example, settings, behaviour) to help inform management strategies and assess progress.\n\nBe aware that investigations (other than those recommended in recommendation\xa01.2.6) are unlikely to reveal an underlying disorder in a child with faltering growth who appears well with no other clinical concerns.\n\nIf a child with faltering growth develops new clinical symptoms or signs after the initial assessment, reconsider whether investigations are needed.\n\n## Interventions for faltering growth\n\nTogether with parents and carers, establish a management plan with specific goals for every infant or child where there are concerns about faltering growth. This plan could include:\n\nassessments or investigations\n\ninterventions\n\nclinical and growth monitoring\n\nwhen reassessment to review progress and achievement of growth goals should happen.\n\nProvide feeding support (see recommendations in NICE's guideline on postnatal care up to 8\xa0weeks after birth) if there is concern about faltering growth in the first weeks of life. Consider whether such feeding support might be helpful in older milk-fed infants, including those having complementary solid foods.\n\nBe aware that while supplementary feeding with infant formula may increase weight gain in a breastfed infant if there is concern about faltering growth, it often results in cessation of breastfeeding.\n\nIf supplementation with an infant formula is given to a breastfed infant because of concern about faltering growth after the early days of life:\n\nsupport the mother to continue breastfeeding\n\nadvise expressing breast milk to promote milk supply and\n\nfeed the infant with any available breast milk before giving any infant formula.\n\nWhen there are concerns about faltering growth, discuss the following, as individually appropriate, with the infant's or child's parents or carers:\n\nencouraging relaxed and enjoyable feeding and mealtimes\n\neating together as a family or with other children\n\nencouraging young children to feed themselves\n\nallowing young children to be 'messy' with their food\n\nmaking sure feeds and mealtimes are not too brief or too long\n\nsetting reasonable boundaries for mealtime behaviour while avoiding punitive approaches\n\navoiding coercive feeding\n\nestablishing regular eating schedules (for example 3\xa0meals and 2\xa0snacks in a day).\n\nIf necessary, based on the assessment, advise on food choices for infants and children that:\n\nare appropriate to the child's developmental stage in terms of quantity, type and food texture\n\noptimise energy and nutrient density.\n\nIn infants or children who need a further increase in the nutrient density of their diet beyond that achieved through advice on food choices, consider:\n\nshort-term dietary fortification using energy-dense foods\n\nreferral to a paediatric dietitian.\n\nAdvise the parents or carers of infants or children with faltering growth that drinking too many energy-dense drinks, including milk, can reduce a child's appetite for other foods.\n\nConsider a trial of an oral liquid nutritional supplement for infants or children with continuing faltering growth despite other interventions (see recommendations\xa01.2.16 to\xa01.2.22).\n\nRegularly reassess infants and children receiving an oral nutritional supplement for faltering growth to decide if it should be continued. Take into account:\n\nweight change\n\nlinear growth\n\nintake of other foods\n\ntolerance\n\nadherence\n\nthe views of parents or carers.\n\nOnly consider enteral tube feeding for infants and children with faltering growth when:\n\nthere are serious concerns about weight gain and\n\nan appropriate specialist multidisciplinary assessment for possible causes and contributory factors has been completed and\n\nother interventions have been tried without improvement.\n\nIf enteral tube feeding is to be used in an infant or child with faltering growth, make a plan with appropriate multidisciplinary involvement for:\n\nthe goals of the treatment (for example, reaching a specific weight target)\n\nthe strategy for its withdrawal once the goal is reached (for example, progressive reduction together with strategies to promote oral intake).\n\n## Monitoring\n\nIf there are concerns about faltering growth (see recommendation\xa01.2.1), measure the weight at appropriate intervals taking account of factors such as age and the level of concern, but usually no more often than:\n\ndaily if less than 1\xa0month old\n\nweekly between 1–6\xa0months old\n\nfortnightly between 6–12\xa0months\n\nmonthly from 1\xa0year of age.\n\nMonitor weight if there are concerns about faltering growth (see recommendation\xa01.2.1), but be aware that weighing children more frequently than is needed (see recommendation\xa01.2.27) may add to parental anxiety (for example, minor short-term changes may cause unnecessary concern).\n\nBe aware that weight loss is unusual except in the early days of life, and may be a reason for increased concern and more frequent weighing than is recommended (see recommendation\xa01.2.27).\n\nIf there are concerns about faltering growth monitor length or height at intervals, but no more often than every 3\xa0months.\n\n## Referral\n\nIf an infant or child with faltering growth has any of the following discuss with, or refer to, an appropriate paediatric specialist care service:\n\nsymptoms or signs that may indicate an underlying disorder\n\na failure to respond to interventions delivered in a primary care setting\n\nslow linear growth or unexplained short stature (see recommendation\xa01.2.3)\n\nrapid weight loss or severe undernutrition\n\nfeatures that cause safeguarding concerns (see the NICE guideline on child maltreatment).\n\nDo not admit infants or children with faltering growth to hospital unless they are acutely unwell or there is a specific indication requiring inpatient care, such as a plan to begin tube feeding (see recommendation\xa01.2.25).\n\n# Organisation of care\n\nEnsure there is a pathway of care for infants and children where there are concerns about faltering growth or weight loss in the early days of life that:\n\nclearly sets out the roles of healthcare professionals in primary and secondary care settings\n\nestablishes and makes clear the process for referral to and coordination of specialist care in the pathway.\n\nProvide community-based care for infants and children where there are faltering growth concerns or weight loss in the early days of life with a team (the 'primary care team') that includes, for example:\n\na midwife\n\na health visitor\n\na GP.\n\nEnsure that the primary care team has access to the following healthcare professionals with expertise relevant to faltering growth:\n\ninfant feeding specialist\n\nconsultant paediatrician\n\npaediatric dietitian\n\nspeech and language therapist with expertise in feeding and eating difficulties\n\nclinical psychologist\n\noccupational therapist.\n\nConsider identifying a lead healthcare professional to coordinate care and to act as the first point of contact for parents of children with faltering growth, for example if several professionals are involved.\n\n# Information and support\n\nRecognise the emotional impact that concerns about faltering growth or weight loss in the early days can have on parents and carers and offer them information about available:\n\nprofessional support\n\npeer support.\n\nFollow the principles in the NICE guidelines on patient experience in NHS services, babies, children and young people's experience of healthcare and shared decision making in relation to communication (including different formats and languages), information and shared decision making.\n\nProvide information on faltering growth or weight loss in the early days of life, to parents or carers that is:\n\nspecific to them and their child\n\nclearly explained and understandable to them\n\nspoken and in writing.\n\nIf there is concern about faltering growth in an infant or child or weight loss in the early days of life, discuss with the parents or carers:\n\nthe reasons for the concern, and how the growth measurements are interpreted\n\nany worries or issues they may have\n\nany possible or likely causes or factors that may be contributing to the problem\n\nthe management plan (see recommendation\xa01.2.15).\n\n# Terms used in this guideline\n\n## Child\n\nPre-school children from 1\xa0year of age.\n\n## Food or feeding aversion\n\nBehaviours sometimes observed in infants or children indicating a persistent unwillingness to eat. Such behaviours, depending upon age, might include signs of distress when presented with food, spitting of food or avoidance behaviour.\n\n## Infant\n\nA baby up to 1\xa0year of age.\n\n## Linear growth\n\nThis is the increase in length (under 2\xa0years of age) or height (2\xa0years or older) over time in infants and children.\n\n## Oral liquid nutritional supplement\n\nA high-energy liquid feed designed for enteral use, usually selected and prescribed after specialist advice from a paediatric dietitian.\n\n## Undernutrition\n\nThis is what happens when nutrition is not sufficient. An infant or child with undernutrition may be abnormally thin, may weigh less than expected for their length or height, and if prolonged, undernutrition can lead to stunting (length or height less than expected for age).", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "The term 'faltering growth' (previously called 'failure to thrive') is widely used to refer to a slower rate of weight gain in childhood than expected for age and sex. The term faltering growth is preferred as periods of slow growth may represent temporary variation from the expected pattern and the word 'failure' may be seen as pejorative. Various definitions of faltering growth have been used in the past, meaning estimates of prevalence in the UK vary widely.\n\nThe World Health Organization (WHO) has produced growth standards, based on longitudinal studies of healthy breastfed infants. These standards, along with UK term and preterm infant growth data, have been incorporated into UK WHO growth charts for monitoring growth in UK children. A child's weight, length or height and head circumference can be plotted on these charts to provide a visual representation of growth over time. Epidemiological data suggest that healthy children usually progress relatively consistently along a growth centile.\n\nNewborn infants normally lose weight in the early days of life. Persisting or large weight losses can cause concern in parents, carers and health professionals about ineffective establishment of feeding. In older children, faltering growth can occur when nutritional intake does not meet a child's specific energy requirements. Undernutrition presents as a relatively slow weight gain, demonstrated by downward movement across weight centiles on the growth chart.\n\nChildren with faltering growth may be identified by routine growth monitoring or by parental or health professional concern. Standard management is usually community based, with support and advice provided to increase energy intake and manage challenging feeding behaviour. Some children will be referred to paediatric dieticians or paediatricians for further assessment and management.\n\nCertain health conditions predispose children to faltering growth (for example, cystic fibrosis or coeliac disease). Specific treatment for these conditions can improve or restore expected rates of weight gain. In children with no specific cause for faltering growth, simple interventions to increase nutritional intake may be effective in improving weight gain. Faltering growth in early childhood may be associated with persisting problems with appetite and feeding.\n\nThe cause of faltering growth in the absence of a specific underlying health condition is likely to be complex and multifactorial. In the past, child neglect or socioeconomic and educational disadvantage were often considered to be likely contributors. While neglected children may be undernourished, neglect is an uncommon explanation for faltering growth. Similarly, significant associations with socioeconomic or educational factors have not been demonstrated.\n\nThere is variation across the UK in care provided for infants, children and families where concerns are raised about early weight loss or faltering growth. There is cultural and socioeconomic variation in starting and continuing breastfeeding, the approach to introducing complementary solid food and choice of foods, feeding behaviour and parental acceptance of feeding support and advice.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# High energy liquid feed supplements\n\nDo high energy liquid feed supplements improve growth in children with faltering growth?\n\n## Why this is important\n\nIt seems logical to attempt to treat inadequate dietary intake with food of some kind, and high energy liquid dietary supplements appear to be effective when used in older adults. Although they are also widely promoted for use in children, little research on their efficacy has been done. Experimental research suggests that high energy liquid feed supplements may supress appetite and displace normal diet, and one case series found that when high energy liquid feed supplements were withdrawn appetite improved with no impact on weight. Further research is important to establish whether their effectiveness justifies their cost and the suppressant effect on appetite.\n\n# Feeding interventions for the management of neonatal weight loss\n\nWhat is the effectiveness of feeding interventions compared with usual care/advice for breastfed neonates (up to 28\xa0days old) with weight loss of greater than\xa010%?\n\n## Why this is important\n\nWeight loss in breastfeeding infants in the first month of life can cause anxiety for parents and healthcare professionals. It can also incur costs to the NHS from admissions of the infant to hospital, with the potential for cessation of exclusive breastfeeding with its associated long-term health benefits.\n\nPractice varies across the UK. Robust evidence about which feeding interventions improve outcomes could inform practice, potentially reducing unnecessary and costly interventions and supporting parent–infant relationships and physical and emotional health.\n\n# Behavioural interventions\n\nWhat is the effectiveness of behavioural interventions compared with usual care/advice for children with faltering growth?\n\n## Why this is important\n\nHealth visitors provide behavioural interventions for faltering growth in community settings. This is carried out with the aim to optimise the Healthy Child Programme and provide support and build relationships with parents and children. Behavioural interventions are time consuming and therefore incur costs. Evidence for the specific components of behavioural interventions are scarce and if found to be effective they could have short-term and longer-term preventative results. A standardised approach to behavioural interventions could both improve clinical practice and save costs.\n\n# Frequency of monitoring\n\nHow frequently should children be measured to identify faltering growth?\n\n## Why this is important\n\nIt is important to know whether a particular frequency or schedule of measurement of infants and children would identify faltering growth at an earlier age and contribute to an earlier catch‑up in weight. Present practice suggests routine measurements be taken at the time of routine childhood immunisation. Is this schedule of measurement the most likely to confirm whether an infant or child has faltering growth as early as possible? It is unclear whether the present pattern of measurement is most effective for children for whom there are concerns about their growth. If an altered schedule of routine measurement was found to be identifying faltering growth at an earlier age and contribute to an early catch‑up in weight, it would be necessary to consider how best to deliver such a schedule to the entire population of infants and children.\n\n# Support needs of parents\n\nWhat are the experiences and concerns of parents of children with faltering growth?\n\n## Why this is important\n\nHaving a child with faltering growth can be a distressing experience. Parents can feel blamed or unheard. Faltering growth happens when children are young so can have a long-term impact on the child–parent relationship. There are no studies that describe parental experiences or concerns and therefore there is a gap in the evidence. Research on this topic would help to improve understanding of the needs and concerns of parents who have children with faltering growth, which will then enable healthcare professionals to better address them. Understanding the experiences, expectations and needs of parents should inform the design of effective intervention strategies that are tailored to the family."}
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https://www.nice.org.uk/guidance/ng75
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This guideline covers recognition, assessment and monitoring of faltering growth in infants and children. It includes a definition of growth thresholds for concern and identifying the risk factors for, and possible causes of, faltering growth. It also covers interventions, when to refer, service design, and information and support.
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af84df6bb1645b97f256bccbfa2db40d01bed9f2
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nice
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Cetuximab and panitumumab for previously untreated metastatic colorectal cancer
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Cetuximab and panitumumab for previously untreated metastatic colorectal cancer
Evidence-based recommendations on cetuximab (Erbitux) and panitumumab (Vectibix) for previously untreated RAS wild-type metastatic colorectal cancer in adults.
# Recommendations
Cetuximab is recommended, within its marketing authorisation, as an option for previously untreated epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer in adults in combination with:
‑fluorouracil, folinic acid and oxaliplatin (FOLFOX) or
‑fluorouracil, folinic acid and irinotecan (FOLFIRI).
Panitumumab is recommended, within its marketing authorisation, as an option for previously untreated RAS wild-type metastatic colorectal cancer in adults in combination with:
FOLFOX or
FOLFIRI.
The drugs are recommended only when the companies provide them with the discount agreed in the patient access scheme (for panitumumab) or commercial access agreement (for cetuximab).# The technologies
Cetuximab
Panitumumab
Description of the technologies
Cetuximab (Erbitux, Merck Serono) is a chimeric monoclonal IgG1 antibody that is specifically directed against epidermal growth factor receptor (EGFR).
Panitumumab (Vectibix, Amgen) is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to human EGFR.
Marketing authorisations
Cetuximab has a marketing authorisation in the UK for treating 'patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer:
in combination with irinotecan-based chemotherapy,
in first-line in combination with FOLFOX,
as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan'.
Panitumumab has a marketing authorisation in the UK for treating 'adult patients with wild-type RAS metastatic colorectal cancer (mCRC):
in first-line in combination with FOLFOX or FOLFIRI .
in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens'.
Please note this appraisal considered the previously untreated population only.
Monotherapy for previously treated mCRC was not within the scope of the appraisal.
Adverse reactions
The most frequently reported adverse reactions are skin reactions, hypomagnesaemia and infusion-related reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The most frequently reported adverse reactions are skin reactions and gastrointestinal disorders. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended doses and schedules
Cetuximab is given by intravenous infusion once a week. The first dose of cetuximab is 400 mg/m2 body surface area. All further doses are 250 mg/m2 of cetuximab given weekly.
Panitumumab is given by intravenous infusion once every 2 weeks at a dose of 6 mg/kg of body weight.
Prices
Cetuximab costs £178.10 per 20‑ml vial and £890.50 per 100‑ml vial (excluding VAT, 'British national formulary' online, October 2015).
The pricing arrangement considered during guidance development was that Merck had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of cetuximab with the discount applied at the point of purchase or invoice. After guidance publication in March 2017, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.
Panitumumab costs £379.29 per 5‑ml vial and £1,517.16 per 20‑ml vial (excluding VAT, BNF online, October 2015).
The company has agreed a patient access scheme with the Department of Health, providing a simple discount to the list price of panitumumab with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence from a number of sources, including from the companies and from the assessment group, an independent group which evaluated each company's submission, reviewed the clinical evidence, and developed a cost-effectiveness model. See the committee papers for full details of the evidence.# Committee discussion
# Review objectives
The appraisal committee recognised that this appraisal reviewed the NICE technology appraisal guidance on:
Cetuximab for the first-line treatment of metastatic colorectal cancer, which before this review recommended up to 16 weeks of treatment with cetuximab only in a subgroup of people with metastases confined to the liver.
Panitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer, which did not recommend treatment with panitumumab because the company did not submit evidence.The committee understood that the guidance was being reviewed because the marketing authorisations for cetuximab and panitumumab had changed since the previous appraisal. The change narrows the marketing authorisation to exclude a genotype that responds poorly to cetuximab and panitumumab. The committee also understood that cetuximab and panitumumab had been available on the Cancer Drugs Fund. The committee reviewed the data available on the clinical and cost effectiveness of cetuximab and panitumumab, having considered evidence on the nature of previously untreated metastatic colorectal cancer and the value placed on the benefits of cetuximab and panitumumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical practice
The committee discussed the current management of metastatic colorectal cancer and considered the population relevant for this appraisal. The committee heard from NHS England at the fourth appraisal committee meeting that managing colorectal cancer with liver-only metastases has evolved over the course of this appraisal. It heard that clinicians continue to offer surgical resection, which may improve prognosis, to people with metastases confined to the liver and that treatment with cetuximab or panitumumab makes it easier for surgeons to resect tumours. The committee heard from the clinical experts, that if the metastases are not resectable after treatment, the person would be offered up to 3 lines of chemotherapy. It heard that few people have successful resection, meaning that there is a greater emphasis on using cetuximab and panitumumab palliatively for people with liver-only metastases. The committee noted that this was in line with palliative use of these treatments in people with widespread metastases, who have a biological treatment (such as cetuximab or panitumumab) with chemotherapy and then up to 2 further lines of chemotherapy alone. It heard that the aim of palliative treatment is to slow disease progression early, and to prolong life. The committee concluded that there are 2 purposes of treatment: to shrink tumour tissue for surgical resection and to palliate.
The committee was aware that previous guidance recommended cetuximab only in a subgroup of patients with metastases confined to the liver and included a stopping rule at 16 weeks (see section 4.1). During this appraisal, commentators and consultees, including NHS England, stated that people with metastases confined to the liver no longer represent a distinct subgroup in clinical practice and that resection was likely to be done after the best response to treatment, rather than at 16 weeks as with the stopping rule. The committee also heard that the stopping rule is difficult to implement in practice, because it can mean withdrawing a palliative treatment from people. The committee concluded that people with metastases confined to the liver were no longer a distinct subgroup in current clinical practice and did not further consider this subgroup separately from the overall population. In addition, it concluded that it was inappropriate to implement a stopping rule in people with metastatic colorectal cancer.
The committee considered the most appropriate comparators for cetuximab and panitumumab for treating RAS wild-type tumours in people with metastatic disease. It heard from the clinical experts that they use combinations including oxaliplatin (for example, FOLFOX) and irinotecan (for example, FOLFIRI). The committee understood that there are 2 different delivery schedules for FOLFOX treatment, FOLFOX4 and FOLFOX6, and heard from the clinical experts that FOLFOX6 is more commonly used in clinical practice in England. The committee heard that cetuximab is usually given with FOLFIRI and that panitumumab is usually given with FOLFOX, because there is a stronger evidence base for these combinations than for cetuximab plus FOLFOX or panitumumab plus FOLFIRI. The committee was aware that other chemotherapy regimens, such as XELOX (oxaliplatin and capecitabine), were listed among the comparators in the scope but heard from the clinical experts and the assessment group that these drugs were not routinely offered in clinical practice in the NHS. The committee concluded that the appropriate comparators for this appraisal were FOLFOX and FOLFIRI for both cetuximab and panitumumab.
The committee considered how frequently cetuximab is administered in clinical practice. It was aware the summary of product characteristics for cetuximab recommends a weekly dose of 250 mg/m2 body surface area. However, the committee heard from the clinical experts and from NHS England that in practice a dose of 500 mg/m2 body surface area is given every 2 weeks, which reduces administration costs. The committee was concerned that cetuximab given every 2 weeks may not have the same effectiveness as cetuximab given weekly, as done in the trials. At the fourth appraisal committee meeting, the committee heard from the company that a study (CECOG/CORE2) in a similar population showed that the effectiveness of cetuximab given every 2 weeks or weekly may be the same and that the Cancer Drugs Fund chose to offer cetuximab every 2 weeks on the basis of this evidence. The committee was aware that NICE's guide to the methods of technology appraisal states that the committee 'does not normally make recommendations regarding the use of a drug outside the terms of its marketing authorisation'. It noted that the guide also states that evidence relating to using the technology under appraisal outside the terms of its marketing authorisation may inform deliberations. The committee concluded that it would take into account the lower costs of administration in clinical practice.
# Clinical effectiveness
The committee discussed the clinical trial evidence for cetuximab and panitumumab in people with RAS wild-type metastatic colorectal cancer. The assessment group included 3 main randomised clinical trials of cetuximab and panitumumab in its base-case model: OPUS (cetuximab plus FOLFOX compared with FOLFOX alone), CRYSTAL (cetuximab plus FOLFIRI compared with FOLFIRI alone), and PRIME (panitumumab plus FOLFOX compared with FOLFOX alone).
The committee heard that the evidence for cetuximab and panitumumab in patients with RAS wild-type colorectal cancer was based on post-hoc subgroup analyses. Although based on small data sets, it understood from the clinical experts that knowledge about metastatic colorectal cancer and biomarkers has changed. The committee agreed that it was appropriate to use data from post-hoc subgroup analyses for its decision-making.
The committee heard from the assessment group that the survival data were likely confounded by different second and further lines of treatment across the trial arms. These treatments are associated with prolonged survival and are not widely available in the NHS. The committee noted that, in response to the appraisal consultation document, the assessment group adjusted for subsequent treatments (see section 4.12).The committee concluded that, for the purpose of this appraisal, the populations in the clinical trials of cetuximab and panitumumab were broadly generalisable to clinical practice in the NHS.
## Network meta-analysis results: previously untreated RAS wild-type metastatic colorectal cancer
Cetuximab plus FOLFIRI increased progression-free survival (hazard ratio 0.56; 95% credible interval 0.41 to 0.76) and overall survival (HR 0.69; 95% CrI 0.54 to 0.88) compared with FOLFIRI alone.
Cetuximab plus FOLFOX increased progression-free survival (HR 0.53; 95% CrI 0.27 to 1.04) and might have increased overall survival (HR 0.94; 95% CrI 0.56 to 1.57) compared with FOLFOX alone. The committee noted that large credible intervals surrounded the estimated hazard ratios and that this evidence was based on a very small clinical trial (OPUS). The committee heard that the clinical experts consider FOLFOX and FOLFIRI to be broadly equivalent. The committee concluded that cetuximab plus either FOLFOX or FOLFIRI increased progression-free survival and overall survival in people with previously untreated RAS wild-type metastatic colorectal cancer.
Panitumumab plus FOLFOX increased progression-free survival (HR 0.72; 95% CrI 0.58 to 0.90) and overall survival (HR 0.77; 95% CrI 0.64 to 0.93) compared with FOLFOX alone. There was no estimate for panitumumab plus FOLFIRI compared with FOLFIRI alone because the assessment group could not identify any eligible studies. In its response to the assessment group's additional work, Amgen stated that that there were results presented in its submission. The committee noted that these studies were either not carried out in people with previously untreated metastatic colorectal cancer or were single-arm studies and so it was not possible to use these in the network meta-analysis. It noted that panitumumab was licensed for use with either FOLFOX or FOLFIRI and recalled the advice from the clinical experts that FOLFOX and FOLFIRI had similar effectiveness (see section 4.8). The committee agreed that although it would have preferred to see evidence for the clinical effectiveness of panitumumab plus FOLFIRI, the clinical effectiveness of panitumumab plus FOLFIRI was likely to be similar to that of panitumumab plus FOLFOX in people with previously untreated RAS wild-type metastatic colorectal cancer. The committee concluded that panitumumab plus either FOLFOX or FOLFIRI increased progression-free survival and overall survival in people with previously untreated RAS wild-type metastatic colorectal cancer.
There was no statistically significant difference in progression-free survival (HR 0.74; 95% CrI 0.36 to 1.49) or overall survival (HR 1.22; 95% CrI 0.71 to 2.11) when comparing cetuximab plus FOLFOX with panitumumab plus FOLFOX. The committee noted that the evidence for panitumumab plus FOLFOX compared with cetuximab plus FOLFOX was mixed, and it was unclear whether one treatment was more effective than the other. It heard from the clinical experts that they considered cetuximab and panitumumab to have equal effectiveness (see section 4.8) and that it is helpful to be able to choose between them. The committee concluded that cetuximab and panitumumab were likely to have similar effectiveness in treating RAS wild-type metastatic colorectal cancer.
The committee heard from the clinical experts that they estimate that, for metastases which are unresectable before treatment, chemotherapy with or without cetuximab or panitumumab will shrink them enough to allow resection in about 15% of all people. The committee noted that the assessment group used trial data in its model, in which the resection rate in the overall population was up to around 20%. The committee heard from the clinical experts that it was implausible for there to be such discrepancies in the rates from the clinical trials, given the similarity in effectiveness of cetuximab and panitumumab. The committee heard from Amgen that PRIME was not powered to look at resection rates as an outcome. The committee acknowledged the uncertainty in the resection rates, but concluded that it was appropriate to use the trial data for the resection rates.
# Cost effectiveness
## Structure of the model
The committee considered whether the assessment group's model reflected clinical practice. The committee noted that, in its base-case model, the assessment group simulated a cohort of people with RAS wild-type metastatic colorectal cancer starting on first-line treatment, assumed that a proportion of them then have surgery to resect liver metastases, and calculated this separately for each treatment arm. For people who do not have resection despite first-line treatment, the assessment group modelled:
first-line progression-free survival for each therapy
second-line treatment with FOLFOX or FOLFIRI
third-line treatment with best supportive care.For people who have resection of liver metastases, the assessment group did not model further treatments; instead, it modelled progression-free survival and progressed-disease after resection. In the model, people who had resection of liver metastases lived longer than people who did not have resections. The assessment group derived utility values from trial-based EQ‑5D data. The committee concluded that the assessment group's model reflected clinical practice.
## Modelling of second-line drugs
The assessment group stated that data on mortality for cetuximab and panitumumab from trials may have been confounded by second-line drugs that are not commonly used in the NHS and which prolong survival (see section 4.6). The companies and the assessment group investigated methods to correct for imbalances in subsequent treatments. The committee noted that the companies had provided adjusted measures of effectiveness; Amgen used the inverse probability of censoring weighted method for panitumumab, whereas Merck Serono used the rank-preserving structural failure time method for cetuximab. These methods provided adjusted estimates of overall survival, which were then used in the model instead of overall-survival data from the clinical trials. The committee noted that, although the adjusted overall survival changed the incremental cost-effectiveness ratios (ICERs), the size of the effect was small. The assessment group explained that the small number of patients progressing to further treatments in the clinical trials meant that the adjustments were unlikely to have a large effect. The committee concluded that, although the effect of these adjustments on survival were small, they were more plausible than the unadjusted estimates.
## Proportion of people who have resection of liver metastases
The committee discussed the assessment group's estimates of the proportion of people in the overall population who have their liver metastases resected after first-line treatment. It recalled that resection may improve progression-free survival and overall survival (see section 4.2), which would increase the effectiveness of cetuximab or panitumumab in the model. The committee was aware that the resection rates in NICE's previous appraisal for cetuximab were higher (30% to 43%) than in the current appraisal (about 7% to 20%). It recognised that the rates in the previous appraisal were based on clinical expert opinion and the results of an open-label phase II trial comparing cetuximab plus FOLFOX with cetuximab plus FOLFIRI (the CELIM trial). The committee heard that the population in CELIM was people with KRAS wild-type metastatic colorectal cancer who had liver-limited metastases. The committee agreed that the population in CELIM was narrower than the population relevant to the current appraisal. In this appraisal, the committee was aware that, because of the improved prognosis after resection, the cost-effectiveness results were sensitive to the resection rates. The committee agreed that it was unlikely that there would be a large difference in resection rates between treatments (see section 4.11), but noted that the rates used in the model were directly from the clinical trials. The committee concluded that the resection rates used in the model were more appropriate than those used in the previous appraisal.
## Treatment costs
The committee was aware that the treatment costs for cetuximab were partly based on the weight of the patient. The committee heard from Merck Serono that, rather than using a single mean weight of around 85 kg, the assessment group should have accounted for a distribution of weights when calculating treatment dose and cost. It noted that cetuximab dosing is based on body surface area, which the assessment group estimated from body weight, and that panitumumab dosing is based directly on body weight. The committee concluded that using a distribution of body weight was more appropriate than using only the mean and so it took into account the assessment group's ICERs using the distribution of weights for both cetuximab and panitumumab.
# Cost-effectiveness results and conclusions
The committee considered the cost-effectiveness results for cetuximab and panitumumab in all patients. The committee recalled its preferred assumptions to consider cetuximab given 2‑weekly and to adjust survival for subsequent treatments (see section 4.13). The committee noted that the assessment group's ICERs for cetuximab plus FOLFIRI compared with FOLFIRI alone and panitumumab plus FOLFOX compared with FOLFOX alone were all below £50,000 per quality-adjusted life year (QALY) gained. The exact ICERs are not reported to prevent calculation of the discount associated with the patient access scheme and commercial access agreement.
The committee noted that it had not been presented with ICERs consistent with its preferred assumptions for some comparisons:
Cetuximab plus FOLFOX compared with FOLFOX alone: It noted that ICERs adjusted for subsequent treatments were not presented because of limited data. It recalled hearing that the clinical experts considered FOLFOX and FOLFIRI to be broadly equivalent (see section 4.8). The committee concluded that the ICER for cetuximab plus FOLFOX compared with FOLFOX alone was likely to be similar to that for cetuximab plus FOLFIRI compared with FOLFIRI alone (see section 4.16).
Panitumumab plus FOLFIRI compared with FOLFIRI alone: It noted that ICERs were not presented because of a lack of relevant clinical evidence (see section 4.9). It recalled its earlier conclusion that the effectiveness of panitumumab plus FOLFIRI was likely to be similar to that of panitumumab plus FOLFOX. The committee concluded that the ICER for panitumumab plus FOLFIRI compared with FOLFIRI alone was likely to be similar to that for panitumumab plus FOLFOX compared with FOLFOX alone (see section 4.16).
# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. Having previously concluded that the end-of-life criteria were met for the overall population, but not for the subgroup of people with metastases confined to the liver, the committee limited its discussion to the overall population at the fourth appraisal committee meeting. The committee concluded that the end-of-life criteria were met in the overall population based on the following discussions:
The committee considered the life expectancy of people with RAS wild-type metastatic colorectal cancer with either FOLFOX or FOLFIRI, using estimates from the assessment group's model. For the overall population, it noted that mean life-expectancy estimates were below 24 months for FOLFIRI when adjusted for subsequent treatments. The committee noted that the estimates for FOLFOX were slightly above 24 months. It recalled its earlier conclusion that FOLFOX and FOLFIRI were likely to be broadly equivalent (see section 4.8) and was aware that there was uncertainty about the estimates. The committee concluded that the criterion for short life expectancy was met.
The committee considered how long, on average, cetuximab and panitumumab extended life in the whole population, based on the estimates in the assessment group's model. It noted that estimates were above a mean of 3 months for both cetuximab with FOLFIRI and panitumumab with FOLFOX when adjusted for subsequent treatments. The committee was aware that estimates adjusted for subsequent treatments were not available for cetuximab with FOLFOX but recalled its earlier conclusion that FOLFOX and FOLFIRI were likely to be broadly equivalent (see section 4.8). The committee concluded that both cetuximab and panitumumab met the criterion of extension to life when considering the whole population.
## Conclusion
The committee concluded that panitumumab and cetuximab plus either FOLFOX or FOLFIRI could be considered a cost-effective use of NHS resources for previously untreated RAS wild-type metastatic colorectal cancer in adults.
# Innovation
The committee heard from the companies that they consider cetuximab and panitumumab to be innovative treatments and a step-change in managing metastatic colorectal cancer, because their targeted mechanisms of action mean that those people with colorectal cancer that is most likely to respond (that is, RAS wild-type) have treatment. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs.
# Pharmaceutical Price Regulation Scheme (PPRS) 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.
# Summary of appraisal committee's key conclusions
TA439
Appraisal title:
Section
Key conclusions
Cetuximab is recommended, within its marketing authorisation, as an option for previously untreated epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer in adults in combination with:
‑fluorouracil, folinic acid and oxaliplatin (FOLFOX) or
‑fluorouracil, folinic acid and irinotecan (FOLFIRI).
Panitumumab is recommended, within its marketing authorisation, as an option for previously untreated RAS wild-type metastatic colorectal cancer in adults in combination with:
FOLFOX or
FOLFIRI.
The committee concluded that people with metastases confined to the liver no longer represent a clinically relevant subgroup of people with metastatic colorectal cancer.
The committee heard that cetuximab is given every 2 weeks in practice and agreed to consider the reduced administration costs.
Current practice
Clinical need of patients, including the availability of alternative treatments
The prognosis of people with metastatic colorectal cancer may be improved by resection of metastases. When possible, resecting the primary tumour and metastases is carried out. Chemotherapy regimens may be used before surgery to shrink the metastases and make them suitable for resection.
The technologies
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee heard from the companies that they consider cetuximab and panitumumab to be innovative treatments and a step-change in managing metastatic colorectal cancer, because their targeted mechanisms of action mean that those people with colorectal cancer that is most likely to respond (that is, RAS wild-type) have treatment.
What is the position of the treatment in the pathway of care for the condition?
Cetuximab and panitumumab may be combined with chemotherapy before surgery to shrink metastases and make them suitable for resection. Cetuximab and panitumumab may also be offered to people with widespread disease as a palliative treatment when the objective is to slow disease progression as soon as possible.
Adverse reactions
The most frequently reported adverse reactions associated with the use of cetuximab and panitumumab are skin reactions.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The clinical evidence for cetuximab came from 2 key clinical trials: OPUS and CRYSTAL. The clinical evidence for panitumumab came from 1 key clinical trial: PRIME. The trials compared cetuximab or panitumumab with combination treatments that did not include these drugs. The evidence for cetuximab and panitumumab in people with RAS wild-type colorectal cancer was based on post-hoc subgroup analyses of clinical trial data.
Relevance to general clinical practice in the NHS
The populations in the clinical trials differed from patients in clinical practice in England. For example, second and further lines of treatment used in the trials are not widely available in the NHS.
Uncertainties generated by the evidence
Survival data from the clinical trials were confounded by the use of different second and further lines of treatment across the trial arms. These treatments are associated with prolonged survival. The effect of cetuximab and panitumumab was also potentially confounded by relying on post-hoc analyses. The true size of the benefit was a source of uncertainty in the clinical- and cost-effectiveness results because the evidence for cetuximab and panitumumab was based on small data sets.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
A subgroup of people with metastases confined to the liver was considered, but after advice from NHS England, this was no longer deemed a clinically relevant subgroup.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The assessment group's network meta-analysis showed that cetuximab plus FOLFIRI and panitumumab plus FOLFOX were more effective than chemotherapy alone. The evidence for cetuximab plus FOLFOX was less conclusive. This evidence was based on a very small clinical trial, OPUS. Clinical experts stated that cetuximab and panitumumab probably had similar effectiveness. There were uncertainties about the results of the network meta-analysis and the credible intervals around the hazard ratios were large.
How has the new clinical evidence that has emerged since the original appraisal (TA176) influenced the current (preliminary) recommendations?
Although the current data are more mature than in NICE's technology appraisal guidance on cetuximab for the first-line treatment of metastatic colorectal cancer, there is more uncertainty in the evidence base because it involved smaller populations (based on the stricter definition of wild-type status in the new marketing authorisations).
Evidence for cost effectiveness
Availability and nature of evidence
The committee concluded that the assessment group's model reflected clinical practice.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The adjustment for further treatments was a source of uncertainty. The committee concluded that, although the effect of these adjustments on survival were small, they were more plausible than the unadjusted estimates.
The difference in resection rates between treatment arms was a source of uncertainty. Although it was appropriate to source these from the clinical trials, the discrepancies between them were considered clinically implausible.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
Utility values were derived from trial-based EQ‑5D data. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
What are the key drivers of cost effectiveness?
Giving cetuximab every 2 weeks was the most important driver of cost effectiveness.
Most likely cost-effectiveness estimate (given as an ICER)
The committee noted the base-case incremental cost-effectiveness ratios (ICERs), and further noted that the model was associated with uncertainties about the estimates of cost effectiveness from the network meta-analysis and the estimates of resection rates. Despite this, it concluded that they were within the range normally considered to be a cost-effective use of NHS resources for the whole population with previously untreated RAS wild-type metastatic colorectal cancer.
How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA176) influenced the current (preliminary) recommendations?
Resection rates were higher in the original appraisal, ranging from 30% to 43% compared with about 7% to 20% in the current appraisal. This is likely to influence cost effectiveness.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
The committee concluded that both cetuximab plus chemotherapy and panitumumab plus chemotherapy fulfilled NICE's final Cancer Drugs Fund technology appraisal process and methods advice to be considered as life-extending, end-of-life treatments in the overall population of people with RAS wild-type metastatic colorectal cancer.
Equalities considerations and social value judgements
Not applicable.
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{'Recommendations': 'Cetuximab is recommended, within its marketing authorisation, as an option for previously untreated epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer in adults in combination with:\n\n‑fluorouracil, folinic acid and oxaliplatin (FOLFOX) or\n\n‑fluorouracil, folinic acid and irinotecan (FOLFIRI).\n\nPanitumumab is recommended, within its marketing authorisation, as an option for previously untreated RAS wild-type metastatic colorectal cancer in adults in combination with:\n\nFOLFOX or\n\nFOLFIRI.\n\nThe drugs are recommended only when the companies provide them with the discount agreed in the patient access scheme (for panitumumab) or commercial access agreement (for cetuximab).', 'The technologies': "Cetuximab\n\nPanitumumab\n\nDescription of the technologies\n\nCetuximab (Erbitux, Merck Serono) is a chimeric monoclonal IgG1 antibody that is specifically directed against epidermal growth factor receptor (EGFR).\n\nPanitumumab (Vectibix, Amgen) is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to human EGFR.\n\nMarketing authorisations\n\nCetuximab has a marketing authorisation in the UK for treating 'patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer:\n\nin combination with irinotecan-based chemotherapy,\n\nin first-line in combination with FOLFOX,\n\nas a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan'.\n\nPanitumumab has a marketing authorisation in the UK for treating 'adult patients with wild-type RAS metastatic colorectal cancer (mCRC):\n\nin first-line in combination with FOLFOX or FOLFIRI [folinic acid, fluorouracil and irinotecan].\n\nin second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).\n\nas monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens'.\n\nPlease note this appraisal considered the previously untreated population only.\n\nMonotherapy for previously treated mCRC was not within the scope of the appraisal.\n\nAdverse reactions\n\nThe most frequently reported adverse reactions are skin reactions, hypomagnesaemia and infusion-related reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe most frequently reported adverse reactions are skin reactions and gastrointestinal disorders. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended doses and schedules\n\nCetuximab is given by intravenous infusion once a week. The first dose of cetuximab is 400\xa0mg/m2 body surface area. All further doses are 250\xa0mg/m2 of cetuximab given weekly.\n\nPanitumumab is given by intravenous infusion once every 2\xa0weeks at a dose of 6\xa0mg/kg of body weight.\n\nPrices\n\nCetuximab costs £178.10 per 20‑ml vial and £890.50 per 100‑ml vial (excluding VAT, 'British national formulary' [BNF] online, October 2015).\n\nThe pricing arrangement considered during guidance development was that Merck had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of cetuximab with the discount applied at the point of purchase or invoice. After guidance publication in March 2017, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.\n\nPanitumumab costs £379.29 per 5‑ml vial and £1,517.16 per 20‑ml vial (excluding VAT, BNF online, October 2015).\n\nThe company has agreed a patient access scheme with the Department of Health, providing a simple discount to the list price of panitumumab with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Evidence': "The appraisal committee (section\xa06) considered evidence from a number of sources, including from the companies and from the assessment group, an independent group which evaluated each company's submission, reviewed the clinical evidence, and developed a cost-effectiveness model. See the committee papers for full details of the evidence.", 'Committee discussion': "# Review objectives\n\nThe appraisal committee recognised that this appraisal reviewed the NICE technology appraisal guidance on:\n\nCetuximab for the first-line treatment of metastatic colorectal cancer, which before this review recommended up to 16\xa0weeks of treatment with cetuximab only in a subgroup of people with metastases confined to the liver.\n\nPanitumumab in combination with chemotherapy for the treatment of metastatic colorectal cancer, which did not recommend treatment with panitumumab because the company did not submit evidence.The committee understood that the guidance was being reviewed because the marketing authorisations for cetuximab and panitumumab had changed since the previous appraisal. The change narrows the marketing authorisation to exclude a genotype that responds poorly to cetuximab and panitumumab. The committee also understood that cetuximab and panitumumab had been available on the Cancer Drugs Fund. The committee reviewed the data available on the clinical and cost effectiveness of cetuximab and panitumumab, having considered evidence on the nature of previously untreated metastatic colorectal cancer and the value placed on the benefits of cetuximab and panitumumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical practice\n\nThe committee discussed the current management of metastatic colorectal cancer and considered the population relevant for this appraisal. The committee heard from NHS England at the fourth appraisal committee meeting that managing colorectal cancer with liver-only metastases has evolved over the course of this appraisal. It heard that clinicians continue to offer surgical resection, which may improve prognosis, to people with metastases confined to the liver and that treatment with cetuximab or panitumumab makes it easier for surgeons to resect tumours. The committee heard from the clinical experts, that if the metastases are not resectable after treatment, the person would be offered up to 3\xa0lines of chemotherapy. It heard that few people have successful resection, meaning that there is a greater emphasis on using cetuximab and panitumumab palliatively for people with liver-only metastases. The committee noted that this was in line with palliative use of these treatments in people with widespread metastases, who have a biological treatment (such as cetuximab or panitumumab) with chemotherapy and then up to 2\xa0further lines of chemotherapy alone. It heard that the aim of palliative treatment is to slow disease progression early, and to prolong life. The committee concluded that there are 2\xa0purposes of treatment: to shrink tumour tissue for surgical resection and to palliate.\n\nThe committee was aware that previous guidance recommended cetuximab only in a subgroup of patients with metastases confined to the liver and included a stopping rule at 16\xa0weeks (see section\xa04.1). During this appraisal, commentators and consultees, including NHS England, stated that people with metastases confined to the liver no longer represent a distinct subgroup in clinical practice and that resection was likely to be done after the best response to treatment, rather than at 16\xa0weeks as with the stopping rule. The committee also heard that the stopping rule is difficult to implement in practice, because it can mean withdrawing a palliative treatment from people. The committee concluded that people with metastases confined to the liver were no longer a distinct subgroup in current clinical practice and did not further consider this subgroup separately from the overall population. In addition, it concluded that it was inappropriate to implement a stopping rule in people with metastatic colorectal cancer.\n\nThe committee considered the most appropriate comparators for cetuximab and panitumumab for treating RAS wild-type tumours in people with metastatic disease. It heard from the clinical experts that they use combinations including oxaliplatin (for example, FOLFOX) and irinotecan (for example, FOLFIRI). The committee understood that there are 2\xa0different delivery schedules for FOLFOX treatment, FOLFOX4 and FOLFOX6, and heard from the clinical experts that FOLFOX6 is more commonly used in clinical practice in England. The committee heard that cetuximab is usually given with FOLFIRI and that panitumumab is usually given with FOLFOX, because there is a stronger evidence base for these combinations than for cetuximab plus FOLFOX or panitumumab plus FOLFIRI. The committee was aware that other chemotherapy regimens, such as XELOX (oxaliplatin and capecitabine), were listed among the comparators in the scope but heard from the clinical experts and the assessment group that these drugs were not routinely offered in clinical practice in the NHS. The committee concluded that the appropriate comparators for this appraisal were FOLFOX and FOLFIRI for both cetuximab and panitumumab.\n\nThe committee considered how frequently cetuximab is administered in clinical practice. It was aware the summary of product characteristics for cetuximab recommends a weekly dose of 250\xa0mg/m2 body surface area. However, the committee heard from the clinical experts and from NHS England that in practice a dose of 500\xa0mg/m2 body surface area is given every 2\xa0weeks, which reduces administration costs. The committee was concerned that cetuximab given every 2\xa0weeks may not have the same effectiveness as cetuximab given weekly, as done in the trials. At the fourth appraisal committee meeting, the committee heard from the company that a study (CECOG/CORE2) in a similar population showed that the effectiveness of cetuximab given every 2\xa0weeks or weekly may be the same and that the Cancer Drugs Fund chose to offer cetuximab every 2\xa0weeks on the basis of this evidence. The committee was aware that NICE's guide to the methods of technology appraisal states that the committee 'does not normally make recommendations regarding the use of a drug outside the terms of its marketing authorisation'. It noted that the guide also states that evidence relating to using the technology under appraisal outside the terms of its marketing authorisation may inform deliberations. The committee concluded that it would take into account the lower costs of administration in clinical practice.\n\n# Clinical effectiveness\n\nThe committee discussed the clinical trial evidence for cetuximab and panitumumab in people with RAS wild-type metastatic colorectal cancer. The assessment group included 3\xa0main randomised clinical trials of cetuximab and panitumumab in its base-case model: OPUS (cetuximab plus FOLFOX compared with FOLFOX alone), CRYSTAL (cetuximab plus FOLFIRI compared with FOLFIRI alone), and PRIME (panitumumab plus FOLFOX compared with FOLFOX alone).\n\nThe committee heard that the evidence for cetuximab and panitumumab in patients with RAS wild-type colorectal cancer was based on post-hoc subgroup analyses. Although based on small data sets, it understood from the clinical experts that knowledge about metastatic colorectal cancer and biomarkers has changed. The committee agreed that it was appropriate to use data from post-hoc subgroup analyses for its decision-making.\n\nThe committee heard from the assessment group that the survival data were likely confounded by different second and further lines of treatment across the trial arms. These treatments are associated with prolonged survival and are not widely available in the NHS. The committee noted that, in response to the appraisal consultation document, the assessment group adjusted for subsequent treatments (see section\xa04.12).The committee concluded that, for the purpose of this appraisal, the populations in the clinical trials of cetuximab and panitumumab were broadly generalisable to clinical practice in the NHS.\n\n## Network meta-analysis results: previously untreated RAS wild-type metastatic colorectal cancer\n\nCetuximab plus FOLFIRI increased progression-free survival (hazard ratio [HR] 0.56; 95% credible interval [CrI] 0.41 to 0.76) and overall survival (HR\xa00.69; 95%\xa0CrI 0.54 to 0.88) compared with FOLFIRI alone.\n\nCetuximab plus FOLFOX increased progression-free survival (HR\xa00.53; 95%\xa0CrI 0.27 to 1.04) and might have increased overall survival (HR\xa00.94; 95%\xa0CrI 0.56 to 1.57) compared with FOLFOX alone. The committee noted that large credible intervals surrounded the estimated hazard ratios and that this evidence was based on a very small clinical trial (OPUS). The committee heard that the clinical experts consider FOLFOX and FOLFIRI to be broadly equivalent. The committee concluded that cetuximab plus either FOLFOX or FOLFIRI increased progression-free survival and overall survival in people with previously untreated RAS wild-type metastatic colorectal cancer.\n\nPanitumumab plus FOLFOX increased progression-free survival (HR\xa00.72; 95%\xa0CrI 0.58 to 0.90) and overall survival (HR\xa00.77; 95%\xa0CrI 0.64 to 0.93) compared with FOLFOX alone. There was no estimate for panitumumab plus FOLFIRI compared with FOLFIRI alone because the assessment group could not identify any eligible studies. In its response to the assessment group's additional work, Amgen stated that that there were results presented in its submission. The committee noted that these studies were either not carried out in people with previously untreated metastatic colorectal cancer or were single-arm studies and so it was not possible to use these in the network meta-analysis. It noted that panitumumab was licensed for use with either FOLFOX or FOLFIRI and recalled the advice from the clinical experts that FOLFOX and FOLFIRI had similar effectiveness (see section\xa04.8). The committee agreed that although it would have preferred to see evidence for the clinical effectiveness of panitumumab plus FOLFIRI, the clinical effectiveness of panitumumab plus FOLFIRI was likely to be similar to that of panitumumab plus FOLFOX in people with previously untreated RAS wild-type metastatic colorectal cancer. The committee concluded that panitumumab plus either FOLFOX or FOLFIRI increased progression-free survival and overall survival in people with previously untreated RAS wild-type metastatic colorectal cancer.\n\nThere was no statistically significant difference in progression-free survival (HR\xa00.74; 95%\xa0CrI 0.36 to 1.49) or overall survival (HR\xa01.22; 95%\xa0CrI 0.71 to 2.11) when comparing cetuximab plus FOLFOX with panitumumab plus FOLFOX. The committee noted that the evidence for panitumumab plus FOLFOX compared with cetuximab plus FOLFOX was mixed, and it was unclear whether one treatment was more effective than the other. It heard from the clinical experts that they considered cetuximab and panitumumab to have equal effectiveness (see section\xa04.8) and that it is helpful to be able to choose between them. The committee concluded that cetuximab and panitumumab were likely to have similar effectiveness in treating RAS wild-type metastatic colorectal cancer.\n\nThe committee heard from the clinical experts that they estimate that, for metastases which are unresectable before treatment, chemotherapy with or without cetuximab or panitumumab will shrink them enough to allow resection in about 15% of all people. The committee noted that the assessment group used trial data in its model, in which the resection rate in the overall population was up to around 20%. The committee heard from the clinical experts that it was implausible for there to be such discrepancies in the rates from the clinical trials, given the similarity in effectiveness of cetuximab and panitumumab. The committee heard from Amgen that PRIME was not powered to look at resection rates as an outcome. The committee acknowledged the uncertainty in the resection rates, but concluded that it was appropriate to use the trial data for the resection rates.\n\n# Cost effectiveness\n\n## Structure of the model\n\nThe committee considered whether the assessment group's model reflected clinical practice. The committee noted that, in its base-case model, the assessment group simulated a cohort of people with RAS wild-type metastatic colorectal cancer starting on first-line treatment, assumed that a proportion of them then have surgery to resect liver metastases, and calculated this separately for each treatment arm. For people who do not have resection despite first-line treatment, the assessment group modelled:\n\nfirst-line progression-free survival for each therapy\n\nsecond-line treatment with FOLFOX or FOLFIRI\n\nthird-line treatment with best supportive care.For people who have resection of liver metastases, the assessment group did not model further treatments; instead, it modelled progression-free survival and progressed-disease after resection. In the model, people who had resection of liver metastases lived longer than people who did not have resections. The assessment group derived utility values from trial-based EQ‑5D data. The committee concluded that the assessment group's model reflected clinical practice.\n\n## Modelling of second-line drugs\n\nThe assessment group stated that data on mortality for cetuximab and panitumumab from trials may have been confounded by second-line drugs that are not commonly used in the NHS and which prolong survival (see section\xa04.6). The companies and the assessment group investigated methods to correct for imbalances in subsequent treatments. The committee noted that the companies had provided adjusted measures of effectiveness; Amgen used the inverse probability of censoring weighted method for panitumumab, whereas Merck Serono used the rank-preserving structural failure time method for cetuximab. These methods provided adjusted estimates of overall survival, which were then used in the model instead of overall-survival data from the clinical trials. The committee noted that, although the adjusted overall survival changed the incremental cost-effectiveness ratios (ICERs), the size of the effect was small. The assessment group explained that the small number of patients progressing to further treatments in the clinical trials meant that the adjustments were unlikely to have a large effect. The committee concluded that, although the effect of these adjustments on survival were small, they were more plausible than the unadjusted estimates.\n\n## Proportion of people who have resection of liver metastases\n\nThe committee discussed the assessment group's estimates of the proportion of people in the overall population who have their liver metastases resected after first-line treatment. It recalled that resection may improve progression-free survival and overall survival (see section\xa04.2), which would increase the effectiveness of cetuximab or panitumumab in the model. The committee was aware that the resection rates in NICE's previous appraisal for cetuximab were higher (30% to 43%) than in the current appraisal (about 7% to 20%). It recognised that the rates in the previous appraisal were based on clinical expert opinion and the results of an open-label phase\xa0II trial comparing cetuximab plus FOLFOX with cetuximab plus FOLFIRI (the CELIM trial). The committee heard that the population in CELIM was people with KRAS wild-type metastatic colorectal cancer who had liver-limited metastases. The committee agreed that the population in CELIM was narrower than the population relevant to the current appraisal. In this appraisal, the committee was aware that, because of the improved prognosis after resection, the cost-effectiveness results were sensitive to the resection rates. The committee agreed that it was unlikely that there would be a large difference in resection rates between treatments (see section\xa04.11), but noted that the rates used in the model were directly from the clinical trials. The committee concluded that the resection rates used in the model were more appropriate than those used in the previous appraisal.\n\n## Treatment costs\n\nThe committee was aware that the treatment costs for cetuximab were partly based on the weight of the patient. The committee heard from Merck Serono that, rather than using a single mean weight of around 85\xa0kg, the assessment group should have accounted for a distribution of weights when calculating treatment dose and cost. It noted that cetuximab dosing is based on body surface area, which the assessment group estimated from body weight, and that panitumumab dosing is based directly on body weight. The committee concluded that using a distribution of body weight was more appropriate than using only the mean and so it took into account the assessment group's ICERs using the distribution of weights for both cetuximab and panitumumab.\n\n# Cost-effectiveness results and conclusions\n\nThe committee considered the cost-effectiveness results for cetuximab and panitumumab in all patients. The committee recalled its preferred assumptions to consider cetuximab given 2‑weekly and to adjust survival for subsequent treatments (see section\xa04.13). The committee noted that the assessment group's ICERs for cetuximab plus FOLFIRI compared with FOLFIRI alone and panitumumab plus FOLFOX compared with FOLFOX alone were all below £50,000 per quality-adjusted life year (QALY) gained. The exact ICERs are not reported to prevent calculation of the discount associated with the patient access scheme and commercial access agreement.\n\nThe committee noted that it had not been presented with ICERs consistent with its preferred assumptions for some comparisons:\n\nCetuximab plus FOLFOX compared with FOLFOX alone: It noted that ICERs adjusted for subsequent treatments were not presented because of limited data. It recalled hearing that the clinical experts considered FOLFOX and FOLFIRI to be broadly equivalent (see section\xa04.8). The committee concluded that the ICER for cetuximab plus FOLFOX compared with FOLFOX alone was likely to be similar to that for cetuximab plus FOLFIRI compared with FOLFIRI alone (see section\xa04.16).\n\nPanitumumab plus FOLFIRI compared with FOLFIRI alone: It noted that ICERs were not presented because of a lack of relevant clinical evidence (see section\xa04.9). It recalled its earlier conclusion that the effectiveness of panitumumab plus FOLFIRI was likely to be similar to that of panitumumab plus FOLFOX. The committee concluded that the ICER for panitumumab plus FOLFIRI compared with FOLFIRI alone was likely to be similar to that for panitumumab plus FOLFOX compared with FOLFOX alone (see section\xa04.16).\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. Having previously concluded that the end-of-life criteria were met for the overall population, but not for the subgroup of people with metastases confined to the liver, the committee limited its discussion to the overall population at the fourth appraisal committee meeting. The committee concluded that the end-of-life criteria were met in the overall population based on the following discussions:\n\nThe committee considered the life expectancy of people with RAS wild-type metastatic colorectal cancer with either FOLFOX or FOLFIRI, using estimates from the assessment group's model. For the overall population, it noted that mean life-expectancy estimates were below 24\xa0months for FOLFIRI when adjusted for subsequent treatments. The committee noted that the estimates for FOLFOX were slightly above 24\xa0months. It recalled its earlier conclusion that FOLFOX and FOLFIRI were likely to be broadly equivalent (see section\xa04.8) and was aware that there was uncertainty about the estimates. The committee concluded that the criterion for short life expectancy was met.\n\nThe committee considered how long, on average, cetuximab and panitumumab extended life in the whole population, based on the estimates in the assessment group's model. It noted that estimates were above a mean of 3\xa0months for both cetuximab with FOLFIRI and panitumumab with FOLFOX when adjusted for subsequent treatments. The committee was aware that estimates adjusted for subsequent treatments were not available for cetuximab with FOLFOX but recalled its earlier conclusion that FOLFOX and FOLFIRI were likely to be broadly equivalent (see section\xa04.8). The committee concluded that both cetuximab and panitumumab met the criterion of extension to life when considering the whole population.\n\n## Conclusion\n\nThe committee concluded that panitumumab and cetuximab plus either FOLFOX or FOLFIRI could be considered a cost-effective use of NHS resources for previously untreated RAS wild-type metastatic colorectal cancer in adults.\n\n# Innovation\n\nThe committee heard from the companies that they consider cetuximab and panitumumab to be innovative treatments and a step-change in managing metastatic colorectal cancer, because their targeted mechanisms of action mean that those people with colorectal cancer that is most likely to respond (that is, RAS wild-type) have treatment. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of QALYs.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA439\n\nAppraisal title:\n\nSection\n\nKey conclusions\n\nCetuximab is recommended, within its marketing authorisation, as an option for previously untreated epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer in adults in combination with:\n\n‑fluorouracil, folinic acid and oxaliplatin (FOLFOX) or\n\n‑fluorouracil, folinic acid and irinotecan (FOLFIRI).\n\nPanitumumab is recommended, within its marketing authorisation, as an option for previously untreated RAS wild-type metastatic colorectal cancer in adults in combination with:\n\nFOLFOX or\n\nFOLFIRI.\n\nThe committee concluded that people with metastases confined to the liver no longer represent a clinically relevant subgroup of people with metastatic colorectal cancer.\n\nThe committee heard that cetuximab is given every 2\xa0weeks in practice and agreed to consider the reduced administration costs.\n\n, 1.2, 4.3, 4.5\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe prognosis of people with metastatic colorectal cancer may be improved by resection of metastases. When possible, resecting the primary tumour and metastases is carried out. Chemotherapy regimens may be used before surgery to shrink the metastases and make them suitable for resection.\n\n\n\nThe technologies\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard from the companies that they consider cetuximab and panitumumab to be innovative treatments and a step-change in managing metastatic colorectal cancer, because their targeted mechanisms of action mean that those people with colorectal cancer that is most likely to respond (that is, RAS wild-type) have treatment.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nCetuximab and panitumumab may be combined with chemotherapy before surgery to shrink metastases and make them suitable for resection. Cetuximab and panitumumab may also be offered to people with widespread disease as a palliative treatment when the objective is to slow disease progression as soon as possible.\n\n\n\nAdverse reactions\n\nThe most frequently reported adverse reactions associated with the use of cetuximab and panitumumab are skin reactions.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe clinical evidence for cetuximab came from 2\xa0key clinical trials: OPUS and CRYSTAL. The clinical evidence for panitumumab came from 1\xa0key clinical trial: PRIME. The trials compared cetuximab or panitumumab with combination treatments that did not include these drugs. The evidence for cetuximab and panitumumab in people with RAS wild-type colorectal cancer was based on post-hoc subgroup analyses of clinical trial data.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe populations in the clinical trials differed from patients in clinical practice in England. For example, second and further lines of treatment used in the trials are not widely available in the NHS.\n\n\n\nUncertainties generated by the evidence\n\nSurvival data from the clinical trials were confounded by the use of different second and further lines of treatment across the trial arms. These treatments are associated with prolonged survival. The effect of cetuximab and panitumumab was also potentially confounded by relying on post-hoc analyses. The true size of the benefit was a source of uncertainty in the clinical- and cost-effectiveness results because the evidence for cetuximab and panitumumab was based on small data sets.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nA subgroup of people with metastases confined to the liver was considered, but after advice from NHS England, this was no longer deemed a clinically relevant subgroup.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe assessment group's network meta-analysis showed that cetuximab plus FOLFIRI and panitumumab plus FOLFOX were more effective than chemotherapy alone. The evidence for cetuximab plus FOLFOX was less conclusive. This evidence was based on a very small clinical trial, OPUS. Clinical experts stated that cetuximab and panitumumab probably had similar effectiveness. There were uncertainties about the results of the network meta-analysis and the credible intervals around the hazard ratios were large.\n\n−4.10\n\nHow has the new clinical evidence that has emerged since the original appraisal (TA176) influenced the current (preliminary) recommendations?\n\nAlthough the current data are more mature than in NICE's technology appraisal guidance on cetuximab for the first-line treatment of metastatic colorectal cancer, there is more uncertainty in the evidence base because it involved smaller populations (based on the stricter definition of wild-type status in the new marketing authorisations).\n\n, 4.6\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee concluded that the assessment group's model reflected clinical practice.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe adjustment for further treatments was a source of uncertainty. The committee concluded that, although the effect of these adjustments on survival were small, they were more plausible than the unadjusted estimates.\n\nThe difference in resection rates between treatment arms was a source of uncertainty. Although it was appropriate to source these from the clinical trials, the discrepancies between them were considered clinically implausible.\n\n, 4.11\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nUtility values were derived from trial-based EQ‑5D data. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years.\n\n, 4.20\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNot applicable.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nGiving cetuximab every 2\xa0weeks was the most important driver of cost effectiveness.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee noted the base-case incremental cost-effectiveness ratios (ICERs), and further noted that the model was associated with uncertainties about the estimates of cost effectiveness from the network meta-analysis and the estimates of resection rates. Despite this, it concluded that they were within the range normally considered to be a cost-effective use of NHS resources for the whole population with previously untreated RAS wild-type metastatic colorectal cancer.\n\n, 4.17, 4.19\n\nHow has the new cost-effectiveness evidence that has emerged since the original appraisal (TA176) influenced the current (preliminary) recommendations?\n\nResection rates were higher in the original appraisal, ranging from 30% to 43% compared with about 7% to 20% in the current appraisal. This is likely to influence cost effectiveness.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nThe committee concluded that both cetuximab plus chemotherapy and panitumumab plus chemotherapy fulfilled NICE's final Cancer Drugs Fund technology appraisal process and methods advice to be considered as life-extending, end-of-life treatments in the overall population of people with RAS wild-type metastatic colorectal cancer.\n\n\n\n\n\nEqualities considerations and social value judgements\n\nNot applicable.\n\n–"}
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https://www.nice.org.uk/guidance/ta439
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Evidence-based recommendations on cetuximab (Erbitux) and panitumumab (Vectibix) for previously untreated RAS wild-type metastatic colorectal cancer in adults.
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Intermediate care including reablement
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Intermediate care including reablement
This guideline covers referral and assessment for intermediate care and how to deliver the service. Intermediate care is a multidisciplinary service that helps people to be as independent as possible. It provides support and rehabilitation to people at risk of hospital admission or who have been in hospital. It aims to ensure people transfer from hospital to the community in a timely way and to prevent unnecessary admissions to hospitals and residential care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The term 'intermediate care' in this guideline refers to all 4 service models of intermediate care described in terms used in this guideline.
# Core principles of intermediate care, including reablement
Ensure that intermediate care practitioners:
develop goals in a collaborative way that optimises independence and wellbeing
adopt a person-centred approach, taking into account cultural differences and preferences.
At all stages of assessment and delivery, ensure good communication between intermediate care practitioners and:
-ther agencies
people using the service and their families and carers.
Intermediate care practitioners should:
work in partnership with the person to find out what they want to achieve and understand what motivates them
focus on the person's own strengths and help them realise their potential to regain independence
build the person's knowledge, skills, resilience and confidence
learn to observe and guide and not automatically intervene, even when the person is struggling to perform an activity, such as dressing themselves or preparing a snack
support positive risk taking.
Ensure that the person using intermediate care and their family and carers know who to speak to if they have any questions or concerns about the service, and how to contact them.
Offer the person the information they need to make decisions about their care and support, and to get the most out of the intermediate care service. Offer this information in a range of accessible formats, for example:
verbally
in written format (in plain English)
in other accessible formats, such as braille or Easy Read
translated into other languages
provided by a trained, qualified interpreter.
# Supporting infrastructure
Consider making home-based intermediate care, reablement, bed-based intermediate care and crisis response all available locally. Deliver these services in an integrated way so that people can move easily between them, depending on their changing support needs.
Ensure that intermediate care is provided in an integrated way by working towards the following:
a single point of access for those referring to the service
a management structure across all services that includes a single accountable person, such as a team leader
a single assessment process
a shared understanding of what intermediate care aims to do
an agreed approach to outcome measurement for reporting and benchmarking.
Contract and monitor intermediate care in a way that allows services to be flexible and person centred. For recommendations on delivering flexible services, see NICE's guideline on home care.
Ensure that intermediate care teams work proactively with practitioners referring into the service so they understand:
the service and what it involves
how it differs from other services
the ethos of intermediate care, specifically that it aims to support people to build independence and improve their quality of life
that intermediate care is free for the period of delivery.
Ensure that mechanisms are in place to promote good communication within intermediate care teams. These might include:
regular team meetings to share feedback and review progress
shared notes
-pportunities for team members to express their views and concerns.
Ensure that the intermediate care team has a clear route of referral to and engagement with commonly used services, for example:
general practice
podiatry
pharmacy
mental health and dementia services
specialist and longer-term rehabilitation services
housing services
voluntary, community and faith services
specialist advice, for example around cultural or language issues.
Consider deploying staff flexibly across intermediate care, where possible following the person from hospital to a community bed‑based service or directly to their home.
Ensure that the composition of intermediate care teams reflects the different needs and circumstances of people using the service.
Ensure that intermediate care teams include a broad range of disciplines. The core team should include practitioners with skills and competences in the following:
delivering intermediate care packages
nursing
social work
therapies, for example occupational therapy, physiotherapy and speech and language therapy
comprehensive geriatric assessment.
# Assessment of need for intermediate care
This section relates to the assessment of a person's support needs. It could be undertaken by a range of professionals, for example therapists, nursing staff or social workers, working in various locations. It aims to ensure that the type of intermediate care support is appropriate for the person's needs and circumstances.
Assess people for intermediate care if it is likely that specific support and rehabilitation would improve their ability to live independently and they:
are at risk of hospital admission or have been in hospital and need help to regain independence or
are living at home and having increasing difficulty with daily life through illness or disability.
Do not exclude people from intermediate care based on whether they have a particular condition, such as dementia, or live in particular circumstances, such as prison, residential care or temporary accommodation.
During assessment identify the person's abilities, needs and wishes so that they can be referred for the most appropriate support.
Actively involve people using services (and their families and carers, as appropriate) in assessments for intermediate care and in decisions such as the setting in which it is provided.
When assessing people for intermediate care, explain to them (and their families and carers, as appropriate) about advocacy services and how to contact them if they wish.
# Referral into intermediate care
People may be referred into the services described in this section by either health or social care practitioners. The location of intermediate care will vary depending on how different areas configure the service to meet local circumstances and needs. Intermediate care could be commissioned by either health or social care commissioners, or jointly as part of an integrated working approach.
Consider providing intermediate care to people in their own homes wherever practical, making any adjustments, for example equipment or adaptations, needed to enable this to happen.
Offer reablement as a first option to people being considered for home care, if it has been assessed that reablement could improve their independence.
For people already using home care, consider reablement as part of the review or reassessment process. Be aware that this may mean providing reablement alongside home care. Take into account the person's needs and preferences when considering reablement and work closely with the home care provider.
Consider reablement for people living with dementia, to support them to maintain and improve their independence and wellbeing.
Consider bed-based intermediate care for people who are in an acute but stable condition but not fit for safe transfer home. Be aware that if the move to bed-based intermediate care takes longer than 2 days it is likely to be less successful.
Refer people to crisis response if they have experienced an urgent increase in health or social care needs and:
the cause of the deterioration has been identified
their support can be safely managed in their own home or care home
the need for more detailed medical assessments has been addressed.
The crisis response service should raise awareness of its purpose and function among other local services such as housing and the voluntary sector. This means making sure they understand:
the service and what it involves
how it differs from other types of intermediate care
how to refer to the service.
# Entering intermediate care
Discuss with the person the aims and objectives of intermediate care and record these discussions. In particular, explain clearly:
that intermediate care is designed to support them to live more independently, achieve their own goals and have a better quality of life
that intermediate care works with existing support networks, including friends, family and carers
how working closely together and taking an active part in their support can produce the best outcomes.
When a person starts using intermediate care, give their family and carers:
information about the service's aims, how it works and the support it will and will not provide
information about resources in the local community that can support them
-pportunities to express their wishes and preferences, alongside those of the person using the service
-pportunities to ask questions about the service and what it involves.
For bed-based intermediate care, start the service within 2 days of receiving an appropriate referral. Be aware that delays in starting intermediate care increase the risk of further deterioration and reduced independence.
## Crisis response
Ensure that the crisis response can be started within 2 hours from receipt of a referral when necessary.
As part of the assessment process, ensure that crisis response services identify the person's ongoing support needs and make arrangements for the person's ongoing support.
Establish close links between crisis response and diagnostics (for example, GP, X‑ray or blood tests) so that people can be diagnosed quickly if needed.
## Person-centred planning
When planning the person's intermediate care:
assess and promote the person's ability to self-manage
tell the person what will be involved
be aware that the person needs to give consent for their information to be shared
tell the person that intermediate care is a short-term service and explain what is likely to happen afterwards.
Carry out a risk assessment as part of planning for intermediate care and then regularly afterwards, as well as when something significant changes. This should include:
assessing the risks associated with the person carrying out particular activities, including taking and looking after their own medicines
assessing the risks associated with their environment
balancing the risk of a particular activity with the person's wishes, wellbeing, independence and quality of life. For recommendations on supporting people in residential care to take and look after their medicines themselves, see NICE's guidelines on managing medicines in care homes and medicines optimisation.
Complete and document a risk plan with the person (and their family and carers, as appropriate) as part of the intermediate care planning process. Ensure that the risk plan includes:
strategies to manage risk; for example, specialist equipment, use of verbal prompts and use of support from others
the implications of taking the risk for the person and the member of staff.
## Agreeing goals
Discuss and agree intermediate care goals with the person. Make sure these goals:
are based on specific and measurable outcomes
take into account the person's health and wellbeing
reflect what the intermediate care service is designed to achieve
reflect what the person wants to achieve both during the period in intermediate care, and in the longer term
take into account how the person is affected by their conditions or experiences
take into account the best interests and expressed wishes of the person.
Recognise that participation in social and leisure activities are legitimate goals of intermediate care.
Document the intermediate care goals in an accessible format and give a copy to the person, and to their family and carers if the person agrees to this.
# Delivering intermediate care
Take a flexible, outcomes-focused approach to delivering intermediate care that is tailored to the person's social, emotional and cognitive and communication needs and abilities.
Review people's goals with them regularly. Adjust the period of intermediate care depending on the progress people are making towards their goals.
Ensure that staff across organisations work together to coordinate review and reassessment, building on current assessment and information. Develop integrated ways of working, for example, joint meetings and training and multidisciplinary team working.
Ensure that specialist support is available to people who need it (for example, in response to complex health conditions), either by training intermediate care staff or by working with specialist organisations.
Ensure that an intermediate care diary (or record) is completed and kept with the person. This should:
provide a detailed day-to-day log of all the support given, documenting the person's progress towards goals and highlighting their needs, preferences and experiences
be updated by intermediate care staff at every visit
be accessible to the person themselves, who should be encouraged to read and contribute to it
keep the person (and their family and carers, as appropriate) and other staff fully informed about what has been provided and about any incidents or changes.
Ensure that intermediate care staff avoid missing visits to people's homes. Be aware that missing visits can have serious implications for the person's health or wellbeing, particularly if they live alone or lack mental capacity.
Contact the person (or their family or carer) if intermediate care staff are going to be late or unable to visit.
# Transition from intermediate care
Before the person finishes intermediate care, providers of intermediate care should give them information about how they can refer themselves back into the service, should their needs or circumstances change.
Ensure good communication between intermediate care staff and other agencies. There should be a clear plan for when people transfer between services, or when the intermediate care service ends. This should:
be documented and agreed with the person and their family or carers
include contact details for the service
include a contingency plan should anything go wrong. For recommendations on communication during transition between services, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.
Give people information about other sources of support available at the end of intermediate care, including support for carers.
# Training and development
Ensure that all staff delivering intermediate care understand:
the service and what it involves
the roles and responsibilities of all team members
how it differs from other services
the ethos of intermediate care, specifically that it aims to support people to build independence
how to work collaboratively with people to agree person-centred goals
positive risk taking.
Ensure that intermediate care staff are able to recognise and respond to:
common conditions, such as diabetes; mental health and neurological conditions, including dementia; frailty; stroke; physical and learning disabilities; sensory loss; and multi-morbidity
common support needs, such as nutrition, hydration, continence, and issues related to overall skin integrity
common support needs, such as dealing with bereavement and end of life
deterioration in the person's health or circumstances.
Provide intermediate care staff with opportunities for:
-bserving the work of another member of staff
enhancing their knowledge and skills in relation to delivering intermediate care
reflecting on their practice together.Document these development activities and record that people have achieved the required level of competence.
Ensure that intermediate care staff have the skills to support people to:
-ptimise recovery
take control of their lives
regain as much independence as possible.
# Terms used in this guideline
## Bed-based intermediate care
Assessment and interventions provided in a bed-based setting, such as an acute hospital, community hospital, residential care home, nursing home, stand-alone intermediate care facility, independent sector facility, local authority facility or other bed-based setting. Bed-based intermediate care aims to prevent unnecessary admissions to acute hospitals and premature admissions to long-term care, and to support timely discharge from hospital. For most people, interventions last up to 6 weeks. Services are usually delivered by a multidisciplinary team but most commonly by healthcare professionals or care staff (in care homes).
## Crisis response
Community-based services provided to people in their own home or a care home. These services aim to avoid hospital admissions. Crisis response usually involves an assessment, and may provide short-term interventions (usually up to 48 hours). Crisis response is delivered by a multidisciplinary team but most commonly by healthcare professionals.
## Home-based intermediate care
Community-based services that provide assessment and interventions to people in their own home or a care home. These services aim to prevent hospital admissions, support faster recovery from illness, support timely discharge from hospital, and maximise independent living. For most people interventions last up to 6 weeks. Services are delivered by a multidisciplinary team but most commonly by healthcare professionals or care staff (in care homes).
## Home care
Care provided in a person's own home by paid care workers which helps them with their daily life. It is also known as domiciliary care. Home care workers are usually employed by an independent agency, and the service may be arranged by the local council or by the person receiving home care (or someone acting on their behalf).
## Intermediate care
A range of integrated services that: promote faster recovery from illness; prevent unnecessary acute hospital admissions and premature admissions to long-term care; support timely discharge from hospital; and maximise independent living. Intermediate care services are usually delivered for no longer than 6 weeks and often for as little as 1 to 2 weeks. Four service models of intermediate care are available: bed-based intermediate care, crisis response, home-based intermediate care, and reablement.
## Person-centred approach
An approach that puts the person at the centre of their support and goal planning. It is based around the person's strengths, needs, preferences and priorities. It involves treating them as an equal partner and considering whether they may benefit from intermediate care, regardless of their living arrangements, socioeconomic status or health conditions.
## Positive risk taking
This involves balancing the positive benefits gained from taking risks against the negative effects of attempting to avoid risk altogether.
## Reablement
Assessment and interventions provided to people in their home (or care home) aiming to help them recover skills and confidence and maximise their independence. For most people interventions last up to 6 weeks. Reablement is delivered by a multidisciplinary team but most commonly by social care practitioners.
For other social care terms see the Think Local, Act Personal Care and Support Jargon Buster.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Some issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:
Ensuring an integrated approach to intermediate care. Currently, the 4 service models of intermediate care tend to operate separately, delivered by different staff and funded from different budgets. Moving to a more integrated approach for planning, funding and delivery of all 4 models, including transferable assessments that are accepted across all services, would improve the experience for people using the services. However, such changes may be difficult to achieve.
Starting bed-based intermediate care services within 2 days (and crisis response within 2 hours) of receiving an appropriate referral. Rapid provision of the right intermediate care service will benefit people using the services, and may help reduce pressure on hospital beds. However, this approach will prove challenging in light of the current financial pressures and demands on the services.
Making sure the aims, objectives and purpose of intermediate care are understood by people using the services, their families, and professionals from the wider health and social care system. There is currently a lack of understanding that the term 'intermediate care' includes intermediate care services funded by the healthcare system and reablement services funded by social care. In addition, there is low awareness that active rehabilitation or reablement is quite different from ongoing care and support.
Developing leadership that promotes clarity of purpose and good communication within each service, and provides guidance and support to staff. This leadership will help staff working in intermediate care services to deliver a service focused on enabling and supporting independence, and optimising wellbeing.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. Taking part in the National Audit of Intermediate Care (NAIC) will help to provide a benchmark for measuring progress and will add to the national data on intermediate care.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
The NHS and social care sectors are experiencing unprecedented pressure due to increasing demand from people living longer, often with complex needs or impairments and 1 or more long-term conditions. Admission to hospital and delays in hospital discharge can create significant anxiety, physical and psychological deterioration, and increased dependence. Multidisciplinary services that focus on rehabilitation and enablement can support people and their families to recover, regain independence, and return or remain at home.
Intermediate care uses a range of service models to help people be as independent as possible. It can prevent hospital admissions, facilitate an earlier, smoother discharge, or be an alternative to residential care. It can also offer people living at home who experience difficulties with daily activities a means to maintain their independence.
This guideline focuses on the 4 service models included in the NHS Benchmarking Network's National Audit of Intermediate Care summary report 2014:
bed-based intermediate care
home-based intermediate care
crisis response
reablement.
These services are for adults aged 18 years or over and are delivered in a range of settings, such as:
community settings, including:
people's own homes
temporary accommodation
specialist housing, such as sheltered, warden-supported or extra care housing
supported living housing (including shared lives schemes)
day centres
residential and nursing care homes
dedicated intermediate care and reablement facilities
acute, community and day hospitals
prisons.
The concept of intermediate care was developed in 2000 in the Department of Health's NHS Plan and implemented in England through their National Service Framework for Older People. Reablement specifically received policy support in 2010 when it was recognised as a means of prolonging or regaining independence.
The Department of Health and Social Care's Care and Support White Paper subsequently announced the transfer of funds from the NHS Commissioning Board to local councils in 2013–14. Most recently, NHS commissioners and local authorities have been required, via the government's Better Care Fund and the NHS Five Year Forward View, to take a more integrated approach to planning by pooling budgets to support models of integrated care and support, including reablement and intermediate care. The Care Act 2014 requires that services, including intermediate care, should consider how person-centred support is planned to promote individual wellbeing.
This guideline covers intermediate care services provided by the NHS and social care, and how these are best planned and delivered alongside services provided by the voluntary and independent sector. It identifies the key components of the intermediate care pathway (see below), and how services can work together with the person and their support networks to deliver effective intermediate care. The guideline draws on the evidence base to highlight best practice, making recommendations that aim to provide equity of access and a more integrated approach to provision. It also aims to bring greater coherence, parity and responsiveness to service delivery, reducing duplication of effort and clarifying responsibilities for service providers.
Local areas may take different approaches to configuring their intermediate care service depending on existing resources and team structures, but the pathway should always include the following functions (described in more detail in the recommendations):
Assessing the need for intermediate care – this includes gathering information about the person and deciding which intermediate care setting is most appropriate. If the person is in hospital, their assessment may include developing goals to include in the referral to the intermediate care team. If the person is at home the assessment may be completed by a social worker, community nurse, crisis response team, or community social care occupational therapist.
Acceptance by the intermediate care service – an individual plan is then developed by the intermediate care team, based on the person's assessment. Goals are agreed with the person and then reviewed regularly. The plan should contain enough information so that staff visiting the person and providing their rehabilitation know what needs to be done.
Delivery of the service – this should always be based on the agreed plan, and if problems arise then support staff should be able to contact the assessing practitioner in the intermediate care team.
A formal review – this should be undertaken as the person approaches achieving their goals with a clear plan for transition from the intermediate care service. If the person has ongoing support needs there may be a handover to a new home care provider or day service. If the person has achieved their desired level of independence the plan may include information about how to refer themselves back into the service if they need to, and links to community services that can support them.
To find out what NICE has said on topics related to this guideline, see our web page on adult social care.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Optimal time between referral and starting intermediate care
What is the optimal time between referral to and starting intermediate care in terms of effectiveness and cost effectiveness and in terms of people's experiences?
## Why this is important
Recommendation 1.5.3 states that for bed-based intermediate care, the service should start within 2 days of a referral being received. There is moderate-quality evidence to suggest that if the referral is made from acute care then the person's condition will begin to deteriorate if intermediate care does not start within 2 days. There is no clear evidence about the most effective timescale for people whose referral is being made in different circumstances, for example if they are at home and being referred for home-based intermediate care or reablement to prevent hospital admission or improve independence.
A comparative evaluation is needed to assess outcomes associated with different lengths of time between referral and starting the 4 intermediate care service models. Also, to assess the resource impact and overall cost effectiveness of different waiting times. Effectiveness and cost-effectiveness research should be complemented by qualitative data from people receiving and delivering the service to investigate their views and experiences and the perceived impact on the person's level of independence and quality of life.
# Team composition for home-based intermediate care
How effective and cost effective are different approaches, in terms of team structure and composition, to providing home-based intermediate care for adults?
## Why this is important
The skill mix and competency of a home-based intermediate care team can influence the quality of care and outcomes. The evidence on views and experiences of home-based intermediate care is exclusively from health and social care practitioners, with no evidence from other care and support practitioners from the community.
Comparative studies are needed to determine the effectiveness and cost effectiveness of different approaches to delivering home-based care and support, in terms of team skills, structure and composition. A better understanding of how these factors influence quality of care could improve outcomes for people who use home-based intermediate care.
Qualitative studies are also needed to explore the views and experiences of a wider range of care and support practitioners. This will help practitioners learn about and understand each other's roles, which will improve their delivery and quality of care.
# Crisis response
What are the barriers and facilitators to providing an effective and cost effective crisis response service, with particular reference to different models for structuring delivery of this service?
## Why this is important
There is no evidence on the effectiveness and cost effectiveness of crisis response services. The evidence that is available shows that practitioners and people using this service found the short-term support provided (up to 48 hours) too limited to address the needs of older people. It is also unclear if health and social care practitioners fully understand the purpose of the crisis response service when making referrals.
Comparative studies are needed to evaluate the different approaches to structuring the delivery of crisis response services to improve outcomes.
Cost information is also needed. This needs to be supplemented by qualitative data to explore how well the crisis response service is understood among practitioners.
# Dementia care
How effective and cost effective is intermediate care including reablement for supporting people living with dementia?
## Why this is important
Some intermediate care and reablement services support people living with dementia. However, others specifically exclude people with a dementia diagnosis, because they are perceived as being unlikely to benefit. There is limited evidence on the effectiveness and cost effectiveness of using intermediate care and reablement to support people with dementia.
There is no evidence on the views and experiences of people living with dementia, their family and carers, or health, social care and housing practitioners, in relation to the support they receive from intermediate care and reablement services.
Comparative effectiveness and cost-effectiveness studies are needed to evaluate the different approaches to delivering support to people with dementia. This will help to ensure that both a person's specialist dementia needs and their intermediate care and reablement needs are accommodated in the most effective way. The studies should include a comparison of care provided by a specialist dementia team with that provided by a generalist team; and access versus no access to memory services. These need to be supplemented with qualitative studies that report the views and experiences of people living with dementia, their family and carers, and practitioners.
# Reablement
How effective and cost effective are repeated periods of reablement, and reablement that lasts longer than 6 weeks?
## Why this is important
The evidence that reablement is more effective than home care at improving people's outcomes is based on data from 1 period of reablement. In current practice, people can use reablement repeatedly. There is no evidence on the outcomes and costs for people who use reablement more than once.
In addition, there is no peer-reviewed study that measures the impact of different durations of reablement for different population groups. This is important because in practice, reablement is funded for up to 6 weeks only. However, some people are offered reablement for a period of more than 6 weeks based on their identified needs. At present there is very limited knowledge about the costs and outcomes of reablement as provided to different population groups, and the optimal duration for these groups.
Longitudinal studies of a naturalistic design with a control group are needed to follow up people who have received reablement several times or over a longer period than 6 weeks, or both.
Comparative studies are also needed to understand the long-term impact of duration on costs and patient outcomes, by comparing 6‑week reablement services with services that last longer than 6 weeks.
# A single point of access for intermediate care
How effective and cost effective is introducing a single point of access to intermediate care?
## Why this is important
There is evidence that poor integration between health and social care is a barrier to successfully implementing intermediate care. A management structure that has a single point of access can help to improve communication between teams and speed up referral and access to services.
Comparative studies are needed to evaluate the effectiveness and cost effectiveness of introducing a management structure that has a single point of access versus a structure with no single point of access. This will help to reduce the length of time from referral to receipt of intermediate care.
# Duration and intensity of home-based intermediate care
How effective and cost effective are different approaches, in terms of duration and intensity, to providing home-based intermediate care for adults?
## Why this is important
There is some evidence that people who used home-based intermediate care found their care ended too suddenly at 6 weeks, and poor communication compounded this negative perception. The optimal time limit can differ depending on people's health and care and support needs.
Studies of comparative designs are needed to assess the effectiveness and cost effectiveness of different intensities and durations of home-based intermediate care for people with a range of care needs.
# Support for black and minority ethnic groups
How effective and cost effective are different approaches to supporting people from black and minority ethnic groups using intermediate care?
## Why this is important
Addressing the cultural, language and religious needs of black and minority ethnic groups can remove some of the barriers to accessing support services. There is no evidence on the effectiveness and cost effectiveness of intermediate care in supporting people from black or minority ethnic groups to access intermediate care and reablement.
Comparative effectiveness and cost-effectiveness studies are needed to evaluate 'what works' in terms of planning and delivering intermediate care for minority groups. This includes all 4 service models of intermediate care. Qualitative data are needed on the views and experiences of people from black and minority ethnic groups, their family, carers, practitioners and voluntary support groups to inform the development of a service that meets the needs of this population.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe term 'intermediate care' in this guideline refers to all 4 service models of intermediate care described in terms used in this guideline.\n\n# Core principles of intermediate care, including reablement\n\nEnsure that intermediate care practitioners:\n\ndevelop goals in a collaborative way that optimises independence and wellbeing\n\nadopt a person-centred approach, taking into account cultural differences and preferences.\n\nAt all stages of assessment and delivery, ensure good communication between intermediate care practitioners and:\n\nother agencies\n\npeople using the service and their families and carers.\n\nIntermediate care practitioners should:\n\nwork in partnership with the person to find out what they want to achieve and understand what motivates them\n\nfocus on the person's own strengths and help them realise their potential to regain independence\n\nbuild the person's knowledge, skills, resilience and confidence\n\nlearn to observe and guide and not automatically intervene, even when the person is struggling to perform an activity, such as dressing themselves or preparing a snack\n\nsupport positive risk taking.\n\nEnsure that the person using intermediate care and their family and carers know who to speak to if they have any questions or concerns about the service, and how to contact them.\n\nOffer the person the information they need to make decisions about their care and support, and to get the most out of the intermediate care service. Offer this information in a range of accessible formats, for example:\n\nverbally\n\nin written format (in plain English)\n\nin other accessible formats, such as braille or Easy Read\n\ntranslated into other languages\n\nprovided by a trained, qualified interpreter.\n\n# Supporting infrastructure\n\nConsider making home-based intermediate care, reablement, bed-based intermediate care and crisis response all available locally. Deliver these services in an integrated way so that people can move easily between them, depending on their changing support needs.\n\nEnsure that intermediate care is provided in an integrated way by working towards the following:\n\na single point of access for those referring to the service\n\na management structure across all services that includes a single accountable person, such as a team leader\n\na single assessment process\n\na shared understanding of what intermediate care aims to do\n\nan agreed approach to outcome measurement for reporting and benchmarking.\n\nContract and monitor intermediate care in a way that allows services to be flexible and person centred. For recommendations on delivering flexible services, see NICE's guideline on home care.\n\nEnsure that intermediate care teams work proactively with practitioners referring into the service so they understand:\n\nthe service and what it involves\n\nhow it differs from other services\n\nthe ethos of intermediate care, specifically that it aims to support people to build independence and improve their quality of life\n\nthat intermediate care is free for the period of delivery.\n\nEnsure that mechanisms are in place to promote good communication within intermediate care teams. These might include:\n\nregular team meetings to share feedback and review progress\n\nshared notes\n\nopportunities for team members to express their views and concerns.\n\nEnsure that the intermediate care team has a clear route of referral to and engagement with commonly used services, for example:\n\ngeneral practice\n\npodiatry\n\npharmacy\n\nmental health and dementia services\n\nspecialist and longer-term rehabilitation services\n\nhousing services\n\nvoluntary, community and faith services\n\nspecialist advice, for example around cultural or language issues.\n\nConsider deploying staff flexibly across intermediate care, where possible following the person from hospital to a community bed‑based service or directly to their home.\n\nEnsure that the composition of intermediate care teams reflects the different needs and circumstances of people using the service.\n\nEnsure that intermediate care teams include a broad range of disciplines. The core team should include practitioners with skills and competences in the following:\n\ndelivering intermediate care packages\n\nnursing\n\nsocial work\n\ntherapies, for example occupational therapy, physiotherapy and speech and language therapy\n\ncomprehensive geriatric assessment.\n\n# Assessment of need for intermediate care\n\nThis section relates to the assessment of a person's support needs. It could be undertaken by a range of professionals, for example therapists, nursing staff or social workers, working in various locations. It aims to ensure that the type of intermediate care support is appropriate for the person's needs and circumstances.\n\nAssess people for intermediate care if it is likely that specific support and rehabilitation would improve their ability to live independently and they:\n\nare at risk of hospital admission or have been in hospital and need help to regain independence or\n\nare living at home and having increasing difficulty with daily life through illness or disability.\n\nDo not exclude people from intermediate care based on whether they have a particular condition, such as dementia, or live in particular circumstances, such as prison, residential care or temporary accommodation.\n\nDuring assessment identify the person's abilities, needs and wishes so that they can be referred for the most appropriate support.\n\nActively involve people using services (and their families and carers, as appropriate) in assessments for intermediate care and in decisions such as the setting in which it is provided.\n\nWhen assessing people for intermediate care, explain to them (and their families and carers, as appropriate) about advocacy services and how to contact them if they wish.\n\n# Referral into intermediate care\n\nPeople may be referred into the services described in this section by either health or social care practitioners. The location of intermediate care will vary depending on how different areas configure the service to meet local circumstances and needs. Intermediate care could be commissioned by either health or social care commissioners, or jointly as part of an integrated working approach.\n\nConsider providing intermediate care to people in their own homes wherever practical, making any adjustments, for example equipment or adaptations, needed to enable this to happen.\n\nOffer reablement as a first option to people being considered for home care, if it has been assessed that reablement could improve their independence.\n\nFor people already using home care, consider reablement as part of the review or reassessment process. Be aware that this may mean providing reablement alongside home care. Take into account the person's needs and preferences when considering reablement and work closely with the home care provider.\n\nConsider reablement for people living with dementia, to support them to maintain and improve their independence and wellbeing.\n\nConsider bed-based intermediate care for people who are in an acute but stable condition but not fit for safe transfer home. Be aware that if the move to bed-based intermediate care takes longer than 2\xa0days it is likely to be less successful.\n\nRefer people to crisis response if they have experienced an urgent increase in health or social care needs and:\n\nthe cause of the deterioration has been identified\n\ntheir support can be safely managed in their own home or care home\n\nthe need for more detailed medical assessments has been addressed.\n\nThe crisis response service should raise awareness of its purpose and function among other local services such as housing and the voluntary sector. This means making sure they understand:\n\nthe service and what it involves\n\nhow it differs from other types of intermediate care\n\nhow to refer to the service.\n\n# Entering intermediate care\n\nDiscuss with the person the aims and objectives of intermediate care and record these discussions. In particular, explain clearly:\n\nthat intermediate care is designed to support them to live more independently, achieve their own goals and have a better quality of life\n\nthat intermediate care works with existing support networks, including friends, family and carers\n\nhow working closely together and taking an active part in their support can produce the best outcomes.\n\nWhen a person starts using intermediate care, give their family and carers:\n\ninformation about the service's aims, how it works and the support it will and will not provide\n\ninformation about resources in the local community that can support them\n\nopportunities to express their wishes and preferences, alongside those of the person using the service\n\nopportunities to ask questions about the service and what it involves.\n\nFor bed-based intermediate care, start the service within 2\xa0days of receiving an appropriate referral. Be aware that delays in starting intermediate care increase the risk of further deterioration and reduced independence.\n\n## Crisis response\n\nEnsure that the crisis response can be started within 2\xa0hours from receipt of a referral when necessary.\n\nAs part of the assessment process, ensure that crisis response services identify the person's ongoing support needs and make arrangements for the person's ongoing support.\n\nEstablish close links between crisis response and diagnostics (for example, GP, X‑ray or blood tests) so that people can be diagnosed quickly if needed.\n\n## Person-centred planning\n\nWhen planning the person's intermediate care:\n\nassess and promote the person's ability to self-manage\n\ntell the person what will be involved\n\nbe aware that the person needs to give consent for their information to be shared\n\ntell the person that intermediate care is a short-term service and explain what is likely to happen afterwards.\n\nCarry out a risk assessment as part of planning for intermediate care and then regularly afterwards, as well as when something significant changes. This should include:\n\nassessing the risks associated with the person carrying out particular activities, including taking and looking after their own medicines\n\nassessing the risks associated with their environment\n\nbalancing the risk of a particular activity with the person's wishes, wellbeing, independence and quality of life. For recommendations on supporting people in residential care to take and look after their medicines themselves, see NICE's guidelines on managing medicines in care homes and medicines optimisation. [This recommendation is adapted from NICE's guideline on home care]\n\nComplete and document a risk plan with the person (and their family and carers, as appropriate) as part of the intermediate care planning process. Ensure that the risk plan includes:\n\nstrategies to manage risk; for example, specialist equipment, use of verbal prompts and use of support from others\n\nthe implications of taking the risk for the person and the member of staff.[This recommendation is adapted from NICE's guideline on home care]\n\n## Agreeing goals\n\nDiscuss and agree intermediate care goals with the person. Make sure these goals:\n\nare based on specific and measurable outcomes\n\ntake into account the person's health and wellbeing\n\nreflect what the intermediate care service is designed to achieve\n\nreflect what the person wants to achieve both during the period in intermediate care, and in the longer term\n\ntake into account how the person is affected by their conditions or experiences\n\ntake into account the best interests and expressed wishes of the person.\n\nRecognise that participation in social and leisure activities are legitimate goals of intermediate care.\n\nDocument the intermediate care goals in an accessible format and give a copy to the person, and to their family and carers if the person agrees to this.\n\n# Delivering intermediate care\n\nTake a flexible, outcomes-focused approach to delivering intermediate care that is tailored to the person's social, emotional and cognitive and communication needs and abilities.\n\nReview people's goals with them regularly. Adjust the period of intermediate care depending on the progress people are making towards their goals.\n\nEnsure that staff across organisations work together to coordinate review and reassessment, building on current assessment and information. Develop integrated ways of working, for example, joint meetings and training and multidisciplinary team working.\n\nEnsure that specialist support is available to people who need it (for example, in response to complex health conditions), either by training intermediate care staff or by working with specialist organisations. [This recommendation is adapted from NICE's guideline on home care]\n\nEnsure that an intermediate care diary (or record) is completed and kept with the person. This should:\n\nprovide a detailed day-to-day log of all the support given, documenting the person's progress towards goals and highlighting their needs, preferences and experiences\n\nbe updated by intermediate care staff at every visit\n\nbe accessible to the person themselves, who should be encouraged to read and contribute to it\n\nkeep the person (and their family and carers, as appropriate) and other staff fully informed about what has been provided and about any incidents or changes.\n\nEnsure that intermediate care staff avoid missing visits to people's homes. Be aware that missing visits can have serious implications for the person's health or wellbeing, particularly if they live alone or lack mental capacity. [This recommendation is adapted from NICE's guideline on home care]\n\nContact the person (or their family or carer) if intermediate care staff are going to be late or unable to visit. [This recommendation is adapted from NICE's guideline on home care]\n\n# Transition from intermediate care\n\nBefore the person finishes intermediate care, providers of intermediate care should give them information about how they can refer themselves back into the service, should their needs or circumstances change.\n\nEnsure good communication between intermediate care staff and other agencies. There should be a clear plan for when people transfer between services, or when the intermediate care service ends. This should:\n\nbe documented and agreed with the person and their family or carers\n\ninclude contact details for the service\n\ninclude a contingency plan should anything go wrong. For recommendations on communication during transition between services, see NICE's guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\nGive people information about other sources of support available at the end of intermediate care, including support for carers.\n\n# Training and development\n\nEnsure that all staff delivering intermediate care understand:\n\nthe service and what it involves\n\nthe roles and responsibilities of all team members\n\nhow it differs from other services\n\nthe ethos of intermediate care, specifically that it aims to support people to build independence\n\nhow to work collaboratively with people to agree person-centred goals\n\npositive risk taking.\n\nEnsure that intermediate care staff are able to recognise and respond to:\n\ncommon conditions, such as diabetes; mental health and neurological conditions, including dementia; frailty; stroke; physical and learning disabilities; sensory loss; and multi-morbidity\n\ncommon support needs, such as nutrition, hydration, continence, and issues related to overall skin integrity\n\ncommon support needs, such as dealing with bereavement and end of life\n\ndeterioration in the person's health or circumstances.[This recommendation is adapted from NICE's guideline on home care]\n\nProvide intermediate care staff with opportunities for:\n\nobserving the work of another member of staff\n\nenhancing their knowledge and skills in relation to delivering intermediate care\n\nreflecting on their practice together.Document these development activities and record that people have achieved the required level of competence.\n\nEnsure that intermediate care staff have the skills to support people to:\n\noptimise recovery\n\ntake control of their lives\n\nregain as much independence as possible.\n\n# Terms used in this guideline\n\n## Bed-based intermediate care\n\nAssessment and interventions provided in a bed-based setting, such as an acute hospital, community hospital, residential care home, nursing home, stand-alone intermediate care facility, independent sector facility, local authority facility or other bed-based setting. Bed-based intermediate care aims to prevent unnecessary admissions to acute hospitals and premature admissions to long-term care, and to support timely discharge from hospital. For most people, interventions last up to 6\xa0weeks. Services are usually delivered by a multidisciplinary team but most commonly by healthcare professionals or care staff (in care homes).\n\n## Crisis response\n\nCommunity-based services provided to people in their own home or a care home. These services aim to avoid hospital admissions. Crisis response usually involves an assessment, and may provide short-term interventions (usually up to 48\xa0hours). Crisis response is delivered by a multidisciplinary team but most commonly by healthcare professionals.\n\n## Home-based intermediate care\n\nCommunity-based services that provide assessment and interventions to people in their own home or a care home. These services aim to prevent hospital admissions, support faster recovery from illness, support timely discharge from hospital, and maximise independent living. For most people interventions last up to 6\xa0weeks. Services are delivered by a multidisciplinary team but most commonly by healthcare professionals or care staff (in care homes).\n\n## Home care\n\nCare provided in a person's own home by paid care workers which helps them with their daily life. It is also known as domiciliary care. Home care workers are usually employed by an independent agency, and the service may be arranged by the local council or by the person receiving home care (or someone acting on their behalf).\n\n## Intermediate care\n\nA range of integrated services that: promote faster recovery from illness; prevent unnecessary acute hospital admissions and premature admissions to long-term care; support timely discharge from hospital; and maximise independent living. Intermediate care services are usually delivered for no longer than 6\xa0weeks and often for as little as 1 to 2\xa0weeks. Four service models of intermediate care are available: bed-based intermediate care, crisis response, home-based intermediate care, and reablement.\n\n## Person-centred approach\n\nAn approach that puts the person at the centre of their support and goal planning. It is based around the person's strengths, needs, preferences and priorities. It involves treating them as an equal partner and considering whether they may benefit from intermediate care, regardless of their living arrangements, socioeconomic status or health conditions.\n\n## Positive risk taking\n\nThis involves balancing the positive benefits gained from taking risks against the negative effects of attempting to avoid risk altogether.\n\n## Reablement\n\nAssessment and interventions provided to people in their home (or care home) aiming to help them recover skills and confidence and maximise their independence. For most people interventions last up to 6 weeks. Reablement is delivered by a multidisciplinary team but most commonly by social care practitioners.\n\nFor other social care terms see the Think Local, Act Personal Care and Support Jargon Buster.", 'Putting this guideline into practice': "NICE has produced tools and resources to help you put this guideline into practice.\n\nSome issues were highlighted that might need specific thought when implementing the recommendations. These were raised during the development of this guideline. They are:\n\nEnsuring an integrated approach to intermediate care. Currently, the 4 service models of intermediate care tend to operate separately, delivered by different staff and funded from different budgets. Moving to a more integrated approach for planning, funding and delivery of all 4 models, including transferable assessments that are accepted across all services, would improve the experience for people using the services. However, such changes may be difficult to achieve.\n\nStarting bed-based intermediate care services within 2\xa0days (and crisis response within 2\xa0hours) of receiving an appropriate referral. Rapid provision of the right intermediate care service will benefit people using the services, and may help reduce pressure on hospital beds. However, this approach will prove challenging in light of the current financial pressures and demands on the services.\n\nMaking sure the aims, objectives and purpose of intermediate care are understood by people using the services, their families, and professionals from the wider health and social care system. There is currently a lack of understanding that the term 'intermediate care' includes intermediate care services funded by the healthcare system and reablement services funded by social care. In addition, there is low awareness that active rehabilitation or reablement is quite different from ongoing care and support.\n\nDeveloping leadership that promotes clarity of purpose and good communication within each service, and provides guidance and support to staff. This leadership will help staff working in intermediate care services to deliver a service focused on enabling and supporting independence, and optimising wellbeing.\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners. Taking part in the National Audit of Intermediate Care (NAIC) will help to provide a benchmark for measuring progress and will add to the national data on intermediate care.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.", 'Context': "The NHS and social care sectors are experiencing unprecedented pressure due to increasing demand from people living longer, often with complex needs or impairments and 1 or more long-term conditions. Admission to hospital and delays in hospital discharge can create significant anxiety, physical and psychological deterioration, and increased dependence. Multidisciplinary services that focus on rehabilitation and enablement can support people and their families to recover, regain independence, and return or remain at home.\n\nIntermediate care uses a range of service models to help people be as independent as possible. It can prevent hospital admissions, facilitate an earlier, smoother discharge, or be an alternative to residential care. It can also offer people living at home who experience difficulties with daily activities a means to maintain their independence.\n\nThis guideline focuses on the 4 service models included in the NHS Benchmarking Network's National Audit of Intermediate Care summary report 2014:\n\nbed-based intermediate care\n\nhome-based intermediate care\n\ncrisis response\n\nreablement.\n\nThese services are for adults aged 18 years or over and are delivered in a range of settings, such as:\n\ncommunity settings, including:\n\n\n\npeople's own homes\n\ntemporary accommodation\n\nspecialist housing, such as sheltered, warden-supported or extra care housing\n\nsupported living housing (including shared lives schemes)\n\nday centres\n\n\n\nresidential and nursing care homes\n\ndedicated intermediate care and reablement facilities\n\nacute, community and day hospitals\n\nprisons.\n\nThe concept of intermediate care was developed in 2000 in the Department of Health's NHS Plan and implemented in England through their National Service Framework for Older People. Reablement specifically received policy support in 2010 when it was recognised as a means of prolonging or regaining independence.\n\nThe Department of Health and Social Care's Care and Support White Paper subsequently announced the transfer of funds from the NHS Commissioning Board to local councils in 2013–14. Most recently, NHS commissioners and local authorities have been required, via the government's Better Care Fund and the NHS Five Year Forward View, to take a more integrated approach to planning by pooling budgets to support models of integrated care and support, including reablement and intermediate care. The Care Act 2014 requires that services, including intermediate care, should consider how person-centred support is planned to promote individual wellbeing.\n\nThis guideline covers intermediate care services provided by the NHS and social care, and how these are best planned and delivered alongside services provided by the voluntary and independent sector. It identifies the key components of the intermediate care pathway (see below), and how services can work together with the person and their support networks to deliver effective intermediate care. The guideline draws on the evidence base to highlight best practice, making recommendations that aim to provide equity of access and a more integrated approach to provision. It also aims to bring greater coherence, parity and responsiveness to service delivery, reducing duplication of effort and clarifying responsibilities for service providers.\n\nLocal areas may take different approaches to configuring their intermediate care service depending on existing resources and team structures, but the pathway should always include the following functions (described in more detail in the recommendations):\n\nAssessing the need for intermediate care – this includes gathering information about the person and deciding which intermediate care setting is most appropriate. If the person is in hospital, their assessment may include developing goals to include in the referral to the intermediate care team. If the person is at home the assessment may be completed by a social worker, community nurse, crisis response team, or community social care occupational therapist.\n\nAcceptance by the intermediate care service – an individual plan is then developed by the intermediate care team, based on the person's assessment. Goals are agreed with the person and then reviewed regularly. The plan should contain enough information so that staff visiting the person and providing their rehabilitation know what needs to be done.\n\nDelivery of the service – this should always be based on the agreed plan, and if problems arise then support staff should be able to contact the assessing practitioner in the intermediate care team.\n\nA formal review – this should be undertaken as the person approaches achieving their goals with a clear plan for transition from the intermediate care service. If the person has ongoing support needs there may be a handover to a new home care provider or day service. If the person has achieved their desired level of independence the plan may include information about how to refer themselves back into the service if they need to, and links to community services that can support them.\n\nTo find out what NICE has said on topics related to this guideline, see our web page on adult social care.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Optimal time between referral and starting intermediate care\n\nWhat is the optimal time between referral to and starting intermediate care in terms of effectiveness and cost effectiveness and in terms of people's experiences?\n\n## Why this is important\n\nRecommendation 1.5.3 states that for bed-based intermediate care, the service should start within 2\xa0days of a referral being received. There is moderate-quality evidence to suggest that if the referral is made from acute care then the person's condition will begin to deteriorate if intermediate care does not start within 2\xa0days. There is no clear evidence about the most effective timescale for people whose referral is being made in different circumstances, for example if they are at home and being referred for home-based intermediate care or reablement to prevent hospital admission or improve independence.\n\nA comparative evaluation is needed to assess outcomes associated with different lengths of time between referral and starting the 4 intermediate care service models. Also, to assess the resource impact and overall cost effectiveness of different waiting times. Effectiveness and cost-effectiveness research should be complemented by qualitative data from people receiving and delivering the service to investigate their views and experiences and the perceived impact on the person's level of independence and quality of life.\n\n# Team composition for home-based intermediate care\n\nHow effective and cost effective are different approaches, in terms of team structure and composition, to providing home-based intermediate care for adults?\n\n## Why this is important\n\nThe skill mix and competency of a home-based intermediate care team can influence the quality of care and outcomes. The evidence on views and experiences of home-based intermediate care is exclusively from health and social care practitioners, with no evidence from other care and support practitioners from the community.\n\nComparative studies are needed to determine the effectiveness and cost effectiveness of different approaches to delivering home-based care and support, in terms of team skills, structure and composition. A better understanding of how these factors influence quality of care could improve outcomes for people who use home-based intermediate care.\n\nQualitative studies are also needed to explore the views and experiences of a wider range of care and support practitioners. This will help practitioners learn about and understand each other's roles, which will improve their delivery and quality of care.\n\n# Crisis response\n\nWhat are the barriers and facilitators to providing an effective and cost effective crisis response service, with particular reference to different models for structuring delivery of this service?\n\n## Why this is important\n\nThere is no evidence on the effectiveness and cost effectiveness of crisis response services. The evidence that is available shows that practitioners and people using this service found the short-term support provided (up to 48\xa0hours) too limited to address the needs of older people. It is also unclear if health and social care practitioners fully understand the purpose of the crisis response service when making referrals.\n\nComparative studies are needed to evaluate the different approaches to structuring the delivery of crisis response services to improve outcomes.\n\nCost information is also needed. This needs to be supplemented by qualitative data to explore how well the crisis response service is understood among practitioners.\n\n# Dementia care\n\nHow effective and cost effective is intermediate care including reablement for supporting people living with dementia?\n\n## Why this is important\n\nSome intermediate care and reablement services support people living with dementia. However, others specifically exclude people with a dementia diagnosis, because they are perceived as being unlikely to benefit. There is limited evidence on the effectiveness and cost effectiveness of using intermediate care and reablement to support people with dementia.\n\nThere is no evidence on the views and experiences of people living with dementia, their family and carers, or health, social care and housing practitioners, in relation to the support they receive from intermediate care and reablement services.\n\nComparative effectiveness and cost-effectiveness studies are needed to evaluate the different approaches to delivering support to people with dementia. This will help to ensure that both a person's specialist dementia needs and their intermediate care and reablement needs are accommodated in the most effective way. The studies should include a comparison of care provided by a specialist dementia team with that provided by a generalist team; and access versus no access to memory services. These need to be supplemented with qualitative studies that report the views and experiences of people living with dementia, their family and carers, and practitioners.\n\n# Reablement\n\nHow effective and cost effective are repeated periods of reablement, and reablement that lasts longer than 6\xa0weeks?\n\n## Why this is important\n\nThe evidence that reablement is more effective than home care at improving people's outcomes is based on data from 1 period of reablement. In current practice, people can use reablement repeatedly. There is no evidence on the outcomes and costs for people who use reablement more than once.\n\nIn addition, there is no peer-reviewed study that measures the impact of different durations of reablement for different population groups. This is important because in practice, reablement is funded for up to 6\xa0weeks only. However, some people are offered reablement for a period of more than 6\xa0weeks based on their identified needs. At present there is very limited knowledge about the costs and outcomes of reablement as provided to different population groups, and the optimal duration for these groups.\n\nLongitudinal studies of a naturalistic design with a control group are needed to follow up people who have received reablement several times or over a longer period than 6\xa0weeks, or both.\n\nComparative studies are also needed to understand the long-term impact of duration on costs and patient outcomes, by comparing 6‑week reablement services with services that last longer than 6\xa0weeks.\n\n# A single point of access for intermediate care\n\nHow effective and cost effective is introducing a single point of access to intermediate care?\n\n## Why this is important\n\nThere is evidence that poor integration between health and social care is a barrier to successfully implementing intermediate care. A management structure that has a single point of access can help to improve communication between teams and speed up referral and access to services.\n\nComparative studies are needed to evaluate the effectiveness and cost effectiveness of introducing a management structure that has a single point of access versus a structure with no single point of access. This will help to reduce the length of time from referral to receipt of intermediate care.\n\n# Duration and intensity of home-based intermediate care\n\nHow effective and cost effective are different approaches, in terms of duration and intensity, to providing home-based intermediate care for adults?\n\n## Why this is important\n\nThere is some evidence that people who used home-based intermediate care found their care ended too suddenly at 6\xa0weeks, and poor communication compounded this negative perception. The optimal time limit can differ depending on people's health and care and support needs.\n\nStudies of comparative designs are needed to assess the effectiveness and cost effectiveness of different intensities and durations of home-based intermediate care for people with a range of care needs.\n\n# Support for black and minority ethnic groups\n\nHow effective and cost effective are different approaches to supporting people from black and minority ethnic groups using intermediate care?\n\n## Why this is important\n\nAddressing the cultural, language and religious needs of black and minority ethnic groups can remove some of the barriers to accessing support services. There is no evidence on the effectiveness and cost effectiveness of intermediate care in supporting people from black or minority ethnic groups to access intermediate care and reablement.\n\nComparative effectiveness and cost-effectiveness studies are needed to evaluate 'what works' in terms of planning and delivering intermediate care for minority groups. This includes all 4 service models of intermediate care. Qualitative data are needed on the views and experiences of people from black and minority ethnic groups, their family, carers, practitioners and voluntary support groups to inform the development of a service that meets the needs of this population."}
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https://www.nice.org.uk/guidance/ng74
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This guideline covers referral and assessment for intermediate care and how to deliver the service. Intermediate care is a multidisciplinary service that helps people to be as independent as possible. It provides support and rehabilitation to people at risk of hospital admission or who have been in hospital. It aims to ensure people transfer from hospital to the community in a timely way and to prevent unnecessary admissions to hospitals and residential care.
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3c843dcc84853eb52200f5b78a930373c79f3b3b
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nice
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Type 2 diabetes: prevention in people at high risk
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Type 2 diabetes: prevention in people at high risk
This guideline covers how to identify adults at high risk of type 2 diabetes. It aims to remind practitioners that age is no barrier to being at high risk of, or developing, the condition. It also aims to help them provide those at high risk with an effective and appropriate intensive lifestyle-change programme to prevent or delay the onset of type 2 diabetes. The recommendations in this guideline can be used alongside the NHS Health Check programme.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Risk assessment
GPs and other health professionals and community practitioners in health and community venues should implement a two-stage strategy to identify people at high risk of type 2 diabetes (and those with undiagnosed type 2 diabetes). First, a risk assessment should be offered (see recommendation 1.1.3). Second, where necessary, a blood test should be offered to confirm whether people have type 2 diabetes or are at high risk (see recommendation 1.1.4).
Service providers including pharmacists, managers of local health and community services and voluntary organisations, employers and leaders of faith groups should offer validated self-assessment questionnaires or validated web-based tools (for examples, see the Diabetes UK website). They should also provide the information needed to complete and interpret them. The tools should be available in local health, community and social care venues. Examples of possible health venues include: community pharmacies, dental surgeries, NHS walk-in centres and opticians. Examples of community and social care venues include: workplaces, job centres, local authority leisure services, shops, libraries, faith centres, residential and respite care homes and day centres (for older adults and for adults with learning disabilities).
Public health, primary care and community services should publicise local opportunities for risk assessment and the benefits of preventing (or delaying the onset of) type 2 diabetes. The information should be up-to-date and provided in a variety of formats. It should also be tailored for different groups and communities. For example, by offering translation services and information in languages used locally.
Where risk assessment is conducted by health professionals in NHS venues outside general practice (for example, in community pharmacies) the professionals involved should ensure the results are passed on to the person's GP.
GPs should keep records of all risk assessment results to ensure appropriate follow-up and continuity of care.
Where self-assessment is offered in community venues, health professionals and community practitioners in those venues should encourage people with an intermediate or high risk score to visit their GP to discuss how to manage their risk. Those at high risk should be offered a blood test by their GP.
Ensure health professionals and community practitioners involved with risk assessments in community venues communicate closely with, and receive support from, NHS diabetes risk-assessment and prevention services. They should aim to ensure continuity of care and avoid unnecessary duplication of risk assessments.
Managers in primary and secondary healthcare should ensure staff actively seek out and offer risk assessments to people who might not realise they could be at high risk. This includes people with particular conditions that can increase the risk such as: cardiovascular disease, hypertension, obesity, stroke, polycystic ovary syndrome, a history of gestational diabetes and mental health problems. In addition, people with learning disabilities and those attending accident and emergency, emergency medical admissions units, vascular and renal surgery units and ophthalmology departments may be at high risk.
# Encouraging people to have a risk assessment
Encourage the following to have a risk assessment:
all eligible adults aged 40 and above, except pregnant women
people aged 25 to 39 of South Asian, Chinese, African-Caribbean, black African and other high-risk black and minority ethnic groups, except pregnant women
adults with conditions that increase the risk of type 2 diabetes.Particular conditions can increase the risk of type 2 diabetes. These include: cardiovascular disease, hypertension, obesity, stroke, polycystic ovary syndrome, a history of gestational diabetes and mental health problems. People with learning disabilities and those attending accident and emergency, emergency medical admissions units, vascular and renal surgery units and ophthalmology departments may also be at high risk. NICE's guideline on non-alcoholic fatty liver disease notes that it increases the risk of type 2 diabetes.
Explain to people why, even though they feel healthy, they can still be at risk of developing type 2 diabetes. Explain the implications of being at risk and that this can be reduced by making lifestyle changes.
Tell people how and where they can be assessed, including at their GP surgery or community pharmacy. Make people aware that they can use a validated self-assessment questionnaire or validated web-based tools (for examples, see the Diabetes UK website). Explain that those who are eligible can be assessed by the NHS Health Check programme. (This programme is for people aged 40 to 74 who are not on a disease register and have not been diagnosed with coronary heart disease, hypertension, atrial fibrillation, stroke, transient ischaemic attack, type 2 diabetes or kidney disease. They will be treated and managed using established healthcare pathways.)
Encourage people who are less likely to attend a GP surgery to go elsewhere for a risk assessment. Possibilities include community pharmacies, dental surgeries, NHS walk-in centres and opticians. Assessments may also be offered in community venues. Examples include: workplaces, job centres, local authority leisure facilities, shops, libraries, faith centres, residential and respite care homes and day centres (for older adults and for adults with learning disabilities).
Advise people with type 2 diabetes to encourage family members to have their risk assessed.
# Risk identification (stage 1)
GPs and other primary healthcare professionals should use a validated computer-based risk-assessment tool to identify people on their practice register who may be at high risk of type 2 diabetes. The tool should use routinely available data from patients' electronic health records. If a computer-based risk-assessment tool is not available, they should provide a validated self-assessment questionnaire, for example, the Diabetes Risk Score assessment tool. This is available to health professionals on request from Diabetes UK.
GPs and other primary healthcare professionals should not exclude people from assessment, investigation or intervention on the basis of age, as everyone can reduce their risk, including people aged 75 years and over.
Pharmacists, opticians, occupational health nurses and community leaders should offer a validated self-assessment questionnaire to adults aged 40 and over, people of South Asian and Chinese descent aged 25 to 39, and adults with conditions that increase the risk of type 2 diabetes, other than pregnant women. Or they should tell people how to access specific, validated online self-assessment tools, such as the Diabetes Risk Score featured on the Diabetes UK website. Particular conditions can increase the risk of type 2 diabetes. These include: cardiovascular disease, hypertension, obesity, stroke, polycystic ovary syndrome, a history of gestational diabetes and mental health problems. People with learning disabilities and those attending accident and emergency, emergency medical admissions units, vascular and renal surgery units and ophthalmology departments may also be at high risk. NICE's guideline on non-alcoholic fatty liver disease notes that it increases the risk of type 2 diabetes.
Pharmacists, opticians, occupational health nurses and community leaders involved in risk assessments should advise people with a high risk score to contact their GP or practice nurse for a blood test. The aim is to check if they have type 2 diabetes or to confirm their level of risk and discuss how to reduce it.
All providers of risk assessments should explain to those attending for a type 2 diabetes risk assessment the implications of being at high risk and the consequences of developing the condition.
All providers of risk assessments should discuss with those attending for a type 2 diabetes risk assessment how to prevent or delay the onset of the condition. This includes being more physically active, achieving and maintaining a healthy weight, eating less fat and eating more dietary fibre. They should also tell people where to get advice and support to maintain these lifestyle changes in the long term.
# Risk identification (stage 2)
Trained healthcare professionals should offer venous blood tests (fasting plasma glucose or HbA1c) to adults with high risk scores (stage 2 of the identification process). They should also consider a blood test for those aged 25 and over of South Asian or Chinese descent whose body mass index (BMI) is greater than 23 kg/m2. The aim is to:
determine the risk of progression to type 2 diabetes (a fasting plasma glucose of 5.5 to 6.9 mmol/l or an HbA1c level of 42 to 47 mmol/mol indicates high risk) or
identify possible type 2 diabetes by using fasting plasma glucose, HbA1c or an oral glucose tolerance test (OGTT), according to World Health Organization (WHO) HbA1c criteria.
Ensure HbA1c tests, including point-of-care tests, conform to expert consensus reports on appropriate use and national quality specifications (see NHS Diabetes website and WHO guidance on using HbA1c for diagnosing diabetes. The tests should only be carried out by trained staff.
# Matching interventions to risk
See why the committee made the 2017 recommendations on intensive lifestyle-change programmes .
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For people at low risk (that is, those who have a low or intermediate risk score), tell the person that they are currently at low risk, which does not mean they are not at risk – or that their risk will not increase in the future. Offer them brief advice.
As part of brief advice:
Discuss people's risk factors and how they could improve their lifestyle to reduce overall risk.
Offer encouragement and reassurance.
Offer verbal and written information about culturally appropriate local services and facilities that could help them change their lifestyle. Examples could include information or support to: improve their diet (including details of any local markets offering cheap fruit and vegetables); increase their physical activity and reduce the amount of time spent being sedentary (including details about walking or other local physical activity groups and low-cost recreation facilities). The information should be provided in a range of formats and languages.
For people with a moderate risk (a high risk score, but with a fasting plasma glucose less than 5.5 mmol/l or HbA1c of less than 42 mmol/mol ):
Tell the person that they are currently at moderate risk, and their risks could increase in the future. Explain that it is possible to reduce the risk. Briefly discuss their particular risk factors, identify which ones can be modified and discuss how they can achieve this by changing their lifestyle.
Offer them a brief intervention to help them change their lifestyle: give information about services that use evidence-based behaviour-change techniques that could help them change, bearing in mind their risk profile. Services cited could include walking programmes, slimming clubs or structured weight-loss programmes. (See recommendations 1.11.1 to 1.14.3.)
Discuss whether they would like to join a structured weight-loss programme. Explain that this would involve an individual assessment and tailored advice about diet, physical activity and behaviour change. Let them know which local programmes offer this support – and where to find them.
For people confirmed as being at high risk (a high risk score and fasting plasma glucose of 5.5–6.9 mmol/l or HbA1c of 42 to 47 mmol/mol ):
Tell the person they are currently at high risk but that this does not necessarily mean they will progress to type 2 diabetes. Explain that the risk can be reduced. Briefly discuss their particular risk factors, identify which ones can be modified and discuss how they can achieve this by changing their lifestyle.
Offer them a referral to a local, evidence-based, quality-assured intensive lifestyle-change programme(see recommendations 1.8.1 to 1.10.2). In addition, give them details of where to obtain independent advice from health professionals.
When commissioning local or national services to deliver intensive lifestyle-change programmes (see recommendations 1.8.1 to 1.10.2) where the availability of places is limited, prioritise people with a fasting plasma glucose of 6.5 to 6.9 mmol/l or HbA1c of 44 to 47 mmol/mol .
Ensure that intensive lifestyle-change programmes are designed to help as many people as possible to access and take part in them (see sections 1.1.5 and 1.16 for recommendations on providing information and services, and supporting lifestyle change in people who may need particular support).
For people with possible type 2 diabetes (fasting plasma glucose of, 7.0 mmol/l or above, or HbA1c of 48 mmol/mol or above, but no symptoms of type 2 diabetes):
Carry out a second blood test. If type 2 diabetes is confirmed, treat this in accordance with NICE's guideline on managing type 2 diabetes. Ensure blood testing conforms to national quality specifications.
If type 2 diabetes is not confirmed, offer them a referral to a local, quality-assured, intensive lifestyle-change programme (see recommendations 1.8.1 to 1.10.2).
For people with a high risk score who prefer not to have a blood test, or who do not use primary healthcare services, discuss the importance of early diagnosis to help reduce the risk of long-term complications. Use clinical judgement, based on the person's risk score, to decide whether to offer them a brief intervention or a referral to an intensive lifestyle-change programme (see recommendations 1.8.1 to 1.10.2).
# Reassessing risk
Keep an up-to-date register of people's level of risk. Introduce a recall system to contact and invite people for regular review, using the two-stage strategy (see recommendations 1.1.3 and 1.1.4).
Offer a reassessment based on the level of risk. Use clinical judgement to determine when someone might need to be reassessed more frequently, based on their combination of risk factors (such as their body mass index , relevant illnesses or conditions, ethnicity and age).
For people at low risk (with a low or intermediate risk score) offer to reassess them at least every 5 years to match the timescales used by the NHS Health Check programme. Use a validated risk-assessment tool.
For people at moderate risk (a high risk score, but with a fasting plasma glucose less than 5.5 mmol/l, or HbA1c less than 42 mmol/mol ), offer to reassess them at least every 3 years.
For people at high risk (a high risk score and fasting plasma glucose of 5.5 to 6.9 mmol/l, or HbA1c of 42 to 47 mmol/mol ), offer a blood test at least once a year (preferably using the same type of test). Also offer to assess their weight or BMI. This includes people without symptoms of type 2 diabetes whose:
first blood test measured fasting plasma glucose at 7.0 mmol/l or above, or an HbA1c of 48 mmol/mol (6.5%) or greater, but
whose second blood test did not confirm a diagnosis of type 2 diabetes.
At least once a year, review the lifestyle changes people at high risk have made. Use the review to help reinforce their dietary and physical activity goals, as well as checking their risk factors. The review could also provide an opportunity to help people 'restart', if lifestyle changes have not been maintained.
# Commissioning risk identification and intensive lifestyle-change programmes
Health and wellbeing boards and public health commissioners should make type 2 diabetes prevention a priority in the joint health and wellbeing strategy. They should identify local needs by:
Using anonymised, regional and local health data and routinely collected surveillance data on specific population groups or geographical areas to inform the joint strategic needs assessment.
Mapping local diet, weight management and physical activity services and interventions (for example, slimming clubs). This should include details about locations, opening times and accessibility, staffing levels and the range of professional skills available. It should also include details of any tailored support provided by trained personnel.
Health and wellbeing boards and public health commissioners, working with clinical commissioning groups, should develop a comprehensive and coordinated type 2 diabetes prevention commissioning plan, based on the data collated. This should include:
Action to raise awareness of the risks of type 2 diabetes.
A proactive, two-stage approach to identifying people at high risk (and those with undiagnosed type 2 diabetes).
Evidence-based, quality-assured intensive lifestyle-change programmes.
Health and wellbeing boards and public health commissioners, working with clinical commissioning groups, should ensure the commissioning plan:
Sets out organisational responsibilities for local type 2 diabetes risk assessments. These could take place in primary care or community pharmacies as part of, or as a local addition to, the NHS Health Check programme, or as a self-assessment in community venues and workplaces.
Establishes arrangements to invite people of South Asian and Chinese descent aged 25 and over for a risk assessment at least once every 5 years. (Invitations and follow-up could be integrated within the NHS Health Check programme.)
Encourages employers in public and private sector organisations to include risk assessments in their occupational health service contracts.
Supports the development of coordinated referral pathways for evidence-based and quality-assured intensive lifestyle-change programmes that cover physical activity, weight management and diet, and which teach behaviour-change techniques.
Makes it clear that everyone (including older people, those from minority ethnic groups and vulnerable or socially disadvantaged people) should be offered risk assessments and intensive lifestyle-change programmes at times, and in locations, that meet their needs.
Makes provision for people who may have difficulty accessing, or are unlikely to access, services in conventional healthcare venues.
Makes it clear that risk-assessment services and intensive lifestyle-change programmes should be delivered by trained practitioners (see recommendations 1.18.1 to 1.18.5).
Health and wellbeing boards and public health commissioners, working with clinical commissioning groups, should integrate the commissioning plan with the joint health and wellbeing strategy. They should ensure it is delivered through services operating across the NHS, local authorities and other organisations in the private, community and voluntary sectors.
Health and wellbeing boards and public health commissioners should regularly evaluate services in the context of these recommendations and changing local needs. They should use local accountability mechanisms (for example, health scrutiny reports) to examine specific issues.
Health and wellbeing boards and public health commissioners should evaluate or compare the different service options and make the findings publicly available. Assessments should focus on changes in participants' physical activity levels, weight and dietary intake (of fat, saturated fat and fibre) over 12 to 24 months.
# Quality-assured, intensive lifestyle-change programmes: design and delivery
Provide specially designed and quality-assured intensive lifestyle-change programmes for groups of 10 to 15 people at high risk of developing type 2 diabetes.
Involve the target community (including community leaders) in planning the design and delivery of the programme to ensure it is sensitive and flexible to the needs, abilities and cultural or religious norms of local people. For example, the programme should offer practical learning opportunities, particularly for those who have difficulties with communication or literacy or whose first language is not English.
Ensure programmes are delivered by practitioners with relevant knowledge and skills who have received externally accredited training (see recommendations 1.18.1 to 1.18.5). Where relevant expertise is lacking, involve health professionals and specialists (such as dietitians and health psychologists) in the design and delivery of services.
Ensure programmes adopt a person-centred, empathy-building approach. This includes finding ways to help participants make gradual changes by understanding their beliefs, needs and preferences. It also involves building their confidence and self-efficacy over time.
Ensure programme components are delivered in a logical progression. For example: discussion of the risks and potential benefits of lifestyle change; exploration of someone's motivation to change; action planning; self-monitoring and self-regulation.
Ensure groups meet at least eight times over a period of 9 to 18 months. Participants should have at least 16 hours of contact time either within a group, on a one-to-one basis or using a mixture of both approaches.
Offer more intensive support at the start of the programme by delivering core sessions frequently (for example, weekly or fortnightly). Reduce the frequency of sessions over time to encourage more independent lifestyle management.
Allow time between sessions for participants to make gradual changes to their lifestyle – and to reflect on and learn from their experiences. Also allow time during sessions for them to share this learning with the group.
Deliver programmes in a range of venues such as workplaces, leisure, community and faith centres, and outpatient departments and clinics. Run them at different times, including during evenings and at weekends, to ensure they are as accessible as possible.
As part of the programme, offer referral to, or seek advice from, people with specialist training where necessary. For example, refer someone to a dietitian for assessment and specialist dietary advice if required.
Offer follow-up sessions at regular intervals (for example, every 3 months) for at least 2 years following the initial intervention period. The aim is to reinforce the positive behaviour change and to provide support, in case of relapse. Larger group sizes may be feasible for these maintenance sessions.
Link the programmes with weight management and other prevention initiatives that help people to change their diet or become more physically active.
# Quality-assured, intensive lifestyle-change programmes: content
Intensive lifestyle-change programmes should offer ongoing tailored advice, support and encouragement to help people:
undertake at least a level of physical activity that is in line with government recommendations (see the UK Chief Medical Officers' physical activity guidelines for more information)
gradually lose weight to reach and maintain a BMI within the healthy range
increase their consumption of wholegrains, vegetables and other foods that are high in dietary fibre
reduce the total amount of fat in their diet
eat less saturated fat.
Established behaviour-change techniques should be used (see NICE's guideline on behaviour change: general approaches), including at least all of the following:
Information provision: to raise awareness of the benefits of and types of lifestyle changes needed to achieve and maintain a healthy weight, building on what participants already know.
Exploration and reinforcement of participants' reasons for wanting to change and their confidence about making changes. This may include using motivational interviewing or similar techniques suitably adapted for use in groups.
Goal setting: prompting participants to set achievable and personally relevant short- and long-term goals (for example, to lose 5–10% of their weight in 1 year is a realistic initial target, or to be more physically active).
Action planning: prompting participants to produce action plans detailing what specific physical activity or eating behaviour they intend to change – and when, where and how this will happen. They should start with achievable and sustainable short-term goals and set graded tasks (starting with an easy task and gradually increasing the difficulty as they progress towards their goal). The aim is to move over time towards long-term, lifestyle change.
Coping plans and relapse prevention: prompting participants to identify and find ways to overcome barriers to making permanent changes to their exercise and eating habits. This could include the use of strategies such as impulse-control techniques (to improve management of food cravings).
Participants in intensive lifestyle-change programmes should be encouraged to involve a family member, friend or carer who can offer emotional, information, planning or other practical support to help them make the necessary changes. For example, they may be able to join the participant in physical activities, help them to plan changes, make or accept changes to the family's diet or free up the participant's time so they can take part in preventive activities. (It may sometimes be appropriate to encourage the participant to get support from the whole family.)
Participants should be encouraged to use self-regulation techniques. This includes self-monitoring (for example, by weighing themselves, or measuring their waist circumference or both). They should also review their progress towards achieving their goals, identify and find ways to solve problems and then revise their goals and action plans, where necessary. The aim is to encourage them to learn from experience.
# Quality-assured, intensive lifestyle-change programmes: evaluation
Evaluate intensive lifestyle-change programmes by recording people's health outcomes at 12 months, or more frequently, if appropriate (for example, every 6 months). As a minimum, include the following measures:
number and demographics of adults registered
level of attendance
changes in the amount of moderate to vigorous physical activity undertaken each week
changes in dietary intake, with a focus on total intake of fat, saturated fat and fibre
changes in weight, waist circumference or BMI
changes in fasting plasma glucose or HbA1c levels.
Conduct an annual audit of how the programme was delivered. For example, check the:
number of educators involved
level of training
number and demographics of adults registered
level of uptake for example, the percentage of those invited who attend the first session
programme content (for example, the use of behaviour-change techniques and empathy-building skills)
methods of delivery.
# Raising awareness of the importance of physical activity
Find out what people already know about the benefits of physical activity and the problems associated with a sedentary lifestyle. Where necessary, provide this information. In addition, explain that being more physically active can help reduce their risk of type 2 diabetes, even when that is the only lifestyle change they make.
Explain the government recommendations for weekly physical activity (see the UK Chief Medical Officers' physical activity guidelines for more information).
In cases where it is unrealistic to expect someone to meet the recommended minimum, explain that even small increases in physical activity will be beneficial – and can act as a basis for future improvements.
Explain that people should also reduce the amount of time they spend sitting at a computer or watching TV. Encourage them to be more active during work breaks, for example, by going for a walk at lunchtime.
Explain that some people may need to be more physically active to help lose weight or maintain weight loss (see NICE's guideline on obesity).
# Providing tailored advice on physical activity
Help people to identify which of their activities involve 'moderate' or 'vigorous' physical activity and the extent to which they are meeting the national minimum recommendation on physical activity. Use a validated tool such as the Department of Health's general practitioner physical activity questionnaire or the international physical activity questionnaire (IPAQ).
Encourage people to choose physical activities they enjoy or that fit easily within their daily lives. For example, they may choose to do specific activities such as walking, cycling, swimming, dancing or aerobics. Or they could build physical activity into their daily life – for example, by walking or cycling instead of using a car for short journeys, and by taking the stairs instead of the lift.
Encourage people to set short and long-term goals for example, on how far they walk or cycle, or the number or length of activities undertaken every week. In addition, encourage them to keep a record of their activity for example, by using a pedometer, and to record the things that make it easier or harder. Help them to find other ways to identify and overcome any barriers to physical activity.
Consider referring people who want structured or supervised exercise to an exercise referral scheme or supervised exercise sessions, as part of an intensive lifestyle-change programme.
Provide information on local opportunities for physical activity.
For more recommendations on increasing physical activity, see NICE's guidelines on physical activity in the workplace, physical activity and the environment, walking and cycling, physical activity: brief advice for adults in primary care, and exercise referral schemes.
# Weight management advice
Advise and encourage overweight and obese people to reduce their weight gradually by reducing their calorie intake. Explain that losing 5 to 10% of their weight in 1 year is a realistic initial target that would help reduce their risk of type 2 diabetes and also lead to other, significant health benefits.
Use evidence-based behaviour-change techniques to help overweight and obese people eat less, be more physically active and make long term changes to their diet that result in steady weight loss (see recommendations 1.14.1 to 1.14.3).
Motivate and support overweight and obese people to continue to lose weight until they have achieved – and can maintain – a BMI within the healthy range. (For the general population, the healthy range is between 18.5 and 24.9 kg/m2. For people of South Asian or Chinese descent, the range is likely to be between 18.5 and 22.9 kg/m2.)
Encourage people to check their weight and waist measurement periodically. Provide brief advice about how to measure their waist correctly (for an example, visit the British Heart Foundation website).
Offer people with a BMI of 30 kg/m2 or more (27.5 kg/m2 or more if South Asian or Chinese) a structured weight-loss programme as part of, or to supplement, the intensive lifestyle-change programme. Or, if more appropriate, offer them a referral to a dietitian or another appropriately trained health professional. Ensure they are given a personal assessment and tailored advice about diet, physical activity and what techniques to use to help change their behaviour.
GPs and other health professionals should continue to monitor, support and care for people with a BMI of 30 kg/m2 or more (27.5 kg/m2 or more if South Asian or Chinese) who join slimming clubs or other weight-loss programmes.
GPs should consider offering orlistat, in conjunction with a low-fat diet, to help those who are unable to lose weight by lifestyle-change alone (see recommendations 1.20.1 to 1.20.6).
If the weight management interventions in recommendations 1.13.1 to 1.13.7 have been unsuccessful, refer people to a specialist obesity management service (see NICE's guideline on obesity).
# Dietary advice
Find out what people already know about the types and amounts of food and drink that can help reduce the risk of type 2 diabetes. Provide this information where necessary. Explain that increasing dietary fibre intake and reducing fat intake (particularly saturated fat) can help reduce the chances of developing type 2 diabetes.
Help people to assess their diet and identify where and how they could make it healthier, taking into account their individual needs, preferences and circumstances. (For example, take into account whether they need to lose weight or if they have a limited income.)
Encourage people to:
Increase their consumption of foods that are high in fibre, such as wholegrain bread and cereals, beans and lentils, vegetables and fruit.
Choose foods that are lower in fat and saturated fat, for example, by replacing products high in saturated fat (such as butter, ghee, some margarines or coconut oil) with versions made with vegetable oils that are high in unsaturated fat, or using low-fat spreads.
Choose skimmed or semi-skimmed milk and low-fat yoghurts, instead of cream and full-fat milk and dairy products.
Choose fish and lean meats instead of fatty meat and processed meat products (such as sausages and burgers).
Grill, bake, poach or steam food instead of frying or roasting (for example, choose a baked potato instead of chips).
Avoid food high in fat such as mayonnaise, chips, crisps, pastries, poppadums (papads) and samosas.
Choose fruit, unsalted nuts or low-fat yoghurt as snacks instead of cakes, biscuits, bombay mix or crisps.
# Vulnerable groups: information and services
Provide up-to-date information in a variety of formats about local opportunities for risk assessment and the benefits of preventing (or delaying the onset of) type 2 diabetes. This should be tailored for different groups and communities. For example, messages could be provided in a visual, Braille or audio format.
Provide integrated risk-assessment services and intensive lifestyle-change programmes for prisons and residential homes, as appropriate.
Offer longer appointment times or outreach services to discuss the options following a risk assessment and blood test.
Ensure intensive lifestyle-change programmes are delivered by sensitive, well trained and dedicated people who are also trained to work with vulnerable groups.
Offer to refer travellers and people from other mobile populations to prevention initiatives in the area they are moving to. Or use electronic communications (for example, telephone or text messages as appropriate) to deliver programmes or provide ongoing support. Ensure confidentiality is maintained.
# Vulnerable groups: supporting lifestyle change
Ensure all staff involved in the care of vulnerable groups understand the risk factors for type 2 diabetes and how they can help people reduce their risk. Staff should also be able to recognise and address (where possible) issues which mean someone gives their health a low priority.
Make all staff aware of the benefits of physical activity and reducing the time spent being sedentary. Where possible, encourage them to increase the opportunities for those in their care to be physically active.
Ensure staff offer to refer people to risk-assessment services and quality-assured, intensive lifestyle-change programmes in the community. Or, where necessary, arrange for them to be provided in convenient, familiar local venues such as residential care homes or day centres. (See also recommendations 1.1.1 to 1.10.2 for advice on risk assessment and intensive lifestyle-change programmes.)
Educate those involved in buying or preparing food in residential care, day centres and psychiatric units about what constitutes a healthy diet and how to prepare healthy meals.
# Intensive lifestyle-change programmes: quality assurance
Set up a national accreditation body to benchmark, audit, accredit and share effective practice in type 2 diabetes prevention. This body should:
Conduct research to establish and implement effective practice.
Provide a national, quality-assured training programme and a central database of effective curriculum resources for intensive lifestyle-change programmes. The programme and resources should meet criteria developed by the Department of Health and Diabetes UK Patient Education Working Group (PEWG).
Evaluate the effectiveness of the national training and accreditation programme. This includes its impact on practice and outcomes for participants.
# Training and professional development
In recommendations 1.18.1 to 1.18.3 the people and organisations who should work with the national accreditation body are commissioners and providers of public health services; managers of type 2 diabetes risk-assessment and prevention services; schools of medicine, healthcare faculties, royal colleges and professional associations offering professional healthcare qualifications such as dietetics, nursing, physiotherapy, podiatry and occupational health; voluntary organisations; commercial training organisations.
The national accreditation body for type 2 diabetes prevention (see recommendation 1.17.1) should work with others to:
ensure training about risk factors for type 2 diabetes and how to prevent or delay it, is part of the core curriculum for healthcare undergraduates and postgraduates
provide training for health professionals and community practitioners on how to provide brief advice and brief interventions
provide accredited training which meets nationally defined criteria for health professionals and community practitioners who are delivering risk assessments and intensive lifestyle-change programmes, and for other providers of advice on diet and physical activity who may wish to develop a type 2 diabetes prevention programme
provide additional, specialised training for those working with vulnerable groups including, for example, people with mental health problems or learning disabilities, refugees and gypsy and traveller populations.
The national accreditation body for type 2 diabetes prevention and others should ensure training on delivering risk assessments, intensive lifestyle-change programmes, dietary and physical activity advice increases participants' understanding of type 2 diabetes and its complications. It should also cover: behaviour-change theories and techniques, awareness-raising, how to communicate risk and how to tailor interventions to meet individual need. In addition, participants should learn how to assess, audit and evaluate type 2 diabetes prevention programmes.
The national accreditation body for type 2 diabetes prevention and others should establish competencies for practice and provide accredited training for other potential providers such as lay educators or voluntary sector organisations.
Managers of type 2 diabetes risk assessment and prevention services should provide opportunities at least every 3 years for staff to attend accredited training and refresher courses on how to deliver an intensive lifestyle-change programme. Training should be cascaded down through the team(s) via formal and informal in-service training. In addition, peer review processes should be used to encourage sharing of good practice.
Managers of type 2 diabetes risk assessment and prevention services should offer training to community and faith leaders, staff in local authority leisure services, day centres, residential and respite care homes and staff in occupational health departments. The training should cover:
how to carry out an initial risk assessment using validated self-assessment risk questionnaires
effective ways to communicate someone's level of risk, the consequences of type 2 diabetes and the benefits of change
how to give brief advice on reducing the risk of type 2 diabetes
how to refer on for appropriate interventions.
# Metformin
See why the committee made the 2017 recommendation on metformin .
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Use clinical judgement on whether (and when) to offer metformin to support lifestyle change for people whose HbA1c or fasting plasma glucose blood test results have deteriorated if:
this has happened despite their participation in intensive lifestyle-change programmes or
they are unable to participate in an intensive lifestyle-change programmeparticularly if they have a BMI greater than 35.The study on which this recommendation is based used standard-release metformin. Some standard- or modified-release metformin products have since extended their marketing authorisations to include reducing the risk or delaying the onset of type 2 diabetes in adults who are at high risk and are progressing towards type 2 diabetes despite intensive lifestyle change for 3 to 6 months. See NICE's information on prescribing medicines.
Discuss with the person the potential benefits and limitations of taking metformin, taking into account their risk and the amount of effort needed to change their lifestyle to reduce that risk. Explain that long-term lifestyle change can be more effective than drugs in preventing or delaying type 2 diabetes. Encourage them to adopt a healthy diet and be as active as possible. Where appropriate, stress the added health and social benefits of physical activity (for example, point out that it helps reduce the risk of heart disease, improves mental health and can be a good way of making friends). Advise them that they might need to take metformin for the rest of their lives and inform them about possible side effects.
Continue to offer advice on diet and physical activity along with support to achieve their lifestyle and weight-loss goals.
Check the person's renal function before starting treatment, and then twice yearly (more often if they are older or if deterioration is suspected).
Start with a low dose (for example, 500 mg once daily) and then increase gradually as tolerated, to 1500 to 2000 mg daily. If the person is intolerant of standard metformin consider using modified-release metformin.
Prescribe metformin for 6 to 12 months initially. Monitor the person's fasting plasma glucose or HbA1c levels at 3 month intervals and stop the drug if no effect is seen.
# Orlistat
Use clinical judgement on whether to offer orlistat to people with a BMI of 28.0 kg/m2 or more, as part of an overall plan for managing obesity. Take into account the person's risk and the level of weight loss and lifestyle change required to reduce this risk.
Discuss the potential benefits and limitations of taking orlistat and its side effects.
Advise the person to follow a low-fat diet that provides 30% of daily food energy as fat, distributed over three main meals a day. Offer information and regular support from a dietitian or another appropriate healthcare professional.
Agree a weight-loss goal with the person and regularly review it with them.
Review the use of orlistat after 12 weeks. If the person has not lost at least 5% of their original body weight, use clinical judgement to decide whether to stop the orlistat. However, as with adults who have type 2 diabetes, those at high risk of the condition may lose weight more slowly than average, so less strict goals may be appropriate.
Use orlistat for more than 12 months (usually for weight maintenance) only after discussing the potential benefits, limitations and side effects with the person concerned. # Rationale and impact of the new recommendations
# Intensive lifestyle-change programmes and metformin
This section explains why the committee made the 2017 recommendations on intensive lifestyle-change programmes and metformin.
## Why the committee made the recommendations
A health economic model showed that lifestyle-change programmes are cost effective for all people at high risk of diabetes, providing support to the existing recommendation to offer the intervention to this group of people. The model also showed that lifestyle-change programmes are particularly cost effective for people with higher HbA1c or fasting plasma glucose levels. Therefore, the committee determined that, in instances where offering the intervention to all high-risk people is not possible due to capacity constraints, lifestyle-change programmes should be prioritised for people with a fasting plasma glucose of 6.5 to 6.9 mmol/l or HbA1c of 44 to 47 mmol/mol. The committee also agreed that people should be given information about their diabetes risk because this was recommended in the previous version of NICE guidance on type 2 diabetes prevention based on the expert view of the previous committee.
The committee also recognised that people with mental illness or dementia often have poorer physical health and would therefore benefit from testing and, if needed, intervention to reduce their risk of type 2 diabetes. Therefore an additional recommendation was made to ensure that intensive lifestyle-change programmes are designed to help as many people as possible to access and take part in them.
The results of the economic modelling also showed that, in the high-risk population overall and in most subgroups, lifestyle-change programmes are more clinically and cost effective than metformin. They also showed that, compared with control alone, metformin is cost effective in the high-risk population overall, and for most subgroups. Therefore, the committee agreed that metformin could be used in support of lifestyle change when blood test results have deteriorated despite someone taking part in these programmes or if they can't take part for some reason. They also agreed that metformin could be used for people whose BMI is over 35 when their blood test results have deteriorated because the model showed that metformin is particularly clinically and cost effective for this group.
## Impact of the recommendations on practice
The 2012 version of this guideline recommended that intensive lifestyle-change programmes should be offered to people at high risk of type 2 diabetes. The committee also recognised that intensive lifestyle-change programmes should be designed to help as many people as possible to access and take part in them. However, providing these programmes to all these people has a large resource impact. To make the most of resources commissioners may need to prioritise subsets of the population.
The NHS Diabetes Prevention Programme is currently being implemented throughout England in response to the 2012 recommendations in this guideline. Implementing the 2017 recommendations will allow this programme to be initially targeted at groups of the population who will benefit most, in a way that is consistent across the UK.
The updated recommendation on metformin reflects current practice, so the committee noted that it shouldn't have an impact.# Context
Diabetes is a chronic disease characterised by an inability to regulate blood glucose. It is one of the most prevalent and costly chronic diseases. There are 3.9 million people living with diabetes in the UK, and 90% of those with the condition have type 2 diabetes. Type 2 diabetes occurs when the pancreas no longer produces enough insulin to maintain a normal blood glucose level, or the body is unable to use the insulin that is produced (known as insulin resistance).
People with type 2 diabetes have an increased risk of coronary heart disease, peripheral vascular disease and stroke, and they are more likely to have hypertension, dyslipidaemia (abnormal blood lipid and lipoprotein levels) and obesity. People who are overweight or obese are more likely to develop type 2 diabetes, and the risk rises as body weight increases.
NHS England, Public Health England and Diabetes UK have developed the NHS Diabetes Prevention Programme (NHS DPP), which is based on recommendations from this guideline. The NHS DPP interventions are commissioned centrally by NHS England. Given that there are an estimated 5 million people at risk of type 2 diabetes in England, and that the NHS DPP interventions will be available to only 100,000 people annually, there is a need to identify and prioritise which people are likely to benefit most from the intervention.
This guidance focuses on identifying people at high risk of type 2 diabetes and offering them effective lifestyle-change programmes to prevent or delay the condition. In the 2017 update, the level of risk needed to be reviewed to identify when individualised interventions should be used to prevent the development of type 2 diabetes, in terms of individual risk and NHS resources. The clinical and cost effectiveness of intensive lifestyle modification programmes in subgroups of this high-risk population were assessed to help commissioners target the intervention to people who will gain most benefit. The update also assessed the clinical and cost effectiveness of metformin and digitally delivered lifestyle interventions among the same population subgroups.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Identification and monitoring
Which combination of risk-assessment tools and blood tests (HbA1c or fasting plasma glucose ) are most cost effective and effective at identifying and assessing the risk of type 2 diabetes among populations at high risk? In addition, how frequently should testing take place to be efficient? How does effectiveness and cost effectiveness vary for different black and minority ethnic groups, for example, African-Caribbean and black African; people aged 18 to 40, people aged 75 and over, and for high-risk vulnerable adults?
What are the demographic characteristics and rates of progression to type 2 diabetes among people with a high risk score but normal blood glucose levels (fasting plasma glucose of less than 5.5 mmol/l or HbA1c of less than 42 mmol/mol)? How does this compare with people who have both a high risk score and blood glucose levels that indicate impaired glucose regulation (fasting plasma glucose 5.5 to 6.9 mmol/l or HbA1c 42 to 47 mmol/mol (6.0 to 6.4%)?
What are the most effective and cost-effective methods of increasing uptake of type 2 diabetes risk assessments and monitoring among those at greatest risk? Those at greatest risk include people from lower socioeconomic and black and minority ethnic groups, and those aged 75 or over.
# Lifestyle interventions
Which components of an intensive lifestyle-change programme contribute most to the effectiveness and cost effectiveness of interventions to prevent or delay type 2 diabetes in those at high risk? How does this vary for different black and minority ethnic groups, for people of different ages for example, aged 18 to 24, 25 to 39 and 75 and over, and for vulnerable adults?
How effective and cost effective are different types of dietary regime in reducing short- and long-term blood glucose levels and preventing or delaying type 2 diabetes? How does this vary for different subgroups, for example, African-Caribbean and black African and other minority ethnic groups and for people of different ages, for example, aged 18 to 24, 25 to 39 and 75 and over?
How effective and cost effective are different types (and levels and frequency) of physical activity in reducing short- and long-term blood glucose levels and preventing or delaying type 2 diabetes? How does this vary for different subgroups, for example, different black and minority ethnic groups and people of different ages, for example, aged 18 to 24, 25 to 39 and 75 and over?
# Vulnerable groups
What are the most effective and cost-effective methods for identifying, assessing and managing the risk of type 2 diabetes among high-risk, vulnerable adults? This group includes: frail older adults, homeless people, those with severe mental illness, learning or physical disabilities, prisoners, refugees, recent migrants and travellers.
# Digitally delivered intensive lifestyle-change programmes
What is the effectiveness of providing digitally delivered intensive lifestyle-change programmes in preventing type 2 diabetes in adults at high risk of type 2 diabetes?
## Why this is important
There is a lack of good quality evidence on the effectiveness of digitally delivered intensive lifestyle-change programmes in preventing type 2 diabetes.
More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Glossary
# Behaviour change
Evidence-based behaviour-change advice includes:
helping people to understand the short, medium and longer-term consequences of health-related behaviour
helping people to feel positive about the benefits of changing their behaviour
building the person's confidence in their ability to make and sustain changes
recognising how social contexts and relationships may affect a person's behaviour
helping plan changes in terms of easy steps over time
identifying and planning for situations that might undermine the changes people are trying to make (including planning explicit 'if–then' coping strategies to prevent relapse)
encouraging people to make a personal commitment to adopt health-enhancing behaviours by setting (and recording) achievable goals in particular contexts, over a specified time
helping people to use self-regulation techniques (such as self-monitoring, progress review, relapse management and goal revision) to encourage learning from experience
encouraging people to engage the support of others to help them to achieve their behaviour-change goals.
# Brief advice
Typically, for diabetes prevention, brief advice might consist of a 5 to 15 minute consultation. The aim is to help someone make an informed choice about whether to make lifestyle changes to reduce their risk of diabetes. The discussion covers what that might involve and why it would be beneficial. Practitioners may provide written information in a range of formats and languages about the benefits and, if the person is interested in making changes, may discuss how these can be achieved and sustained in the long term.
# Brief intervention
Brief interventions for diabetes prevention can be delivered by GPs, nurses, healthcare assistants and professionals in primary healthcare and the community. They may be delivered in groups or on a one-to-one basis. They aim to improve someone's diet and help them to be more physically active. A patient-centred or 'shared decision-making' communication style is adopted to encourage people to make choices and have a sense of 'ownership' of their lifestyle goals and individual action plans. Providers of brief interventions should be trained in the use of evidence-based behaviour-change techniques for supporting weight loss through lifestyle change.
# Computer-based risk-assessment tools
These tools identify a set of risk characteristics in patient health records. They can be used to interrogate GP patient databases and provide a summary score to indicate someone's level of risk. Examples include the Cambridge diabetes risk score and the Leicester practice score.
# Diabetes prevention programmes
Diabetes prevention programmes comprise two integrated components: first, risk identification services and second, intensive lifestyle-change programmes. Participants are acknowledged as the decision-makers throughout the process. Also see 'Intensive lifestyle-change programmes'.
# High risk
High risk is defined as a fasting plasma glucose level of 5.5 to 6.9 mmol/l or an HbA1c level of 42 to 47 mmol/mol (6.0 to 6.4%). These terms are used instead of specific numerical scores because risk assessment tools have different scoring systems. Examples of risk assessment tools include: Diabetes risk score assessment tool, QDiabetes risk calculator and Leicester practice risk score. Risk can also be assessed using the NHS Health Check.
# Glycated haemoglobin (HbA1c)
Glycated haemoglobin (HbA1c) forms when red cells are exposed to glucose in the plasma. The HbA1c test reflects average plasma glucose over the previous 8 to 12 weeks. Unlike the oral glucose tolerance test, an HbA1c test can be performed at any time of the day and does not require any special preparation, such as fasting.
HbA1c is a continuous risk factor for type 2 diabetes. This means there is no fixed point when people are (or are not) at risk. The World Health Organization recommends a level of 48 mmol/mol (6.5%) for HbA1c as the cut-off point for diagnosing type 2 diabetes in non-pregnant adults. For the purposes of this guidance, the range 42–47 mmol/mol (6.0 to 6.4%) is considered to be 'high risk'.
# Impaired fasting glucose (IFG)
Impaired fasting glucose is defined as a fasting plasma glucose between 6.1 and 6.9 mmol/l.
# Impaired glucose tolerance
This is a risk factor for future diabetes and/or other adverse outcomes. The current WHO diagnostic criteria for impaired glucose tolerance are: a fasting plasma glucose of less than 7.0 mmol/l and a 2-hour venous plasma glucose (after ingestion of 75 g oral glucose load) of 7.8 mmol/l or greater, and less than 11.1 mmol/l.
# Impaired glucose regulation (IGR)
This is a risk factor for future diabetes and/or other adverse outcomes. The term covers blood glucose levels that are above the normal range but are not high enough for the diagnosis of type 2 diabetes. It is used to describe the presence of impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) as defined by the WHO.
IFG is defined as fasting plasma glucose 6.1 to 6.9 mmol/l. IGT is defined as a fasting plasma glucose (FPG) less than 7 mmol/l and 2-hour venous plasma glucose (after ingestion of 75 g oral glucose load) of 7.8 mmol/l or greater and less than 11.1 mmol/l.
Impaired fasting glucose and impaired glucose tolerance can occur as isolated, mutually exclusive conditions or together, that is, fasting plasma glucose between 6.1 and 6.9 mmol/l and 2-hour glucose of 7.8 mmol/l or greater and less than 11.1 mmol/l during the oral glucose tolerance test.
# Intensive lifestyle-change programmes
A structured and coordinated range of interventions provided in different venues for people identified as being at high risk of developing type 2 diabetes (following a risk assessment and a blood test). The aim is to help people become more physically active and to improve their diet. If the person is overweight or obese, the programme should result in weight loss. Programmes may be delivered to individuals or groups (or involve a mix of both) depending on the resources available. They can be provided by primary care teams and public, private or community organisations with expertise in dietary advice, weight management and physical activity.
# Level of risk
The terms 'high', 'intermediate' and 'low' risk are used to refer to the results from a risk assessment tool. Examples of validated risk assessment tools are available in the NHS Health Check best practice guidance. These terms are used instead of specific numerical scores because the tools have different scoring systems. The term 'moderate risk' is used to denote a high risk assessment score where a blood test did not confirm that risk (FPG less than 5.5 mmol/l or HbA1c less than 42 mmol/mol ). A fasting plasma glucose of 5.5 to 6.9 mmol/l or an HbA1c level of 42 to 47 mmol/mol indicates high risk.
# Moderate-intensity physical activity
The UK Chief Medical Officers' physical activity guidelines sets out physical activity recommendations. The definition of moderate physical activity is included in the glossary of the report (see the UK Chief Medical Officers' physical activity guidelines for more information).
# Oral glucose tolerance test
An oral glucose tolerance test involves measuring the blood glucose level after fasting, and then 2 hours after drinking a standard 75 g glucose drink. Fasting is defined as no calorie intake for at least 8 hours. More than one test on separate days is required for diagnosis in the absence of hyperglycaemic symptoms.
# Vigorous-intensity physical activity
Vigorous-intensity physical activity requires a large amount of effort, causes rapid breathing and a substantial increase in heart rate. Examples include running and climbing briskly up a hill. On an absolute scale, vigorous intensity is defined as physical activity that is above 6 metabolic equivalents (METs).
# Vulnerable groups
Adults from vulnerable groups whose risk of type 2 diabetes may be increased by a medical condition, or who may not realise they are at risk or who are less likely to access healthcare services. This includes people with severe mental health problems, learning disabilities, physical disabilities or sensory disabilities; people who live in hostels, nursing or residential homes, residential mental health or psychiatric care units, secure hospitals, prisons or remand centres; and people who are part of a mobile population such as travellers, asylum seekers and refugees.
# Weight-loss programmes
Effective weight-loss programmes are structured lifestyle-change programmes to help people lose weight in a sustainable way. They:
are based on an assessment of the individual
address the reasons why someone might find it difficult to lose weight
are tailored to individual needs and choices
are sensitive to the person's weight concerns
are based on a balanced, healthy diet
encourage regular physical activity
utilise behaviour-change strategies.
# Weight management
In this guidance, the term weight management includes:
assessing and monitoring body weight
preventing someone from becoming overweight (body mass index of 25 to 29.9 kg/m², or 23 to 27.4 kg/m2 if they are of South Asian or Chinese descent)
preventing someone from becoming obese (BMI greater than or equal to 30 kg/m², or 27.5 kg/m2 or above if they are of South Asian or Chinese descent)
helping someone who is overweight or obese to achieve and maintain a 5 to 10% weight loss and progress to a healthy weight (BMI of 18.5 to 24.9 kg/m², or 18.5 to 22.9 kg/m2 if they are of South Asian or Chinese descent) by adopting a healthy diet and being physically active.
For other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.# Finding more information
You can see everything NICE says on this topic in the NICE Pathway on preventing type2 diabetes.
To find NICE guidance on related topics, including guidance in development, see our topic page for diabetes.
For full details of the evidence and the guideline committee's discussions, see the supporting documents. You can also find information about how the guideline was developed.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Recommendations ': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Risk assessment\n\nGPs and other health professionals and community practitioners in health and community venues should implement a two-stage strategy to identify people at high risk of type\xa02 diabetes (and those with undiagnosed type\xa02 diabetes). First, a risk assessment should be offered (see recommendation 1.1.3). Second, where necessary, a blood test should be offered to confirm whether people have type\xa02 diabetes or are at high risk (see recommendation 1.1.4). \n\nService providers including pharmacists, managers of local health and community services and voluntary organisations, employers and leaders of faith groups should offer validated self-assessment questionnaires or validated web-based tools (for examples, see the Diabetes UK website). They should also provide the information needed to complete and interpret them. The tools should be available in local health, community and social care venues. Examples of possible health venues include: community pharmacies, dental surgeries, NHS walk-in centres and opticians. Examples of community and social care venues include: workplaces, job centres, local authority leisure services, shops, libraries, faith centres, residential and respite care homes and day centres (for older adults and for adults with learning disabilities). \n\nPublic health, primary care and community services should publicise local opportunities for risk assessment and the benefits of preventing (or delaying the onset of) type\xa02 diabetes. The information should be up-to-date and provided in a variety of formats. It should also be tailored for different groups and communities. For example, by offering translation services and information in languages used locally. \n\nWhere risk assessment is conducted by health professionals in NHS venues outside general practice (for example, in community pharmacies) the professionals involved should ensure the results are passed on to the person's GP. \n\nGPs should keep records of all risk assessment results to ensure appropriate follow-up and continuity of care. \n\nWhere self-assessment is offered in community venues, health professionals and community practitioners in those venues should encourage people with an intermediate or high risk score to visit their GP to discuss how to manage their risk. Those at high risk should be offered a blood test by their GP. \n\nEnsure health professionals and community practitioners involved with risk assessments in community venues communicate closely with, and receive support from, NHS diabetes risk-assessment and prevention services. They should aim to ensure continuity of care and avoid unnecessary duplication of risk assessments. \n\nManagers in primary and secondary healthcare should ensure staff actively seek out and offer risk assessments to people who might not realise they could be at high risk. This includes people with particular conditions that can increase the risk such as: cardiovascular disease, hypertension, obesity, stroke, polycystic ovary syndrome, a history of gestational diabetes and mental health problems. In addition, people with learning disabilities and those attending accident and emergency, emergency medical admissions units, vascular and renal surgery units and ophthalmology departments may be at high risk. \n\n# Encouraging people to have a risk assessment\n\nEncourage the following to have a risk assessment:\n\nall eligible adults aged 40 and above, except pregnant women\n\npeople aged 25 to 39 of South Asian, Chinese, African-Caribbean, black African and other high-risk black and minority ethnic groups, except pregnant women\n\nadults with conditions that increase the risk of type\xa02 diabetes.Particular conditions can increase the risk of type\xa02 diabetes. These include: cardiovascular disease, hypertension, obesity, stroke, polycystic ovary syndrome, a history of gestational diabetes and mental health problems. People with learning disabilities and those attending accident and emergency, emergency medical admissions units, vascular and renal surgery units and ophthalmology departments may also be at high risk. NICE's guideline on non-alcoholic fatty liver disease notes that it increases the risk of type\xa02 diabetes. \n\nExplain to people why, even though they feel healthy, they can still be at risk of developing type\xa02 diabetes. Explain the implications of being at risk and that this can be reduced by making lifestyle changes. \n\nTell people how and where they can be assessed, including at their GP surgery or community pharmacy. Make people aware that they can use a validated self-assessment questionnaire or validated web-based tools (for examples, see the Diabetes UK website). Explain that those who are eligible can be assessed by the NHS Health Check programme. (This programme is for people aged 40 to 74 who are not on a disease register and have not been diagnosed with coronary heart disease, hypertension, atrial fibrillation, stroke, transient ischaemic attack, type\xa02 diabetes or kidney disease. They will be treated and managed using established healthcare pathways.) \n\nEncourage people who are less likely to attend a GP surgery to go elsewhere for a risk assessment. Possibilities include community pharmacies, dental surgeries, NHS walk-in centres and opticians. Assessments may also be offered in community venues. Examples include: workplaces, job centres, local authority leisure facilities, shops, libraries, faith centres, residential and respite care homes and day centres (for older adults and for adults with learning disabilities). \n\nAdvise people with type\xa02 diabetes to encourage family members to have their risk assessed. \n\n# Risk identification (stage 1)\n\nGPs and other primary healthcare professionals should use a validated computer-based risk-assessment tool to identify people on their practice register who may be at high risk of type\xa02 diabetes. The tool should use routinely available data from patients' electronic health records. If a computer-based risk-assessment tool is not available, they should provide a validated self-assessment questionnaire, for example, the Diabetes Risk Score assessment tool. This is available to health professionals on request from Diabetes UK. \n\nGPs and other primary healthcare professionals should not exclude people from assessment, investigation or intervention on the basis of age, as everyone can reduce their risk, including people aged 75 years and over. \n\nPharmacists, opticians, occupational health nurses and community leaders should offer a validated self-assessment questionnaire to adults aged 40 and over, people of South Asian and Chinese descent aged 25 to 39, and adults with conditions that increase the risk of type\xa02 diabetes, other than pregnant women. Or they should tell people how to access specific, validated online self-assessment tools, such as the Diabetes Risk Score featured on the Diabetes UK website. Particular conditions can increase the risk of type\xa02 diabetes. These include: cardiovascular disease, hypertension, obesity, stroke, polycystic ovary syndrome, a history of gestational diabetes and mental health problems. People with learning disabilities and those attending accident and emergency, emergency medical admissions units, vascular and renal surgery units and ophthalmology departments may also be at high risk. NICE's guideline on non-alcoholic fatty liver disease notes that it increases the risk of type\xa02 diabetes. \n\nPharmacists, opticians, occupational health nurses and community leaders involved in risk assessments should advise people with a high risk score to contact their GP or practice nurse for a blood test. The aim is to check if they have type\xa02 diabetes or to confirm their level of risk and discuss how to reduce it. \n\nAll providers of risk assessments should explain to those attending for a type\xa02 diabetes risk assessment the implications of being at high risk and the consequences of developing the condition. \n\nAll providers of risk assessments should discuss with those attending for a type\xa02 diabetes risk assessment how to prevent or delay the onset of the condition. This includes being more physically active, achieving and maintaining a healthy weight, eating less fat and eating more dietary fibre. They should also tell people where to get advice and support to maintain these lifestyle changes in the long term. \n\n# Risk identification (stage 2)\n\nTrained healthcare professionals should offer venous blood tests (fasting plasma glucose [FPG] or HbA1c) to adults with high risk scores (stage\xa02 of the identification process). They should also consider a blood test for those aged 25 and over of South Asian or Chinese descent whose body mass index (BMI) is greater than 23\xa0kg/m2. The aim is to:\n\ndetermine the risk of progression to type\xa02 diabetes (a fasting plasma glucose of 5.5 to 6.9\xa0mmol/l or an HbA1c level of 42 to 47\xa0mmol/mol [6.0 to 6.4%] indicates high risk) or\n\nidentify possible type\xa02 diabetes by using fasting plasma glucose, HbA1c or an oral glucose tolerance test (OGTT), according to World Health Organization (WHO) HbA1c criteria. \n\nEnsure HbA1c tests, including point-of-care tests, conform to expert consensus reports on appropriate use and national quality specifications (see NHS Diabetes website and WHO guidance on using HbA1c for diagnosing diabetes. The tests should only be carried out by trained staff. \n\n# Matching interventions to risk\n\nSee why the committee made the 2017 recommendations on intensive lifestyle-change programmes\xa0.\n\nLoading. Please wait.\n\nFor people at low risk (that is, those who have a low or intermediate risk score), tell the person that they are currently at low risk, which does not mean they are not at risk – or that their risk will not increase in the future. Offer them brief advice. \n\nAs part of brief advice:\n\nDiscuss people's risk factors and how they could improve their lifestyle to reduce overall risk.\n\nOffer encouragement and reassurance.\n\nOffer verbal and written information about culturally appropriate local services and facilities that could help them change their lifestyle. Examples could include information or support to: improve their diet (including details of any local markets offering cheap fruit and vegetables); increase their physical activity and reduce the amount of time spent being sedentary (including details about walking or other local physical activity groups and low-cost recreation facilities). The information should be provided in a range of formats and languages. \n\nFor people with a moderate risk (a high risk score, but with a fasting plasma glucose less than 5.5\xa0mmol/l or HbA1c of less than 42\xa0mmol/mol [6.0%]):\n\nTell the person that they are currently at moderate risk, and their risks could increase in the future. Explain that it is possible to reduce the risk. Briefly discuss their particular risk factors, identify which ones can be modified and discuss how they can achieve this by changing their lifestyle.\n\nOffer them a brief intervention to help them change their lifestyle: give information about services that use evidence-based behaviour-change techniques that could help them change, bearing in mind their risk profile. Services cited could include walking programmes, slimming clubs or structured weight-loss programmes. (See recommendations 1.11.1 to 1.14.3.)\n\nDiscuss whether they would like to join a structured weight-loss programme. Explain that this would involve an individual assessment and tailored advice about diet, physical activity and behaviour change. Let them know which local programmes offer this support – and where to find them. \n\nFor people confirmed as being at high risk (a high risk score and fasting plasma glucose of 5.5–6.9\xa0mmol/l or HbA1c of 42 to 47\xa0mmol/mol [6.0 to 6.4%]):\n\nTell the person they are currently at high risk but that this does not necessarily mean they will progress to type\xa02 diabetes. Explain that the risk can be reduced. Briefly discuss their particular risk factors, identify which ones can be modified and discuss how they can achieve this by changing their lifestyle.\n\nOffer them a referral to a local, evidence-based, quality-assured intensive lifestyle-change programme(see recommendations 1.8.1 to 1.10.2). In addition, give them details of where to obtain independent advice from health professionals. \n\nWhen commissioning local or national services to deliver intensive lifestyle-change programmes (see recommendations 1.8.1 to 1.10.2) where the availability of places is limited, prioritise people with a fasting plasma glucose of 6.5 to 6.9\xa0mmol/l or HbA1c of 44 to 47\xa0mmol/mol [6.2 to 6.4%]. \n\nEnsure that intensive lifestyle-change programmes are designed to help as many people as possible to access and take part in them (see sections 1.1.5 and 1.16 for recommendations on providing information and services, and supporting lifestyle change in people who may need particular support). \n\nFor people with possible type\xa02 diabetes (fasting plasma glucose of, 7.0\xa0mmol/l or above, or HbA1c of 48\xa0mmol/mol [6.5%] or above, but no symptoms of type\xa02 diabetes):\n\nCarry out a second blood test. If type\xa02 diabetes is confirmed, treat this in accordance with NICE's guideline on managing type\xa02 diabetes. Ensure blood testing conforms to national quality specifications.\n\nIf type\xa02 diabetes is not confirmed, offer them a referral to a local, quality-assured, intensive lifestyle-change programme (see recommendations 1.8.1 to 1.10.2). \n\nFor people with a high risk score who prefer not to have a blood test, or who do not use primary healthcare services, discuss the importance of early diagnosis to help reduce the risk of long-term complications. Use clinical judgement, based on the person's risk score, to decide whether to offer them a brief intervention or a referral to an intensive lifestyle-change programme (see recommendations 1.8.1 to 1.10.2). \n\n# Reassessing risk\n\nKeep an up-to-date register of people's level of risk. Introduce a recall system to contact and invite people for regular review, using the two-stage strategy (see recommendations 1.1.3 and 1.1.4). \n\nOffer a reassessment based on the level of risk. Use clinical judgement to determine when someone might need to be reassessed more frequently, based on their combination of risk factors (such as their body mass index [BMI], relevant illnesses or conditions, ethnicity and age). \n\nFor people at low risk (with a low or intermediate risk score) offer to reassess them at least every 5\xa0years to match the timescales used by the NHS Health Check programme. Use a validated risk-assessment tool. \n\nFor people at moderate risk (a high risk score, but with a fasting plasma glucose less than 5.5\xa0mmol/l, or HbA1c less than 42\xa0mmol/mol [6.0%]), offer to reassess them at least every 3\xa0years. \n\nFor people at high risk (a high risk score and fasting plasma glucose of 5.5 to 6.9\xa0mmol/l, or HbA1c of 42 to 47\xa0mmol/mol [6.0 to 6.4%]), offer a blood test at least once a\xa0year (preferably using the same type of test). Also offer to assess their weight or BMI. This includes people without symptoms of type\xa02 diabetes whose:\n\nfirst blood test measured fasting plasma glucose at 7.0\xa0mmol/l or above, or an HbA1c of 48\xa0mmol/mol (6.5%) or greater, but\n\nwhose second blood test did not confirm a diagnosis of type\xa02 diabetes. \n\nAt least once a\xa0year, review the lifestyle changes people at high risk have made. Use the review to help reinforce their dietary and physical activity goals, as well as checking their risk factors. The review could also provide an opportunity to help people 'restart', if lifestyle changes have not been maintained. \n\n# Commissioning risk identification and intensive lifestyle-change programmes\n\nHealth and wellbeing boards and public health commissioners should make type\xa02 diabetes prevention a priority in the joint health and wellbeing strategy. They should identify local needs by:\n\nUsing anonymised, regional and local health data and routinely collected surveillance data on specific population groups or geographical areas to inform the joint strategic needs assessment.\n\nMapping local diet, weight management and physical activity services and interventions (for example, slimming clubs). This should include details about locations, opening times and accessibility, staffing levels and the range of professional skills available. It should also include details of any tailored support provided by trained personnel. \n\nHealth and wellbeing boards and public health commissioners, working with clinical commissioning groups, should develop a comprehensive and coordinated type\xa02 diabetes prevention commissioning plan, based on the data collated. This should include:\n\nAction to raise awareness of the risks of type\xa02 diabetes.\n\nA proactive, two-stage approach to identifying people at high risk (and those with undiagnosed type\xa02 diabetes).\n\nEvidence-based, quality-assured intensive lifestyle-change programmes. \n\nHealth and wellbeing boards and public health commissioners, working with clinical commissioning groups, should ensure the commissioning plan:\n\nSets out organisational responsibilities for local type\xa02 diabetes risk assessments. These could take place in primary care or community pharmacies as part of, or as a local addition to, the NHS Health Check programme, or as a self-assessment in community venues and workplaces.\n\nEstablishes arrangements to invite people of South Asian and Chinese descent aged 25 and over for a risk assessment at least once every 5\xa0years. (Invitations and follow-up could be integrated within the NHS Health Check programme.)\n\nEncourages employers in public and private sector organisations to include risk assessments in their occupational health service contracts.\n\nSupports the development of coordinated referral pathways for evidence-based and quality-assured intensive lifestyle-change programmes that cover physical activity, weight management and diet, and which teach behaviour-change techniques.\n\nMakes it clear that everyone (including older people, those from minority ethnic groups and vulnerable or socially disadvantaged people) should be offered risk assessments and intensive lifestyle-change programmes at times, and in locations, that meet their needs.\n\nMakes provision for people who may have difficulty accessing, or are unlikely to access, services in conventional healthcare venues.\n\nMakes it clear that risk-assessment services and intensive lifestyle-change programmes should be delivered by trained practitioners (see recommendations 1.18.1 to 1.18.5). \n\nHealth and wellbeing boards and public health commissioners, working with clinical commissioning groups, should integrate the commissioning plan with the joint health and wellbeing strategy. They should ensure it is delivered through services operating across the NHS, local authorities and other organisations in the private, community and voluntary sectors. \n\nHealth and wellbeing boards and public health commissioners should regularly evaluate services in the context of these recommendations and changing local needs. They should use local accountability mechanisms (for example, health scrutiny reports) to examine specific issues. \n\nHealth and wellbeing boards and public health commissioners should evaluate or compare the different service options and make the findings publicly available. Assessments should focus on changes in participants' physical activity levels, weight and dietary intake (of fat, saturated fat and fibre) over 12 to 24\xa0months. \n\n# Quality-assured, intensive lifestyle-change programmes: design and delivery\n\nProvide specially designed and quality-assured intensive lifestyle-change programmes for groups of 10 to 15 people at high risk of developing type\xa02 diabetes. \n\nInvolve the target community (including community leaders) in planning the design and delivery of the programme to ensure it is sensitive and flexible to the needs, abilities and cultural or religious norms of local people. For example, the programme should offer practical learning opportunities, particularly for those who have difficulties with communication or literacy or whose first language is not English. \n\nEnsure programmes are delivered by practitioners with relevant knowledge and skills who have received externally accredited training (see recommendations 1.18.1 to 1.18.5). Where relevant expertise is lacking, involve health professionals and specialists (such as dietitians and health psychologists) in the design and delivery of services. \n\nEnsure programmes adopt a person-centred, empathy-building approach. This includes finding ways to help participants make gradual changes by understanding their beliefs, needs and preferences. It also involves building their confidence and self-efficacy over time. \n\nEnsure programme components are delivered in a logical progression. For example: discussion of the risks and potential benefits of lifestyle change; exploration of someone's motivation to change; action planning; self-monitoring and self-regulation. \n\nEnsure groups meet at least eight times over a period of 9 to 18\xa0months. Participants should have at least 16\xa0hours of contact time either within a group, on a one-to-one basis or using a mixture of both approaches. \n\nOffer more intensive support at the start of the programme by delivering core sessions frequently (for example, weekly or fortnightly). Reduce the frequency of sessions over time to encourage more independent lifestyle management. \n\nAllow time between sessions for participants to make gradual changes to their lifestyle – and to reflect on and learn from their experiences. Also allow time during sessions for them to share this learning with the group. \n\nDeliver programmes in a range of venues such as workplaces, leisure, community and faith centres, and outpatient departments and clinics. Run them at different times, including during evenings and at weekends, to ensure they are as accessible as possible. \n\nAs part of the programme, offer referral to, or seek advice from, people with specialist training where necessary. For example, refer someone to a dietitian for assessment and specialist dietary advice if required. \n\nOffer follow-up sessions at regular intervals (for example, every 3\xa0months) for at least 2\xa0years following the initial intervention period. The aim is to reinforce the positive behaviour change and to provide support, in case of relapse. Larger group sizes may be feasible for these maintenance sessions. \n\nLink the programmes with weight management and other prevention initiatives that help people to change their diet or become more physically active. \n\n# Quality-assured, intensive lifestyle-change programmes: content\n\nIntensive lifestyle-change programmes should offer ongoing tailored advice, support and encouragement to help people:\n\nundertake at least a level of physical activity that is in line with government recommendations (see the UK Chief Medical Officers' physical activity guidelines for more information)\n\ngradually lose weight to reach and maintain a BMI within the healthy range\n\nincrease their consumption of wholegrains, vegetables and other foods that are high in dietary fibre\n\nreduce the total amount of fat in their diet\n\neat less saturated fat. \n\nEstablished behaviour-change techniques should be used (see NICE's guideline on behaviour change: general approaches), including at least all of the following:\n\nInformation provision: to raise awareness of the benefits of and types of lifestyle changes needed to achieve and maintain a healthy weight, building on what participants already know.\n\nExploration and reinforcement of participants' reasons for wanting to change and their confidence about making changes. This may include using motivational interviewing or similar techniques suitably adapted for use in groups.\n\nGoal setting: prompting participants to set achievable and personally relevant short- and long-term goals (for example, to lose 5–10% of their weight in 1\xa0year is a realistic initial target, or to be more physically active).\n\nAction planning: prompting participants to produce action plans detailing what specific physical activity or eating behaviour they intend to change – and when, where and how this will happen. They should start with achievable and sustainable short-term goals and set graded tasks (starting with an easy task and gradually increasing the difficulty as they progress towards their goal). The aim is to move over time towards long-term, lifestyle change.\n\nCoping plans and relapse prevention: prompting participants to identify and find ways to overcome barriers to making permanent changes to their exercise and eating habits. This could include the use of strategies such as impulse-control techniques (to improve management of food cravings). \n\nParticipants in intensive lifestyle-change programmes should be encouraged to involve a family member, friend or carer who can offer emotional, information, planning or other practical support to help them make the necessary changes. For example, they may be able to join the participant in physical activities, help them to plan changes, make or accept changes to the family's diet or free up the participant's time so they can take part in preventive activities. (It may sometimes be appropriate to encourage the participant to get support from the whole family.) \n\nParticipants should be encouraged to use self-regulation techniques. This includes self-monitoring (for example, by weighing themselves, or measuring their waist circumference or both). They should also review their progress towards achieving their goals, identify and find ways to solve problems and then revise their goals and action plans, where necessary. The aim is to encourage them to learn from experience. \n\n# Quality-assured, intensive lifestyle-change programmes: evaluation\n\nEvaluate intensive lifestyle-change programmes by recording people's health outcomes at 12\xa0months, or more frequently, if appropriate (for example, every 6\xa0months). As a minimum, include the following measures:\n\nnumber and demographics of adults registered\n\nlevel of attendance\n\nchanges in the amount of moderate to vigorous physical activity undertaken each week\n\nchanges in dietary intake, with a focus on total intake of fat, saturated fat and fibre\n\nchanges in weight, waist circumference or BMI\n\nchanges in fasting plasma glucose or HbA1c levels. \n\nConduct an annual audit of how the programme was delivered. For example, check the:\n\nnumber of educators involved\n\nlevel of training\n\nnumber and demographics of adults registered\n\nlevel of uptake for example, the percentage of those invited who attend the first session\n\nprogramme content (for example, the use of behaviour-change techniques and empathy-building skills)\n\nmethods of delivery. \n\n# Raising awareness of the importance of physical activity\n\nFind out what people already know about the benefits of physical activity and the problems associated with a sedentary lifestyle. Where necessary, provide this information. In addition, explain that being more physically active can help reduce their risk of type\xa02 diabetes, even when that is the only lifestyle change they make. \n\nExplain the government recommendations for weekly physical activity (see the UK Chief Medical Officers' physical activity guidelines for more information). \n\nIn cases where it is unrealistic to expect someone to meet the recommended minimum, explain that even small increases in physical activity will be beneficial – and can act as a basis for future improvements. \n\nExplain that people should also reduce the amount of time they spend sitting at a computer or watching TV. Encourage them to be more active during work breaks, for example, by going for a walk at lunchtime. \n\nExplain that some people may need to be more physically active to help lose weight or maintain weight loss (see NICE's guideline on obesity). \n\n# Providing tailored advice on physical activity\n\nHelp people to identify which of their activities involve 'moderate' or 'vigorous' physical activity and the extent to which they are meeting the national minimum recommendation on physical activity. Use a validated tool such as the Department of Health's general practitioner physical activity questionnaire or the international physical activity questionnaire (IPAQ). \n\nEncourage people to choose physical activities they enjoy or that fit easily within their daily lives. For example, they may choose to do specific activities such as walking, cycling, swimming, dancing or aerobics. Or they could build physical activity into their daily life – for example, by walking or cycling instead of using a car for short journeys, and by taking the stairs instead of the lift. \n\nEncourage people to set short and long-term goals for example, on how far they walk or cycle, or the number or length of activities undertaken every week. In addition, encourage them to keep a record of their activity for example, by using a pedometer, and to record the things that make it easier or harder. Help them to find other ways to identify and overcome any barriers to physical activity. \n\nConsider referring people who want structured or supervised exercise to an exercise referral scheme or supervised exercise sessions, as part of an intensive lifestyle-change programme. \n\nProvide information on local opportunities for physical activity. \n\nFor more recommendations on increasing physical activity, see NICE's guidelines on physical activity in the workplace, physical activity and the environment, walking and cycling, physical activity: brief advice for adults in primary care, and exercise referral schemes.\n\n# Weight management advice\n\nAdvise and encourage overweight and obese people to reduce their weight gradually by reducing their calorie intake. Explain that losing 5 to 10% of their weight in 1\xa0year is a realistic initial target that would help reduce their risk of type\xa02 diabetes and also lead to other, significant health benefits. \n\nUse evidence-based behaviour-change techniques to help overweight and obese people eat less, be more physically active and make long term changes to their diet that result in steady weight loss (see recommendations 1.14.1 to 1.14.3). \n\nMotivate and support overweight and obese people to continue to lose weight until they have achieved – and can maintain – a BMI within the healthy range. (For the general population, the healthy range is between 18.5 and 24.9\xa0kg/m2. For people of South Asian or Chinese descent, the range is likely to be between 18.5 and 22.9\xa0kg/m2.) \n\nEncourage people to check their weight and waist measurement periodically. Provide brief advice about how to measure their waist correctly (for an example, visit the British Heart Foundation website). \n\nOffer people with a BMI of 30\xa0kg/m2 or more (27.5\xa0kg/m2 or more if South Asian or Chinese) a structured weight-loss programme as part of, or to supplement, the intensive lifestyle-change programme. Or, if more appropriate, offer them a referral to a dietitian or another appropriately trained health professional. Ensure they are given a personal assessment and tailored advice about diet, physical activity and what techniques to use to help change their behaviour. \n\nGPs and other health professionals should continue to monitor, support and care for people with a BMI of 30\xa0kg/m2 or more (27.5\xa0kg/m2 or more if South Asian or Chinese) who join slimming clubs or other weight-loss programmes. \n\nGPs should consider offering orlistat, in conjunction with a low-fat diet, to help those who are unable to lose weight by lifestyle-change alone (see recommendations 1.20.1 to 1.20.6). \n\nIf the weight management interventions in recommendations 1.13.1 to 1.13.7 have been unsuccessful, refer people to a specialist obesity management service (see NICE's guideline on obesity). \n\n# Dietary advice\n\nFind out what people already know about the types and amounts of food and drink that can help reduce the risk of type\xa02 diabetes. Provide this information where necessary. Explain that increasing dietary fibre intake and reducing fat intake (particularly saturated fat) can help reduce the chances of developing type\xa02 diabetes. \n\nHelp people to assess their diet and identify where and how they could make it healthier, taking into account their individual needs, preferences and circumstances. (For example, take into account whether they need to lose weight or if they have a limited income.) \n\nEncourage people to:\n\nIncrease their consumption of foods that are high in fibre, such as wholegrain bread and cereals, beans and lentils, vegetables and fruit.\n\nChoose foods that are lower in fat and saturated fat, for example, by replacing products high in saturated fat (such as butter, ghee, some margarines or coconut oil) with versions made with vegetable oils that are high in unsaturated fat, or using low-fat spreads.\n\nChoose skimmed or semi-skimmed milk and low-fat yoghurts, instead of cream and full-fat milk and dairy products.\n\nChoose fish and lean meats instead of fatty meat and processed meat products (such as sausages and burgers).\n\nGrill, bake, poach or steam food instead of frying or roasting (for example, choose a baked potato instead of chips).\n\nAvoid food high in fat such as mayonnaise, chips, crisps, pastries, poppadums (papads) and samosas.\n\nChoose fruit, unsalted nuts or low-fat yoghurt as snacks instead of cakes, biscuits, bombay mix or crisps. \n\n# Vulnerable groups: information and services\n\nProvide up-to-date information in a variety of formats about local opportunities for risk assessment and the benefits of preventing (or delaying the onset of) type\xa02 diabetes. This should be tailored for different groups and communities. For example, messages could be provided in a visual, Braille or audio format. \n\nProvide integrated risk-assessment services and intensive lifestyle-change programmes for prisons and residential homes, as appropriate. \n\nOffer longer appointment times or outreach services to discuss the options following a risk assessment and blood test. \n\nEnsure intensive lifestyle-change programmes are delivered by sensitive, well trained and dedicated people who are also trained to work with vulnerable groups. \n\nOffer to refer travellers and people from other mobile populations to prevention initiatives in the area they are moving to. Or use electronic communications (for example, telephone or text messages as appropriate) to deliver programmes or provide ongoing support. Ensure confidentiality is maintained. \n\n# Vulnerable groups: supporting lifestyle change\n\nEnsure all staff involved in the care of vulnerable groups understand the risk factors for type\xa02 diabetes and how they can help people reduce their risk. Staff should also be able to recognise and address (where possible) issues which mean someone gives their health a low priority. \n\nMake all staff aware of the benefits of physical activity and reducing the time spent being sedentary. Where possible, encourage them to increase the opportunities for those in their care to be physically active. \n\nEnsure staff offer to refer people to risk-assessment services and quality-assured, intensive lifestyle-change programmes in the community. Or, where necessary, arrange for them to be provided in convenient, familiar local venues such as residential care homes or day centres. (See also recommendations 1.1.1 to 1.10.2 for advice on risk assessment and intensive lifestyle-change programmes.) \n\nEducate those involved in buying or preparing food in residential care, day centres and psychiatric units about what constitutes a healthy diet and how to prepare healthy meals. \n\n# Intensive lifestyle-change programmes: quality assurance\n\nSet up a national accreditation body to benchmark, audit, accredit and share effective practice in type\xa02 diabetes prevention. This body should:\n\nConduct research to establish and implement effective practice.\n\nProvide a national, quality-assured training programme and a central database of effective curriculum resources for intensive lifestyle-change programmes. The programme and resources should meet criteria developed by the Department of Health and Diabetes UK Patient Education Working Group (PEWG).\n\nEvaluate the effectiveness of the national training and accreditation programme. This includes its impact on practice and outcomes for participants. \n\n# Training and professional development\n\nIn recommendations 1.18.1 to 1.18.3 the people and organisations who should work with the national accreditation body are commissioners and providers of public health services; managers of type\xa02 diabetes risk-assessment and prevention services; schools of medicine, healthcare faculties, royal colleges and professional associations offering professional healthcare qualifications such as dietetics, nursing, physiotherapy, podiatry and occupational health; voluntary organisations; commercial training organisations.\n\nThe national accreditation body for type\xa02 diabetes prevention (see recommendation 1.17.1) should work with others to:\n\nensure training about risk factors for type\xa02 diabetes and how to prevent or delay it, is part of the core curriculum for healthcare undergraduates and postgraduates\n\nprovide training for health professionals and community practitioners on how to provide brief advice and brief interventions\n\nprovide accredited training which meets nationally defined criteria for health professionals and community practitioners who are delivering risk assessments and intensive lifestyle-change programmes, and for other providers of advice on diet and physical activity who may wish to develop a type\xa02 diabetes prevention programme\n\nprovide additional, specialised training for those working with vulnerable groups including, for example, people with mental health problems or learning disabilities, refugees and gypsy and traveller populations. \n\nThe national accreditation body for type\xa02 diabetes prevention and others should ensure training on delivering risk assessments, intensive lifestyle-change programmes, dietary and physical activity advice increases participants' understanding of type\xa02 diabetes and its complications. It should also cover: behaviour-change theories and techniques, awareness-raising, how to communicate risk and how to tailor interventions to meet individual need. In addition, participants should learn how to assess, audit and evaluate type\xa02 diabetes prevention programmes. \n\nThe national accreditation body for type\xa02 diabetes prevention and others should establish competencies for practice and provide accredited training for other potential providers such as lay educators or voluntary sector organisations. \n\nManagers of type\xa02 diabetes risk assessment and prevention services should provide opportunities at least every 3\xa0years for staff to attend accredited training and refresher courses on how to deliver an intensive lifestyle-change programme. Training should be cascaded down through the team(s) via formal and informal in-service training. In addition, peer review processes should be used to encourage sharing of good practice. \n\nManagers of type\xa02 diabetes risk assessment and prevention services should offer training to community and faith leaders, staff in local authority leisure services, day centres, residential and respite care homes and staff in occupational health departments. The training should cover:\n\nhow to carry out an initial risk assessment using validated self-assessment risk questionnaires\n\neffective ways to communicate someone's level of risk, the consequences of type\xa02 diabetes and the benefits of change\n\nhow to give brief advice on reducing the risk of type\xa02 diabetes\n\nhow to refer on for appropriate interventions. \n\n# Metformin\n\nSee why the committee made the 2017 recommendation on metformin\xa0.\n\nLoading. Please wait.\n\nUse clinical judgement on whether (and when) to offer metformin to support lifestyle change for people whose HbA1c or fasting plasma glucose blood test results have deteriorated if:\n\nthis has happened despite their participation in intensive lifestyle-change programmes or\n\nthey are unable to participate in an intensive lifestyle-change programmeparticularly if they have a BMI greater than 35.The study on which this recommendation is based used standard-release metformin. Some standard- or modified-release metformin products have since extended their marketing authorisations to include reducing the risk or delaying the onset of type\xa02 diabetes in adults who are at high risk and are progressing towards type\xa02 diabetes despite intensive lifestyle change for 3 to 6\xa0months. See NICE's information on prescribing medicines. \n\nDiscuss with the person the potential benefits and limitations of taking metformin, taking into account their risk and the amount of effort needed to change their lifestyle to reduce that risk. Explain that long-term lifestyle change can be more effective than drugs in preventing or delaying type\xa02 diabetes. Encourage them to adopt a healthy diet and be as active as possible. Where appropriate, stress the added health and social benefits of physical activity (for example, point out that it helps reduce the risk of heart disease, improves mental health and can be a good way of making friends). Advise them that they might need to take metformin for the rest of their lives and inform them about possible side effects. \n\nContinue to offer advice on diet and physical activity along with support to achieve their lifestyle and weight-loss goals. \n\nCheck the person's renal function before starting treatment, and then twice yearly (more often if they are older or if deterioration is suspected). \n\nStart with a low dose (for example, 500\xa0mg once daily) and then increase gradually as tolerated, to 1500 to 2000\xa0mg daily. If the person is intolerant of standard metformin consider using modified-release metformin. \n\nPrescribe metformin for 6 to 12\xa0months initially. Monitor the person's fasting plasma glucose or HbA1c levels at 3\xa0month intervals and stop the drug if no effect is seen. \n\n# Orlistat\n\nUse clinical judgement on whether to offer orlistat to people with a BMI of 28.0\xa0kg/m2 or more, as part of an overall plan for managing obesity. Take into account the person's risk and the level of weight loss and lifestyle change required to reduce this risk. \n\nDiscuss the potential benefits and limitations of taking orlistat and its side effects. \n\nAdvise the person to follow a low-fat diet that provides 30% of daily food energy as fat, distributed over three main meals a day. Offer information and regular support from a dietitian or another appropriate healthcare professional. \n\nAgree a weight-loss goal with the person and regularly review it with them. \n\nReview the use of orlistat after 12\xa0weeks. If the person has not lost at least 5% of their original body weight, use clinical judgement to decide whether to stop the orlistat. However, as with adults who have type\xa02 diabetes, those at high risk of the condition may lose weight more slowly than average, so less strict goals may be appropriate. \n\nUse orlistat for more than 12\xa0months (usually for weight maintenance) only after discussing the potential benefits, limitations and side effects with the person concerned. ", 'Rationale and impact of the new recommendations': "# Intensive lifestyle-change programmes and metformin\n\nThis section explains why the committee made the 2017 recommendations on intensive lifestyle-change programmes and metformin.\n\n## Why the committee made the recommendations\n\nA health economic model showed that lifestyle-change programmes are cost effective for all people at high risk of diabetes, providing support to the existing recommendation to offer the intervention to this group of people. The model also showed that lifestyle-change programmes are particularly cost effective for people with higher HbA1c or fasting plasma glucose levels. Therefore, the committee determined that, in instances where offering the intervention to all high-risk people is not possible due to capacity constraints, lifestyle-change programmes should be prioritised for people with a fasting plasma glucose of 6.5 to 6.9\xa0mmol/l or HbA1c of 44 to 47\xa0mmol/mol. The committee also agreed that people should be given information about their diabetes risk because this was recommended in the previous version of NICE guidance on type\xa02 diabetes prevention based on the expert view of the previous committee.\n\nThe committee also recognised that people with mental illness or dementia often have poorer physical health and would therefore benefit from testing and, if needed, intervention to reduce their risk of type\xa02 diabetes. Therefore an additional recommendation was made to ensure that intensive lifestyle-change programmes are designed to help as many people as possible to access and take part in them.\n\nThe results of the economic modelling also showed that, in the high-risk population overall and in most subgroups, lifestyle-change programmes are more clinically and cost effective than metformin. They also showed that, compared with control alone, metformin is cost effective in the high-risk population overall, and for most subgroups. Therefore, the committee agreed that metformin could be used in support of lifestyle change when blood test results have deteriorated despite someone taking part in these programmes or if they can't take part for some reason. They also agreed that metformin could be used for people whose BMI is over\xa035 when their blood test results have deteriorated because the model showed that metformin is particularly clinically and cost effective for this group.\n\n## Impact of the recommendations on practice\n\nThe 2012 version of this guideline recommended that intensive lifestyle-change programmes should be offered to people at high risk of type\xa02 diabetes. The committee also recognised that intensive lifestyle-change programmes should be designed to help as many people as possible to access and take part in them. However, providing these programmes to all these people has a large resource impact. To make the most of resources commissioners may need to prioritise subsets of the population.\n\nThe NHS Diabetes Prevention Programme is currently being implemented throughout England in response to the 2012 recommendations in this guideline. Implementing the 2017 recommendations will allow this programme to be initially targeted at groups of the population who will benefit most, in a way that is consistent across the UK.\n\nThe updated recommendation on metformin reflects current practice, so the committee noted that it shouldn't have an impact.", 'Context': 'Diabetes is a chronic disease characterised by an inability to regulate blood glucose. It is one of the most prevalent and costly chronic diseases. There are 3.9\xa0million people living with diabetes in the UK, and 90% of those with the condition have type\xa02 diabetes. Type\xa02 diabetes occurs when the pancreas no longer produces enough insulin to maintain a normal blood glucose level, or the body is unable to use the insulin that is produced (known as insulin resistance).\n\nPeople with type\xa02 diabetes have an increased risk of coronary heart disease, peripheral vascular disease and stroke, and they are more likely to have hypertension, dyslipidaemia (abnormal blood lipid and lipoprotein levels) and obesity. People who are overweight or obese are more likely to develop type\xa02 diabetes, and the risk rises as body weight increases.\n\nNHS England, Public Health England and Diabetes UK have developed the NHS Diabetes Prevention Programme (NHS DPP), which is based on recommendations from this guideline. The NHS DPP interventions are commissioned centrally by NHS England. Given that there are an estimated 5 million people at risk of type\xa02 diabetes in England, and that the NHS DPP interventions will be available to only 100,000 people annually, there is a need to identify and prioritise which people are likely to benefit most from the intervention.\n\nThis guidance focuses on identifying people at high risk of type\xa02 diabetes and offering them effective lifestyle-change programmes to prevent or delay the condition. In the 2017 update, the level of risk needed to be reviewed to identify when individualised interventions should be used to prevent the development of type\xa02 diabetes, in terms of individual risk and NHS resources. The clinical and cost effectiveness of intensive lifestyle modification programmes in subgroups of this high-risk population were assessed to help commissioners target the intervention to people who will gain most benefit. The update also assessed the clinical and cost effectiveness of metformin and digitally delivered lifestyle interventions among the same population subgroups.', 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Identification and monitoring\n\nWhich combination of risk-assessment tools and blood tests (HbA1c or fasting plasma glucose [FPG]) are most cost effective and effective at identifying and assessing the risk of type\xa02 diabetes among populations at high risk? In addition, how frequently should testing take place to be efficient? How does effectiveness and cost effectiveness vary for different black and minority ethnic groups, for example, African-Caribbean and black African; people aged 18 to 40, people aged 75 and over, and for high-risk vulnerable adults? \n\nWhat are the demographic characteristics and rates of progression to type\xa02 diabetes among people with a high risk score but normal blood glucose levels (fasting plasma glucose of less than 5.5\xa0mmol/l or HbA1c of less than 42\xa0mmol/mol)? How does this compare with people who have both a high risk score and blood glucose levels that indicate impaired glucose regulation (fasting plasma glucose 5.5 to 6.9\xa0mmol/l or HbA1c 42 to 47\xa0mmol/mol (6.0 to 6.4%)? \n\nWhat are the most effective and cost-effective methods of increasing uptake of type\xa02 diabetes risk assessments and monitoring among those at greatest risk? Those at greatest risk include people from lower socioeconomic and black and minority ethnic groups, and those aged 75 or over. \n\n# Lifestyle interventions\n\nWhich components of an intensive lifestyle-change programme contribute most to the effectiveness and cost effectiveness of interventions to prevent or delay type\xa02 diabetes in those at high risk? How does this vary for different black and minority ethnic groups, for people of different ages for example, aged 18 to 24, 25 to 39 and 75 and over, and for vulnerable adults? \n\nHow effective and cost effective are different types of dietary regime in reducing short- and long-term blood glucose levels and preventing or delaying type\xa02 diabetes? How does this vary for different subgroups, for example, African-Caribbean and black African and other minority ethnic groups and for people of different ages, for example, aged 18 to 24, 25 to 39 and 75 and over? \n\nHow effective and cost effective are different types (and levels and frequency) of physical activity in reducing short- and long-term blood glucose levels and preventing or delaying type\xa02 diabetes? How does this vary for different subgroups, for example, different black and minority ethnic groups and people of different ages, for example, aged 18 to 24, 25 to 39 and 75 and over? \n\n# Vulnerable groups\n\nWhat are the most effective and cost-effective methods for identifying, assessing and managing the risk of type\xa02 diabetes among high-risk, vulnerable adults? This group includes: frail older adults, homeless people, those with severe mental illness, learning or physical disabilities, prisoners, refugees, recent migrants and travellers. \n\n# Digitally delivered intensive lifestyle-change programmes\n\nWhat is the effectiveness of providing digitally delivered intensive lifestyle-change programmes in preventing type\xa02 diabetes in adults at high risk of type\xa02 diabetes?\n\n## Why this is important\n\nThere is a lack of good quality evidence on the effectiveness of digitally delivered intensive lifestyle-change programmes in preventing type\xa02 diabetes. \n\nMore detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.', 'Glossary': "# Behaviour change\n\nEvidence-based behaviour-change advice includes:\n\nhelping people to understand the short, medium and longer-term consequences of health-related behaviour\n\nhelping people to feel positive about the benefits of changing their behaviour\n\nbuilding the person's confidence in their ability to make and sustain changes\n\nrecognising how social contexts and relationships may affect a person's behaviour\n\nhelping plan changes in terms of easy steps over time\n\nidentifying and planning for situations that might undermine the changes people are trying to make (including planning explicit 'if–then' coping strategies to prevent relapse)\n\nencouraging people to make a personal commitment to adopt health-enhancing behaviours by setting (and recording) achievable goals in particular contexts, over a specified time\n\nhelping people to use self-regulation techniques (such as self-monitoring, progress review, relapse management and goal revision) to encourage learning from experience\n\nencouraging people to engage the support of others to help them to achieve their behaviour-change goals.\n\n# Brief advice\n\nTypically, for diabetes prevention, brief advice might consist of a 5 to 15\xa0minute consultation. The aim is to help someone make an informed choice about whether to make lifestyle changes to reduce their risk of diabetes. The discussion covers what that might involve and why it would be beneficial. Practitioners may provide written information in a range of formats and languages about the benefits and, if the person is interested in making changes, may discuss how these can be achieved and sustained in the long term.\n\n# Brief intervention\n\nBrief interventions for diabetes prevention can be delivered by GPs, nurses, healthcare assistants and professionals in primary healthcare and the community. They may be delivered in groups or on a one-to-one basis. They aim to improve someone's diet and help them to be more physically active. A patient-centred or 'shared decision-making' communication style is adopted to encourage people to make choices and have a sense of 'ownership' of their lifestyle goals and individual action plans. Providers of brief interventions should be trained in the use of evidence-based behaviour-change techniques for supporting weight loss through lifestyle change.\n\n# Computer-based risk-assessment tools\n\nThese tools identify a set of risk characteristics in patient health records. They can be used to interrogate GP patient databases and provide a summary score to indicate someone's level of risk. Examples include the Cambridge diabetes risk score and the Leicester practice score.\n\n# Diabetes prevention programmes\n\nDiabetes prevention programmes comprise two integrated components: first, risk identification services and second, intensive lifestyle-change programmes. Participants are acknowledged as the decision-makers throughout the process. Also see 'Intensive lifestyle-change programmes'.\n\n# High risk\n\nHigh risk is defined as a fasting plasma glucose level of 5.5 to 6.9\xa0mmol/l or an HbA1c level of 42 to 47\xa0mmol/mol (6.0 to 6.4%). These terms are used instead of specific numerical scores because risk assessment tools have different scoring systems. Examples of risk assessment tools include: Diabetes risk score assessment tool, QDiabetes risk calculator and Leicester practice risk score. Risk can also be assessed using the NHS Health Check.\n\n# Glycated haemoglobin (HbA1c)\n\nGlycated haemoglobin (HbA1c) forms when red cells are exposed to glucose in the plasma. The HbA1c test reflects average plasma glucose over the previous 8 to 12\xa0weeks. Unlike the oral glucose tolerance test, an HbA1c test can be performed at any time of the day and does not require any special preparation, such as fasting.\n\nHbA1c is a continuous risk factor for type\xa02 diabetes. This means there is no fixed point when people are (or are not) at risk. The World Health Organization recommends a level of 48\xa0mmol/mol (6.5%) for HbA1c as the cut-off point for diagnosing type\xa02 diabetes in non-pregnant adults. For the purposes of this guidance, the range 42–47\xa0mmol/mol (6.0 to 6.4%) is considered to be 'high risk'.\n\n# Impaired fasting glucose (IFG)\n\nImpaired fasting glucose is defined as a fasting plasma glucose between 6.1 and 6.9\xa0mmol/l.\n\n# Impaired glucose tolerance\n\nThis is a risk factor for future diabetes and/or other adverse outcomes. The current WHO diagnostic criteria for impaired glucose tolerance are: a fasting plasma glucose of less than 7.0\xa0mmol/l and a 2-hour venous plasma glucose (after ingestion of 75\xa0g oral glucose load) of 7.8\xa0mmol/l or greater, and less than 11.1\xa0mmol/l.\n\n# Impaired glucose regulation (IGR)\n\nThis is a risk factor for future diabetes and/or other adverse outcomes. The term covers blood glucose levels that are above the normal range but are not high enough for the diagnosis of type\xa02 diabetes. It is used to describe the presence of impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) as defined by the WHO.\n\nIFG is defined as fasting plasma glucose 6.1 to 6.9\xa0mmol/l. IGT is defined as a fasting plasma glucose (FPG) less than 7\xa0mmol/l and 2-hour venous plasma glucose (after ingestion of 75\xa0g oral glucose load) of 7.8\xa0mmol/l or greater and less than 11.1\xa0mmol/l.\n\nImpaired fasting glucose and impaired glucose tolerance can occur as isolated, mutually exclusive conditions or together, that is, fasting plasma glucose between 6.1 and 6.9\xa0mmol/l and 2-hour glucose of 7.8\xa0mmol/l or greater and less than 11.1\xa0mmol/l during the oral glucose tolerance test.\n\n# Intensive lifestyle-change programmes\n\nA structured and coordinated range of interventions provided in different venues for people identified as being at high risk of developing type\xa02 diabetes (following a risk assessment and a blood test). The aim is to help people become more physically active and to improve their diet. If the person is overweight or obese, the programme should result in weight loss. Programmes may be delivered to individuals or groups (or involve a mix of both) depending on the resources available. They can be provided by primary care teams and public, private or community organisations with expertise in dietary advice, weight management and physical activity.\n\n# Level of risk\n\nThe terms 'high', 'intermediate' and 'low' risk are used to refer to the results from a risk assessment tool. Examples of validated risk assessment tools are available in the NHS Health Check best practice guidance. These terms are used instead of specific numerical scores because the tools have different scoring systems. The term 'moderate risk' is used to denote a high risk assessment score where a blood test did not confirm that risk (FPG less than 5.5\xa0mmol/l or HbA1c less than 42\xa0mmol/mol [6.0%]). A fasting plasma glucose of 5.5 to 6.9\xa0mmol/l or an HbA1c level of 42 to 47\xa0mmol/mol [6.0 to 6.4%] indicates high risk.\n\n# Moderate-intensity physical activity\n\nThe UK Chief Medical Officers' physical activity guidelines sets out physical activity recommendations. The definition of moderate physical activity is included in the glossary of the report (see the UK Chief Medical Officers' physical activity guidelines for more information).\n\n# Oral glucose tolerance test\n\nAn oral glucose tolerance test involves measuring the blood glucose level after fasting, and then 2\xa0hours after drinking a standard 75\xa0g glucose drink. Fasting is defined as no calorie intake for at least 8\xa0hours. More than one test on separate days is required for diagnosis in the absence of hyperglycaemic symptoms.\n\n# Vigorous-intensity physical activity\n\nVigorous-intensity physical activity requires a large amount of effort, causes rapid breathing and a substantial increase in heart rate. Examples include running and climbing briskly up a hill. On an absolute scale, vigorous intensity is defined as physical activity that is above 6 metabolic equivalents (METs).\n\n# Vulnerable groups\n\nAdults from vulnerable groups whose risk of type\xa02 diabetes may be increased by a medical condition, or who may not realise they are at risk or who are less likely to access healthcare services. This includes people with severe mental health problems, learning disabilities, physical disabilities or sensory disabilities; people who live in hostels, nursing or residential homes, residential mental health or psychiatric care units, secure hospitals, prisons or remand centres; and people who are part of a mobile population such as travellers, asylum seekers and refugees.\n\n# Weight-loss programmes\n\nEffective weight-loss programmes are structured lifestyle-change programmes to help people lose weight in a sustainable way. They:\n\nare based on an assessment of the individual\n\naddress the reasons why someone might find it difficult to lose weight\n\nare tailored to individual needs and choices\n\nare sensitive to the person's weight concerns\n\nare based on a balanced, healthy diet\n\nencourage regular physical activity\n\nutilise behaviour-change strategies.\n\n# Weight management\n\nIn this guidance, the term weight management includes:\n\nassessing and monitoring body weight\n\npreventing someone from becoming overweight (body mass index [BMI] of 25 to 29.9\xa0kg/m², or 23 to 27.4\xa0kg/m2 if they are of South Asian or Chinese descent)\n\npreventing someone from becoming obese (BMI greater than or equal to 30\xa0kg/m², or 27.5\xa0kg/m2 or above if they are of South Asian or Chinese descent)\n\nhelping someone who is overweight or obese to achieve and maintain a 5 to 10% weight loss and progress to a healthy weight (BMI of 18.5 to 24.9\xa0kg/m², or 18.5 to 22.9\xa0kg/m2 if they are of South Asian or Chinese descent) by adopting a healthy diet and being physically active.\n\nFor other public health and social care terms see the Think Local, Act Personal Care and Support Jargon Buster.", 'Finding more information ': "You can see everything NICE says on this topic in the NICE Pathway on preventing type2 diabetes.\n\nTo find NICE guidance on related topics, including guidance in development, see our topic page for diabetes.\n\nFor full details of the evidence and the guideline committee's discussions, see the supporting documents. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ph38
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This guideline covers how to identify adults at high risk of type 2 diabetes. It aims to remind practitioners that age is no barrier to being at high risk of, or developing, the condition. It also aims to help them provide those at high risk with an effective and appropriate intensive lifestyle-change programme to prevent or delay the onset of type 2 diabetes. The recommendations in this guideline can be used alongside the NHS Health Check programme.
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9328dea6c0a486d00d00131f7d2b377cb269cebc
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nice
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Ab externo canaloplasty for primary open-angle glaucoma
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Ab externo canaloplasty for primary open-angle glaucoma
Evidence-based recommendations on ab externo canaloplasty for primary open-angle glaucoma in adults. This involves widening the eye’s main draining canal by inserting a tiny tube, then removing the tube and stitching the canal to keep it open.
# Recommendations
Current evidence on the safety and efficacy of ab externo canaloplasty for primary open-angle glaucoma is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.
Ab externo canaloplasty for primary open-angle glaucoma should only be done by clinicians with specific training in the procedure.# Indications and current treatments
Primary open-angle glaucoma is a chronic condition associated with elevated intraocular pressure. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.
Treatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.# The procedure
Ab externo canaloplasty is a surgical technique that aims to reduce intraocular pressure by improving drainage of aqueous fluid from the eye. It is done under local or general anaesthetic. A superficial hinged flap of sclera is made and a deeper flap excised, exposing the Schlemm's canal. An ultrasound imaging system is used to identify the canal and to visualise the surgical instruments when they are in the canal. A microcatheter with an illuminated tip is introduced into the canal and advanced around its entire circumference. As the catheter tip advances, viscoelastic fluid is injected into the canal to dilate it. When catheterisation of the entire canal is complete a suture is tied to the tip of the microcatheter and it is withdrawn, pulling the suture into the canal. The suture is cut, tied in a loop encircling the inner wall of the canal and tightened. This widens the canal. The superficial flap is sutured.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a systematic review and meta-analysis of 1,498 eyes, comparing canaloplasty with trabeculectomy, there was no statistically significant difference between groups for complete success rates (maximum postoperative intraocular pressure of 18 mmHg without medication) and qualified success rates (maximum IOP of 18 mmHg with or without medication) after the procedure. In a case series of 224 patients who had canaloplasty, the complete success rates at 1-, 2- and 3‑year follow‑up were 44% (64/144), 38% (30/80) and 31% (9/29) respectively, and the qualified success rates were 75% (108/44), 74% (59/80) and 59% (17/29) respectively.
In the systematic review and meta-analysis of 1,498 eyes, the mean IOP reduction was 9.94 mmHg (95% confidence interval 8.42 to 11.45) and was statistically significantly lower in the canaloplasty group (mean difference between groups −3.61, 95% CI −5.53 to −1.69 mmHg) at 1‑year follow‑up. In a review of 914 eyes treated by canaloplasty alone (n=777 eyes) or with phacoemulsification (n=137 eyes), the mean IOP reduction (after a maximum of 36 months' follow‑up) ranged from 29% to 66% with canaloplasty alone and from 42% to 46% with canaloplasty plus phacoemulsification. In the case series of 224 patients, there was a statistically significant decrease in mean IOP (±standard deviation ) from 29.4±7.9 mmHg before surgery to 16.8±4.2 mmHg at 1 year, 17.1±4.7 mmHg at 2 years and 16.9±3.1 mmHg at 42 months (p<0.0001).
In the systematic review and meta-analysis of 1,498 eyes, the mean reduction in antiglaucoma medication use was 2.11 (95% CI 1.80 to 2.42) 1 year after canaloplasty, and there was no statistically significant difference in medication reduction between groups (mean difference −0.37, 95% CI −0.83 to 0.08). In the review of 914 eyes, mean medication use reduction (after a maximum of 36 months' follow‑up) ranged from 25% to 100% with canaloplasty alone and from 66% to 86% with canaloplasty plus phacoemulsification. In a randomised controlled trial of 59 patients comparing phaco-canaloplasty (n=29) with phaco-non-penetrating deep sclerectomy (n=30), there was a statistically significant decrease in the mean (±SD) number of medications used in both groups, from 2.64±0.68 before surgery to 0.27±0.67 at 1 year in the phaco-canaloplasty group and from 2.89±0.94 to 0.55±0.94 in the phaco-non-penetrating deep sclerectomy group (p<0.05 for the difference within groups, no statistically significant difference between groups).
In a retrospective comparative study of 327 patients who had canaloplasty (n=175) or trabeculectomy (n=152), which collected self-reported questionnaire data 2 years after surgery, the mean score (±SD) for satisfaction with results of surgery (ranging from 0, totally discontented, to 10, totally contented) was statistically significantly higher in the canaloplasty group (8.09±2.71) compared with the trabeculectomy group (7.46±2.61, p=0.034). In the same study, there were statistically significantly fewer revision surgeries reported in the canaloplasty group (mean number of revision surgeries per patient 0.12±0.43) compared with the trabeculectomy group (0.67±1.14, p<0.001). Also, patients were statistically significantly more likely to have a positive mood after canaloplasty (2.30±0.83) compared with trabeculectomy (1.96±0.87, p=0.009), stress caused by surgery or follow‑ups and treatments was statistically significantly lower with canaloplasty (4.18±0.86 and 4.36±0.80 respectively) compared with trabeculectomy (3.59±1.12 and 3.40±1.20 respectively; p<0.001), and nonvisual and visual ocular symptoms were statistically significantly lower in the canaloplasty group (p<0.05).
The specialist advisers listed the following key efficacy outcomes: intraocular pressure reduction and reduced use of glaucoma medication.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Intraocular pressure (IOP) of more than 30 mmHg after the procedure was reported in 2% to 9% of eyes in a review of 914 eyes treated by canaloplasty alone (n=777 eyes) or by canaloplasty with phacoemulsification (n=137 eyes) at a maximum of 36 months' follow‑up.
Hyphaema (greater than 1 mm layered blood) was statistically significantly more frequent in the canaloplasty group than in the trabeculectomy group at 1‑year follow‑up, in a systematic review and meta-analysis of 1,498 eyes (odds ratio 9.24, 95% confidence interval 3.09 to 27.60). The incidence of hyphaema in the canaloplasty group was 25% (304/1221). Hyphaema was reported in 23% (7/30) of patients treated by canaloplasty and in 1 patient treated by trabeculectomy within 90 days of the procedure in a randomised controlled trial (RCT) of 62 patients.
Descemet's membrane detachment was only seen in the canaloplasty group, with an incidence of 3% (37/1185) at 1‑year follow‑up in the systematic review and meta-analysis of 1,498 eyes. Descemet's membrane detachment was reported in 2% to 6% of eyes in the review of 914 eyes at a maximum of 36 months' follow‑up. Microperforation of Descemet's membrane during the procedure was reported in 7% (2/30) of patients treated by canaloplasty in the RCT of 62 patients comparing canaloplasty (n=30) with trabeculectomy (n=32). Trabeculo Descemet's membrane rupture was reported in 1 patient in each group during the procedure in an RCT of 59 patients treated by phaco-canaloplasty (n=29) or phaco-non-penetrating deep sclerectomy (n=30).
Hypotony was statistically significantly less frequent after canaloplasty than after trabeculectomy at 1‑year follow‑up, in the systematic review and meta-analysis of 1,498 eyes (OR 0.32, 95% CI 0.13 to 0.80). The incidence of hypotony in the canaloplasty group was 9% (94/1091). Flat anterior chamber was reported in 0% to 2% of eyes in the review of 914 eyes, and persistent hypotony was reported in 0% to 1% of eyes.
Central retinal artery occlusion was reported in 1 out of 36 patients in the phaco-canaloplasty group and in none of the patients in the trabeculectomy group in a retrospective comparative study of 77 patients.
Ocular decompression retinopathy was reported in a single case report 1 day after canaloplasty. It was treated with tobramycin and dexamethasone. Three months after canaloplasty, IOP remained in control at 16 mmHg and all retinal haemorrhages had completely resolved.
Choroidal effusion or detachment was statistically significantly less frequent in the canaloplasty group than in the trabeculectomy group, in the systematic review and meta-analysis of 1,498 eyes within 1 year of the procedure (OR 0.25, 95% CI 0.06 to 0.97). Choroidal detachment was reported in 7% (2/29) of patients who had phaco-canaloplasty and in none of the patients who had phaco-non-penetrating deep sclerectomy, in the RCT of 59 patients.
Cataract formation was reported in 0% to 8% of eyes in the review of 914 eyes at a maximum of 36 months' follow‑up.
Anterior synechiae during the procedure was reported in 1 patient treated by canaloplasty in the RCT of 62 patients. It was treated by surgical peripheral iridotomy.
Conjunctival leak incidence was not statistically significantly different between the canaloplasty group and the trabeculectomy group within 1‑year follow‑up, in the systematic review and meta-analysis of 1,498 eyes (OR 0.72, 95% CI 0.16 to 3.14). Conjunctival leak was reported in 10% (3/30) of patients treated by canaloplasty and in 9% (3/32) of patients treated by trabeculectomy within 90 days of the procedure in the RCT of 62 patients.
Corneal erosion was reported in 1 patient treated by canaloplasty and in 44% (14/32) of patients treated by trabeculectomy within 90 days of the procedure in the RCT of 62 patients.
Detectable conjunctival bleb was reported in 2% (17/899) of patients after canaloplasty, in the systematic review and meta-analysis of 1,498 eyes.
Cells in the anterior chamber after the procedure were reported in 2 patients who had phaco-canaloplasty and in 1 patient who had phaco-non-penetrating deep sclerectomy, in the RCT of 59 patients.
Iris incarceration was reported in 1 patient in each group in the RCT of 59 patients who had phaco-canaloplasty or phaco-non-penetrating deep sclerectomy.
Suture cheese wiring was reported in 0% to 2% of eyes in the review of 914 eyes.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any anecdotal adverse events or theoretical adverse events.# Further information
For related NICE guidance, see the NICE website.
Patient commentary was sought but none was received.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2677-0
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{'Recommendations': 'Current evidence on the safety and efficacy of ab externo canaloplasty for primary open-angle glaucoma is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.\n\nAb externo canaloplasty for primary open-angle glaucoma should only be done by clinicians with specific training in the procedure.', 'Indications and current treatments': 'Primary open-angle glaucoma is a chronic condition associated with elevated intraocular pressure. It leads to progressive damage to the optic nerve. Early stages are usually asymptomatic but as the condition progresses it causes visual impairment and, if untreated, blindness.\n\nTreatment is usually eye drops containing drugs that either reduce the production of aqueous humor or increase its drainage. Surgical procedures such as trabeculectomy, drainage tubes, deep sclerectomy, viscocanalostomy or laser trabeculoplasty may also be used.', 'The procedure': "Ab externo canaloplasty is a surgical technique that aims to reduce intraocular pressure by improving drainage of aqueous fluid from the eye. It is done under local or general anaesthetic. A superficial hinged flap of sclera is made and a deeper flap excised, exposing the Schlemm's canal. An ultrasound imaging system is used to identify the canal and to visualise the surgical instruments when they are in the canal. A microcatheter with an illuminated tip is introduced into the canal and advanced around its entire circumference. As the catheter tip advances, viscoelastic fluid is injected into the canal to dilate it. When catheterisation of the entire canal is complete a suture is tied to the tip of the microcatheter and it is withdrawn, pulling the suture into the canal. The suture is cut, tied in a loop encircling the inner wall of the canal and tightened. This widens the canal. The superficial flap is sutured.", 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a systematic review and meta-analysis of 1,498\xa0eyes, comparing canaloplasty with trabeculectomy, there was no statistically significant difference between groups for complete success rates (maximum postoperative intraocular pressure [IOP] of 18\xa0mmHg without medication) and qualified success rates (maximum IOP of 18\xa0mmHg with or without medication) after the procedure. In a case series of 224\xa0patients who had canaloplasty, the complete success rates at 1-, 2- and 3‑year follow‑up were 44% (64/144), 38% (30/80) and 31% (9/29) respectively, and the qualified success rates were 75% (108/44), 74% (59/80) and 59% (17/29) respectively.\n\nIn the systematic review and meta-analysis of 1,498\xa0eyes, the mean IOP reduction was 9.94\xa0mmHg (95% confidence interval [CI] 8.42 to 11.45) and was statistically significantly lower in the canaloplasty group (mean difference between groups −3.61, 95% CI −5.53 to −1.69\xa0mmHg) at 1‑year follow‑up. In a review of 914\xa0eyes treated by canaloplasty alone (n=777\xa0eyes) or with phacoemulsification (n=137\xa0eyes), the mean IOP reduction (after a maximum of 36\xa0months' follow‑up) ranged from 29% to 66% with canaloplasty alone and from 42% to 46% with canaloplasty plus phacoemulsification. In the case series of 224\xa0patients, there was a statistically significant decrease in mean IOP (±standard deviation [SD]) from 29.4±7.9\xa0mmHg before surgery to 16.8±4.2\xa0mmHg at 1\xa0year, 17.1±4.7\xa0mmHg at 2\xa0years and 16.9±3.1\xa0mmHg at 42\xa0months (p<0.0001).\n\nIn the systematic review and meta-analysis of 1,498\xa0eyes, the mean reduction in antiglaucoma medication use was\xa02.11 (95%\xa0CI 1.80 to 2.42) 1\xa0year after canaloplasty, and there was no statistically significant difference in medication reduction between groups (mean difference −0.37, 95%\xa0CI −0.83 to 0.08). In the review of 914\xa0eyes, mean medication use reduction (after a maximum of 36\xa0months' follow‑up) ranged from 25% to 100% with canaloplasty alone and from 66% to 86% with canaloplasty plus phacoemulsification. In a randomised controlled trial of 59\xa0patients comparing phaco-canaloplasty (n=29) with phaco-non-penetrating deep sclerectomy (n=30), there was a statistically significant decrease in the mean (±SD) number of medications used in both groups, from 2.64±0.68 before surgery to 0.27±0.67 at 1\xa0year in the phaco-canaloplasty group and from 2.89±0.94 to 0.55±0.94 in the phaco-non-penetrating deep sclerectomy group (p<0.05 for the difference within groups, no statistically significant difference between groups).\n\nIn a retrospective comparative study of 327\xa0patients who had canaloplasty (n=175) or trabeculectomy (n=152), which collected self-reported questionnaire data 2\xa0years after surgery, the mean score (±SD) for satisfaction with results of surgery (ranging from\xa00, totally discontented, to\xa010, totally contented) was statistically significantly higher in the canaloplasty group (8.09±2.71) compared with the trabeculectomy group (7.46±2.61, p=0.034). In the same study, there were statistically significantly fewer revision surgeries reported in the canaloplasty group (mean number of revision surgeries per patient 0.12±0.43) compared with the trabeculectomy group (0.67±1.14, p<0.001). Also, patients were statistically significantly more likely to have a positive mood after canaloplasty (2.30±0.83) compared with trabeculectomy (1.96±0.87, p=0.009), stress caused by surgery or follow‑ups and treatments was statistically significantly lower with canaloplasty (4.18±0.86 and 4.36±0.80 respectively) compared with trabeculectomy (3.59±1.12 and 3.40±1.20 respectively; p<0.001), and nonvisual and visual ocular symptoms were statistically significantly lower in the canaloplasty group (p<0.05).\n\nThe specialist advisers listed the following key efficacy outcomes: intraocular pressure reduction and reduced use of glaucoma medication.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIntraocular pressure (IOP) of more than 30\xa0mmHg after the procedure was reported in 2% to 9% of eyes in a review of 914\xa0eyes treated by canaloplasty alone (n=777\xa0eyes) or by canaloplasty with phacoemulsification (n=137\xa0eyes) at a maximum of 36\xa0months' follow‑up.\n\nHyphaema (greater than 1\xa0mm layered blood) was statistically significantly more frequent in the canaloplasty group than in the trabeculectomy group at 1‑year follow‑up, in a systematic review and meta-analysis of 1,498\xa0eyes (odds ratio [OR] 9.24, 95% confidence interval [CI] 3.09 to 27.60). The incidence of hyphaema in the canaloplasty group was 25% (304/1221). Hyphaema was reported in 23% (7/30) of patients treated by canaloplasty and in 1\xa0patient treated by trabeculectomy within 90\xa0days of the procedure in a randomised controlled trial (RCT) of 62\xa0patients.\n\nDescemet's membrane detachment was only seen in the canaloplasty group, with an incidence of 3% (37/1185) at 1‑year follow‑up in the systematic review and meta-analysis of 1,498\xa0eyes. Descemet's membrane detachment was reported in 2% to 6% of eyes in the review of 914\xa0eyes at a maximum of 36\xa0months' follow‑up. Microperforation of Descemet's membrane during the procedure was reported in 7% (2/30) of patients treated by canaloplasty in the RCT of 62\xa0patients comparing canaloplasty (n=30) with trabeculectomy (n=32). Trabeculo Descemet's membrane rupture was reported in 1\xa0patient in each group during the procedure in an RCT of 59\xa0patients treated by phaco-canaloplasty (n=29) or phaco-non-penetrating deep sclerectomy (n=30).\n\nHypotony was statistically significantly less frequent after canaloplasty than after trabeculectomy at 1‑year follow‑up, in the systematic review and meta-analysis of 1,498\xa0eyes (OR\xa00.32, 95%\xa0CI 0.13 to 0.80). The incidence of hypotony in the canaloplasty group was 9% (94/1091). Flat anterior chamber was reported in 0% to 2% of eyes in the review of 914\xa0eyes, and persistent hypotony was reported in 0% to 1% of eyes.\n\nCentral retinal artery occlusion was reported in 1\xa0out of 36\xa0patients in the phaco-canaloplasty group and in none of the patients in the trabeculectomy group in a retrospective comparative study of 77\xa0patients.\n\nOcular decompression retinopathy was reported in a single case report 1\xa0day after canaloplasty. It was treated with tobramycin and dexamethasone. Three months after canaloplasty, IOP remained in control at 16\xa0mmHg and all retinal haemorrhages had completely resolved.\n\nChoroidal effusion or detachment was statistically significantly less frequent in the canaloplasty group than in the trabeculectomy group, in the systematic review and meta-analysis of 1,498\xa0eyes within 1\xa0year of the procedure (OR\xa00.25, 95%\xa0CI 0.06 to 0.97). Choroidal detachment was reported in 7% (2/29) of patients who had phaco-canaloplasty and in none of the patients who had phaco-non-penetrating deep sclerectomy, in the RCT of 59\xa0patients.\n\nCataract formation was reported in 0% to 8% of eyes in the review of 914\xa0eyes at a maximum of 36\xa0months' follow‑up.\n\nAnterior synechiae during the procedure was reported in 1\xa0patient treated by canaloplasty in the RCT of 62\xa0patients. It was treated by surgical peripheral iridotomy.\n\nConjunctival leak incidence was not statistically significantly different between the canaloplasty group and the trabeculectomy group within 1‑year follow‑up, in the systematic review and meta-analysis of 1,498\xa0eyes (OR\xa00.72, 95%\xa0CI 0.16 to\xa03.14). Conjunctival leak was reported in 10% (3/30) of patients treated by canaloplasty and in 9% (3/32) of patients treated by trabeculectomy within 90\xa0days of the procedure in the RCT of 62\xa0patients.\n\nCorneal erosion was reported in 1\xa0patient treated by canaloplasty and in 44% (14/32) of patients treated by trabeculectomy within 90\xa0days of the procedure in the RCT of 62\xa0patients.\n\nDetectable conjunctival bleb was reported in 2% (17/899) of patients after canaloplasty, in the systematic review and meta-analysis of 1,498\xa0eyes.\n\nCells in the anterior chamber after the procedure were reported in 2\xa0patients who had phaco-canaloplasty and in 1\xa0patient who had phaco-non-penetrating deep sclerectomy, in the RCT of 59\xa0patients.\n\nIris incarceration was reported in 1\xa0patient in each group in the RCT of 59\xa0patients who had phaco-canaloplasty or phaco-non-penetrating deep sclerectomy.\n\nSuture cheese wiring was reported in 0% to 2% of eyes in the review of 914\xa0eyes.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers did not list any anecdotal adverse events or theoretical adverse events.", 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2677-0'}
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https://www.nice.org.uk/guidance/ipg591
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Evidence-based recommendations on ab externo canaloplasty for primary open-angle glaucoma in adults. This involves widening the eye’s main draining canal by inserting a tiny tube, then removing the tube and stitching the canal to keep it open.
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3e0e1edfcc4ae4b1375d7ab021d61b28f40140fd
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nice
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High-intensity focused ultrasound for symptomatic breast fibroadenoma
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High-intensity focused ultrasound for symptomatic breast fibroadenoma
Evidence-based recommendations on high-intensity focused ultrasound for symptomatic breast fibroadenoma in adults. This involves using high-frequency sound waves to heat up the tissues in the lump.
# Recommendations
The evidence on high-intensity focused ultrasound for symptomatic breast fibroadenoma raises no major safety concerns. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to do high-intensity focused ultrasound for symptomatic breast fibroadenoma should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having high-intensity focused ultrasound for symptomatic breast fibroadenoma (see section 7.1).
Patients should be informed about all the alternative treatment options, which could include conservative treatment.
Further research should include publication of patient-reported outcome measures and studies with long-term follow-up.# Indications and current treatments
Breast fibroadenomas are common benign masses that often develop during puberty, although they can occur in women of any age. The condition is rare in men. Simple fibroadenomas are usually 1 cm to 3 cm in size but giant fibroadenomas can be over 5 cm. They do not usually increase in size and some may disappear overtime. The condition is diagnosed by breast examination, and ultrasound or mammography. A needle core biopsy can be used for histological confirmation. Fibroadenomas are usually painless but can become painful and cause deformity.
If a fibroadenoma is asymptomatic, it does not need to be treated and no follow-up is necessary. However, any growth or other changes to the fibroadenoma should be reported. When symptomatic, fibroadenomas can be removed surgically or by vacuum-assisted mammotomy, which can be done under general or local anaesthesia.# The procedure
High-intensity focused ultrasound for breast fibroadenomas is a minimally invasive thermoablative technique that can be done at an outpatient clinic under local anaesthesia and sedation. A focusing ultrasound device delivers the treatment and allows for simultaneous imaging of the treatment area. The technology uses sound waves that propagate through the tissues, generating local heat and inducing coagulative necrosis, protein denaturation and cellular destruction. A strong acute inflammatory response follows. Remodelling of the chronic inflammatory response lasts for up to 3 months and involves cellular regeneration, proliferation, migration and removal of debris.
Tumour size reduction should happen gradually with no need for further intervention.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a case series of 42 women (51 fibroadenomas) treated by high-intensity focused ultrasound (HIFU), 63% (29/46) of the fibroadenomas had reduced in size by 30% at 2 months, 67% (32/48) had reduced by 50% at 6 months and 87% (40/46) had reduced by 60% at 12 months. In a non-randomised controlled study of 40 women, in which 20 were treated by HIFU and 20 were in a control group, fibroadenoma size was statistically significantly reduced by 17% at 2 weeks (standard deviation 19%, p=0.021) and by 31% at 3 months (SD 53%, p=0.022) in the HIFU group. In the same study, fibroadenoma size reduction was statistically significantly different in women treated by HIFU (44%, SD 39%, p=0.016) compared with women in the control group (5%, SD 46%, p=0.53) at 6‑month follow-up; complete fibroadenoma reduction was reported in 33% (4/20) of women in the HIFU group at 12‑month follow-up. In a case series of 10 patients treated by HIFU, fibroadenoma diameter was reduced by 50% in 100% (10/10) of patients at 3‑month follow-up. In a case series of 9 patients treated by magnetic resonance-guided HIFU, fibroadenomas size was reduced to 1.3 cm3 (mean, SD 1.1 cm3) from a baseline of 1.9 cm3 (mean, SD 1.5 cm3) in 50% (6/12) of treatments at 6‑month follow-up. In a case series of 20 patients, fibroadenoma size was statistically significantly reduced in patients treated only once by HIFU from 0.78 ml (0.35 ml to 2.24 ml) at baseline to 0.35 ml (0.06 ml to 1.21 ml, p<0.001) at 2‑year follow-up, and in patients treated twice from 2.66 ml (0.52 ml to 3.01 ml) to 0.21 ml (0.09 ml to 1.66 ml, p=0.003) at 2‑year follow-up.
In the non-randomised controlled study of 40 women, 10% (2/20) of fibroadenomas treated by HIFU did not change in size at 6‑month follow-up.
In the case series of 9 patients treated by magnetic resonance-guided HIFU, technical failure was reported in 42% (5/12) of fibroadenoma treatments.
In the case series of 42 women, 61% (31/51) of the fibroadenomas had caused discomfort before the procedure, which had resolved in 100% of the women at 12‑month follow-up. In the same study, at baseline, 35% (18/51) of fibroadenomas were associated with pain, which had resolved in 100% of patients at 12‑month follow-up. In the non-randomised controlled study of 40 women, complete pain reduction was reported by 75% (6/8) of women treated by HIFU at 6‑month follow-up.
In the case series of 20 patients treated by HIFU, for symptom disappearance, 45% (9/20) of patients were completely satisfied, and satisfaction was high in 50% (10/20) and low in 5% (1/20) of patients. In the same case series, for cosmetic results, 95% (19/20) of patients were completely satisfied and satisfaction was high in 5% (1/20) of patients.
The specialist advisers listed key efficacy outcomes as reduction in lesion size, relief or resolution of symptoms, cost effectiveness, recurrence of symptoms in the short and long term, and time taken to do the procedure.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Discomfort or burning sensation assessed with a visual analogue scale (VAS, 0=no pain, 10=very severe pain) was reported by 90% (18/20) of women (mean score 6.4, standard deviation 3.2) treated by high-intensity focused ultrasound (HIFU) in a non-randomised controlled study of 40 women. In the same study, persistent pain assessed with a VAS was reported by 10% (2/20) of women in the HIFU group (mean score 1.6, SD 1.9) within 3 months of treatment. Pain during treatment was reported as being slight in 36% (4/11), moderate in 18% (2/11) and severe in 9% (1/11) of the procedures in a case series of 9 women (11 fibroadenomas) treated by magnetic resonance-guided HIFU. Pain after treatment measured by a VAS (0=no pain to 100=extreme pain) was 40.7 (±24.6) after the first ablation and 34.9 (±17.9) after the second ablation (p value not reported), in a case series of 20 patients treated by HIFU.
Numbness of the skin was reported by 1 woman of 20 treated by HIFU in the non-randomised controlled study of 40 women. Mild to moderate tenderness was reported by 45% (9/20) of patients up to 1 week after the first HIFU session, and by 57% (4/7) of patients after the second HIFU session in the case series of 20 patients.
Superficial skin burn with blistering was reported in 6% (3/51) of fibroadenomas after the procedure in a case series of 42 women (51 fibroadenomas) treated by HIFU. A first-degree skin burn was reported in 1 woman of 20 treated by HIFU in the non-randomised controlled study of 40 women. A first-degree skin burn with hyperpigmentation visible after 6 months was reported in 1 woman of 7, who had more than 1 fibroadenoma, in the case series of 20 women treated by HIFU.
Hyperpigmentation of the skin was reported in 1 woman within days after the procedure in the case series of 42 women treated by HIFU. Hyperpigmentation of the skin was reported by 30% (6/20) of women treated by HIFU at 3 months and 20% (4/20) at 6 months in the non-randomised controlled study of 40 women.
Subcutaneous induration was reported in 1 woman of 42 at 12‑month follow-up in the case series of 42 women treated by HIFU. Subcutaneous oedema was reported in 25% (4/20) of women in the case series of 20 women treated by HIFU.
Ecchymosis was reported by 45% (9/20) of women treated by HIFU in the non-randomised controlled study of 40 women.
Erythema was reported by 30% (6/20) of women treated by HIFU in the non-randomised controlled study of 40 women. Mild to moderate erythema that resolved within 1 week was reported by 29% (2/7) of women, who had more than 1 fibroadenoma, treated by HIFU in the case series of 20 patients.
Dimpling of the skin was reported by 1 woman of 20 treated by HIFU in the non-randomised controlled study of 40 women.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed no anecdotal adverse events. They considered that the following were theoretical adverse events: poor cosmetic outcome, infection and severe fibrosis.# Further information
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
For related NICE guidance, see the NICE website.
Patient commentary was sought but none was received.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2679-4
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{'Recommendations': "The evidence on high-intensity focused ultrasound for symptomatic breast fibroadenoma raises no major safety concerns. Evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do high-intensity focused ultrasound for symptomatic breast fibroadenoma should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having high-intensity focused ultrasound for symptomatic breast fibroadenoma (see section\xa07.1).\n\nPatients should be informed about all the alternative treatment options, which could include conservative treatment.\n\nFurther research should include publication of patient-reported outcome measures and studies with long-term follow-up.", 'Indications and current treatments': 'Breast fibroadenomas are common benign masses that often develop during puberty, although they can occur in women of any age. The condition is rare in men. Simple fibroadenomas are usually 1\xa0cm to 3\xa0cm in size but giant fibroadenomas can be over 5\xa0cm. They do not usually increase in size and some may disappear overtime. The condition is diagnosed by breast examination, and ultrasound or mammography. A needle core biopsy can be used for histological confirmation. Fibroadenomas are usually painless but can become painful and cause deformity.\n\nIf a fibroadenoma is asymptomatic, it does not need to be treated and no follow-up is necessary. However, any growth or other changes to the fibroadenoma should be reported. When symptomatic, fibroadenomas can be removed surgically or by vacuum-assisted mammotomy, which can be done under general or local anaesthesia.', 'The procedure': 'High-intensity focused ultrasound for breast fibroadenomas is a minimally invasive thermoablative technique that can be done at an outpatient clinic under local anaesthesia and sedation. A focusing ultrasound device delivers the treatment and allows for simultaneous imaging of the treatment area. The technology uses sound waves that propagate through the tissues, generating local heat and inducing coagulative necrosis, protein denaturation and cellular destruction. A strong acute inflammatory response follows. Remodelling of the chronic inflammatory response lasts for up to 3\xa0months and involves cellular regeneration, proliferation, migration and removal of debris.\n\nTumour size reduction should happen gradually with no need for further intervention.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a case series of 42\xa0women (51\xa0fibroadenomas) treated by high-intensity focused ultrasound (HIFU), 63% (29/46) of the fibroadenomas had reduced in size by 30% at 2\xa0months, 67% (32/48) had reduced by 50% at 6\xa0months and 87% (40/46) had reduced by 60% at 12\xa0months. In a non-randomised controlled study of 40\xa0women, in which 20\xa0were treated by HIFU and 20\xa0were in a control group, fibroadenoma size was statistically significantly reduced by 17% at 2\xa0weeks (standard deviation [SD]\xa019%, p=0.021) and by 31% at 3\xa0months (SD\xa053%, p=0.022) in the HIFU group. In the same study, fibroadenoma size reduction was statistically significantly different in women treated by HIFU (44%, SD\xa039%, p=0.016) compared with women in the control group (5%, SD\xa046%, p=0.53) at 6‑month follow-up; complete fibroadenoma reduction was reported in 33% (4/20) of women in the HIFU group at 12‑month follow-up. In a case series of 10\xa0patients treated by HIFU, fibroadenoma diameter was reduced by 50% in 100% (10/10) of patients at 3‑month follow-up. In a case series of 9\xa0patients treated by magnetic resonance-guided HIFU, fibroadenomas size was reduced to 1.3\xa0cm3 (mean, SD\xa01.1\xa0cm3) from a baseline of 1.9\xa0cm3 (mean, SD\xa01.5\xa0cm3) in 50% (6/12) of treatments at 6‑month follow-up. In a case series of 20\xa0patients, fibroadenoma size was statistically significantly reduced in patients treated only once by HIFU from 0.78\xa0ml (0.35\xa0ml to 2.24\xa0ml) at baseline to 0.35\xa0ml (0.06\xa0ml to 1.21\xa0ml, p<0.001) at 2‑year follow-up, and in patients treated twice from 2.66\xa0ml (0.52\xa0ml to 3.01\xa0ml) to 0.21\xa0ml (0.09\xa0ml to 1.66\xa0ml, p=0.003) at 2‑year follow-up.\n\nIn the non-randomised controlled study of 40\xa0women, 10% (2/20) of fibroadenomas treated by HIFU did not change in size at 6‑month follow-up.\n\nIn the case series of 9\xa0patients treated by magnetic resonance-guided HIFU, technical failure was reported in 42% (5/12) of fibroadenoma treatments.\n\nIn the case series of 42\xa0women, 61% (31/51) of the fibroadenomas had caused discomfort before the procedure, which had resolved in 100% of the women at 12‑month follow-up. In the same study, at baseline, 35% (18/51) of fibroadenomas were associated with pain, which had resolved in 100% of patients at 12‑month follow-up. In the non-randomised controlled study of 40\xa0women, complete pain reduction was reported by 75% (6/8) of women treated by HIFU at 6‑month follow-up.\n\nIn the case series of 20\xa0patients treated by HIFU, for symptom disappearance, 45% (9/20) of patients were completely satisfied, and satisfaction was high in 50% (10/20) and low in 5% (1/20) of patients. In the same case series, for cosmetic results, 95% (19/20) of patients were completely satisfied and satisfaction was high in 5% (1/20) of patients.\n\nThe specialist advisers listed key efficacy outcomes as reduction in lesion size, relief or resolution of symptoms, cost effectiveness, recurrence of symptoms in the short and long term, and time taken to do the procedure.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nDiscomfort or burning sensation assessed with a visual analogue scale (VAS, 0=no pain, 10=very severe pain) was reported by 90% (18/20) of women (mean score\xa06.4, standard deviation [SD] 3.2) treated by high-intensity focused ultrasound (HIFU) in a non-randomised controlled study of 40\xa0women. In the same study, persistent pain assessed with a VAS was reported by 10% (2/20) of women in the HIFU group (mean score\xa01.6, SD\xa01.9) within 3\xa0months of treatment. Pain during treatment was reported as being slight in 36% (4/11), moderate in 18% (2/11) and severe in 9% (1/11) of the procedures in a case series of 9\xa0women (11\xa0fibroadenomas) treated by magnetic resonance-guided HIFU. Pain after treatment measured by a VAS (0=no pain to 100=extreme pain) was 40.7 (±24.6) after the first ablation and 34.9 (±17.9) after the second ablation (p\xa0value not reported), in a case series of 20\xa0patients treated by HIFU.\n\nNumbness of the skin was reported by 1\xa0woman of\xa020 treated by HIFU in the non-randomised controlled study of 40\xa0women. Mild to moderate tenderness was reported by 45% (9/20) of patients up to 1\xa0week after the first HIFU session, and by 57% (4/7) of patients after the second HIFU session in the case series of 20\xa0patients.\n\nSuperficial skin burn with blistering was reported in 6% (3/51) of fibroadenomas after the procedure in a case series of 42\xa0women (51\xa0fibroadenomas) treated by HIFU. A first-degree skin burn was reported in 1\xa0woman of\xa020 treated by HIFU in the non-randomised controlled study of 40\xa0women. A first-degree skin burn with hyperpigmentation visible after 6\xa0months was reported in 1\xa0woman of\xa07, who had more than 1\xa0fibroadenoma, in the case series of 20\xa0women treated by HIFU.\n\nHyperpigmentation of the skin was reported in 1\xa0woman within days after the procedure in the case series of 42\xa0women treated by HIFU. Hyperpigmentation of the skin was reported by 30% (6/20) of women treated by HIFU at 3\xa0months and 20% (4/20) at 6\xa0months in the non-randomised controlled study of 40\xa0women.\n\nSubcutaneous induration was reported in 1\xa0woman of\xa042 at 12‑month follow-up in the case series of 42\xa0women treated by HIFU. Subcutaneous oedema was reported in 25% (4/20) of women in the case series of 20\xa0women treated by HIFU.\n\nEcchymosis was reported by 45% (9/20) of women treated by HIFU in the non-randomised controlled study of 40\xa0women.\n\nErythema was reported by 30% (6/20) of women treated by HIFU in the non-randomised controlled study of 40\xa0women. Mild to moderate erythema that resolved within 1\xa0week was reported by 29% (2/7) of women, who had more than 1\xa0fibroadenoma, treated by HIFU in the case series of 20\xa0patients.\n\nDimpling of the skin was reported by 1\xa0woman of\xa020 treated by HIFU in the non-randomised controlled study of 40\xa0women.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed no anecdotal adverse events. They considered that the following were theoretical adverse events: poor cosmetic outcome, infection and severe fibrosis.', 'Further information': 'This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2679-4'}
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https://www.nice.org.uk/guidance/ipg592
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Evidence-based recommendations on high-intensity focused ultrasound for symptomatic breast fibroadenoma in adults. This involves using high-frequency sound waves to heat up the tissues in the lump.
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bc2e871fdb478e958935583fd07ad441b1f24546
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nice
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Sepsis: recognition, diagnosis and early management
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Sepsis: recognition, diagnosis and early management
This guideline covers the recognition, diagnosis and early management of sepsis for all populations. The guideline committee identified that the key issues to be included were: recognition and early assessment, diagnostic and prognostic value of blood markers for sepsis, initial treatment, escalating care, identifying the source of infection, early monitoring, information and support for patients and carers, and training and education.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Identifying people with suspected sepsis
This guidance should be used together with the algorithms organised by age group and treatment location and the risk stratification tools. There are algorithms for:
children under 5 out of hospital
children under 5 in hospital
children aged 5 to 11 years out of hospital
children aged 5 to 11 years in hospital
children and young people aged 12 to 17 out of hospital
children and young people aged 12 to 17 in hospital
adults aged 18 and over out of hospital
adults aged 18 and over in hospital
There are also risk stratification tools for:
children under 5
children aged 5 to 11 years
adults, children and young people aged 12 years and over
Think 'could this be sepsis?' if a person presents with signs or symptoms that indicate possible infection.
Take into account that people with sepsis may have non-specific, non-localised presentations, for example feeling very unwell, and may not have a high temperature.
Pay particular attention to concerns expressed by the person and their family or carers, for example changes from usual behaviour.
Assess people who might have sepsis with extra care if they cannot give a good history (for example, people with English as a second language or people with communication problems).
Assess people with any suspected infection to identify:
possible source of infection
factors that increase risk of sepsis (see section 1.2 on risk factors for sepsis)
any indications of clinical concern, such as new onset abnormalities of behaviour, circulation or respiration.
Identify factors that increase risk of sepsis (see section 1.2 on risk factors for sepsis) or indications of clinical concern such as new onset abnormalities of behaviour, circulation or respiration when deciding during a remote assessment whether to offer a face-to-face-assessment and if so, on the urgency of face-to-face assessment.
Use a structured set of observations (see section 1.3 on 1.3 face-to-face assessment on people with suspected sepsis) to assess people in a face-to-face setting to stratify risk (see section 1.4 on stratifying risk of severe illness or death from sepsis) if sepsis is suspected.
Consider using an early warning score (NEWS2 has been endorsed by NHS England) to assess people with suspected sepsis in acute hospital settings.
Suspect neutropenic sepsis in patients having anticancer treatment who become unwell.
Refer patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care.
Treat people with neutropenic sepsis in line with NICE's guideline on neutropenic sepsis.
# Risk factors for sepsis
Take into account that people in the groups below are at higher risk of developing sepsis:
the very young (under 1 year) and older people (over 75 years) or people who are very frail
people who have impaired immune systems because of illness or drugs, including:
people being treated for cancer with chemotherapy (see recommendation 1.1.9 in the section on identifying people with suspected sepsis)
people who have impaired immune function (for example, people with diabetes, people who have had a splenectomy, or people with sickle cell disease)
people taking long-term steroids
people taking immunosuppressant drugs to treat non-malignant disorders such as rheumatoid arthritis
people who have had surgery, or other invasive procedures, in the past 6 weeks
people with any breach of skin integrity (for example, cuts, burns, blisters or skin infections)
people who misuse drugs intravenously
people with indwelling lines or catheters.
Take into account that women who are pregnant, have given birth or had a termination of pregnancy or miscarriage in the past 6 weeks are in a high risk group for sepsis. In particular, women who:
have impaired immune systems because of illness or drugs (see recommendation 1.1.5 in the section on identifying people with suspected sepsis)
have gestational diabetes or diabetes or other comorbidities
needed invasive procedures (for example, caesarean section, forceps delivery, removal of retained products of conception)
had prolonged rupture of membranes
have or have been in close contact with people with group A streptococcal infection, for example, scarlet fever
have continued vaginal bleeding or an offensive vaginal discharge.
Take into account the following risk factors for early-onset neonatal infection:
invasive group B streptococcal infection in a previous baby
maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy
prelabour rupture of membranes
preterm birth following spontaneous labour (before 37 weeks' gestation)
suspected or confirmed rupture of membranes for more than 18 hours in a preterm birth
intrapartum fever higher than 38°C, or confirmed or suspected chorioamnionitis
parenteral antibiotic treatment given to the woman for confirmed or suspected invasive bacterial infection (such as septicaemia) at any time during labour, or in the 24-hour periods before and after the birth (this does not refer to intrapartum antibiotic prophylaxis)
suspected or confirmed infection in another baby in the case of a multiple pregnancy.
# Face-to-face assessment of people with suspected sepsis
Assess temperature, heart rate, respiratory rate, blood pressure, level of consciousness and oxygen saturation in young people and adults with suspected sepsis.
Assess temperature, heart rate, respiratory rate, level of consciousness, oxygen saturation and capillary refill time in children under 12 years with suspected sepsis.
Measure blood pressure of children under 5 years if heart rate or capillary refill time is abnormal and facilities to measure blood pressure, including a correctly-sized blood pressure cuff, are available.
Measure blood pressure of children aged 5 to 11 years who might have sepsis if facilities to measure blood pressure, including a correctly-sized cuff, are available.
Only measure blood pressure in children under 12 years in community settings if facilities to measure blood pressure, including a correctly-sized cuff, are available and taking a measurement does not cause a delay in assessment or treatment.
Measure oxygen saturation in community settings if equipment is available and taking a measurement does not cause a delay in assessment or treatment.
Examine people with suspected sepsis for mottled or ashen appearance, cyanosis of the skin, lips or tongue, non-blanching rash of the skin, any breach of skin integrity (for example, cuts, burns or skin infections) or other rash indicating potential infection.
Ask the person, parent or carer about frequency of urination in the past 18 hours.
# Stratifying risk of severe illness or death from sepsis
Use the person's history and physical examination results to grade risk of severe illness or death from sepsis using criteria based on age (see tables 1, 2 and 3).
## Adults, children and young people aged 12 years and over
Category
High risk criteria
Moderate to high risk criteria
Low risk criteria
History
Objective evidence of new altered mental state
History from patient, friend or relative of new onset of altered behaviour or mental state
History of acute deterioration of functional ability
Impaired immune system (illness or drugs including oral steroids)
Trauma, surgery or invasive procedures in the last 6 weeks
Normal behaviour
Respiratory
Raised respiratory rate: 25 breaths per minute or more
New need for oxygen (40% FiO2 or more) to maintain saturation more than 92% (or more than 88% in known chronic obstructive pulmonary disease)
Raised respiratory rate: 21 to 24 breaths per minute
No high risk or moderate to high risk criteria met
Blood pressure
Systolic blood pressure 90 mmHg or less or systolic blood pressure more than 40 mmHg below normal
Systolic blood pressure 91 to 100 mmHg
No high risk or moderate to high risk criteria met
Circulation and hydration
Raised heart rate: more than 130 beats per minute
Not passed urine in previous 18 hours.
For catheterised patients, passed less than 0.5 ml/kg of urine per hour
Raised heart rate: 91 to 130 beats per minute (for pregnant women 100 to 130 beats per minute) or new onset arrhythmia
Not passed urine in the past 12 to 18 hours
For catheterised patients, passed 0.5 ml/kg to 1 ml/kg of urine per hour
No high risk or moderate to high risk criteria met
Temperature
Tympanic temperature less than 36°C
Skin
Mottled or ashen appearance
Cyanosis of skin, lips or tongue
Non-blanching rash of skin
Signs of potential infection, including redness, swelling or discharge at surgical site or breakdown of wound
No non-blanching rash
A downloadable version of this table is also available.
Recognise that adults, children and young people aged 12 years and over with suspected sepsis and any of the symptoms or signs below are at high risk of severe illness or death from sepsis:
-bjective evidence of new altered mental state
respiratory rate of 25 breaths per minute or above, or new need for 40% oxygen or more to maintain oxygen saturation more than 92% (or more than 88% in known chronic obstructive pulmonary disease)
heart rate of more than 130 beats per minute
systolic blood pressure of 90 mmHg or less, or systolic blood pressure more than 40 mmHg below normal
not passed urine in previous 18 hours (for catheterised patients, passed less than 0.5 ml/kg/hour)
mottled or ashen appearance
cyanosis of the skin, lips or tongue
non-blanching rash of the skin.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Recognise that adults, children and young people aged 12 years and over with suspected sepsis and any of the symptoms or signs below are at moderate to high risk of severe illness or death from sepsis:
history of new-onset changed behaviour or change in mental state, as reported by the person, a friend or relative
history of acute deterioration of functional ability
impaired immune system (illness or drugs, including oral steroids)
trauma, surgery or invasive procedure in the past 6 weeks
respiratory rate of 21 to 24 breaths per minute
heart rate of 91 to 130 beats per minute or new-onset arrhythmia, or if pregnant heart rate of 100 to 130 beats per minute
systolic blood pressure of 91 to 100 mmHg
not passed urine in the past 12 to 18 hours (for catheterised patients, passed 0.5 ml/kg/hour to 1 ml/kg/hour)
tympanic temperature less than 36°C
signs of potential infection, including increased redness, swelling or discharge at a surgical site, or breakdown of a wound.
Consider adults, children and young people aged 12 years and over with suspected sepsis who do not meet any high or moderate to high risk criteria to be at low risk of severe illness or death from sepsis.
## Children aged 5 to 11 years
Category
Age
High risk criteria
Moderate to high risk criteria
Low risk criteria
Behaviour
Any
Objective evidence of altered behaviour or mental state
Appears ill to a healthcare professional
Does not wake or if roused does not stay awake
Not behaving normally
Decreased activity
Parent or carer concern that the child is behaving differently from usual
Behaving normally
Respiratory
Any
Oxygen saturation of less than 90% in air or increased oxygen requirement over baseline
Oxygen saturation of less than 92% in air or increased oxygen requirement over baseline
No high risk or moderate to high risk criteria met
Respiratory
Aged 5 years
Raised respiratory rate: 29 breaths per minute or more
Raised respiratory rate: 24 to 28 breaths per minute
No high risk or moderate to high risk criteria met
Respiratory
Aged 6 to 7 years
Raised respiratory rate: 27 breaths per minute or more
Raised respiratory rate: 24 to 26 breaths per minute
No high risk or moderate to high risk criteria met
Respiratory
Aged 8 to 11 years
Raised respiratory rate: 25 breaths per minute or more
Raised respiratory rate: 22 to 24 breaths per minute
No high risk or moderate to high risk criteria met
Circulation and hydration
Any
Heart rate less than 60 beats per minute
Capillary refill time of 3 seconds or more
Reduced urine output
For catheterised patients, passed less than 1 ml/kg of urine per hour
No high risk or moderate to high risk criteria met
Circulation and hydration
Aged 5 years
Raised heart rate: 130 beats per minute or more
Raised heart rate: 120 to 129 beats per minute
No high risk or moderate to high risk criteria met
Circulation and hydration
Aged 6 to 7 years
Raised heart rate: 120 beats per minute or more
Raised heart rate: 110 to 119 beats per minute
No high risk or moderate to high risk criteria met
Circulation and hydration
Aged 8 to 11 years
Raised heart rate: 115 beats per minute or more
Raised heart rate: 105 to 114 beats per minute
No high risk or moderate to high risk criteria met
Temperature
Any
Tympanic temperature less than 36°C
Skin
Any
Mottled or ashen appearance
Cyanosis of skin, lips or tongue
Non-blanching rash of skin
Other
Any
Leg pain
Cold hands or feet
No high or moderate to high risk criteria met
Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
A downloadable version of this table is also available.
Recognise that children aged 5 to 11 years with suspected sepsis and any of the symptoms or signs below are at high risk of severe illness or death from sepsis:
has objective evidence of altered behaviour or mental state, or appears ill to a healthcare professional, or does not wake (or if roused, does not stay awake)
respiratory rate:
aged 5 years, 29 breaths per minute or more
aged 6 to 7 years, 27 breaths per minute or more
aged 8 to 11 years, 25 breaths per minute or more
-xygen saturation of less than 90% in air or increased oxygen requirement over baseline
heart rate:
aged 5 years, 130 beats per minute or more
aged 6 to 7 years, 120 beats per minute or more
aged 8 to 11 years, 115 beats per minute or more
-r heart rate less than 60 beats per minute at any age
mottled or ashen appearance
cyanosis of the skin, lips or tongue
non-blanching rash of the skin.
Recognise that children aged 5 to 11 years with suspected sepsis and any of the symptoms or signs below are at moderate to high risk of severe illness or death from sepsis:
not responding normally to social cues or decreased activity, or parent or carer concern that the child is behaving differently from usual
respiratory rate:
aged 5 years, 24 to 28 breaths per minute
aged 6 to 7 years, 24 to 26 breaths per minute
aged 8 to 11 years, 22 to 24 breaths per minute
-xygen saturation of less than 92% in air or increased oxygen requirement over baseline
heart rate:
aged 5 years, 120 to 129 beats per minute
aged 6 to 7 years, 110 to 119 beats per minute
aged 8 to 11 years, 105 to 114 beats per minute
-r capillary refill time of 3 seconds or more
reduced urine output, or for catheterised patients passed less than 1 ml/kg of urine per hour
tympanic temperature less than 36°C
have leg pain or cold hands or feet.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Consider children aged 5 to 11 years with suspected sepsis who do not meet any high or moderate to high risk criteria to be at low risk of severe illness or death from sepsis.
## Children aged under 5 years
Category
Age
High risk criteria
Moderate to high risk criteria
Low risk criteria
Behaviour
Any
No response to social cues
Appears ill to a healthcare professional
Does not wake, or if roused does not stay awake
Weak high-pitched or continuous cry
Not responding normally to social cues
No smile
Wakes only with prolonged stimulation
Decreased activity
Parent or carer concern that child is behaving differently from usual
Responds normally to social cues
Content or smiles
Stays awake or awakens quickly
Strong normal cry or not crying
Respiratory
Any
Grunting
Apnoea
Oxygen saturation of less than 90% in air or increased oxygen requirement over baseline
Oxygen saturation of less than 92% in air or increased oxygen requirement over baseline
Nasal flaring
No high risk or moderate to high risk criteria met
Respiratory
Under 1 year
Raised respiratory rate: 60 breaths per minute or more
Raised respiratory rate: 50 to 59 breaths per minute
No high risk or moderate to high risk criteria met
Respiratory
to 2 years
Raised respiratory rate: 50 breaths per minute or more
Raised respiratory rate: 40 to 49 breaths per minute
No high risk or moderate to high risk criteria met
Respiratory
to 4 years
Raised respiratory rate: 40 breaths per minute or more
Raised respiratory rate: 35 to 39 breaths per minute
No high risk or moderate to high risk criteria met
Circulation and hydration
Any
Bradycardia: heart rate less than 60 beats per minute
Capillary refill time of 3 seconds or more
Reduced urine output
For catheterised patients, passed less than 1 ml/kg of urine per hour
No high risk or moderate to high risk criteria met
Circulation and hydration
Under 1 year
Rapid heart rate: 160 beats per minute or more
Rapid heart rate: 150 to 159 beats per minute
No high risk or moderate to high risk criteria met
Circulation and hydration
to 2 years
Rapid heart rate: 150 beats per minute or more
Rapid heart rate: 140 to 149 beats per minute
No high risk or moderate to high risk criteria met
Circulation and hydration
to 4 years
Rapid heart rate: 140 beats per minute or more
Rapid heart rate: 130 to 139 beats per minute
No high risk or moderate to high risk criteria met
Skin
Any
Mottled or ashen appearance
Cyanosis of skin, lips or tongue
Non-blanching rash of skin
Pallor of skin, lips or tongue
Normal colour
Temperature
Any
Less than 36ºC
Temperature
Under 3 months
°C or more
Temperature
to 6 months
°C or more
Other
Any
Leg pain
Cold hands or feet
No high risk or high to moderate risk criteria met
Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
This table is adapted from NICE's guideline on fever in under 5s. A downloadable version of this table is also available.
Recognise that children aged under 5 years with suspected sepsis and any of the symptoms or signs below are at high risk of severe illness or death from sepsis:
behaviour:
no response to social cues
appears ill to a healthcare professional
does not wake, or if roused does not stay awake
weak, high-pitched or continuous cry
heart rate:
aged under 1 year, 160 beats per minute or more
aged 1 to 2 years, 150 beats per minute or more
aged 3 to 4 years, 140 beats per minute or more
heart rate less than 60 beats per minute at any age
respiratory rate:
aged under 1 year, 60 breaths per minute or more
aged 1 to 2 years, 50 breaths per minute or more
aged 3 to 4 years, 40 breaths per minute or more
grunting
apnoea
-xygen saturation of less than 90% in air or increased oxygen requirement over baseline
mottled or ashen appearance
cyanosis of the skin, lips or tongue
non-blanching rash of the skin
aged under 3 months and temperature 38°C or more
temperature less than 36°C.
Recognise that children aged under 5 years with suspected sepsis and any of the symptoms or signs below are at moderate to high risk of severe illness or death from sepsis:
behaviour:
not responding normally to social cues
no smile
wakes only with prolonged stimulation
decreased activity
parent or carer concern that the child is behaving differently from usual
respiratory rate:
aged under 1 year, 50 to 59 breaths per minute
aged 1 to 2 years, 40 to 49 breaths per minute
aged 3 to 4 years, 35 to 39 breaths per minute
-xygen saturation less than 92% in air or increased oxygen requirement over baseline
nasal flaring
heart rate:
aged under 1 year, 150 to 159 beats per minute
aged 1 to 2 years, 140 to 149 beats per minute
aged 3 to 4 years 130 to 139 beats per minute
capillary refill time of 3 seconds or more
reduced urine output, or for catheterised patients passed less than 1 ml/kg of urine per hour
pallor of skin, lips or tongue reported by parent or carer
aged 3 to 6 months and temperature 39°C or over
have leg pain or cold hands or feet. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Consider children aged under 5 years with suspected sepsis who do not meet any high or moderate to high risk criteria to be at low risk of severe illness or death from sepsis.
## Children, young people and adults with suspected sepsis
## Temperature in suspected sepsis
Do not use a person's temperature as the sole predictor of sepsis.
Do not rely on fever or hypothermia to rule sepsis either in or out.
Ask the person with suspected sepsis and their family or carers about any recent fever or rigors.
Take into account that some groups of people with sepsis may not develop a raised temperature. These include:
people who are older or very frail
people having treatment for cancer
people severely ill with sepsis
young infants or children.
Take into account that a rise in temperature can be a physiological response, for example after surgery or trauma.
## Heart rate in suspected sepsis
Interpret the heart rate of a person with suspected sepsis in context, taking into account that:
baseline heart rate may be lower in young people and adults who are fit
baseline heart rate in pregnancy is 10 to 15 beats per minute more than normal
-lder people with an infection may not develop an increased heart rate
-lder people may develop a new arrhythmia in response to infection rather than an increased heart rate
heart rate response may be affected by medicines such as beta-blockers.
## Blood pressure in suspected sepsis
Interpret blood pressure in the context of a person's previous blood pressure, if known. Be aware that the presence of normal blood pressure does not exclude sepsis in children and young people.
## Confusion, mental state and cognitive state in suspected sepsis
Interpret a person's mental state in the context of their normal function and treat changes as being significant.
Be aware that changes in cognitive function may be subtle and assessment should include history from patient and family or carers.
Take into account that changes in cognitive function may present as changes in behaviour or irritability in both children and in adults with dementia.
Take into account that changes in cognitive function in older people may present as acute changes in functional abilities.
## Oxygen saturation in suspected sepsis
Take into account that if peripheral oxygen saturation is difficult to measure in a person with suspected sepsis, this may indicate poor peripheral circulation because of shock.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
# Managing suspected sepsis outside acute hospital settings
Refer all people with suspected sepsis outside acute hospital settings for emergency medical care by the most appropriate means of transport (usually 999 ambulance) if:
they meet any high risk criteria (see tables 1, 2 and 3) or
they are aged under 17 years and their immunity is impaired by drugs or illness and they have any moderate to high risk criteria.Emergency care requires facilities for resuscitation to be available and depending on local services may be emergency department, medical admissions unit and for children may be paediatric ambulatory unit or paediatric medical admissions unit.
Assess all people with suspected sepsis outside acute hospital settings with any moderate to high risk criteria to:
make a definitive diagnosis of their condition
decide whether they can be treated safely outside hospital.If a definitive diagnosis is not reached or the person cannot be treated safely outside an acute hospital setting, refer them urgently for emergency care.
Provide people with suspected sepsis, who do not have any high or moderate to high risk criteria information about symptoms to monitor and how to access medical care if they are concerned.
# Managing and treating suspected sepsis in acute hospital settings
## Adults, children and young people aged 12 years and over with suspected sepsis who meet 1 or more high risk criteria
For adults, children and young people aged 12 years and over who have suspected sepsis and 1 or more high risk criteria:
arrange for immediate review by the senior clinical decision maker to assess the person and think about alternative diagnoses to sepsis A 'senior clinical decision maker' for people aged 18 years or over should be someone who is authorised to prescribe antibiotics, such as a doctor of grade CT3/ST3 or above or equivalent, such as an advanced nurse practitioner with antibiotic prescribing responsibilities, depending on local arrangements. A 'senior decision maker' for people aged 12 to 17 years is a paediatric or emergency care qualified doctor of grade ST4 or above or equivalent.
carry out a venous blood test for the following:
blood gas including glucose and lactate measurement
blood culture
full blood count
C-reactive protein
urea and electrolytes
creatinine
a clotting screen
give a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.7 antibiotic treatment in people with suspected sepsis
discuss with a consultant.Appropriate consultant may be the consultant under whom the patient is admitted or a consultant covering acute medicine, anaesthetics.
For adults, children and young people aged 12 years and over with suspected sepsis and any high risk criteria and lactate over 4 mmol/litre, or systolic blood pressure less than 90 mmHg:
give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis and
refer to critical care for review of management including need for central venous access and initiation of inotropes or vasopressors.Referral may be a formal referral process or discussion with specialist in intensive care or intensive care outreach team.Critical care means an intensivist or intensive care outreach team, or specialist in intensive care or paediatric intensive care.
For adults, children and young people aged 12 years and over with suspected sepsis and any high risk criteria and lactate between 2 and 4 mmol/litre:
give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis.
For adults, children and young people aged 12 years and over with suspected sepsis and any high risk criteria and lactate below 2 mmol/litre:
consider giving intravenous fluid bolus (in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis).
Monitor people with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30 minutes depending on setting. Physiological track and trigger systems should be used to monitor all adult patients in acute hospital settings.
Monitor the mental state of adults, children and young people aged 12 years and over with suspected sepsis. Consider using a scale such as the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale.
Alert a consultant to attend in person if an adult, child or young person aged 12 years or over with suspected sepsis and any high risk criteria fails to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated by any of:
systolic blood pressure persistently below 90 mmHg
reduced level of consciousness despite resuscitation
respiratory rate over 25 breaths per minute or a new need for mechanical ventilation
lactate not reduced by more than 20% of initial value within 1 hour.
## Adults, children and young people aged 12 years and over with suspected sepsis who meet 2 or more moderate to high risk criteria
For adults, children and young people aged 12 years and over with suspected sepsis and 2 or more moderate to high risk criteria, or systolic blood pressure 91 to 100 mmHg, carry out a venous blood test for the following:
blood gas, including glucose and lactate measurement
blood culture
full blood count
C-reactive protein
urea and electrolytes
creatinineand arrange for a clinician to review the person's condition and venous lactate results within 1 hour of meeting criteria in an acute hospital setting.A 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.
For adults, children and young people aged 12 years and over with suspected sepsis who meet 2 or more moderate to high risk criteria and have lactate over 2 mmol/litre or evidence of acute kidney injury, treat as high risk and follow recommendations 1.6.1 to 1.6.7.For definition of acute kidney injury, see NICE's guideline on acute kidney injury.
For adults, children and young people aged 12 years and over with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2 mmol/litre, no evidence of acute kidney injury and in whom a definitive condition cannot be identified:
repeat structured assessment at least hourly
ensure review by a senior clinical decision maker within 3 hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for people aged 18 years or over should be someone who is authorised to prescribe antibiotics, such as a doctor of grade CT3/ST3 or above or equivalent, such as an advanced nurse practitioner with antibiotic prescribing responsibilities, depending on local arrangements. A 'senior decision maker' for people aged 12 to 17 years is a paediatric or emergency care qualified doctor of grade ST4 or above or equivalent. For definition of acute kidney injury, see NICE's guideline on acute kidney injury.
For adults, children and young people aged 12 years and over with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2 mmol/litre, no evidence of acute kidney injuryand in whom a definitive condition or infection can be identified and treated:
manage the definitive condition
if appropriate, discharge with information depending on the setting (see recommendations 1.11.5 and 1.11.6). For definition of acute kidney injury, see NICE's guideline on acute kidney injury.
## Adults, children and young people aged 12 years and over with suspected sepsis who meet only 1 moderate to high risk criterion
For adults, children and young people aged 12 years and over with suspected sepsis who meet only 1 moderate to high risk criterion:
arrange clinician review within 1 hour of meeting criterion for clinical assessment in an acute hospital settingA 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.
perform blood tests if indicated.
For adults, children and young people aged 12 years and over with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition can be identified and treated:
manage the definitive condition
if appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).
For adults, children and young people aged 12 years and over with suspected sepsis who meet only 1 moderate to high risk criterion, have lactate of less than 2 mmol/litre, no evidence of acute kidney injury and in whom a definitive condition cannot be identified:
repeat structured assessment at least hourly
ensure review by a senior clinical decision maker within 3 hours of meeting moderate to high criterion in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for people aged 18 years or over should be someone who is authorised to prescribe antibiotics, such as a doctor of grade CT3/ST3 or above or equivalent, such as an advanced nurse practitioner with antibiotic prescribing responsibilities, depending on local arrangements. A 'senior decision maker' for people aged 12 to 17 years is a paediatric or emergency care qualified doctor of grade ST4 or above or equivalent. For definition of acute kidney injury, see NICE's guideline on acute kidney injury.
## Adults, children and young people aged 12 years and over with suspected sepsis and no high risk or moderate to high risk criteria
Arrange clinical assessment of adults, children and young people aged 12 years and over who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.Clinical assessment should be carried out by a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.
## Children aged 5 to 11 years
## Children aged 5 to 11 years with suspected sepsis who meet 1 or more high risk criteria
For children aged 5 to 11 years who have suspected sepsis and 1 or more high risk criteria:
arrange for immediate review by the senior clinical decision maker to assess the child and think about alternative diagnoses to sepsisA 'senior clinical decision maker' for children aged 5 to 11 years is a paediatric or emergency care doctor of grade ST4 or above or equivalent.
carry out a venous blood test for the following:
blood gas, including glucose and lactate measurement
blood culture
full blood count
C-reactive protein
urea and electrolytes
creatinine
a clotting screen
give a broad-spectrum antimicrobial (see section 1.7) at the maximum recommended dose without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting)
discuss with a consultant.
For children aged 5 to 11 years with suspected sepsis and any high risk criteria and lactate over 4 mmol/litre:
give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis and
refer to critical care for review of central access and initiation of inotropes or vasopressors.Referral may be a formal referral process or discussion with specialist in intensive care or intensive care outreach team.Critical care means an intensivist or intensive care outreach team, or specialist in intensive care or paediatric intensive care.
For children aged 5 to 11 years with suspected sepsis and any high risk criteria and lactate between 2 and 4 mmol/litre:
give intravenous fluid bolus as soon as possible (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis.
For children aged 5 to 11 years with suspected sepsis and any high risk criteria and lactate below 2 mmol/litre:
consider giving intravenous fluid bolus in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis.
Monitor children with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30 minutes depending on setting. Physiological track and trigger systems should be used to monitor all children in acute hospital settings.
Monitor the mental state of children aged 5 to 11 years with suspected sepsis. Consider using the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale.
Alert a consultant to attend in person if a child aged 5 to 11 years with suspected sepsis and any high risk criteria fails to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated by any of:
reduced level of consciousness despite resuscitation
heart rate or respiratory rate fulfil high risk criteria
lactate remains over 2 mmol/litre after 1 hour.
## Children aged 5 to 11 years with suspected sepsis who meet 2 or more moderate to high risk criteria
For children aged 5 to 11 years with suspected sepsis and 2 or more moderate to high risk criteria:
carry out a venous blood test for the following:
blood gas, including glucose and lactate measurement
blood culture
full blood count
C-reactive protein
urea and electrolytes
creatinine
arrange for a clinician to review the person's condition and venous lactate results within 1 hour of meeting criteria in an acute hospital setting.
For children aged 5 to 11 years with suspected sepsis who meet 2 or more moderate to high risk criteria and have lactate over 2 mmol/litre, treat as high risk and follow recommendations 1.6.16 to 1.6.22.
For children aged 5 to 11 years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2 mmol/litre, and in whom a definitive condition cannot be identified:
repeat structured assessment at least hourly
ensure review by a senior clinical decision maker within 3 hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged 5–11 years is a paediatric or emergency care doctor of grade ST4 or above or equivalent.
For children aged 5 to 11 years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2 mmol/litre, and in whom a definitive condition or infection can be identified and treated:
manage the definitive condition, and
if appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).
## Children aged 5 to 11 years with suspected sepsis who meet only 1 moderate to high risk criterion
For children aged 5 to 11 years with suspected sepsis who meet only 1 moderate to high risk criterion:
arrange clinician review within 1 hour of meeting 1 moderate to high risk criterion in an acute hospital setting for clinical assessment andA 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.
perform blood tests if indicated.
For children aged 5 to 11 years with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition can be identified and treated:
manage the definitive condition
if appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).
For children aged 5 to 11 years with suspected sepsis who meet only 1 moderate to high risk criterion, and in whom a definitive condition cannot be identified:
repeat structured assessment at least hourly
ensure review by a senior clinical decision maker within 3 hours of meeting a moderate to high risk criterion in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged 5 to 11 years is a paediatric or emergency care doctor of grade ST4 or above or equivalent.
## Children aged 5 to 11 years with suspected sepsis and no high risk or moderate to high risk criteria
Arrange clinical assessment of children aged 5 to 11 years who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.This should be by a medically qualified practitioner or equivalent with prescribing responsibilities.
## Children aged under 5 years
## Children aged under 5 years with suspected sepsis who meet 1 or more high risk criteria
For children aged under 5 years who have suspected sepsis and 1 or more high risk criteria:
arrange for immediate review by the senior clinical decision maker to assess the child and think about alternative diagnoses to sepsis (for example bronchiolitis)A 'senior clinical decision maker' for children aged under 5 years is a paediatric qualified doctor of grade ST4 or above.
carry out a venous blood test for the following:
blood gas, including glucose and lactate measurement
blood culture
full blood count
C-reactive protein
urea and electrolytes
creatinine
a clotting screen
give a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting; see section 1.7).
discuss with a consultant.
For children aged under 5 years with suspected sepsis and any high risk criteria and lactate over 4 mmol/litre:
give intravenous fluid bolus without delay (in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis) and
refer to critical care for review of central access and initiation of inotropes or vasopressors.Referral may be a formal referral process or discussion with specialist in intensive care or intensive care outreach team.Critical care means an intensivist or intensive care outreach team, or specialist in intensive care or paediatric intensive care.
For children aged under 5 years with suspected sepsis and any high risk criteria and lactate between 2 and 4 mmol/litre:
give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis .
For children aged under 5 years with suspected sepsis and any high risk criteria and lactate below 2 mmol/litre, consider giving intravenous fluid bolus in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis .
Monitor children aged under 5 years with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30 minutes depending on setting. Physiological track and trigger systems should be used to monitor all children in acute hospital settings.
Monitor the mental state of children under 5 years with suspected sepsis. Consider using the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale.
Alert a consultant to attend in person if a child aged under 5 years with suspected sepsis and any high risk criteria fails to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated by any of:
reduced level of consciousness despite resuscitation
heart rate or respiratory rate fulfil high risk criteria
lactate over 2 mmol/litre after 1 hour.
Give parenteral antibiotics to infants aged under 3 months as follows:
infants younger than 1 month with fever
all infants aged 1 to 3 months with fever who appear unwell
infants aged 1 to 3 months with white blood cell count less than 5×109/litre or greater than 15×109/litre.
## Children aged under 5 years with suspected sepsis who meet 2 or more moderate to high risk criteria
For children aged under 5 years with suspected sepsis and 2 or more moderate to high risk criteria:
carry out a venous blood test for the following:
blood gas, including glucose and lactate measurement
blood culture
full blood count
C-reactive protein
urea and electrolytes
creatinine
arrange for a clinician to review the person's condition and venous lactate results within 1 hour of meeting 2 or more moderate to high risk criteria in an acute hospital setting.A 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.
For children aged under 5 years with suspected sepsis who meet 2 or more moderate to high risk criteria and have lactate over 2 mmol/litre, treat as high risk and follow recommendations 1.6.31 to 1.6.37.
For children aged under 5 years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2 mmol/litre, and in whom a definitive condition cannot be identified:
repeat structured assessment at least hourly
ensure review by a senior clinical decision maker within 3 hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged under 5 years is a paediatric qualified doctor of grade ST4 or above.
For children aged under 5 years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2 mmol/litre, and in whom a definitive condition or infection can be identified and treated:
manage the definitive condition and
if appropriate, discharge with information depending on the setting (see recommendations 1.11.5 and 1.11.6).
## Children aged under 5 years with suspected sepsis who meet only 1 moderate to high risk criterion
For children aged under 5 years with suspected sepsis who meet only 1 moderate to high risk criterion:
arrange clinician review within 1 hour of meeting a moderate to high risk criterion for clinical assessment and
perform blood tests if indicated.
For children aged under 5 years with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition can be identified and treated:
manage the definitive condition
if appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).
For children aged under 5 years with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition cannot be identified:
repeat structured assessment at least hourly
ensure review by a senior clinical decision maker within 3 hours of meeting a moderate to high risk criterion in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged under 5 years is a paediatric qualified doctor of grade ST4 or above.
## Children aged under 5 years with suspected sepsis and no high risk or moderate to high risk criteria
Arrange clinical assessment of children aged under 5 years who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.Clinical assessment should be carried out by a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.
# Antibiotic treatment in people with suspected sepsis
Pre-alert secondary care (through GP or ambulance service) when any high risk criteria are met in a person with suspected sepsis outside of an acute hospital, and transfer them immediately.
Ensure urgent assessment mechanisms are in place to deliver antibiotics when any high risk criteria are met in secondary care (within 1 hour of meeting a high risk criterion in an acute hospital setting).
Ensure GPs and ambulance services have mechanisms in place to give antibiotics for people with high risk criteria in pre-hospital settings in locations where transfer time is more than 1 hour.
For patients in hospital who have suspected infections, take microbiological samples before prescribing an antimicrobial and review the prescription when the results are available. For people with suspected sepsis take blood cultures before antibiotics are given.
If meningococcal disease is specifically suspected (fever and purpuric rash) give appropriate doses of parenteral benzyl penicillin in community settings and intravenous ceftriaxone in hospital settings.
For all people with suspected sepsis where the source of infection is clear use existing local antimicrobial guidance.
For people aged 18 years and over who need an empirical intravenous antimicrobial for a suspected infection but who have no confirmed diagnosis, use an intravenous antimicrobial from the agreed local formulary and in line with local (where available) or national guidelines.
For people aged up to 17 years (for neonates see recommendation 1.7.12) with suspected community acquired sepsis of any cause give ceftriaxone 80 mg/kg once a day with a maximum dose of 4 g daily at any age.
For people aged up to 17 years with suspected sepsis who are already in hospital, or who are known to have previously been infected with or colonised with ceftriaxone-resistant bacteria, consult local guidelines for choice of antibiotic.
For children younger than 3 months, give an additional antibiotic active against listeria (for example, ampicillin or amoxicillin).
Treat neonates presenting in hospital with suspected sepsis in their first 72 hours with intravenous benzylpenicillin and gentamicin.
Treat neonates who are more than 40 weeks corrected gestational age who present with community acquired sepsis with ceftriaxone 50 mg/kg unless already receiving an intravenous calcium infusion at the time. If 40 weeks corrected gestational age or below or receiving an intravenous calcium infusion use cefotaxime 50 mg/kg every 6 to 12 hours, depending on the age of the neonate.
Follow the recommendations in NICE's guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine when prescribing and using antibiotics to treat people with suspected or confirmed sepsis.
# Intravenous fluids in people with suspected sepsis
If patients over 16 years need intravenous fluid resuscitation, use crystalloids that contain sodium in the range 130 mmol/litre to 154 mmol/litre with a bolus of 500 ml over less than 15 minutes.
If children and young people up to 16 years need intravenous fluid resuscitation, use glucose-free crystalloids that contain sodium in the range 130 to 154 mmol/litre, with a bolus of 10 ml/kg over less than 10 minutes. Take into account pre-existing conditions (for example, cardiac disease or kidney disease), because smaller fluid volumes may be needed.
If neonates need intravenous fluid resuscitation, use glucose-free crystalloids that contain sodium in the range 130 to 154 mmol/litre, with a bolus of 10 ml/kg to 20 ml/kg over less than 10 minutes.
Reassess the patient after completion of the intravenous fluid bolus, and if no improvement give a second bolus. If there is no improvement after a second bolus alert a consultant to attend (in line with recommendations 1.6.7, 1.6.22 and 1.6.37).
Use a pump, or syringe if no pump is available, to deliver intravenous fluids for resuscitation to children under 12 years with suspected sepsis who need fluids in bolus form.
If using a pump or flow controller to deliver intravenous fluids for resuscitation to people over 12 years with suspected sepsis who need fluids in bolus form ensure device is capable of delivering fluid at required rate for example at least 2000 ml/hour in adults.
Do not use starch based solutions or hydroxyethyl starches for fluid resuscitation for people with sepsis.
Consider human albumin solution 4 to 5% for fluid resuscitation only in patients with sepsis and shock.
# Using oxygen in people with suspected sepsis
Give oxygen to achieve a target saturation of 94% to 98% for adult patients or 88% to 92% for those at risk of hypercapnic respiratory failure.
Oxygen should be given to children with suspected sepsis who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
# Finding the source of infection in people with suspected sepsis
Carry out a thorough clinical examination to look for sources of infection, including sources that might need surgical drainage, as part of the initial assessment.
Tailor investigations of the sources of infection to the person's clinical history and findings on examination.
Consider urine analysis and chest X-ray to identify the source of infection in all people with suspected sepsis.
Consider imaging of the abdomen and pelvis if no likely source of infection is identified after clinical examination and initial tests.
Involve the adult or paediatric surgical and gynaecological teams early on if intra-abdominal or pelvic infection is suspected in case surgical treatment is needed.
Do not perform a lumbar puncture without consultant instruction if any of the following contraindications are present:
signs suggesting raised intracranial pressure or reduced or fluctuating level of consciousness (Glasgow Coma Scale score less than 9 or a drop of 3 points or more)
relative bradycardia and hypertension
focal neurological signs
abnormal posture or posturing
unequal, dilated or poorly responsive pupils
papilloedema
abnormal 'doll's eye' movements
shock
extensive or spreading purpura
after convulsions until stabilised
coagulation abnormalities or coagulation results outside the normal range or platelet count below 100x109/litre or receiving anticoagulant therapy
local superficial infection at the lumbar puncture site
respiratory insufficiency in children.
Perform lumbar puncture in the following children with suspected sepsis (unless contraindicated, see contraindications in recommendation 1.10.6):
infants younger than 1 month
all infants aged 1 to 3 months who appear unwell
infants aged 1 to 3 months with a white blood cell count less than 5×109/litre or greater than 15×109/litre.
# Information and support for people with sepsis and their families and carers
## People who have sepsis and their families and carers
Ensure a care team member is nominated to give information to families and carers, particularly in emergency situations such as in the emergency department. This should include:
an explanation that the person has sepsis, and what this means
an explanation of any investigations and the management plan
regular and timely updates on treatment, care and progress.
Ensure information is given without using medical jargon. Check regularly that people understand the information and explanations they are given.
Give people with sepsis and their family members and carers opportunities to ask questions about diagnosis, treatment options, prognosis and complications. Be willing to repeat any information as needed.
Give people with sepsis and their families and carers information about national charities and support groups that provide information about sepsis and the causes of sepsis.
## Information at discharge for people assessed for suspected sepsis, but not diagnosed with sepsis
Give people who have been assessed for sepsis but have been discharged without a diagnosis of sepsis (and their family or carers, if appropriate) verbal and written information about:
what sepsis is, and why it was suspected
what tests and investigations have been done
instructions about which symptoms to monitor
when to get medical attention if their illness continues
how to get medical attention if they need to seek help urgently.
Confirm that people understand the information they have been given, and what actions they should take to get help if they need it.
## Information at discharge for people at increased risk of sepsis
Ensure people who are at increased risk of sepsis (for example after surgery) are told before discharge about symptoms that should prompt them to get medical attention and how to get it.See NICE's guideline on neutropenic sepsis for information for people with neutropenic sepsis (recommendation 1.1.1.1).
## Information at discharge for people who have had sepsis
Ensure people and their families and carers if appropriate have been informed that they have had sepsis.
Ensure discharge notifications to GPs include the diagnosis of sepsis.
Give people who have had sepsis (and their families and carers, when appropriate) opportunities to discuss their concerns. These may include:
why they developed sepsis
whether they are likely to develop sepsis again
if more investigations are necessary
details of any community care needed, for example, related to peripherally inserted central venous catheters (PICC) lines or other intravenous catheters
what they should expect during recovery
arrangements for follow-up, including specific critical care follow up if relevant
possible short-term and long-term problems.
Give people who have had sepsis and their families and carers information about national charities and support groups that provide information about sepsis and causes of sepsis.
Advise carers they have a legal right to have a carer's assessment of their needs, and give them information on how they can get this.See NICE's guideline on rehabilitation after critical illness in adults for recommendations on rehabilitation and follow up after critical illness.See NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s for follow up of people who have had meningococcal septicaemia.
# Training and education
Ensure all healthcare staff and students involved in assessing people's clinical condition are given regular, appropriate training in identifying people who might have sepsis. This includes primary, community care and hospital staff including those working in care homes.
Ensure all healthcare professionals involved in triage or early management are given regular appropriate training in identifying, assessing and managing sepsis. This should include:
risk stratification strategies
local protocols for early treatments, including antibiotics and intravenous fluids
criteria and pathways for escalation, in line with their health care setting.
# Terms used in this guideline
## Sepsis
Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection.
## Suspected sepsis
Suspected sepsis is used to indicate people who might have sepsis and require face-to-face assessment and consideration of urgent intervention.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Epidemiological study on presentation and management of sepsis in England
What is the incidence, presentation and management of sepsis in the United Kingdom?
## Why this is important
The lack of robust UK based epidemiological studies on the incidence and outcomes from sepsis have been clear throughout the guideline development process. A large epidemiological study to collect information about where sepsis is being treated, patient interventions and patient outcomes would provide population based statistics on epidemiology of sepsis which are necessary to support evaluation of interventions, planning of services and service redesign. The mortality and morbidity and service complexity associated with severe infection and sepsis, and the need to use broad spectrum antimicrobials to treat sepsis, justifies the cost required to set up such a study.
# A complex service evaluation of implementation of NICE Sepsis guideline
What effect will the NICE sepsis guideline have on patient care processes and outcomes in the UK over the next 5 years?
## Why this is important
Implementation of NICE's guideline on sepsis will be a challenge to the NHS. A robust evaluation of how NHS service providers adhere to the recommended care processes needs to be carried out over the next 5 years.
A complex evaluation is needed to understand the effect of guidelines on services and on patient outcomes. Evaluation should include assessment of costs and cost effectiveness, the use of a universal audit tool for sepsis patient care that includes evaluation of pre-hospital and secondary care and monitoring of broad spectrum antibiotic use, development of multi-resistant organisms and incidence of antibiotic-related infection such as C. difficile.
# Use of biomarkers to diagnose and initiate treatment
What is the clinical and cost effectiveness of procalcitonin (PCT) point-of-care tests at initial triage for diagnosis of serious infection and the initiation of appropriate antibiotic therapy?
## Why this is important
There is an urgent clinical need for accurate biomarkers of serious bacterial infection (SBI) which provide early diagnosis of SBI, and prompt clinical interventions to improve outcomes. The current tests used in the NHS (white cell count and C-reactive protein) are non-specific and not sensitive enough. Biomarker-guided initiation and termination of antibiotic therapy might be an effective strategy to reduce unnecessary antibiotic use and help prevent further multidrug resistance. The NICE diagnostics guidance on procalcitonin for diagnosing and monitoring sepsis has shown there is not enough evidence in this area.
# Validation of clinical early warning scores in pre-hospital and emergency care settings
Can early warning scores, for example NEWS (national early warning scores for adults) and PEWS (paediatric early warning score), be used to improve the detection of sepsis and facilitate prompt and appropriate clinical response in pre-hospital settings and in emergency departments?
## Why this is important
Delay in detecting and treating sepsis increases mortality. Early detection and appropriate management will reduce morbidity and mortality and will reduce NHS costs by reducing critical care admissions, inappropriate antimicrobial use and length of hospital stay. No high quality data exist on the validation or use of early warning scores in pre-hospital settings or in the emergency department settings. The use of scores might improve communication between pre-hospital settings and hospital settings and allow recognition of people who need more urgent assessment.
# Derivation of clinical decision rules in suspected sepsis
Is it possible to derive and validate a set of clinical decision rules or a predictive tool to rule out sepsis which can be applied to patients presenting to hospital; with suspected sepsis?
## Why this is important
In primary care and emergency departments people with suspected sepsis are often seen by relatively inexperienced doctors. Many of these people will be in low and medium risk groups but evidence is lacking as to who can be sent home safely and who needs intravenous or oral antibiotics. The consequences of getting the decision making wrong can be catastrophic and therefore many patients are potentially over-investigated and admitted inappropriately. Current guidance is dependent on use of individual variables informed by low quality evidence.# Context
Sepsis is a clinical syndrome caused by the body's immune and coagulation systems being switched on by an infection. Sepsis with shock is a life-threatening condition that is characterised by low blood pressure despite adequate fluid replacement, and organ dysfunction or failure. Sepsis is an important cause of death in people of all ages. Both a UK Parliamentary and Health Service Ombudsman enquiry (2013) and a UK National Confidential Enquiry into Patient Outcome and Death (NCEPOD, 2015) highlighted sepsis as being a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined.
Sepsis is difficult to diagnose with certainty. Although people with sepsis may have a history of infection, fever is not present in all cases. The signs and symptoms of sepsis can be very non-specific and can be missed if clinicians do not think 'could this be sepsis?'. In the same way that healthcare professionals consider 'could this pain be cardiac in origin?' when presented with someone of any age with chest pain this guideline aims to make 'could this be sepsis?' the first consideration for anyone presenting with a possible infection.
Detailed guidelines exist for the management of sepsis in adult and paediatric intensive care units, and by intensive care clinicians called to other settings. To reduce avoidable deaths, people with sepsis need to be recognised early and treatment initiated. This guideline aims to ensure healthcare systems in all clinical settings consider sepsis as an immediate life-threatening condition that should be recognised and treated as an emergency. The guideline outlines the immediate actions needed for those with suspicion of sepsis and who are at highest risk of morbidity and mortality from sepsis. It provides a framework for risk assessment, treatment and follow-up or 'safety-netting' of people not needing immediate resuscitation. The intention of this guideline is to ensure that all people with sepsis due to any cause are recognised and initial treatment initiated before definitive treatment on other specific pathways is instituted.
At the time of writing, the terminology around sepsis is changing and new international consensus definitions have been published. Previous terminology included terms SIRS (systematic inflammatory response syndrome), severe sepsis and septic shock but new terminology suggests using terms sepsis and septic shock only . Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host response to infection and septic shock as persisting hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) of 65 mmHg or more and having a serum lactate level of greater than 2 mmol/l despite adequate volume resuscitation. Neither of these definitions are useful in early identification of people at risk and the guideline recommends actions according to clinical parameters that stratify risk of severe illness or death from sepsis.
There is significant overlap between this guideline and other NICE guidance, in particular for the care of acutely ill patients in hospital (see NICE's guideline on acutely ill adults in hospital), the assessment and initial management of fever in under 5s (see NICE's guideline on fever in under 5s), bacterial meningitis and meningococcal septicaemia (see NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s), NICE's guideline on neutropenic sepsis, antibiotics for prevention and treatment of neonatal infection (see NICE's guideline on neonatal infection), and NICE's guideline on pneumonia in adults.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Identifying people with suspected sepsis\n\nThis guidance should be used together with the algorithms organised by age group and treatment location and the risk stratification tools. There are algorithms for:\n\nchildren under 5 out of hospital\n\nchildren under 5 in hospital\n\nchildren aged 5 to 11 years out of hospital\n\nchildren aged 5 to 11 years in hospital\n\nchildren and young people aged 12 to 17 out of hospital\n\nchildren and young people aged 12 to 17 in hospital\n\nadults aged 18 and over out of hospital\n\nadults aged 18 and over in hospital\n\nThere are also risk stratification tools for:\n\nchildren under 5\n\nchildren aged 5 to 11 years\n\nadults, children and young people aged 12\xa0years and over\n\nThink 'could this be sepsis?' if a person presents with signs or symptoms that indicate possible infection.\n\nTake into account that people with sepsis may have non-specific, non-localised presentations, for example feeling very unwell, and may not have a high temperature.\n\nPay particular attention to concerns expressed by the person and their family or carers, for example changes from usual behaviour.\n\nAssess people who might have sepsis with extra care if they cannot give a good history (for example, people with English as a second language or people with communication problems).\n\nAssess people with any suspected infection to identify:\n\npossible source of infection\n\nfactors that increase risk of sepsis (see section 1.2 on risk factors for sepsis)\n\nany indications of clinical concern, such as new onset abnormalities of behaviour, circulation or respiration.\n\nIdentify factors that increase risk of sepsis (see section 1.2 on risk factors for sepsis) or indications of clinical concern such as new onset abnormalities of behaviour, circulation or respiration when deciding during a remote assessment whether to offer a face-to-face-assessment and if so, on the urgency of face-to-face assessment.\n\nUse a structured set of observations (see section 1.3 on 1.3 face-to-face assessment on people with suspected sepsis) to assess people in a face-to-face setting to stratify risk (see section 1.4 on stratifying risk of severe illness or death from sepsis) if sepsis is suspected.\n\nConsider using an early warning score (NEWS2 has been endorsed by NHS England) to assess people with suspected sepsis in acute hospital settings.\n\nSuspect neutropenic sepsis in patients having anticancer treatment who become unwell. [This recommendation is from NICE's guideline on neutropenic sepsis.]\n\nRefer patients with suspected neutropenic sepsis immediately for assessment in secondary or tertiary care. [This recommendation is from NICE's guideline on neutropenic sepsis.]\n\nTreat people with neutropenic sepsis in line with NICE's guideline on neutropenic sepsis.\n\n# Risk factors for sepsis\n\nTake into account that people in the groups below are at higher risk of developing sepsis:\n\nthe very young (under 1\xa0year) and older people (over 75\xa0years) or people who are very frail\n\npeople who have impaired immune systems because of illness or drugs, including:\n\n\n\npeople being treated for cancer with chemotherapy (see recommendation 1.1.9 in the section on identifying people with suspected sepsis)\n\npeople who have impaired immune function (for example, people with diabetes, people who have had a splenectomy, or people with sickle cell disease)\n\npeople taking long-term steroids\n\npeople taking immunosuppressant drugs to treat non-malignant disorders such as rheumatoid arthritis\n\n\n\npeople who have had surgery, or other invasive procedures, in the past 6\xa0weeks\n\npeople with any breach of skin integrity (for example, cuts, burns, blisters or skin infections)\n\npeople who misuse drugs intravenously\n\npeople with indwelling lines or catheters.\n\nTake into account that women who are pregnant, have given birth or had a termination of pregnancy or miscarriage in the past 6\xa0weeks are in a high risk group for sepsis. In particular, women who:\n\nhave impaired immune systems because of illness or drugs (see recommendation 1.1.5 in the section on identifying people with suspected sepsis)\n\nhave gestational diabetes or diabetes or other comorbidities\n\nneeded invasive procedures (for example, caesarean section, forceps delivery, removal of retained products of conception)\n\nhad prolonged rupture of membranes\n\nhave or have been in close contact with people with group A streptococcal infection, for example, scarlet fever\n\nhave continued vaginal bleeding or an offensive vaginal discharge.\n\nTake into account the following risk factors for early-onset neonatal infection:\n\ninvasive group B streptococcal infection in a previous baby\n\nmaternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy\n\nprelabour rupture of membranes\n\npreterm birth following spontaneous labour (before 37\xa0weeks' gestation)\n\nsuspected or confirmed rupture of membranes for more than 18\xa0hours in a preterm birth\n\nintrapartum fever higher than 38°C, or confirmed or suspected chorioamnionitis\n\nparenteral antibiotic treatment given to the woman for confirmed or suspected invasive bacterial infection (such as septicaemia) at any time during labour, or in the 24-hour periods before and after the birth (this does not refer to intrapartum antibiotic prophylaxis)\n\nsuspected or confirmed infection in another baby in the case of a multiple pregnancy.[This recommendation is from NICE's guideline on neonatal infection.]\n\n# Face-to-face assessment of people with suspected sepsis\n\nAssess temperature, heart rate, respiratory rate, blood pressure, level of consciousness and oxygen saturation in young people and adults with suspected sepsis.\n\nAssess temperature, heart rate, respiratory rate, level of consciousness, oxygen saturation and capillary refill time in children under 12\xa0years with suspected sepsis. [This recommendation is adapted from NICE's guideline on fever in under 5s.]\n\nMeasure blood pressure of children under 5\xa0years if heart rate or capillary refill time is abnormal and facilities to measure blood pressure, including a correctly-sized blood pressure cuff, are available. [This recommendation is adapted NICE's guideline on fever in under 5s.]\n\nMeasure blood pressure of children aged 5 to 11 years who might have sepsis if facilities to measure blood pressure, including a correctly-sized cuff, are available.\n\nOnly measure blood pressure in children under 12 years in community settings if facilities to measure blood pressure, including a correctly-sized cuff, are available and taking a measurement does not cause a delay in assessment or treatment.\n\nMeasure oxygen saturation in community settings if equipment is available and taking a measurement does not cause a delay in assessment or treatment.\n\nExamine people with suspected sepsis for mottled or ashen appearance, cyanosis of the skin, lips or tongue, non-blanching rash of the skin, any breach of skin integrity (for example, cuts, burns or skin infections) or other rash indicating potential infection.\n\nAsk the person, parent or carer about frequency of urination in the past 18\xa0hours.\n\n# Stratifying risk of severe illness or death from sepsis\n\nUse the person's history and physical examination results to grade risk of severe illness or death from sepsis using criteria based on age (see tables 1, 2 and 3).\n\n## Adults, children and young people aged 12\xa0years and over\n\nCategory\n\nHigh risk criteria\n\nModerate to high risk criteria\n\nLow\xa0risk\xa0criteria\n\nHistory\n\nObjective evidence of new altered mental state\n\nHistory from patient, friend or relative of new onset of altered behaviour or mental state\n\nHistory of acute deterioration of functional ability\n\nImpaired immune system (illness or drugs including oral steroids)\n\nTrauma, surgery or invasive procedures in the last 6 weeks\n\nNormal behaviour\n\nRespiratory\n\nRaised respiratory rate: 25\xa0breaths per minute or more\n\nNew need for oxygen (40% FiO2 or more) to maintain saturation more than 92% (or more than 88% in known chronic obstructive pulmonary disease)\n\nRaised respiratory rate: 21 to 24 breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nBlood pressure\n\nSystolic blood pressure 90\xa0mmHg or less or systolic blood pressure more than 40 mmHg below normal\n\nSystolic blood pressure 91 to 100 mmHg\n\nNo high risk or moderate to high\xa0risk criteria met\n\nCirculation and hydration\n\nRaised heart rate: more than 130 beats per minute\n\nNot passed urine in previous 18\xa0hours.\n\nFor catheterised patients, passed less than 0.5 ml/kg of urine per hour\n\nRaised heart rate: 91 to 130 beats per minute (for pregnant women 100 to 130 beats per minute) or new onset arrhythmia\n\nNot passed urine in the past 12 to 18 hours\n\nFor catheterised patients, passed 0.5 \xa0ml/kg to 1\xa0ml/kg of urine per hour\n\nNo high risk or moderate to high risk criteria met\n\nTemperature\n\n-\n\nTympanic temperature less than 36°C\n\n-\n\nSkin\n\nMottled or ashen appearance\n\nCyanosis of skin, lips or tongue\n\nNon-blanching rash of skin\n\nSigns of potential infection, including redness, swelling or discharge at surgical site or breakdown of wound\n\nNo non-blanching rash\n\nA downloadable version of this table is also available.\n\nRecognise that adults, children and young people aged 12\xa0years and over with suspected sepsis and any of the symptoms or signs below are at high risk of severe illness or death from sepsis:\n\nobjective evidence of new altered mental state\n\nrespiratory rate of 25\xa0breaths per minute or above, or new need for 40% oxygen or more to maintain oxygen saturation more than 92% (or more than 88% in known chronic obstructive pulmonary disease)\n\nheart rate of more than 130\xa0beats per minute\n\nsystolic blood pressure of 90\xa0mmHg or less, or systolic blood pressure more than 40\xa0mmHg below normal\n\nnot passed urine in previous 18\xa0hours (for catheterised patients, passed less than 0.5\xa0ml/kg/hour)\n\nmottled or ashen appearance\n\ncyanosis of the skin, lips or tongue\n\nnon-blanching rash of the skin.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nRecognise that adults, children and young people aged 12\xa0years and over with suspected sepsis and any of the symptoms or signs below are at moderate to high risk of severe illness or death from sepsis:\n\nhistory of new-onset changed behaviour or change in mental state, as reported by the person, a friend or relative\n\nhistory of acute deterioration of functional ability\n\nimpaired immune system (illness or drugs, including oral steroids)\n\ntrauma, surgery or invasive procedure in the past 6\xa0weeks\n\nrespiratory rate of 21 to 24\xa0breaths per minute\n\nheart rate of 91 to 130\xa0beats per minute or new-onset arrhythmia, or if pregnant heart rate of 100 to 130 beats per minute\n\nsystolic blood pressure of 91 to 100\xa0mmHg\n\nnot passed urine in the past 12 to 18\xa0hours (for catheterised patients, passed 0.5\xa0ml/kg/hour to 1\xa0ml/kg/hour)\n\ntympanic temperature less than 36°C\n\nsigns of potential infection, including increased redness, swelling or discharge at a surgical site, or breakdown of a wound.\n\nConsider adults, children and young people aged 12\xa0years and over with suspected sepsis who do not meet any high or moderate to high risk criteria to be at low risk of severe illness or death from sepsis.\n\n## Children aged 5 to 11\xa0years\n\nCategory\n\nAge\n\nHigh risk criteria\n\nModerate to high risk criteria\n\nLow\xa0risk\xa0criteria\n\nBehaviour\n\nAny\n\nObjective evidence of altered behaviour or mental state\n\nAppears ill to a healthcare professional\n\nDoes not wake or if roused does not stay awake\n\nNot behaving normally\n\nDecreased activity\n\nParent or carer concern that the child is behaving differently from usual\n\nBehaving normally\n\nRespiratory\n\nAny\n\nOxygen saturation of less than 90% in air or increased oxygen requirement over baseline\n\nOxygen saturation of less than 92% in air or increased oxygen requirement over baseline\n\nNo high risk or moderate to high\xa0risk criteria met\n\nRespiratory\n\nAged 5\xa0years\n\nRaised respiratory rate: 29 breaths per minute or more\n\nRaised respiratory rate: 24 to 28\xa0breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nRespiratory\n\nAged 6 to 7\xa0years\n\nRaised respiratory rate: 27 breaths per minute or more\n\nRaised respiratory rate: 24 to 26\xa0breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nRespiratory\n\nAged 8 to 11\xa0years\n\nRaised respiratory rate: 25 breaths per minute or more\n\nRaised respiratory rate: 22 to 24\xa0breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nCirculation and hydration\n\nAny\n\nHeart rate less than\xa060 beats per minute\n\nCapillary refill time of 3\xa0seconds or more\n\nReduced urine output\n\nFor catheterised patients, passed less than 1\xa0ml/kg of urine per hour\n\nNo high risk or moderate to high risk criteria met\n\nCirculation and hydration\n\nAged 5\xa0years\n\nRaised heart rate: 130 beats per minute or more\n\nRaised heart rate: 120 to 129\xa0beats per minute\n\nNo high risk or moderate to high risk criteria met\n\nCirculation and hydration\n\nAged 6 to 7\xa0years\n\nRaised heart rate: 120 beats per minute or more\n\nRaised heart rate: 110 to 119\xa0beats per minute\n\nNo high risk or moderate to high risk criteria met\n\nCirculation and hydration\n\nAged 8 to 11\xa0years\n\nRaised heart rate: 115 beats per minute or more\n\nRaised heart rate: 105 to 114\xa0beats per minute\n\nNo high risk or moderate to high risk criteria met\n\nTemperature\n\nAny\n\n-\n\nTympanic temperature less than 36°C\n\n-\n\nSkin\n\nAny\n\nMottled or ashen appearance\n\nCyanosis of skin, lips or tongue\n\nNon-blanching rash of skin\n\n-\n\n-\n\nOther\n\nAny\n\n-\n\nLeg pain\n\nCold hands or feet\n\nNo high or moderate\xa0to high risk criteria met\n\nBe aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nA downloadable version of this table is also available.\n\nRecognise that children aged 5 to 11\xa0years with suspected sepsis and any of the symptoms or signs below are at high risk of severe illness or death from sepsis:\n\nhas objective evidence of altered behaviour or mental state, or appears ill to a healthcare professional, or does not wake (or if roused, does not stay awake)\n\nrespiratory rate:\n\n\n\naged 5\xa0years, 29\xa0breaths per minute or more\n\naged 6 to 7\xa0years, 27\xa0breaths per minute or more\n\naged 8 to 11\xa0years, 25\xa0breaths per minute or more\n\noxygen saturation of less than 90% in air or increased oxygen requirement over baseline\n\n\n\nheart rate:\n\n\n\naged 5\xa0years, 130\xa0beats per minute or more\n\naged 6 to 7\xa0years, 120\xa0beats per minute or more\n\naged 8 to 11\xa0years, 115\xa0beats per minute or more\n\nor heart rate less than 60 beats per minute at any age\n\n\n\nmottled or ashen appearance\n\ncyanosis of the skin, lips or tongue\n\nnon-blanching rash of the skin.\n\nRecognise that children aged 5 to 11\xa0years with suspected sepsis and any of the symptoms or signs below are at moderate to high risk of severe illness or death from sepsis:\n\nnot responding normally to social cues or decreased activity, or parent or carer concern that the child is behaving differently from usual\n\nrespiratory rate:\n\n\n\naged 5\xa0years, 24 to 28\xa0breaths per minute\n\naged 6 to 7\xa0years, 24 to 26\xa0breaths per minute\n\naged 8 to 11\xa0years, 22 to 24\xa0breaths per minute\n\noxygen saturation of less than 92% in air or increased oxygen requirement over baseline\n\n\n\nheart rate:\n\n\n\naged 5\xa0years, 120 to 129\xa0beats per minute\n\naged 6 to 7\xa0years, 110 to 119\xa0beats per minute\n\naged 8 to 11\xa0years, 105 to 114\xa0beats per minute\n\nor capillary refill time of 3\xa0seconds or more\n\n\n\nreduced urine output, or for catheterised patients passed less than 1\xa0ml/kg of urine per hour\n\ntympanic temperature less than 36°C\n\nhave leg pain or cold hands or feet.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nConsider children aged 5 to 11\xa0years with suspected sepsis who do not meet any high or moderate to high risk criteria to be at low risk of severe illness or death from sepsis.\n\n## Children aged under 5\xa0years\n\nCategory\n\nAge\n\nHigh risk criteria\n\nModerate to high risk criteria\n\nLow\xa0risk\xa0criteria\n\nBehaviour\n\nAny\n\nNo response to social cues\n\nAppears ill to a healthcare professional\n\nDoes not wake, or if roused does not stay awake\n\nWeak high-pitched or continuous cry\n\nNot responding normally to social cues\n\nNo smile\n\nWakes only with prolonged stimulation\n\nDecreased activity\n\nParent or carer concern that child is behaving differently from usual\n\nResponds normally to social cues\n\nContent or smiles\n\nStays awake or awakens quickly\n\nStrong normal cry or not crying\n\nRespiratory\n\nAny\n\nGrunting\n\nApnoea\n\nOxygen saturation of less than 90% in air or increased oxygen requirement over baseline\n\nOxygen saturation of less than 92% in air or increased oxygen requirement over baseline\n\nNasal flaring\n\nNo high risk or moderate to high\xa0risk criteria met\n\nRespiratory\n\nUnder 1\xa0year\n\nRaised respiratory rate: 60 breaths per minute or more\n\nRaised respiratory rate: 50 to 59\xa0breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nRespiratory\n\nto 2\xa0years\n\nRaised respiratory rate: 50 breaths per minute or more\n\nRaised respiratory rate: 40 to 49\xa0breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nRespiratory\n\nto 4\xa0years\n\nRaised respiratory rate: 40 breaths per minute or more\n\nRaised respiratory rate: 35 to 39 breaths per minute\n\nNo high risk or moderate to high\xa0risk criteria met\n\nCirculation and hydration\n\nAny\n\nBradycardia: heart rate less than 60 beats per minute\n\nCapillary refill time of 3\xa0seconds or more\n\nReduced urine output\n\nFor catheterised patients, passed less than 1 ml/kg of urine per hour\n\nNo high risk or moderate to high risk criteria met\n\nCirculation and hydration\n\nUnder 1\xa0year\n\nRapid heart rate: 160\xa0beats per minute or more\n\nRapid heart rate: 150 to 159 beats per minute\n\nNo high risk or moderate to high risk criteria met\n\nCirculation and hydration\n\nto 2\xa0years\n\nRapid heart rate: 150\xa0beats per minute or more\n\nRapid heart rate: 140 to 149 beats per minute\n\nNo high risk or moderate to high risk criteria met\n\nCirculation and hydration\n\nto 4\xa0years\n\nRapid heart rate: 140\xa0beats per minute or more\n\nRapid heart rate: 130 to 139 beats per minute\n\nNo high risk or moderate to high risk criteria met\n\nSkin\n\nAny\n\nMottled or ashen appearance\n\nCyanosis of skin, lips or tongue\n\nNon-blanching rash of skin\n\nPallor of skin, lips or tongue\n\nNormal colour\n\nTemperature\n\nAny\n\nLess than 36ºC\n\n-\n\n-\n\nTemperature\n\nUnder 3\xa0months\n\n°C or more\n\n-\n\n-\n\nTemperature\n\nto 6\xa0months\n\n-\n\n°C or more\n\n-\n\nOther\n\nAny\n\n-\n\nLeg pain\n\nCold hands or feet\n\nNo high risk or high\xa0to moderate risk criteria met\n\nBe aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nThis table is adapted from NICE's guideline on fever in under 5s. A downloadable version of this table is also available.\n\nRecognise that children aged under 5\xa0years with suspected sepsis and any of the symptoms or signs below are at high risk of severe illness or death from sepsis:\n\nbehaviour:\n\n\n\nno response to social cues\n\nappears ill to a healthcare professional\n\ndoes not wake, or if roused does not stay awake\n\nweak, high-pitched or continuous cry\n\n\n\nheart rate:\n\n\n\naged under 1\xa0year, 160\xa0beats per minute or more\n\naged 1 to 2\xa0years, 150\xa0beats per minute or more\n\naged 3 to 4\xa0years, 140\xa0beats per minute or more\n\nheart rate less than 60 beats per minute at any age\n\n\n\nrespiratory rate:\n\n\n\naged under 1\xa0year, 60\xa0breaths per minute or more\n\naged 1 to 2\xa0years, 50\xa0breaths per minute or more\n\naged 3 to 4\xa0years, 40\xa0breaths per minute or more\n\ngrunting\n\napnoea\n\noxygen saturation of less than 90% in air or increased oxygen requirement over baseline\n\n\n\nmottled or ashen appearance\n\ncyanosis of the skin, lips or tongue\n\nnon-blanching rash of the skin\n\naged under 3\xa0months and temperature 38°C or more\n\ntemperature less than 36°C.[This recommendation is adapted from NICE's guideline on fever in under 5s.]\n\nRecognise that children aged under 5\xa0years with suspected sepsis and any of the symptoms or signs below are at moderate to high risk of severe illness or death from sepsis:\n\nbehaviour:\n\n\n\nnot responding normally to social cues\n\nno smile\n\nwakes only with prolonged stimulation\n\ndecreased activity\n\nparent or carer concern that the child is behaving differently from usual\n\n\n\nrespiratory rate:\n\n\n\naged under 1\xa0year, 50 to 59\xa0breaths per minute\n\naged 1 to 2\xa0years, 40 to 49\xa0breaths per minute\n\naged 3 to 4\xa0years, 35 to 39\xa0breaths per minute\n\noxygen saturation less than 92% in air or increased oxygen requirement over baseline\n\nnasal flaring\n\n\n\nheart rate:\n\n\n\naged under 1\xa0year, 150 to 159\xa0beats per minute\n\naged 1 to 2\xa0years, 140 to 149\xa0beats per minute\n\naged 3 to 4\xa0years 130 to 139\xa0beats per minute\n\n\n\ncapillary refill time of 3 seconds or more\n\nreduced urine output, or for catheterised patients passed less than 1\xa0ml/kg of urine per hour\n\npallor of skin, lips or tongue reported by parent or carer\n\naged 3 to 6\xa0months and temperature 39°C or over\n\nhave leg pain or cold hands or feet.[This recommendation is adapted from NICE's guideline on fever in under 5s.] Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nConsider children aged under 5\xa0years with suspected sepsis who do not meet any high or moderate to high risk criteria to be at low risk of severe illness or death from sepsis. [This recommendation is adapted from NICE's guideline on fever in under 5s.]\n\n## Children, young people and adults with suspected sepsis\n\n## Temperature in suspected sepsis\n\nDo not use a person's temperature as the sole predictor of sepsis.\n\nDo not rely on fever or hypothermia to rule sepsis either in or out.\n\nAsk the person with suspected sepsis and their family or carers about any recent fever or rigors.\n\nTake into account that some groups of people with sepsis may not develop a raised temperature. These include:\n\npeople who are older or very frail\n\npeople having treatment for cancer\n\npeople severely ill with sepsis\n\nyoung infants or children.\n\nTake into account that a rise in temperature can be a physiological response, for example after surgery or trauma.\n\n## Heart rate in suspected sepsis\n\nInterpret the heart rate of a person with suspected sepsis in context, taking into account that:\n\nbaseline heart rate may be lower in young people and adults who are fit\n\nbaseline heart rate in pregnancy is 10 to 15 beats per minute more than normal\n\nolder people with an infection may not develop an increased heart rate\n\nolder people may develop a new arrhythmia in response to infection rather than an increased heart rate\n\nheart rate response may be affected by medicines such as beta-blockers.\n\n## Blood pressure in suspected sepsis\n\nInterpret blood pressure in the context of a person's previous blood pressure, if known. Be aware that the presence of normal blood pressure does not exclude sepsis in children and young people.\n\n## Confusion, mental state and cognitive state in suspected sepsis\n\nInterpret a person's mental state in the context of their normal function and treat changes as being significant.\n\nBe aware that changes in cognitive function may be subtle and assessment should include history from patient and family or carers.\n\nTake into account that changes in cognitive function may present as changes in behaviour or irritability in both children and in adults with dementia.\n\nTake into account that changes in cognitive function in older people may present as acute changes in functional abilities.\n\n## Oxygen saturation in suspected sepsis\n\nTake into account that if peripheral oxygen saturation is difficult to measure in a person with suspected sepsis, this may indicate poor peripheral circulation because of shock.Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n# Managing suspected sepsis outside acute hospital settings\n\nRefer all people with suspected sepsis outside acute hospital settings for emergency medical care by the most appropriate means of transport (usually 999 ambulance) if:\n\nthey meet any high risk criteria (see tables 1, 2 and 3) or\n\nthey are aged under 17\xa0years and their immunity is impaired by drugs or illness and they have any moderate to high risk criteria.Emergency care requires facilities for resuscitation to be available and depending on local services may be emergency department, medical admissions unit and for children may be paediatric ambulatory unit or paediatric medical admissions unit.\n\nAssess all people with suspected sepsis outside acute hospital settings with any moderate to high risk criteria to:\n\nmake a definitive diagnosis of their condition\n\ndecide whether they can be treated safely outside hospital.If a definitive diagnosis is not reached or the person cannot be treated safely outside an acute hospital setting, refer them urgently for emergency care.\n\nProvide people with suspected sepsis, who do not have any high or moderate to high risk criteria information about symptoms to monitor and how to access medical care if they are concerned.\n\n# Managing and treating suspected sepsis in acute hospital settings\n\n## Adults, children and young people aged 12\xa0years and over with suspected sepsis who meet 1 or more high risk criteria\n\nFor adults, children and young people aged 12\xa0years and over who have suspected sepsis and 1 or more high risk criteria:\n\narrange for immediate review by the senior clinical decision maker to assess the person and think about alternative diagnoses to sepsis A 'senior clinical decision maker' for people aged 18 years or over should be someone who is authorised to prescribe antibiotics, such as a doctor of grade CT3/ST3 or above or equivalent, such as an advanced nurse practitioner with antibiotic prescribing responsibilities, depending on local arrangements. A 'senior decision maker' for people aged 12 to 17 years is a paediatric or emergency care qualified doctor of grade ST4 or above or equivalent.\n\ncarry out a venous blood test for the following:\n\n\n\nblood gas including glucose and lactate measurement\n\nblood culture\n\nfull blood count\n\nC-reactive protein\n\nurea and electrolytes\n\ncreatinine\n\na clotting screen\n\n\n\ngive a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.7 antibiotic treatment in people with suspected sepsis\n\ndiscuss with a consultant.Appropriate consultant may be the consultant under whom the patient is admitted or a consultant covering acute medicine, anaesthetics.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis and any high risk criteria and lactate over 4\xa0mmol/litre, or systolic blood pressure less than 90\xa0mmHg:\n\ngive intravenous fluid bolus without delay (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis\xa0and\n\nrefer to critical care for review of management including need for central venous access and initiation of inotropes or vasopressors.Referral may be a formal referral process or discussion with specialist in intensive care or intensive care outreach team.Critical care means an intensivist or intensive care outreach team, or specialist in intensive care or paediatric intensive care.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis and any high risk criteria and lactate between 2 and 4\xa0mmol/litre:\n\ngive intravenous fluid bolus without delay (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis and any high risk criteria and lactate below 2\xa0mmol/litre:\n\nconsider giving intravenous fluid bolus (in line with recommendations in section\xa01.8 intravenous fluids in people with suspected sepsis).\n\nMonitor people with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30\xa0minutes depending on setting. Physiological track and trigger systems should be used to monitor all adult patients in acute hospital settings. [This recommendation is adapted from NICE's guideline on acutely ill patients in hospital.]\n\nMonitor the mental state of adults, children and young people aged 12\xa0years and over with suspected sepsis. Consider using a scale such as the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale.\n\nAlert a consultant to attend in person if an adult, child or young person aged 12\xa0years or over with suspected sepsis and any high risk criteria fails to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated by any of:\n\nsystolic blood pressure persistently below 90 mmHg\n\nreduced level of consciousness despite resuscitation\n\nrespiratory rate over 25\xa0breaths per minute or a new need for mechanical ventilation\n\nlactate not reduced by more than 20% of initial value within 1\xa0hour.\n\n## Adults, children and young people aged 12\xa0years and over with suspected sepsis who meet 2 or more moderate to high risk criteria\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis and 2 or more moderate to high risk criteria, or systolic blood pressure 91 to 100\xa0mmHg, carry out a venous blood test for the following:\n\nblood gas, including glucose and lactate measurement\n\nblood culture\n\nfull blood count\n\nC-reactive protein\n\nurea and electrolytes\n\ncreatinineand arrange for a clinician to review the person's condition and venous lactate results within 1\xa0hour of meeting criteria in an acute hospital setting.A 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis who meet 2 or more moderate to high risk criteria and have lactate over 2\xa0mmol/litre or evidence of acute kidney injury, treat as high risk and follow recommendations 1.6.1 to 1.6.7.For definition of acute kidney injury, see NICE's guideline on acute kidney injury.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2\xa0mmol/litre, no evidence of acute kidney injury and in whom a definitive condition cannot be identified:\n\nrepeat structured assessment at least hourly\n\nensure review by a senior clinical decision maker within 3\xa0hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for people aged 18 years or over should be someone who is authorised to prescribe antibiotics, such as a doctor of grade CT3/ST3 or above or equivalent, such as an advanced nurse practitioner with antibiotic prescribing responsibilities, depending on local arrangements. A 'senior decision maker' for people aged 12 to 17 years is a paediatric or emergency care qualified doctor of grade ST4 or above or equivalent. For definition of acute kidney injury, see NICE's guideline on acute kidney injury.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2\xa0mmol/litre, no evidence of acute kidney injuryand in whom a definitive condition or infection can be identified and treated:\n\nmanage the definitive condition\n\nif appropriate, discharge with information depending on the setting (see recommendations 1.11.5 and 1.11.6). For definition of acute kidney injury, see NICE's guideline on acute kidney injury.\n\n## Adults, children and young people aged 12\xa0years and over with suspected sepsis who meet only 1 moderate to high risk criterion\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis who meet only 1 moderate to high risk criterion:\n\narrange clinician review within 1\xa0hour of meeting criterion for clinical assessment in an acute hospital settingA 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.\n\nperform blood tests if indicated.\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition can be identified and treated:\n\nmanage the definitive condition\n\nif appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).\n\nFor adults, children and young people aged 12\xa0years and over with suspected sepsis who meet only 1 moderate to high risk criterion, have lactate of less than 2\xa0mmol/litre, no evidence of acute kidney injury and in whom a definitive condition cannot be identified:\n\nrepeat structured assessment at least hourly\n\nensure review by a senior clinical decision maker within 3\xa0hours of meeting moderate to high criterion in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for people aged 18 years or over should be someone who is authorised to prescribe antibiotics, such as a doctor of grade CT3/ST3 or above or equivalent, such as an advanced nurse practitioner with antibiotic prescribing responsibilities, depending on local arrangements. A 'senior decision maker' for people aged 12 to 17 years is a paediatric or emergency care qualified doctor of grade ST4 or above or equivalent. For definition of acute kidney injury, see NICE's guideline on acute kidney injury.\n\n## Adults, children and young people aged 12\xa0years and over with suspected sepsis and no high risk or moderate to high risk criteria\n\nArrange clinical assessment of adults, children and young people aged 12\xa0years and over who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.Clinical assessment should be carried out by a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.\n\n## Children aged 5 to 11 years\n\n## Children aged 5 to 11\xa0years with suspected sepsis who meet 1 or more high risk criteria\n\nFor children aged 5 to 11\xa0years who have suspected sepsis and 1 or more high risk criteria:\n\narrange for immediate review by the senior clinical decision maker to assess the child and think about alternative diagnoses to sepsisA 'senior clinical decision maker' for children aged 5 to 11\xa0years is a paediatric or emergency care doctor of grade ST4 or above or equivalent.\n\ncarry out a venous blood test for the following:\n\n\n\nblood gas, including glucose and lactate measurement\n\nblood culture\n\nfull blood count\n\nC-reactive protein\n\nurea and electrolytes\n\ncreatinine\n\na clotting screen\n\n\n\ngive a broad-spectrum antimicrobial (see section 1.7) at the maximum recommended dose without delay (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting)\n\ndiscuss with a consultant.\n\nFor children aged 5 to 11\xa0years with suspected sepsis and any high risk criteria and lactate over 4\xa0mmol/litre:\n\ngive intravenous fluid bolus without delay (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis\xa0and\n\nrefer to critical care for review of central access and initiation of inotropes or vasopressors.Referral may be a formal referral process or discussion with specialist in intensive care or intensive care outreach team.Critical care means an intensivist or intensive care outreach team, or specialist in intensive care or paediatric intensive care.\n\nFor children aged 5 to 11\xa0years with suspected sepsis and any high risk criteria and lactate between 2 and 4\xa0mmol/litre:\n\ngive intravenous fluid bolus as soon as possible (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis.\n\nFor children aged 5 to 11\xa0years with suspected sepsis and any high risk criteria and lactate below 2\xa0mmol/litre:\n\nconsider giving intravenous fluid bolus in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis.\n\nMonitor children with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30\xa0minutes depending on setting. Physiological track and trigger systems should be used to monitor all children in acute hospital settings. [This recommendation is adapted from NICE's guideline on acutely ill patients in hospital.]\n\nMonitor the mental state of children aged 5 to 11 years with suspected sepsis. Consider using the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale.\n\nAlert a consultant to attend in person if a child aged 5 to 11\xa0years with suspected sepsis and any high risk criteria fails to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated by any of:\n\nreduced level of consciousness despite resuscitation\n\nheart rate or respiratory rate fulfil high risk criteria\n\nlactate remains over 2\xa0mmol/litre after 1\xa0hour.\n\n## Children aged 5 to 11\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria\n\nFor children aged 5 to 11\xa0years with suspected sepsis and 2 or more moderate to high risk criteria:\n\ncarry out a venous blood test for the following:\n\n\n\nblood gas, including glucose and lactate measurement\n\nblood culture\n\nfull blood count\n\nC-reactive protein\n\nurea and electrolytes\n\ncreatinine\n\n\n\narrange for a clinician to review the person's condition and venous lactate results within 1\xa0hour of meeting criteria in an acute hospital setting.\n\nFor children aged 5 to 11\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria and have lactate over 2\xa0mmol/litre, treat as high risk and follow recommendations 1.6.16 to 1.6.22.\n\nFor children aged 5 to 11\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2\xa0mmol/litre, and in whom a definitive condition cannot be identified:\n\nrepeat structured assessment at least hourly\n\nensure review by a senior clinical decision maker within 3\xa0hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged 5–11\xa0years is a paediatric or emergency care doctor of grade ST4 or above or equivalent.\n\nFor children aged 5 to 11\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2\xa0mmol/litre, and in whom a definitive condition or infection can be identified and treated:\n\nmanage the definitive condition, and\n\nif appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).\n\n## Children aged 5 to 11\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion\n\nFor children aged 5 to 11\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion:\n\narrange clinician review within 1\xa0hour of meeting 1 moderate to high risk criterion in an acute hospital setting for clinical assessment andA 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.\n\nperform blood tests if indicated.\n\nFor children aged 5 to 11\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition can be identified and treated:\n\nmanage the definitive condition\n\nif appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).\n\nFor children aged 5 to 11\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion, and in whom a definitive condition cannot be identified:\n\nrepeat structured assessment at least hourly\n\nensure review by a senior clinical decision maker within 3\xa0hours of meeting a moderate to high risk criterion in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged 5 to 11\xa0years is a paediatric or emergency care doctor of grade ST4 or above or equivalent.\n\n## Children aged 5 to 11\xa0years with suspected sepsis and no high risk or moderate to high risk criteria\n\nArrange clinical assessment of children aged 5 to 11\xa0years who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.This should be by a medically qualified practitioner or equivalent with prescribing responsibilities.\n\n## Children aged under 5\xa0years\n\n## Children aged under 5\xa0years with suspected sepsis who meet 1 or more high risk criteria\n\nFor children aged under 5\xa0years who have suspected sepsis and 1 or more high risk criteria:\n\narrange for immediate review by the senior clinical decision maker to assess the child and think about alternative diagnoses to sepsis (for example bronchiolitis)A 'senior clinical decision maker' for children aged under 5\xa0years is a paediatric qualified doctor of grade ST4 or above.\n\ncarry out a venous blood test for the following:\n\n\n\nblood gas, including glucose and lactate measurement\n\nblood culture\n\nfull blood count\n\nC-reactive protein\n\nurea and electrolytes\n\ncreatinine\n\na clotting screen\n\n\n\ngive a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1\xa0hour of identifying that they meet any high risk criteria in an acute hospital setting; see section 1.7).\n\ndiscuss with a consultant.\n\nFor children aged under 5\xa0years with suspected sepsis and any high risk criteria and lactate over 4\xa0mmol/litre:\n\ngive intravenous fluid bolus without delay (in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis) and\n\nrefer to critical care for review of central access and initiation of inotropes or vasopressors.Referral may be a formal referral process or discussion with specialist in intensive care or intensive care outreach team.Critical care means an intensivist or intensive care outreach team, or specialist in intensive care or paediatric intensive care.\n\nFor children aged under 5 years with suspected sepsis and any high risk criteria and lactate between 2 and 4 mmol/litre:\n\ngive intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis\xa0.\n\nFor children aged under 5 years with suspected sepsis and any high risk criteria and lactate below 2 mmol/litre, consider giving intravenous fluid bolus in line with recommendations in section 1.8 intravenous fluids in people with suspected sepsis\xa0.\n\nMonitor children aged under 5\xa0years with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30 minutes depending on setting. Physiological track and trigger systems should be used to monitor all children in acute hospital settings. [This recommendation is adapted from NICE's guideline on acutely ill patients in hospital.]\n\nMonitor the mental state of children under 5 years with suspected sepsis. Consider using the Glasgow Coma Scale (GCS) or AVPU ('alert, voice, pain, unresponsive') scale.\n\nAlert a consultant to attend in person if a child aged under 5 years with suspected sepsis and any high risk criteria fails to respond within 1\xa0hour of initial antibiotic and/or intravenous fluid resuscitation. Failure to respond is indicated by any of:\n\nreduced level of consciousness despite resuscitation\n\nheart rate or respiratory rate fulfil high risk criteria\n\nlactate over 2\xa0mmol/litre after 1\xa0hour.\n\nGive parenteral antibiotics to infants aged under 3\xa0months as follows:\n\ninfants younger than 1\xa0month with fever\n\nall infants aged 1 to 3\xa0months with fever who appear unwell\n\ninfants aged 1 to 3\xa0months with white blood cell count less than 5×109/litre or greater than 15×109/litre.[This recommendation is from NICE's guideline on fever in under 5s.]\n\n## Children aged under 5\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria\n\nFor children aged under 5\xa0years with suspected sepsis and 2 or more moderate to high risk criteria:\n\ncarry out a venous blood test for the following:\n\n\n\nblood gas, including glucose and lactate measurement\n\nblood culture\n\nfull blood count\n\nC-reactive protein\n\nurea and electrolytes\n\ncreatinine\n\n\n\narrange for a clinician to review the person's condition and venous lactate results within 1\xa0hour of meeting 2 or more moderate to high risk criteria in an acute hospital setting.A 'clinician' should be a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.\n\nFor children aged under 5\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria and have lactate over 2\xa0mmol/litre, treat as high risk and follow recommendations 1.6.31 to 1.6.37.\n\nFor children aged under 5\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2\xa0mmol/litre, and in whom a definitive condition cannot be identified:\n\nrepeat structured assessment at least hourly\n\nensure review by a senior clinical decision maker within 3\xa0hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged under 5\xa0years is a paediatric qualified doctor of grade ST4 or above.\n\nFor children aged under 5\xa0years with suspected sepsis who meet 2 or more moderate to high risk criteria, have lactate of less than 2\xa0mmol/litre, and in whom a definitive condition or infection can be identified and treated:\n\nmanage the definitive condition and\n\nif appropriate, discharge with information depending on the setting (see recommendations 1.11.5 and 1.11.6).\n\n## Children aged under 5\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion\n\nFor children aged under 5\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion:\n\narrange clinician review within 1\xa0hour of meeting a moderate to high risk criterion for clinical assessment and\n\nperform blood tests if indicated.\n\nFor children aged under 5\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition can be identified and treated:\n\nmanage the definitive condition\n\nif appropriate, discharge with information depending on setting (see recommendations 1.11.5 and 1.11.6).\n\nFor children aged under 5\xa0years with suspected sepsis who meet only 1 moderate to high risk criterion and in whom a definitive condition cannot be identified:\n\nrepeat structured assessment at least hourly\n\nensure review by a senior clinical decision maker within 3\xa0hours of meeting a moderate to high risk criterion in an acute hospital setting for consideration of antibiotics.A 'senior clinical decision maker' for children aged under 5\xa0years is a paediatric qualified doctor of grade ST4 or above.\n\n## Children aged under 5\xa0years with suspected sepsis and no high risk or moderate to high risk criteria\n\nArrange clinical assessment of children aged under 5\xa0years who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.Clinical assessment should be carried out by a medically qualified practitioner or equivalent who has antibiotic prescribing responsibilities.\n\n# Antibiotic treatment in people with suspected sepsis\n\nPre-alert secondary care (through GP or ambulance service) when any high risk criteria are met in a person with suspected sepsis outside of an acute hospital, and transfer them immediately.\n\nEnsure urgent assessment mechanisms are in place to deliver antibiotics when any high risk criteria are met in secondary care (within 1\xa0hour of meeting a high risk criterion in an acute hospital setting).\n\nEnsure GPs and ambulance services have mechanisms in place to give antibiotics for people with high risk criteria in pre-hospital settings in locations where transfer time is more than 1\xa0hour.\n\nFor patients in hospital who have suspected infections, take microbiological samples before prescribing an antimicrobial and review the prescription when the results are available. For people with suspected sepsis take blood cultures before antibiotics are given. [This recommendation is adapted from NICE's guideline on antimicrobial stewardship.]\n\nIf meningococcal disease is specifically suspected (fever and purpuric rash) give appropriate doses of parenteral benzyl penicillin in community settings and intravenous ceftriaxone in hospital settings. [This recommendation is adapted from NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.]\n\nFor all people with suspected sepsis where the source of infection is clear use existing local antimicrobial guidance.\n\nFor people aged 18\xa0years and over who need an empirical intravenous antimicrobial for a suspected infection but who have no confirmed diagnosis, use an intravenous antimicrobial from the agreed local formulary and in line with local (where available) or national guidelines. [This recommendation is adapted from NICE's guideline on antimicrobial stewardship.]\n\nFor people aged up to 17\xa0years (for neonates see recommendation 1.7.12) with suspected community acquired sepsis of any cause give ceftriaxone 80 mg/kg once a day with a maximum dose of 4\xa0g daily at any age. [This recommendation is adapted from NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.]\n\nFor people aged up to 17 years with suspected sepsis who are already in hospital, or who are known to have previously been infected with or colonised with ceftriaxone-resistant bacteria, consult local guidelines for choice of antibiotic.\n\nFor children younger than 3\xa0months, give an additional antibiotic active against listeria (for example, ampicillin or amoxicillin). [This recommendation is adapted from NICE's guideline on fever in under 5s.]\n\nTreat neonates presenting in hospital with suspected sepsis in their first 72 hours with intravenous benzylpenicillin and gentamicin. [This recommendation is adapted from NICE's guideline on neonatal infection.]\n\nTreat neonates who are more than 40 weeks corrected gestational age who present with community acquired sepsis with ceftriaxone 50\xa0mg/kg unless already receiving an intravenous calcium infusion at the time. If 40 weeks corrected gestational age or below or receiving an intravenous calcium infusion use cefotaxime 50 mg/kg every 6 to 12 hours, depending on the age of the neonate.\n\nFollow the recommendations in NICE's guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine when prescribing and using antibiotics to treat people with suspected or confirmed sepsis.\n\n# Intravenous fluids in people with suspected sepsis\n\nIf patients over 16\xa0years need intravenous fluid resuscitation, use crystalloids that contain sodium in the range 130 \xa0mmol/litre to 154\xa0mmol/litre with a bolus of 500\xa0ml over less than 15\xa0minutes. [This recommendation is from NICE's guideline on intravenous fluid therapy in adults in hospital.]\n\nIf children and young people up to 16\xa0years need intravenous fluid resuscitation, use glucose-free crystalloids that contain sodium in the range 130 to\xa0154 mmol/litre, with a bolus of 10\xa0ml/kg over less than 10\xa0minutes. Take into account pre-existing conditions (for example, cardiac disease or kidney disease), because smaller fluid volumes may be needed. [This recommendation is from NICE's guideline on intravenous fluid therapy in children and young people in hospital.]\n\nIf neonates need intravenous fluid resuscitation, use glucose-free crystalloids that contain sodium in the range 130 to 154\xa0mmol/litre, with a bolus of 10 ml/kg to 20 ml/kg over less than 10 minutes. [This recommendation is from NICE's guideline on intravenous fluid therapy in children and young people in hospital.]\n\nReassess the patient after completion of the intravenous fluid bolus, and if no improvement give a second bolus. If there is no improvement after a second bolus alert a consultant to attend (in line with recommendations 1.6.7, 1.6.22 and 1.6.37).\n\nUse a pump, or syringe if no pump is available, to deliver intravenous fluids for resuscitation to children under 12 years with suspected sepsis who need fluids in bolus form.\n\nIf using a pump or flow controller to deliver intravenous fluids for resuscitation to people over 12 years with suspected sepsis who need fluids in bolus form ensure device is capable of delivering fluid at required rate for example at least 2000 ml/hour in adults.\n\nDo not use starch based solutions or hydroxyethyl starches for fluid resuscitation for people with sepsis. [This recommendation is adapted from NICE's guidelines on intravenous fluid therapy in adults in hospital and intravenous fluid therapy in children and young people in hospital.]\n\nConsider human albumin solution 4 to 5% for fluid resuscitation only in patients with sepsis and shock. [This recommendation is adapted from NICE's guideline on intravenous fluid therapy in adults in hospital.]\n\n# Using oxygen in people with suspected sepsis\n\nGive oxygen to achieve a target saturation of 94% to 98% for adult patients or 88% to 92% for those at risk of hypercapnic respiratory failure.\n\nOxygen should be given to children with suspected sepsis who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated. [This recommendation is adapted from NICE's guideline on fever in under 5s.]Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n# Finding the source of infection in people with suspected sepsis\n\nCarry out a thorough clinical examination to look for sources of infection, including sources that might need surgical drainage, as part of the initial assessment.\n\nTailor investigations of the sources of infection to the person's clinical history and findings on examination.\n\nConsider urine analysis and chest X-ray to identify the source of infection in all people with suspected sepsis.\n\nConsider imaging of the abdomen and pelvis if no likely source of infection is identified after clinical examination and initial tests.\n\nInvolve the adult or paediatric surgical and gynaecological teams early on if intra-abdominal or pelvic infection is suspected in case surgical treatment is needed.\n\nDo not perform a lumbar puncture without consultant instruction if any of the following contraindications are present:\n\nsigns suggesting raised intracranial pressure or reduced or fluctuating level of consciousness (Glasgow Coma Scale score less than 9 or a drop of 3 points or more)\n\nrelative bradycardia and hypertension\n\nfocal neurological signs\n\nabnormal posture or posturing\n\nunequal, dilated or poorly responsive pupils\n\npapilloedema\n\nabnormal 'doll's eye' movements\n\nshock\n\nextensive or spreading purpura\n\nafter convulsions until stabilised\n\ncoagulation abnormalities or coagulation results outside the normal range or platelet count below 100x109/litre or receiving anticoagulant therapy\n\nlocal superficial infection at the lumbar puncture site\n\nrespiratory insufficiency in children.[This recommendation is adapted from NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.]\n\nPerform lumbar puncture in the following children with suspected sepsis (unless contraindicated, see contraindications in recommendation 1.10.6):\n\ninfants younger than 1\xa0month\n\nall infants aged 1 to 3\xa0months who appear unwell\n\ninfants aged 1 to 3\xa0months with a white blood cell count less than 5×109/litre or greater than 15×109/litre. [This recommendation is adapted from NICE's guideline on fever in under 5s.]\n\n# Information and support for people with sepsis and their families and carers\n\n## People who have sepsis and their families and carers\n\nEnsure a care team member is nominated to give information to families and carers, particularly in emergency situations such as in the emergency department. This should include:\n\nan explanation that the person has sepsis, and what this means\n\nan explanation of any investigations and the management plan\n\nregular and timely updates on treatment, care and progress.\n\nEnsure information is given without using medical jargon. Check regularly that people understand the information and explanations they are given.\n\nGive people with sepsis and their family members and carers opportunities to ask questions about diagnosis, treatment options, prognosis and complications. Be willing to repeat any information as needed.\n\nGive people with sepsis and their families and carers information about national charities and support groups that provide information about sepsis and the causes of sepsis.\n\n## Information at discharge for people assessed for suspected sepsis, but not diagnosed with sepsis\n\nGive people who have been assessed for sepsis but have been discharged without a diagnosis of sepsis (and their family or carers, if appropriate) verbal and written information about:\n\nwhat sepsis is, and why it was suspected\n\nwhat tests and investigations have been done\n\ninstructions about which symptoms to monitor\n\nwhen to get medical attention if their illness continues\n\nhow to get medical attention if they need to seek help urgently.\n\nConfirm that people understand the information they have been given, and what actions they should take to get help if they need it.\n\n## Information at discharge for people at increased risk of sepsis\n\nEnsure people who are at increased risk of sepsis (for example after surgery) are told before discharge about symptoms that should prompt them to get medical attention and how to get it.See NICE's guideline on neutropenic sepsis for information for people with neutropenic sepsis (recommendation 1.1.1.1).\n\n## Information at discharge for people who have had sepsis\n\nEnsure people and their families and carers if appropriate have been informed that they have had sepsis.\n\nEnsure discharge notifications to GPs include the diagnosis of sepsis.\n\nGive people who have had sepsis (and their families and carers, when appropriate) opportunities to discuss their concerns. These may include:\n\nwhy they developed sepsis\n\nwhether they are likely to develop sepsis again\n\nif more investigations are necessary\n\ndetails of any community care needed, for example, related to peripherally inserted central venous catheters (PICC) lines or other intravenous catheters\n\nwhat they should expect during recovery\n\narrangements for follow-up, including specific critical care follow up if relevant\n\npossible short-term and long-term problems.\n\nGive people who have had sepsis and their families and carers information about national charities and support groups that provide information about sepsis and causes of sepsis.\n\nAdvise carers they have a legal right to have a carer's assessment of their needs, and give them information on how they can get this.See NICE's guideline on rehabilitation after critical illness in adults for recommendations on rehabilitation and follow up after critical illness.See NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s for follow up of people who have had meningococcal septicaemia.\n\n# Training and education\n\nEnsure all healthcare staff and students involved in assessing people's clinical condition are given regular, appropriate training in identifying people who might have sepsis. This includes primary, community care and hospital staff including those working in care homes.\n\nEnsure all healthcare professionals involved in triage or early management are given regular appropriate training in identifying, assessing and managing sepsis. This should include:\n\nrisk stratification strategies\n\nlocal protocols for early treatments, including antibiotics and intravenous fluids\n\ncriteria and pathways for escalation, in line with their health care setting.\n\n# Terms used in this guideline\n\n## Sepsis\n\nSepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection.\n\n## Suspected sepsis\n\nSuspected sepsis is used to indicate people who might have sepsis and require face-to-face assessment and consideration of urgent intervention.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Epidemiological study on presentation and management of sepsis in England\n\nWhat is the incidence, presentation and management of sepsis in the United Kingdom?\n\n## Why this is important\n\nThe lack of robust UK based epidemiological studies on the incidence and outcomes from sepsis have been clear throughout the guideline development process. A large epidemiological study to collect information about where sepsis is being treated, patient interventions and patient outcomes would provide population based statistics on epidemiology of sepsis which are necessary to support evaluation of interventions, planning of services and service redesign. The mortality and morbidity and service complexity associated with severe infection and sepsis, and the need to use broad spectrum antimicrobials to treat sepsis, justifies the cost required to set up such a study.\n\n# A complex service evaluation of implementation of NICE Sepsis guideline\n\nWhat effect will the NICE sepsis guideline have on patient care processes and outcomes in the UK over the next 5\xa0years?\n\n## Why this is important\n\nImplementation of NICE's guideline on sepsis will be a challenge to the NHS. A robust evaluation of how NHS service providers adhere to the recommended care processes needs to be carried out over the next 5\xa0years.\n\nA complex evaluation is needed to understand the effect of guidelines on services and on patient outcomes. Evaluation should include assessment of costs and cost effectiveness, the use of a universal audit tool for sepsis patient care that includes evaluation of pre-hospital and secondary care and monitoring of broad spectrum antibiotic use, development of multi-resistant organisms and incidence of antibiotic-related infection such as C. difficile.\n\n# Use of biomarkers to diagnose and initiate treatment\n\nWhat is the clinical and cost effectiveness of procalcitonin (PCT) point-of-care tests at initial triage for diagnosis of serious infection and the initiation of appropriate antibiotic therapy?\n\n## Why this is important\n\nThere is an urgent clinical need for accurate biomarkers of serious bacterial infection (SBI) which provide early diagnosis of SBI, and prompt clinical interventions to improve outcomes. The current tests used in the NHS (white cell count and C-reactive protein) are non-specific and not sensitive enough. Biomarker-guided initiation and termination of antibiotic therapy might be an effective strategy to reduce unnecessary antibiotic use and help prevent further multidrug resistance. The NICE diagnostics guidance on procalcitonin for diagnosing and monitoring sepsis has shown there is not enough evidence in this area.\n\n# Validation of clinical early warning scores in pre-hospital and emergency care settings\n\nCan early warning scores, for example NEWS (national early warning scores for adults) and PEWS (paediatric early warning score), be used to improve the detection of sepsis and facilitate prompt and appropriate clinical response in pre-hospital settings and in emergency departments?\n\n## Why this is important\n\nDelay in detecting and treating sepsis increases mortality. Early detection and appropriate management will reduce morbidity and mortality and will reduce NHS costs by reducing critical care admissions, inappropriate antimicrobial use and length of hospital stay. No high quality data exist on the validation or use of early warning scores in pre-hospital settings or in the emergency department settings. The use of scores might improve communication between pre-hospital settings and hospital settings and allow recognition of people who need more urgent assessment.\n\n# Derivation of clinical decision rules in suspected sepsis\n\nIs it possible to derive and validate a set of clinical decision rules or a predictive tool to rule out sepsis which can be applied to patients presenting to hospital; with suspected sepsis?\n\n## Why this is important\n\nIn primary care and emergency departments people with suspected sepsis are often seen by relatively inexperienced doctors. Many of these people will be in low and medium risk groups but evidence is lacking as to who can be sent home safely and who needs intravenous or oral antibiotics. The consequences of getting the decision making wrong can be catastrophic and therefore many patients are potentially over-investigated and admitted inappropriately. Current guidance is dependent on use of individual variables informed by low quality evidence.", 'Context': "Sepsis is a clinical syndrome caused by the body's immune and coagulation systems being switched on by an infection. Sepsis with shock is a life-threatening condition that is characterised by low blood pressure despite adequate fluid replacement, and organ dysfunction or failure. Sepsis is an important cause of death in people of all ages. Both a UK Parliamentary and Health Service Ombudsman enquiry (2013) and a UK National Confidential Enquiry into Patient Outcome and Death (NCEPOD, 2015) highlighted sepsis as being a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined.\n\nSepsis is difficult to diagnose with certainty. Although people with sepsis may have a history of infection, fever is not present in all cases. The signs and symptoms of sepsis can be very non-specific and can be missed if clinicians do not think 'could this be sepsis?'. In the same way that healthcare professionals consider 'could this pain be cardiac in origin?' when presented with someone of any age with chest pain this guideline aims to make 'could this be sepsis?' the first consideration for anyone presenting with a possible infection.\n\nDetailed guidelines exist for the management of sepsis in adult and paediatric intensive care units, and by intensive care clinicians called to other settings. To reduce avoidable deaths, people with sepsis need to be recognised early and treatment initiated. This guideline aims to ensure healthcare systems in all clinical settings consider sepsis as an immediate life-threatening condition that should be recognised and treated as an emergency. The guideline outlines the immediate actions needed for those with suspicion of sepsis and who are at highest risk of morbidity and mortality from sepsis. It provides a framework for risk assessment, treatment and follow-up or 'safety-netting' of people not needing immediate resuscitation. The intention of this guideline is to ensure that all people with sepsis due to any cause are recognised and initial treatment initiated before definitive treatment on other specific pathways is instituted.\n\nAt the time of writing, the terminology around sepsis is changing and new international consensus definitions have been published. Previous terminology included terms SIRS (systematic inflammatory response syndrome), severe sepsis and septic shock but new terminology suggests using terms sepsis and septic shock only . Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host response to infection and septic shock as persisting hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) of 65 mmHg or more and having a serum lactate level of greater than 2 mmol/l despite adequate volume resuscitation. Neither of these definitions are useful in early identification of people at risk and the guideline recommends actions according to clinical parameters that stratify risk of severe illness or death from sepsis.\n\nThere is significant overlap between this guideline and other NICE guidance, in particular for the care of acutely ill patients in hospital (see NICE's guideline on acutely ill adults in hospital), the assessment and initial management of fever in under 5s (see NICE's guideline on fever in under 5s), bacterial meningitis and meningococcal septicaemia (see NICE's guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s), NICE's guideline on neutropenic sepsis, antibiotics for prevention and treatment of neonatal infection (see NICE's guideline on neonatal infection), and NICE's guideline on pneumonia in adults."}
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https://www.nice.org.uk/guidance/ng51
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This guideline covers the recognition, diagnosis and early management of sepsis for all populations. The guideline committee identified that the key issues to be included were: recognition and early assessment, diagnostic and prognostic value of blood markers for sepsis, initial treatment, escalating care, identifying the source of infection, early monitoring, information and support for patients and carers, and training and education.
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b36d737b4d1ff780944f385a3800d92ea987f416
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nice
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Pembrolizumab for advanced melanoma not previously treated with ipilimumab
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Pembrolizumab for advanced melanoma not previously treated with ipilimumab
Evidence-based recommendations on pembrolizumab (Keytruda) for treating advanced melanoma in adults who have not had ipilimumab.
# Guidance
Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab, in adults, only when the company provides pembrolizumab in line with the commercial access agreement with NHS England.# The technology
Pembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody. It acts on the programmed cell death protein‑1 immune‑checkpoint receptor pathway, blocking its interaction with ligand on the tumour cells. This allows reactivation of anti‑tumour immunity. It has a marketing authorisation in the UK as monotherapy 'for the treatment of advanced (unresectable or metastatic) melanoma in adults'. Pembrolizumab is administered intravenously for 30 minutes at a dose of 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.
The most common (occurring in 1 in 10 people or more) adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue. The most serious adverse reactions were immune‑related adverse reactions and severe infusion‑related reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The acquisition cost of pembrolizumab is £1,315 per 50‑mg vial (excluding VAT; company's submission). The pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in November 2015, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.# The company's submission
The Appraisal Committee (section 7) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the Evidence Review Group (ERG; section 8).
# Clinical effectiveness
The company presented clinical‑effectiveness evidence for pembrolizumab from 2 clinical trials: KEYNOTE‑006 and KEYNOTE‑001. KEYNOTE‑006 was a randomised, international, multicentre, phase III trial of pembrolizumab 10 mg/kg every 2 weeks (n=279) or every 3 weeks (n=277), continued until disease progression or unacceptable toxicity, compared with ipilimumab 3 mg/kg every 3 weeks, continued for 4 doses (n=278). Results were analysed at 2 planned interim analyses, after 6 months of follow‑up (September 2014) and after 9–12 months of follow‑up (March 2015). After the second interim analysis the study was stopped, because the primary endpoint had been met. KEYNOTE‑001 was a combined phase I and II study. Evidence was presented from a sub‑study of this trial, referred to as KEYNOTE‑001 part D: this was a randomised, open‑label study comparing pembrolizumab 2 mg/kg every 3 weeks (n=51; the licensed dose) with 10 mg/kg every 3 weeks (n=52). Both KEYNOTE‑006 and KEYNOTE‑001 part D included people with advanced melanoma, with or without BRAF mutations, who had not had ipilimumab before (previous treatment with 1 or 2 other therapies was permitted).
In KEYNOTE‑006, pembrolizumab was associated with statistically significant increases in both progression‑free survival (first interim analysis) and overall survival (second interim analysis), compared with ipilimumab (table 1). Pembrolizumab was also associated with statistically significantly higher overall response rates compared with ipilimumab (table 1; p<0.001). Pre‑specified subgroup analyses based on demographic and clinical characteristics suggested that the treatment effect associated with pembrolizumab was generally consistent across subgroups, although some variations in effect based on the line of therapy and the expression of ligands for the 'programmed death 1' protein (termed 'PD‑L1 status') were seen. No significant differences in clinical effectiveness between pembrolizumab doses (that is, 10 mg/kg every 3 weeks, 10 mg/kg every 2 weeks or 2 mg/kg every 3 weeks) were seen in either KEYNOTE‑006 or KEYNOTE‑001 part D.
## Table 1 Clinical‑effectiveness outcomes in KEYNOTE‑006
Pembrolizumab
Ipilimumab
n=278
mg/kg every 3 weeks
n=277
mg/kg every 2 weeks
n=279
Progression‑free survival (interim analysis 1)
Median: months (95% CI)
Hazard ratio versus ipilimumab (95% CI)
p<0.00001
p<0.00001
Overall survival (interim analysis 2)
Overall survival at 6 months1: % (95% CI)
Hazard ratio versus ipilimumab (95% CI)
p=0.00358
p=0.00052
Overall response (interim analysis 1)
Overall response rate: % (95% CI)
Abbreviations: CI, confidence interval; n, number of patients.1Median overall survival not reached.
The company presented adverse event data from KEYNOTE‑006, and stated that pembrolizumab was generally well tolerated. It was associated with a similar number of adverse events, but fewer drug‑related grade 3–5 adverse events, serious adverse events, drug‑related serious adverse events and adverse events leading to withdrawal from the trial, compared with ipilimumab (table 2). Pembrolizumab was also associated with fewer high‑grade, immune‑related adverse events than ipilimumab, and fewer people in the pembrolizumab groups withdrew from the trial because of immune‑related adverse events (table 2). The most common treatment‑related adverse events with both pembrolizumab and ipilimumab were fatigue, diarrhoea, rash and itching. The most common grade 3–5 immune‑related adverse events associated with pembrolizumab were colitis and hepatitis.
## Table 2 Summary of adverse events in KEYNOTE‑006
Ipilimumab
Pembrolizumab (both arms combined)
n
n
n
Patients with 1 or more AE
Drug‑related grade 3–5 AE
Serious AE
Drug‑related serious AE
Stopped because of an AE
Immune‑related AEs
Patients with 1 or more AE
Grade 3–5 AE
Stopped because of an AE
Abbreviations: AE, adverse event; n, number of patients.
The company compared the clinical effectiveness of pembrolizumab with ipilimumab, dabrafenib, vemurafenib and dacarbazine in a series of network meta‑analyses. The analyses were performed in a Bayesian framework using a fixed‑effects model, and were based on data from KEYNOTE‑006 and 5 other trials identified in the systematic review. The company presented results from a series of analyses, including 4 alternative network scenarios, 4 time points, and separate analyses of pembrolizumab as either a first‑ or second‑line treatment. It stated that, for the outcomes of progression‑free survival and overall survival, pembrolizumab appeared to have a similar efficacy to vemurafenib and dabrafenib, in people who have had no previous treatment. For example, in network scenario '3b' at the 6‑month time point, pembrolizumab was associated with a hazard ratio for progression‑free survival of 0.80 (95% credible interval 0.32–1.92) compared with dabrafenib, and 0.67 (95% CrI 0.37–1.14) compared with vemurafenib. The corresponding hazard ratios for overall survival were 0.96 (95% CrI 0.46–1.93) and 0.75 (95% CrI 0.40–1.34), compared with dabrafenib and vemurafenib respectively. The company highlighted that pembrolizumab was associated with greater progression‑free survival and overall survival than both ipilimumab (scenario 3b, 6‑month timepoint: hazard ratio for progression‑free survival 0.45, 95% CrI 0.33–0.62; hazard ratio for overall survival 0.59, 95% CrI 0.41–0.84) and dacarbazine (scenario 3b, 6‑month timepoint: hazard ratio for progression‑free survival 0.36, 95% CrI 0.21–0.59; hazard ratio for overall survival 0.54, 95% CrI 0.30–0.91) for previously untreated disease, and was at least as effective as ipilimumab for people who have had 1 previous line of treatment (scenario 3b, 6‑month timepoint: hazard ratio for progression‑free survival 0.74, 95% CrI 0.48–1.12; hazard ratio for overall survival 0.80, 95% CrI 0.52–1.22).
# Cost effectiveness
The company presented an economic model comparing pembrolizumab (2 mg/kg every 3 weeks) with ipilimumab, dabrafenib and vemurafenib. The model comprised 3 states: pre‑progression, post‑progression and death. The model used a cycle length of 1 week and a time horizon of 30 years (lifetime), taking the perspective of the NHS and personal social services, with costs and benefits discounted at a rate of 3.5% per year. The model included costs associated with melanoma treatment, costs in each health state (based on a study of resource use for melanoma treatment in the UK), management of adverse events and complications, and care at the end of life.
The proportion of people in the each health state was based on estimates of progression‑free survival and overall survival:
Progression‑free survival was estimated using Kaplan–Meier curves from the KEYNOTE‑006, BRIM‑3 and BREAK‑3 clinical trials, extrapolated to 30 years based on a Gompertz model (for pembrolizumab and ipilimumab) or a monthly risk of progression taken from NICE's technology appraisal guidance on ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (for dabrafenib and vemurafenib).
Overall survival was estimated by initially using Kaplan–Meier data from clinical trials (for the first 50–60 weeks of the model), followed by published mortality risks based on data from a pooled analysis of long‑term survival data for people with melanoma treated with ipilimumab (Schadendorf et al. ; applied to pembrolizumab and ipilimumab) and NICE's technology appraisal guidance on ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (applied to dabrafenib and vemurafenib). Long‑term survival was based on mortality rates in a published registry study (Balch et al. ).
Utility values were estimated using EuroQol EQ‑5D data from KEYNOTE‑006, by assuming that quality of life decreases as people approach the last months of life. The utility scores decreased from 0.82, for people who were more than 360 days before death, to 0.33 for people in the 30 days before death.
The company's base‑case results are summarised in table 3. These results were based on the discount in the patient access scheme for pembrolizumab and the list prices for all other drugs, and therefore were not used for decision‑making; they are included here for illustration only. Results from the company's model including the patient access schemes for pembrolizumab and all 3 comparators were presented by the ERG; these results are commercial in confidence and cannot be reported here.
## Table 3 Results of the company's base‑case analysis (including pembrolizumab patient access scheme, list price for all comparators; not used for decision‑making)
BRAF mutation‑positive disease
Total cost
Total LYG
Total QALYs
Incr cost
Incr LYG
Incr QALYs
ICER (£/QALY)
Dabrafenib
Pembrolizumab
Vemurafenib
Dominated
Ipilimumab
Dominated
BRAF mutation‑negative disease
Total cost
Total LYG
Total QALYs
Incr cost
Incr LYG
Incr QALYs
ICER (£/QALY)
Pembrolizumab
Ipilimumab
Dominated
Abbreviations: ICER, incremental cost‑effectiveness ratio; Incr, incremental; LYG, life years gained; QALYs, quality‑adjusted life years.
Dominated: provides fewer QALYs at greater cost than the comparator.
In a deterministic sensitivity analysis, the model results for all comparisons were most sensitive to the extrapolation of progression‑free survival for pembrolizumab (shape and treatment effect in the Gompertz model). In the probabilistic sensitivity analysis, the total costs associated with pembrolizumab increased by £10,996 compared with the deterministic results, and the total QALYs decreased by 0.02, whereas the results for ipilimumab, dabrafenib and vemurafenib did not change substantially. The company stated that the change in the results for pembrolizumab was caused by uncertainty in the extrapolation of progression‑free survival from the KEYNOTE‑006 trial, which led to a small number of iterations with high treatment costs. The company also presented 33 scenario analyses, to explore the effects of key assumptions on the model results. These analyses explored the effects of varying the progression‑free survival and overall survival estimates, time horizon, utility estimates, treatment and terminal care costs, treatment duration for pembrolizumab, and the discounting rate. The company stated that these analyses showed that the cost effectiveness of pembrolizumab was robust to most sources of uncertainty.
# ERG comments
The ERG stated that KEYNOTE‑006 was well designed and well conducted. It considered that the population was representative of patients seen in the UK NHS, and patient characteristics were well balanced across treatment groups. However, it noted 3 key concerns about this trial:
The dosage of pembrolizumab (10 mg/kg every 3 weeks) did not match the licensed dose (2 mg/kg every 3 weeks). The ERG noted that the European Public Assessment Report (EPAR) states that no differences between the licensed dose and the studied dose are to be expected. Although this was largely based on data from patients who had previous therapy with ipilimumab, the ERG cautiously accepted this conclusion.
The trial was stopped early, so the overall survival data were immature. The ERG was unclear whether the true impact of pembrolizumab on survival will be identified.
The trial specified a maximum treatment duration of 24 months. The ERG considered that the effect of this rule on clinical outcomes is unknown.
The ERG considered that the clinical assumptions used in the company's network meta‑analysis were reasonable, but the methods of the analysis were flawed. It stated that the populations in the control arms were not comparable, the analysis did not correctly reflect changing hazard ratios over time, and the methods used to adjust for treatment switching in the key trial for vemurafenib may not have been adequate. The ERG considered that the network meta‑analysis did not provide valid treatment effect estimates, particularly for pembrolizumab compared with dabrafenib and vemurafenib.
The ERG's critique of the company's economic model suggested that the model was generally consistent with the NICE reference case. However, it highlighted that the structure of the model led to counterintuitive results – specifically, that pembrolizumab would become less cost effective if its effectiveness at delaying disease progression increased. The ERG stated that this was because delaying disease progression was associated with additional treatment costs but no increase in quality of life. In addition, the ERG expressed concerns about the modelling of overall survival, progression‑free survival, treatment costs and quality of life. It considered that there were limitations in the methods of extrapolation for both progression‑free survival and overall survival. In particular, for overall survival, the ERG stated that there was a risk of selection bias in the data taken from the study by Schadendorf et al. (2015), and there were limitations in the algorithm used to adjust for patient characteristics and the long‑term survival data (from Balch et al. ) used to project long‑term survival. The ERG highlighted that the company's estimates for mortality risk in people treated with pembrolizumab changed erratically during the course of the model and were not clinically plausible. For the analysis of progression‑free survival, the ERG noted limitations including the use of centrally assessed progression, the company's choice of censoring rule, inappropriate use of the proportional hazards assumption and incomplete adjustment for differences in patient characteristics between the dabrafenib, vemurafenib and pembrolizumab trials. The ERG described concerns about the duration of treatment, the weight distribution of the population, and the administration costs of ipilimumab, which meant that the costs of treatment were not accurately estimated. It considered that there were important limitations in the estimation of utility, because of the use of EQ‑5D data based on patients from all regions (rather than UK or European patients only) and the assumption that utility did not change when disease progressed. The ERG highlighted that 75–90% of the cost differences between treatments in the company's model could be attributed to direct treatment costs, and that 87.5% of the health gain with pembrolizumab occurred after 12 months. It therefore considered that the key factors affecting results of the model were drug costs, duration of treatment and overall survival.
The ERG presented a series of exploratory analyses to address their principal concerns about the company's model (see section 3.12). In particular, it changed the modelling of overall survival (using methods developed for NICE's technology appraisal guidance on ipilimumab for previously treated advanced (unresectable or metastatic) melanoma), progression‑free survival and treatment duration, and amended the treatment costs and utility scores. It also presented 2 scenario analyses, in which the duration of progression‑free survival was extended by 3 or 6 years for people whose disease had not progressed after 2 years; the ERG presented results for all analyses using the patient access scheme price for pembrolizumab and the list prices for ipilimumab, dabrafenib and vemurafenib (summarised below) and also using patient access schemes for all drugs (commercial in confidence; cannot be reported here). The ERG's amendments, combined, increased the costs associated with pembrolizumab by £6593 and reduced the total QALYs by 0.18. The amendments also reduced the costs and QALYs associated with ipilimumab (by £2558 and 0.17 respectively), increased the costs and QALYs for vemurafenib (by £7027 and 0.5 respectively), and increased the costs but reduced the QALYs for dabrafenib (by £3,238 and 0.02 respectively). Both of the scenario analyses substantially increased the costs associated with pembrolizumab, but had no effect on the other treatments.
Full details of all the evidence are available.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab and the value placed on the benefits of pembrolizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee discussed the current management of advanced melanoma in the NHS, and the potential place of pembrolizumab in the treatment pathway. It was aware of the disparity between the wording of the marketing authorisation for pembrolizumab and the definition of the population in the scope; it understood that this appraisal specifically considered pembrolizumab for melanoma that had not been previously treated with ipilimumab, and that ipilimumab‑treated melanoma was considered in a separate appraisal. The Committee understood that ipilimumab is the most common treatment option for advanced (unresectable or metastatic) melanoma that does not have a BRAF V600 mutation (BRAF mutation‑negative or 'wild type' disease). For melanoma with BRAF V600 mutations (BRAF mutation‑positive disease), the Committee heard from the clinical experts that the treatment strategy has changed in recent years. In the past, a clear distinction was made between rapidly progressing tumours (which would usually be treated with a BRAF inhibitor – that is, dabrafenib or vemurafenib), and more slowly progressing disease (which may be treated with an immunotherapy agent such as ipilimumab). More recently, the long survival benefit shown in a percentage of patients treated with ipilimumab (based on 5‑year overall survival data) has led to an increasing emphasis on immunotherapy. The Committee also heard from the clinical experts that pembrolizumab appeared to have a faster onset of action and higher response rate than ipilimumab, and may also be more suitable for treating higher‑volume disease. Consequently, although some people with rapidly progressing BRAF mutation‑positive melanoma will continue to have BRAF inhibitors as a first‑line treatment, the clinical experts expected that pembrolizumab would be considered for more people than just those who, in the past, would have had treatment with ipilimumab. The Committee was aware that dacarbazine is now used only after the other available treatments, if at all, because it has not been shown to improve survival compared with supportive care. The Committee concluded that ipilimumab, dabrafenib and vemurafenib were appropriate comparators for people with advanced melanoma that has not previously been treated with ipilimumab.
The Committee considered how pembrolizumab might be used in clinical practice, and in particular whether treatment may be limited to a fixed duration. It noted that the KEYNOTE‑006 trial protocol specified a maximum treatment duration of 2 years, and heard from the company that although the 2‑year point had not yet been reached, the maximum treatment duration will be adhered to as follow‑up continues. The Committee understood that the trial had been unblinded early, after which people in the ipilimumab group could start treatment with pembrolizumab. The Committee heard from the clinical experts that there is no evidence to indicate the optimum duration of treatment with pembrolizumab. The clinical experts considered the likely treatment duration in clinical practice and stated that if a maximum duration were specified, consideration should be given to whether pembrolizumab could be restarted if the disease progressed. The Committee was aware that in KEYNOTE‑006, people could stop treatment if they had a complete response and could restart treatment if their disease progressed, but that there was limited evidence on the clinical effectiveness of this approach. The Committee highlighted that the marketing authorisation for pembrolizumab specifies that treatment should continue until disease progression or unacceptable toxicity. The Committee concluded that, consistent with the limited evidence available, it was appropriate to appraise pembrolizumab in line with its marketing authorisation. However, it appreciated that there is uncertainty about the optimum duration of treatment with pembrolizumab.
The Committee discussed the clinical needs of people with advanced melanoma. It heard from the patient experts that melanoma has a major effect on people's health and quality of life. Having a choice of treatments would be particularly valuable to people with this condition, allowing them and their doctors to choose treatments that take into account their individual needs and preferences and giving them a feeling of more control over their condition. For example, when considering different treatment options, some people might take into account their preferences for oral or intravenous administration, fixed‑duration or continuous treatment, or different side‑effect profiles. The Committee heard from the patient experts that treatment with ipilimumab can be associated with severe side effects, and this may be a major consideration. The Committee concluded that the availability of an effective new treatment option with an acceptable tolerability profile would be valuable for people with advanced melanoma.
The Committee considered the generalisability of the KEYNOTE‑006 trial. It understood that the percentage of people with BRAF mutation‑positive melanoma in this trial (35%) was likely to reflect the use of pembrolizumab if it becomes established in clinical practice. The Committee noted that the dosage of pembrolizumab in KEYNOTE‑006 was 10 mg/kg every 2 or 3 weeks, but that the dosage specified in the marketing authorisation is 2 mg/kg every 3 weeks. It heard from the clinical experts that they expect the 2‑mg/kg dose to be as effective as 10 mg/kg, and there is no evidence for a dose–response effect over this range. The Committee reviewed evidence from the KEYNOTE‑001 trial comparing the 10‑mg/kg and 2‑mg/kg doses, and considered that it had not seen any evidence to suggest a difference in effectiveness. The Committee concluded that the clinical‑effectiveness evidence presented was broadly generalisable to clinical practice in the NHS.
The Committee considered the results of the KEYNOTE‑006 trial. It noted that pembrolizumab provided significant improvements in progression‑free survival, overall survival and overall response rates compared with ipilimumab. However, it noted that the trial was stopped early (because the primary endpoints had been met). Consequently, the evidence available was based on a limited duration of follow‑up and the overall survival data were immature (that is, fewer than half of the people in the trial had died). It therefore considered that the long‑term benefits of pembrolizumab were very uncertain. The Committee acknowledged that further survival data were expected to be available soon, but that there were no data beyond 2 years at the time of the appraisal. The Committee heard from the clinical experts that pembrolizumab was expected to provide a long‑term survival benefit consistent with that shown in the ipilimumab trials. It recognised that this expectation is biologically plausible and that there is currently no evidence to suggest pembrolizumab will differ from ipilimumab in this respect. However, it emphasised that there was not enough clinical evidence to directly support this conclusion. The Committee concluded that pembrolizumab is likely to provide improved clinical effectiveness compared with ipilimumab in the short term, but that the long‑term benefits of pembrolizumab are highly uncertain. The Committee considered that the choice of treatment should be made on an individual basis, taking into account the potential risks and benefits of each treatment.
The Committee discussed the adverse effects associated with pembrolizumab. The Committee heard about the experiences of people with melanoma and clinicians treating them, which suggested that pembrolizumab is often better tolerated than ipilimumab. It heard that pembrolizumab causes less‑severe adverse effects and leads to fewer hospitalisations. The Committee considered that although evidence from KEYNOTE‑006 suggested that pembrolizumab was better tolerated than ipilimumab, the difference was not as dramatic as the individual experiences reported by the experts. It did, however, note that a higher dose (10 mg/kg) was used in the trial, and that this dose might be associated with greater toxicity than the licensed 2‑mg/kg dose. The Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.
The Committee considered the clinical effectiveness of pembrolizumab compared with dabrafenib and vemurafenib. The Committee noted that there was no direct clinical trial evidence comparing pembrolizumab with dabrafenib or vemurafenib. The company had carried out a network meta‑analysis, but the Committee considered that this had a number of methodological flaws. The clinical experts indicated that in clinical practice dabrafenib and vemurafenib are not considered to have different effectiveness and are broadly interchangeable. The Committee understood that the choice between pembrolizumab and dabrafenib or vemurafenib may be made partly on clinical grounds, taking into account disease progression and the preferences of the person having treatment. The Committee considered that the company's meta‑analysis did not provide robust evidence to compare pembrolizumab with dabrafenib and vemurafenib; it therefore concluded that the effectiveness of pembrolizumab compared with dabrafenib and vemurafenib is highly uncertain, and there is not enough evidence to reliably assess their comparative effectiveness. The Committee reiterated that people with melanoma and clinicians should discuss the potential risks and benefits of each treatment when considering therapy options.
# Cost effectiveness
The Committee considered the company's model, which compared pembrolizumab with ipilimumab in BRAF mutation‑negative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutation‑positive disease, for people with advanced (unresectable or metastatic) melanoma that had not been previously treated with ipilimumab. The Committee considered that the Evidence Review Group (ERG) had identified a number of important uncertainties in the economic modelling, and it expressed concerns about some of the company's assumptions. In particular, it highlighted that:
The model results were strongly influenced by extrapolated survival benefits after 12 months. However, there were potential issues with the methods of extrapolation, as highlighted by the ERG (see section 3.12); in particular, the Committee noted the ERG's view that the proportional hazards assumption was not appropriate, there were limitations in the use of data from Schadendorf et al. (2015) and Balch et al. (2001), and the modelled overall survival was consequently not plausible.
The results for dabrafenib and vemurafenib were highly uncertain because of the substantial uncertainty in the comparative clinical effectiveness of these treatments (see section 4.7).
The predicted total costs associated with adverse effects seemed low given the number of events in clinical trials; these costs were not plausible and were unlikely to reflect the costs in clinical practice.
The Committee reviewed the exploratory analyses that the ERG presented to address some of its concerns about the company's modelling (see section 3.13). The Committee noted that the ERG's exploratory analyses, combined, decreased the cost effectiveness of pembrolizumab. It understood that the ERG's scenario analyses primarily aimed to 'stress‑test' the model, and considered that the second scenario (in which progression‑free survival was extended by 6 years for some people; see section 3.13) was at the upper end of the plausible range for the cost‑effectiveness estimate. The Committee concluded that there were a number of uncertainties in the economic modelling, but considered that the company's and ERG's analyses provided sufficient information on which to base a decision.
Having reviewed the company's base case, the scenario and sensitivity analyses, and the exploratory analyses from the ERG, and taking into account all 4 patient access schemes, the Committee concluded that the most plausible incremental cost‑effectiveness ratios (ICERs) for pembrolizumab (compared with ipilimumab in BRAF mutation‑negative disease, and with ipilimumab, dabrafenib and vemurafenib in BRAF mutation‑positive disease) were less than £50,000 per quality‑adjusted life year (QALY) gained. The exact ICERs are confidential and cannot be reported here, because this could allow the discounts in the patient access schemes for ipilimumab, dabrafenib and vemurafenib to be back‑calculated.
The Committee discussed the innovative aspects of pembrolizumab. It noted that the company stated that pembrolizumab is innovative because it has a novel mechanism of action and is expected to provide a durable response for a significant number of people with a high unmet need. The Committee understood that an improved tolerability profile of pembrolizumab compared with ipilimumab may be valuable for some people with melanoma, although it recalled that the benefit in the trial was not as dramatic as the individual experiences reported by the experts (see section 4.6). It also noted that a long‑term survival benefit, similar to ipilimumab, had not yet been confirmed. The Committee concluded that pembrolizumab is innovative, but it could not identify any specific health‑related benefits that had not been captured in the QALY calculation.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee considered that the life expectancy of people with advanced melanoma that has not previously been treated with ipilimumab is short. It understood that the median survival for people with previously untreated melanoma that is treated with ipilimumab, dabrafenib or vemurafenib ranges from about 14 to 20 months. The Committee considered that the extension to life offered by pembrolizumab was somewhat uncertain. It highlighted that the median overall survival was not reached in the KEYNOTE‑006 trial, so the estimates of survival gain were dependent on extrapolation. However, the Committee noted that the estimates for overall survival gain presented by the company and the ERG were consistently greater than 3 months. It therefore concluded that pembrolizumab was likely to provide a survival gain of at least 3 months. Although this is subject to some uncertainty, the Committee considered that it was plausible, objective and robust enough for this criterion to be met. The Committee noted that the company estimated the population for which pembrolizumab is indicated to be about 1300 people, and concluded that this represented a small patient population. The Committee therefore concluded that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.
Taking into account the most plausible ICERs, the uncertainties in the clinical and cost‑effectiveness evidence and the supplementary advice for appraising life‑extending, end‑of‑life treatments, the Committee concluded that, on balance, pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab.
The Committee was aware of NICE's position statement about the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism. It acknowledged 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of pembrolizumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of pembrolizumab for treating advanced melanoma that has not been previously treated with ipilimumab.
# Summary of Appraisal Committee's key conclusions
TA366
Appraisal title: Pembrolizumab for advanced melanoma not previously treated with ipilimumab
Section
Key conclusion
Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab, in adults, when the company provides pembrolizumab with the discount agreed in the patient access scheme.
Pembrolizumab is likely to provide improved short‑term clinical effectiveness and a better tolerability profile compared with ipilimumab. The long‑term benefits compared with ipilimumab and the effectiveness compared with dabrafenib and vemurafenib are highly uncertain.
The most plausible incremental cost‑effectiveness ratios (ICERs) were less than £50,000 per quality‑adjusted life year (QALY) gained.
The Committee concluded that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee heard from the patient experts that melanoma has a major effect on people's health and quality of life, and that having a choice of treatments would be particularly valuable to people with this condition.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?
The Committee noted that pembrolizumab provided significant improvements in progression‑free survival, overall survival and overall response rates, and a better tolerability profile, compared with ipilimumab.
The company stated that pembrolizumab is innovative because it has a novel mechanism of action and is expected to provide a durable response for a significant number of people with a high unmet need. The Committee concluded that pembrolizumab is innovative.
What is the position of the treatment in the pathway of care for the condition?
This appraisal considered pembrolizumab for melanoma that had not been previously treated with ipilimumab.
The Committee heard that pembrolizumab would be considered for more people than just those who, in the past, would have had treatment with ipilimumab, and concluded that ipilimumab, dabrafenib and vemurafenib were appropriate comparators.
Adverse reactions
The most common adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue.
The Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The company presented clinical‑effectiveness evidence for pembrolizumab from 2 clinical trials: KEYNOTE‑006 and KEYNOTE‑001.
The Evidence Review Group (ERG) stated that KEYNOTE‑006 was well designed and well conducted, but noted 3 key concerns about the trial – the dosage of pembrolizumab, the immature survival data and the maximum treatment duration.
Relevance to general clinical practice in the NHS
The Committee noted that the dosage of pembrolizumab in KEYNOTE‑006 was not the same as the marketing authorisation. It understood that the percentage of people with BRAF mutation‑positive melanoma in this trial was likely to reflect clinical practice. The Committee concluded that the clinical‑effectiveness evidence presented was broadly generalisable to clinical practice in the NHS.
Uncertainties generated by the evidence
The Committee identified 4 key uncertainties:
the optimum duration of treatment with pembrolizumab
the long‑term benefits of pembrolizumab compared with ipilimumab
the effectiveness of pembrolizumab compared with dabrafenib and vemurafenib
the extension to life offered by pembrolizumab.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No subgroups were specified in the scope.
Subgroup analyses in KEYNOTE‑006, based on demographic and clinical characteristics, suggested that the treatment effect was generally consistent across subgroups.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
In KEYNOTE‑006, pembrolizumab was associated with statistically significant increases in progression‑free survival, overall survivaland overall response rate, compared with ipilimumab.
The Committee noted that the estimated overall survival gain was consistently greater than 3 months.
The evidence was based on a limited duration of follow‑up and the survival data were immature. The Committee considered that the long‑term benefits of pembrolizumab were highly uncertain.
, table 1, 4.13, 4.5
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered the company's model, which compared pembrolizumab with ipilimumab, vemurafenib and dabrafenib, in people with advanced (unresectable or metastatic) melanoma that had not been previously treated with ipilimumab.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee considered that the ERG had identified a number of important uncertainties in the economic modelling, and it expressed concerns about some of the company's assumptions:
extrapolated survival benefit
clinical effectiveness of pembrolizumab compared with dabrafenib and vemurafenib
costs associated with adverse events.
Incorporation of health‑related quality‑of‑life benefits and utility values
Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?
Utility values were estimated using EuroQol EQ‑5D data from KEYNOTE 006, by assuming that quality of life decreases as people approach the last months of life. The utility scores decreased from 0.82, for people who were more than 360 days before death, to 0.33 for people in the 30 days before death.
The ERG considered that there were important limitations in the estimation of utility, because of the use of EQ‑5D data based on patients from all regions and the assumption that utility did not change when disease progressed.
The Committee could not identify any specific health‑related benefits that had not been captured in the calculation of quality‑adjusted life years (QALYs).
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroups were considered.
What are the key drivers of cost effectiveness?
In a deterministic sensitivity analysis, the model results were most sensitive to the extrapolation of progression‑free survival for pembrolizumab. The company also presented 33 scenario analyses, and stated that the cost effectiveness was robust to most sources of uncertainty.
The ERG considered that the key factors affecting results of the model were drug costs, duration of treatment and overall survival.
Most likely cost‑effectiveness estimate (given as an ICER)
The Committee concluded that the most plausible ICERs for pembrolizumab (compared with ipilimumab, dabrafenib and vemurafenib) were less than £50,000 per QALY gained. The exact ICERs are confidential and cannot be reported here.
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a patient access scheme, in which pembrolizumab is provided with a simple discount to its list price.
The ERG presented analyses incorporating the confidential patient access schemes for pembrolizumab, ipilimumab, dabrafenib and vemurafenib. The Committee took into account all 4 patient access schemes.
End‑of‑life considerations
The Committee understood that the median survival for people with previously untreated melanoma is 14–20 months.
It considered that the extension to life offered by pembrolizumab was somewhat uncertain, but the estimates presented were consistently greater than 3 months.
It noted that the population for which pembrolizumab is indicated is small.
The Committee concluded that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.
Equalities considerations and social value judgements
No equality issues were identified.
–# Review of guidance
The guidance on this technology will be considered for review 3 years after publication. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveNovember 2015
|
{'Guidance': 'Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab, in adults, only when the company provides pembrolizumab in line with the commercial access agreement with NHS England.', 'The technology': "Pembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody. It acts on the programmed cell death protein‑1 immune‑checkpoint receptor pathway, blocking its interaction with ligand on the tumour cells. This allows reactivation of anti‑tumour immunity. It has a marketing authorisation in the UK as monotherapy 'for the treatment of advanced (unresectable or metastatic) melanoma in adults'. Pembrolizumab is administered intravenously for 30\xa0minutes at a dose of 2\xa0mg/kg every 3\xa0weeks until disease progression or unacceptable toxicity.\n\nThe most common (occurring in 1\xa0in\xa010 people or more) adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue. The most serious adverse reactions were immune‑related adverse reactions and severe infusion‑related reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe acquisition cost of pembrolizumab is £1,315 per 50‑mg vial (excluding VAT; company's submission). The pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in November 2015, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.", "The company's submission": "The Appraisal Committee (section\xa07) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the Evidence Review Group (ERG; section\xa08).\n\n# Clinical effectiveness\n\nThe company presented clinical‑effectiveness evidence for pembrolizumab from 2\xa0clinical trials: KEYNOTE‑006 and KEYNOTE‑001. KEYNOTE‑006 was a randomised, international, multicentre, phase\xa0III trial of pembrolizumab 10\xa0mg/kg every 2\xa0weeks (n=279) or every 3\xa0weeks (n=277), continued until disease progression or unacceptable toxicity, compared with ipilimumab 3\xa0mg/kg every 3 weeks, continued for 4\xa0doses (n=278). Results were analysed at 2\xa0planned interim analyses, after 6\xa0months of follow‑up (September 2014) and after 9–12\xa0months of follow‑up (March 2015). After the second interim analysis the study was stopped, because the primary endpoint had been met. KEYNOTE‑001 was a combined phase\xa0I and II study. Evidence was presented from a sub‑study of this trial, referred to as KEYNOTE‑001 part\xa0D: this was a randomised, open‑label study comparing pembrolizumab 2\xa0mg/kg every 3\xa0weeks (n=51; the licensed dose) with 10\xa0mg/kg every 3\xa0weeks (n=52). Both KEYNOTE‑006 and KEYNOTE‑001 part\xa0D included people with advanced melanoma, with or without BRAF mutations, who had not had ipilimumab before (previous treatment with 1\xa0or\xa02 other therapies was permitted).\n\nIn KEYNOTE‑006, pembrolizumab was associated with statistically significant increases in both progression‑free survival (first interim analysis) and overall survival (second interim analysis), compared with ipilimumab (table 1). Pembrolizumab was also associated with statistically significantly higher overall response rates compared with ipilimumab (table 1; p<0.001). Pre‑specified subgroup analyses based on demographic and clinical characteristics suggested that the treatment effect associated with pembrolizumab was generally consistent across subgroups, although some variations in effect based on the line of therapy and the expression of ligands for the 'programmed death\xa01' protein (termed 'PD‑L1 status') were seen. No significant differences in clinical effectiveness between pembrolizumab doses (that is, 10\xa0mg/kg every 3\xa0weeks, 10\xa0mg/kg every 2\xa0weeks or 2\xa0mg/kg every 3 weeks) were seen in either KEYNOTE‑006 or KEYNOTE‑001 part D.\n\n## Table 1 Clinical‑effectiveness outcomes in KEYNOTE‑006\n\n\n\nPembrolizumab\n\nIpilimumab\n\nn=278\n\nmg/kg every 3\xa0weeks\n\nn=277\n\nmg/kg every 2\xa0weeks\n\nn=279\n\nProgression‑free survival (interim analysis\xa01)\n\nMedian: months (95% CI)\n\n(2.9–6.9)\n\n(3.4–6.9)\n\n(2.8–2.9)\n\nHazard ratio versus ipilimumab (95% CI)\n\n(0.47–0.72)\n\np<0.00001\n\n(0.46–0.72)\n\np<0.00001\n\n\n\nOverall survival (interim analysis\xa02)\n\nOverall survival at 6\xa0months1: % (95% CI)\n\n(82.7–90.7)\n\n(80.0–88.5)\n\n(68.7–79.4)\n\nHazard ratio versus ipilimumab (95% CI)\n\n(0.52–0.90)\n\np=0.00358\n\n(0.47–0.83)\n\np=0.00052\n\n\n\nOverall response (interim analysis\xa01)\n\nOverall response rate: % (95% CI)\n\n%(27.4–38.7)\n\n%(28.2–39.6)\n\n%(8.3–16.3)\n\nAbbreviations: CI, confidence interval; n, number of patients.1Median overall survival not reached.\n\nThe company presented adverse event data from KEYNOTE‑006, and stated that pembrolizumab was generally well tolerated. It was associated with a similar number of adverse events, but fewer drug‑related grade\xa03–5\xa0adverse events, serious adverse events, drug‑related serious adverse events and adverse events leading to withdrawal from the trial, compared with ipilimumab (table\xa02). Pembrolizumab was also associated with fewer high‑grade, immune‑related adverse events than ipilimumab, and fewer people in the pembrolizumab groups withdrew from the trial because of immune‑related adverse events (table\xa02). The most common treatment‑related adverse events with both pembrolizumab and ipilimumab were fatigue, diarrhoea, rash and itching. The most common grade\xa03–5 immune‑related adverse events associated with pembrolizumab were colitis and hepatitis.\n\n## Table 2 Summary of adverse events in KEYNOTE‑006\n\n\n\nIpilimumab\n\nPembrolizumab (both arms combined)\n\nn\n\n%\n\nn\n\n%\n\nn\n\n\n\n\n\nPatients with 1 or more AE\n\n\n\n%\n\n\n\n%\n\nDrug‑related grade\xa03–5 AE\n\n\n\n%\n\n\n\n%\n\nSerious AE\n\n\n\n%\n\n\n\n%\n\nDrug‑related serious AE\n\n\n\n%\n\n\n\n%\n\nStopped because of an AE\n\n\n\n%\n\n\n\n%\n\nImmune‑related AEs\n\nPatients with\xa01 or more AE\n\n\n\n%\n\n\n\n%\n\nGrade\xa03–5 AE\n\n\n\n%\n\n\n\n%\n\nStopped because of an AE\n\n\n\n%\n\n\n\n%\n\nAbbreviations: AE, adverse event; n, number of patients.\n\nThe company compared the clinical effectiveness of pembrolizumab with ipilimumab, dabrafenib, vemurafenib and dacarbazine in a series of network meta‑analyses. The analyses were performed in a Bayesian framework using a fixed‑effects model, and were based on data from KEYNOTE‑006 and 5\xa0other trials identified in the systematic review. The company presented results from a series of analyses, including 4\xa0alternative network scenarios, 4\xa0time points, and separate analyses of pembrolizumab as either a first‑ or second‑line treatment. It stated that, for the outcomes of progression‑free survival and overall survival, pembrolizumab appeared to have a similar efficacy to vemurafenib and dabrafenib, in people who have had no previous treatment. For example, in network scenario '3b' at the 6‑month time point, pembrolizumab was associated with a hazard ratio for progression‑free survival of 0.80 (95% credible interval [CrI] 0.32–1.92) compared with dabrafenib, and 0.67 (95% CrI 0.37–1.14) compared with vemurafenib. The corresponding hazard ratios for overall survival were 0.96 (95% CrI 0.46–1.93) and 0.75 (95% CrI 0.40–1.34), compared with dabrafenib and vemurafenib respectively. The company highlighted that pembrolizumab was associated with greater progression‑free survival and overall survival than both ipilimumab (scenario\xa03b, 6‑month timepoint: hazard ratio for progression‑free survival 0.45, 95% CrI 0.33–0.62; hazard ratio for overall survival 0.59, 95% CrI 0.41–0.84) and dacarbazine (scenario 3b, 6‑month timepoint: hazard ratio for progression‑free survival 0.36, 95% CrI 0.21–0.59; hazard ratio for overall survival 0.54, 95% CrI 0.30–0.91) for previously untreated disease, and was at least as effective as ipilimumab for people who have had 1\xa0previous line of treatment (scenario 3b, 6‑month timepoint: hazard ratio for progression‑free survival 0.74, 95% CrI 0.48–1.12; hazard ratio for overall survival 0.80, 95% CrI 0.52–1.22).\n\n# Cost effectiveness\n\nThe company presented an economic model comparing pembrolizumab (2\xa0mg/kg every 3\xa0weeks) with ipilimumab, dabrafenib and vemurafenib. The model comprised 3\xa0states: pre‑progression, post‑progression and death. The model used a cycle length of 1\xa0week and a time horizon of 30\xa0years (lifetime), taking the perspective of the NHS and personal social services, with costs and benefits discounted at a rate of 3.5% per year. The model included costs associated with melanoma treatment, costs in each health state (based on a study of resource use for melanoma treatment in the UK), management of adverse events and complications, and care at the end of life.\n\nThe proportion of people in the each health state was based on estimates of progression‑free survival and overall survival:\n\nProgression‑free survival was estimated using Kaplan–Meier curves from the KEYNOTE‑006, BRIM‑3 and BREAK‑3 clinical trials, extrapolated to 30\xa0years based on a Gompertz model (for pembrolizumab and ipilimumab) or a monthly risk of progression taken from NICE's technology appraisal guidance on ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (for dabrafenib and vemurafenib).\n\nOverall survival was estimated by initially using Kaplan–Meier data from clinical trials (for the first 50–60\xa0weeks of the model), followed by published mortality risks based on data from a pooled analysis of long‑term survival data for people with melanoma treated with ipilimumab (Schadendorf et al. ; applied to pembrolizumab and ipilimumab) and NICE's technology appraisal guidance on ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (applied to dabrafenib and vemurafenib). Long‑term survival was based on mortality rates in a published registry study (Balch et al. ).\n\nUtility values were estimated using EuroQol EQ‑5D data from KEYNOTE‑006, by assuming that quality of life decreases as people approach the last months of life. The utility scores decreased from 0.82, for people who were more than 360\xa0days before death, to 0.33 for people in the 30\xa0days before death.\n\nThe company's base‑case results are summarised in table\xa03. These results were based on the discount in the patient access scheme for pembrolizumab and the list prices for all other drugs, and therefore were not used for decision‑making; they are included here for illustration only. Results from the company's model including the patient access schemes for pembrolizumab and all 3\xa0comparators were presented by the ERG; these results are commercial in confidence and cannot be reported here.\n\n## Table 3 Results of the company's base‑case analysis (including pembrolizumab patient access scheme, list price for all comparators; not used for decision‑making)\n\nBRAF mutation‑positive disease\n\n\n\nTotal cost\n\nTotal LYG\n\nTotal QALYs\n\nIncr cost\n\nIncr LYG\n\nIncr QALYs\n\nICER (£/QALY)\n\nDabrafenib\n\n£71,029\n\n\n\n\n\n‑\n\n‑\n\n‑\n\n‑\n\nPembrolizumab\n\n£76,689\n\n\n\n\n\n£5660\n\n\n\n\n\n£5852\n\nVemurafenib\n\n£83,384\n\n\n\n\n\n£6695\n\n−2.34\n\n−1.40\n\nDominated\n\nIpilimumab\n\n£97,873\n\n\n\n\n\n£21,185\n\n−0.71\n\n−0.44\n\nDominated\n\nBRAF mutation‑negative disease\n\n\n\nTotal cost\n\nTotal LYG\n\nTotal QALYs\n\nIncr cost\n\nIncr LYG\n\nIncr QALYs\n\nICER (£/QALY)\n\nPembrolizumab\n\n£76,689\n\n\n\n\n\n‑\n\n‑\n\n‑\n\n‑\n\nIpilimumab\n\n£97,873\n\n\n\n\n\n£21,185\n\n−0.71\n\n−0.44\n\nDominated\n\nAbbreviations: ICER, incremental cost‑effectiveness ratio; Incr, incremental; LYG, life years gained; QALYs, quality‑adjusted life years.\n\nDominated: provides fewer QALYs at greater cost than the comparator.\n\nIn a deterministic sensitivity analysis, the model results for all comparisons were most sensitive to the extrapolation of progression‑free survival for pembrolizumab (shape and treatment effect in the Gompertz model). In the probabilistic sensitivity analysis, the total costs associated with pembrolizumab increased by £10,996 compared with the deterministic results, and the total QALYs decreased by 0.02, whereas the results for ipilimumab, dabrafenib and vemurafenib did not change substantially. The company stated that the change in the results for pembrolizumab was caused by uncertainty in the extrapolation of progression‑free survival from the KEYNOTE‑006 trial, which led to a small number of iterations with high treatment costs. The company also presented 33\xa0scenario analyses, to explore the effects of key assumptions on the model results. These analyses explored the effects of varying the progression‑free survival and overall survival estimates, time horizon, utility estimates, treatment and terminal care costs, treatment duration for pembrolizumab, and the discounting rate. The company stated that these analyses showed that the cost effectiveness of pembrolizumab was robust to most sources of uncertainty.\n\n# ERG comments\n\nThe ERG stated that KEYNOTE‑006 was well designed and well conducted. It considered that the population was representative of patients seen in the UK NHS, and patient characteristics were well balanced across treatment groups. However, it noted 3\xa0key concerns about this trial:\n\nThe dosage of pembrolizumab (10\xa0mg/kg every 3\xa0weeks) did not match the licensed dose (2\xa0mg/kg every 3\xa0weeks). The ERG noted that the European Public Assessment Report (EPAR) states that no differences between the licensed dose and the studied dose are to be expected. Although this was largely based on data from patients who had previous therapy with ipilimumab, the ERG cautiously accepted this conclusion.\n\nThe trial was stopped early, so the overall survival data were immature. The ERG was unclear whether the true impact of pembrolizumab on survival will be identified.\n\nThe trial specified a maximum treatment duration of 24\xa0months. The ERG considered that the effect of this rule on clinical outcomes is unknown.\n\nThe ERG considered that the clinical assumptions used in the company's network meta‑analysis were reasonable, but the methods of the analysis were flawed. It stated that the populations in the control arms were not comparable, the analysis did not correctly reflect changing hazard ratios over time, and the methods used to adjust for treatment switching in the key trial for vemurafenib may not have been adequate. The ERG considered that the network meta‑analysis did not provide valid treatment effect estimates, particularly for pembrolizumab compared with dabrafenib and vemurafenib.\n\nThe ERG's critique of the company's economic model suggested that the model was generally consistent with the NICE reference case. However, it highlighted that the structure of the model led to counterintuitive results – specifically, that pembrolizumab would become less cost effective if its effectiveness at delaying disease progression increased. The ERG stated that this was because delaying disease progression was associated with additional treatment costs but no increase in quality of life. In addition, the ERG expressed concerns about the modelling of overall survival, progression‑free survival, treatment costs and quality of life. It considered that there were limitations in the methods of extrapolation for both progression‑free survival and overall survival. In particular, for overall survival, the ERG stated that there was a risk of selection bias in the data taken from the study by Schadendorf et al. (2015), and there were limitations in the algorithm used to adjust for patient characteristics and the long‑term survival data (from Balch et al. ) used to project long‑term survival. The ERG highlighted that the company's estimates for mortality risk in people treated with pembrolizumab changed erratically during the course of the model and were not clinically plausible. For the analysis of progression‑free survival, the ERG noted limitations including the use of centrally assessed progression, the company's choice of censoring rule, inappropriate use of the proportional hazards assumption and incomplete adjustment for differences in patient characteristics between the dabrafenib, vemurafenib and pembrolizumab trials. The ERG described concerns about the duration of treatment, the weight distribution of the population, and the administration costs of ipilimumab, which meant that the costs of treatment were not accurately estimated. It considered that there were important limitations in the estimation of utility, because of the use of EQ‑5D data based on patients from all regions (rather than UK or European patients only) and the assumption that utility did not change when disease progressed. The ERG highlighted that 75–90% of the cost differences between treatments in the company's model could be attributed to direct treatment costs, and that 87.5% of the health gain with pembrolizumab occurred after 12\xa0months. It therefore considered that the key factors affecting results of the model were drug costs, duration of treatment and overall survival.\n\nThe ERG presented a series of exploratory analyses to address their principal concerns about the company's model (see section\xa03.12). In particular, it changed the modelling of overall survival (using methods developed for NICE's technology appraisal guidance on ipilimumab for previously treated advanced (unresectable or metastatic) melanoma), progression‑free survival and treatment duration, and amended the treatment costs and utility scores. It also presented 2\xa0scenario analyses, in which the duration of progression‑free survival was extended by 3\xa0or 6\xa0years for people whose disease had not progressed after 2\xa0years; the ERG presented results for all analyses using the patient access scheme price for pembrolizumab and the list prices for ipilimumab, dabrafenib and vemurafenib (summarised below) and also using patient access schemes for all drugs (commercial in confidence; cannot be reported here). The ERG's amendments, combined, increased the costs associated with pembrolizumab by £6593 and reduced the total QALYs by 0.18. The amendments also reduced the costs and QALYs associated with ipilimumab (by £2558 and 0.17 respectively), increased the costs and QALYs for vemurafenib (by £7027 and 0.5 respectively), and increased the costs but reduced the QALYs for dabrafenib (by £3,238 and 0.02 respectively). Both of the scenario analyses substantially increased the costs associated with pembrolizumab, but had no effect on the other treatments.\n\nFull details of all the evidence are available.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab and the value placed on the benefits of pembrolizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed the current management of advanced melanoma in the NHS, and the potential place of pembrolizumab in the treatment pathway. It was aware of the disparity between the wording of the marketing authorisation for pembrolizumab and the definition of the population in the scope; it understood that this appraisal specifically considered pembrolizumab for melanoma that had not been previously treated with ipilimumab, and that ipilimumab‑treated melanoma was considered in a separate appraisal. The Committee understood that ipilimumab is the most common treatment option for advanced (unresectable or metastatic) melanoma that does not have a BRAF V600 mutation (BRAF mutation‑negative or 'wild type' disease). For melanoma with BRAF V600 mutations (BRAF mutation‑positive disease), the Committee heard from the clinical experts that the treatment strategy has changed in recent years. In the past, a clear distinction was made between rapidly progressing tumours (which would usually be treated with a BRAF inhibitor – that is, dabrafenib or vemurafenib), and more slowly progressing disease (which may be treated with an immunotherapy agent such as ipilimumab). More recently, the long survival benefit shown in a percentage of patients treated with ipilimumab (based on 5‑year overall survival data) has led to an increasing emphasis on immunotherapy. The Committee also heard from the clinical experts that pembrolizumab appeared to have a faster onset of action and higher response rate than ipilimumab, and may also be more suitable for treating higher‑volume disease. Consequently, although some people with rapidly progressing BRAF mutation‑positive melanoma will continue to have BRAF inhibitors as a first‑line treatment, the clinical experts expected that pembrolizumab would be considered for more people than just those who, in the past, would have had treatment with ipilimumab. The Committee was aware that dacarbazine is now used only after the other available treatments, if at all, because it has not been shown to improve survival compared with supportive care. The Committee concluded that ipilimumab, dabrafenib and vemurafenib were appropriate comparators for people with advanced melanoma that has not previously been treated with ipilimumab.\n\nThe Committee considered how pembrolizumab might be used in clinical practice, and in particular whether treatment may be limited to a fixed duration. It noted that the KEYNOTE‑006 trial protocol specified a maximum treatment duration of 2\xa0years, and heard from the company that although the 2‑year point had not yet been reached, the maximum treatment duration will be adhered to as follow‑up continues. The Committee understood that the trial had been unblinded early, after which people in the ipilimumab group could start treatment with pembrolizumab. The Committee heard from the clinical experts that there is no evidence to indicate the optimum duration of treatment with pembrolizumab. The clinical experts considered the likely treatment duration in clinical practice and stated that if a maximum duration were specified, consideration should be given to whether pembrolizumab could be restarted if the disease progressed. The Committee was aware that in KEYNOTE‑006, people could stop treatment if they had a complete response and could restart treatment if their disease progressed, but that there was limited evidence on the clinical effectiveness of this approach. The Committee highlighted that the marketing authorisation for pembrolizumab specifies that treatment should continue until disease progression or unacceptable toxicity. The Committee concluded that, consistent with the limited evidence available, it was appropriate to appraise pembrolizumab in line with its marketing authorisation. However, it appreciated that there is uncertainty about the optimum duration of treatment with pembrolizumab.\n\nThe Committee discussed the clinical needs of people with advanced melanoma. It heard from the patient experts that melanoma has a major effect on people's health and quality of life. Having a choice of treatments would be particularly valuable to people with this condition, allowing them and their doctors to choose treatments that take into account their individual needs and preferences and giving them a feeling of more control over their condition. For example, when considering different treatment options, some people might take into account their preferences for oral or intravenous administration, fixed‑duration or continuous treatment, or different side‑effect profiles. The Committee heard from the patient experts that treatment with ipilimumab can be associated with severe side effects, and this may be a major consideration. The Committee concluded that the availability of an effective new treatment option with an acceptable tolerability profile would be valuable for people with advanced melanoma.\n\nThe Committee considered the generalisability of the KEYNOTE‑006 trial. It understood that the percentage of people with BRAF mutation‑positive melanoma in this trial (35%) was likely to reflect the use of pembrolizumab if it becomes established in clinical practice. The Committee noted that the dosage of pembrolizumab in KEYNOTE‑006 was 10\xa0mg/kg every 2\xa0or 3\xa0weeks, but that the dosage specified in the marketing authorisation is 2\xa0mg/kg every 3\xa0weeks. It heard from the clinical experts that they expect the 2‑mg/kg dose to be as effective as 10\xa0mg/kg, and there is no evidence for a dose–response effect over this range. The Committee reviewed evidence from the KEYNOTE‑001 trial comparing the 10‑mg/kg and 2‑mg/kg doses, and considered that it had not seen any evidence to suggest a difference in effectiveness. The Committee concluded that the clinical‑effectiveness evidence presented was broadly generalisable to clinical practice in the NHS.\n\nThe Committee considered the results of the KEYNOTE‑006 trial. It noted that pembrolizumab provided significant improvements in progression‑free survival, overall survival and overall response rates compared with ipilimumab. However, it noted that the trial was stopped early (because the primary endpoints had been met). Consequently, the evidence available was based on a limited duration of follow‑up and the overall survival data were immature (that is, fewer than half of the people in the trial had died). It therefore considered that the long‑term benefits of pembrolizumab were very uncertain. The Committee acknowledged that further survival data were expected to be available soon, but that there were no data beyond 2\xa0years at the time of the appraisal. The Committee heard from the clinical experts that pembrolizumab was expected to provide a long‑term survival benefit consistent with that shown in the ipilimumab trials. It recognised that this expectation is biologically plausible and that there is currently no evidence to suggest pembrolizumab will differ from ipilimumab in this respect. However, it emphasised that there was not enough clinical evidence to directly support this conclusion. The Committee concluded that pembrolizumab is likely to provide improved clinical effectiveness compared with ipilimumab in the short term, but that the long‑term benefits of pembrolizumab are highly uncertain. The Committee considered that the choice of treatment should be made on an individual basis, taking into account the potential risks and benefits of each treatment.\n\nThe Committee discussed the adverse effects associated with pembrolizumab. The Committee heard about the experiences of people with melanoma and clinicians treating them, which suggested that pembrolizumab is often better tolerated than ipilimumab. It heard that pembrolizumab causes less‑severe adverse effects and leads to fewer hospitalisations. The Committee considered that although evidence from KEYNOTE‑006 suggested that pembrolizumab was better tolerated than ipilimumab, the difference was not as dramatic as the individual experiences reported by the experts. It did, however, note that a higher dose (10\xa0mg/kg) was used in the trial, and that this dose might be associated with greater toxicity than the licensed 2‑mg/kg dose. The Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.\n\nThe Committee considered the clinical effectiveness of pembrolizumab compared with dabrafenib and vemurafenib. The Committee noted that there was no direct clinical trial evidence comparing pembrolizumab with dabrafenib or vemurafenib. The company had carried out a network meta‑analysis, but the Committee considered that this had a number of methodological flaws. The clinical experts indicated that in clinical practice dabrafenib and vemurafenib are not considered to have different effectiveness and are broadly interchangeable. The Committee understood that the choice between pembrolizumab and dabrafenib or vemurafenib may be made partly on clinical grounds, taking into account disease progression and the preferences of the person having treatment. The Committee considered that the company's meta‑analysis did not provide robust evidence to compare pembrolizumab with dabrafenib and vemurafenib; it therefore concluded that the effectiveness of pembrolizumab compared with dabrafenib and vemurafenib is highly uncertain, and there is not enough evidence to reliably assess their comparative effectiveness. The Committee reiterated that people with melanoma and clinicians should discuss the potential risks and benefits of each treatment when considering therapy options.\n\n# Cost effectiveness\n\nThe Committee considered the company's model, which compared pembrolizumab with ipilimumab in BRAF mutation‑negative disease, and with ipilimumab, vemurafenib and dabrafenib in BRAF mutation‑positive disease, for people with advanced (unresectable or metastatic) melanoma that had not been previously treated with ipilimumab. The Committee considered that the Evidence Review Group (ERG) had identified a number of important uncertainties in the economic modelling, and it expressed concerns about some of the company's assumptions. In particular, it highlighted that:\n\nThe model results were strongly influenced by extrapolated survival benefits after 12\xa0months. However, there were potential issues with the methods of extrapolation, as highlighted by the ERG (see section\xa03.12); in particular, the Committee noted the ERG's view that the proportional hazards assumption was not appropriate, there were limitations in the use of data from Schadendorf et al. (2015) and Balch et al. (2001), and the modelled overall survival was consequently not plausible.\n\nThe results for dabrafenib and vemurafenib were highly uncertain because of the substantial uncertainty in the comparative clinical effectiveness of these treatments (see section\xa04.7).\n\nThe predicted total costs associated with adverse effects seemed low given the number of events in clinical trials; these costs were not plausible and were unlikely to reflect the costs in clinical practice.\n\nThe Committee reviewed the exploratory analyses that the ERG presented to address some of its concerns about the company's modelling (see section\xa03.13). The Committee noted that the ERG's exploratory analyses, combined, decreased the cost effectiveness of pembrolizumab. It understood that the ERG's scenario analyses primarily aimed to 'stress‑test' the model, and considered that the second scenario (in which progression‑free survival was extended by 6\xa0years for some people; see section\xa03.13) was at the upper end of the plausible range for the cost‑effectiveness estimate. The Committee concluded that there were a number of uncertainties in the economic modelling, but considered that the company's and ERG's analyses provided sufficient information on which to base a decision.\n\nHaving reviewed the company's base case, the scenario and sensitivity analyses, and the exploratory analyses from the ERG, and taking into account all 4\xa0patient access schemes, the Committee concluded that the most plausible incremental cost‑effectiveness ratios (ICERs) for pembrolizumab (compared with ipilimumab in BRAF mutation‑negative disease, and with ipilimumab, dabrafenib and vemurafenib in BRAF mutation‑positive disease) were less than £50,000 per quality‑adjusted life year (QALY) gained. The exact ICERs are confidential and cannot be reported here, because this could allow the discounts in the patient access schemes for ipilimumab, dabrafenib and vemurafenib to be back‑calculated.\n\nThe Committee discussed the innovative aspects of pembrolizumab. It noted that the company stated that pembrolizumab is innovative because it has a novel mechanism of action and is expected to provide a durable response for a significant number of people with a high unmet need. The Committee understood that an improved tolerability profile of pembrolizumab compared with ipilimumab may be valuable for some people with melanoma, although it recalled that the benefit in the trial was not as dramatic as the individual experiences reported by the experts (see section\xa04.6). It also noted that a long‑term survival benefit, similar to ipilimumab, had not yet been confirmed. The Committee concluded that pembrolizumab is innovative, but it could not identify any specific health‑related benefits that had not been captured in the QALY calculation.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee considered that the life expectancy of people with advanced melanoma that has not previously been treated with ipilimumab is short. It understood that the median survival for people with previously untreated melanoma that is treated with ipilimumab, dabrafenib or vemurafenib ranges from about 14\xa0to 20\xa0months. The Committee considered that the extension to life offered by pembrolizumab was somewhat uncertain. It highlighted that the median overall survival was not reached in the KEYNOTE‑006 trial, so the estimates of survival gain were dependent on extrapolation. However, the Committee noted that the estimates for overall survival gain presented by the company and the ERG were consistently greater than 3\xa0months. It therefore concluded that pembrolizumab was likely to provide a survival gain of at least 3\xa0months. Although this is subject to some uncertainty, the Committee considered that it was plausible, objective and robust enough for this criterion to be met. The Committee noted that the company estimated the population for which pembrolizumab is indicated to be about 1300\xa0people, and concluded that this represented a small patient population. The Committee therefore concluded that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.\n\nTaking into account the most plausible ICERs, the uncertainties in the clinical and cost‑effectiveness evidence and the supplementary advice for appraising life‑extending, end‑of‑life treatments, the Committee concluded that, on balance, pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab.\n\nThe Committee was aware of NICE's position statement about the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism. It acknowledged 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of pembrolizumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of pembrolizumab for treating advanced melanoma that has not been previously treated with ipilimumab.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA366\n\nAppraisal title: Pembrolizumab for advanced melanoma not previously treated with ipilimumab\n\nSection\n\nKey conclusion\n\nPembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma that has not been previously treated with ipilimumab, in adults, when the company provides pembrolizumab with the discount agreed in the patient access scheme.\n\nPembrolizumab is likely to provide improved short‑term clinical effectiveness and a better tolerability profile compared with ipilimumab. The long‑term benefits compared with ipilimumab and the effectiveness compared with dabrafenib and vemurafenib are highly uncertain.\n\nThe most plausible incremental cost‑effectiveness ratios (ICERs) were less than £50,000 per quality‑adjusted life year (QALY) gained.\n\nThe Committee concluded that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.\n\n, 4.14, 4.5–4.7, 4.10, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee heard from the patient experts that melanoma has a major effect on people's health and quality of life, and that having a choice of treatments would be particularly valuable to people with this condition.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee noted that pembrolizumab provided significant improvements in progression‑free survival, overall survival and overall response rates, and a better tolerability profile, compared with ipilimumab.\n\nThe company stated that pembrolizumab is innovative because it has a novel mechanism of action and is expected to provide a durable response for a significant number of people with a high unmet need. The Committee concluded that pembrolizumab is innovative.\n\n, 4.6, 4.11\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThis appraisal considered pembrolizumab for melanoma that had not been previously treated with ipilimumab.\n\nThe Committee heard that pembrolizumab would be considered for more people than just those who, in the past, would have had treatment with ipilimumab, and concluded that ipilimumab, dabrafenib and vemurafenib were appropriate comparators.\n\n\n\nAdverse reactions\n\nThe most common adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue.\n\nThe Committee concluded that pembrolizumab is likely to offer a better tolerability profile than ipilimumab.\n\n, 4.6\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe company presented clinical‑effectiveness evidence for pembrolizumab from 2\xa0clinical trials: KEYNOTE‑006 and KEYNOTE‑001.\n\nThe Evidence Review Group (ERG) stated that KEYNOTE‑006 was well designed and well conducted, but noted 3\xa0key concerns about the trial – the dosage of pembrolizumab, the immature survival data and the maximum treatment duration.\n\n, 3.10\n\nRelevance to general clinical practice in the NHS\n\nThe Committee noted that the dosage of pembrolizumab in KEYNOTE‑006 was not the same as the marketing authorisation. It understood that the percentage of people with BRAF mutation‑positive melanoma in this trial was likely to reflect clinical practice. The Committee concluded that the clinical‑effectiveness evidence presented was broadly generalisable to clinical practice in the NHS.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee identified 4\xa0key uncertainties:\n\nthe optimum duration of treatment with pembrolizumab\n\nthe long‑term benefits of pembrolizumab compared with ipilimumab\n\nthe effectiveness of pembrolizumab compared with dabrafenib and vemurafenib\n\nthe extension to life offered by pembrolizumab.\n\n, 4.5, 4.7, 4.13\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNo subgroups were specified in the scope.\n\nSubgroup analyses in KEYNOTE‑006, based on demographic and clinical characteristics, suggested that the treatment effect was generally consistent across subgroups.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nIn KEYNOTE‑006, pembrolizumab was associated with statistically significant increases in progression‑free survival, overall survivaland overall response rate, compared with ipilimumab.\n\nThe Committee noted that the estimated overall survival gain was consistently greater than 3\xa0months.\n\nThe evidence was based on a limited duration of follow‑up and the survival data were immature. The Committee considered that the long‑term benefits of pembrolizumab were highly uncertain.\n\n, table 1, 4.13, 4.5\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the company's model, which compared pembrolizumab with ipilimumab, vemurafenib and dabrafenib, in people with advanced (unresectable or metastatic) melanoma that had not been previously treated with ipilimumab.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered that the ERG had identified a number of important uncertainties in the economic modelling, and it expressed concerns about some of the company's assumptions:\n\nextrapolated survival benefit\n\nclinical effectiveness of pembrolizumab compared with dabrafenib and vemurafenib\n\ncosts associated with adverse events.\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nUtility values were estimated using EuroQol EQ‑5D data from KEYNOTE 006, by assuming that quality of life decreases as people approach the last months of life. The utility scores decreased from 0.82, for people who were more than 360\xa0days before death, to 0.33 for people in the 30\xa0days before death.\n\nThe ERG considered that there were important limitations in the estimation of utility, because of the use of EQ‑5D data based on patients from all regions and the assumption that utility did not change when disease progressed.\n\nThe Committee could not identify any specific health‑related benefits that had not been captured in the calculation of quality‑adjusted life years (QALYs).\n\n, 3.12, 4.11\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroups were considered.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nIn a deterministic sensitivity analysis, the model results were most sensitive to the extrapolation of progression‑free survival for pembrolizumab. The company also presented 33\xa0scenario analyses, and stated that the cost effectiveness was robust to most sources of uncertainty.\n\nThe ERG considered that the key factors affecting results of the model were drug costs, duration of treatment and overall survival.\n\n, 3.12\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee concluded that the most plausible ICERs for pembrolizumab (compared with ipilimumab, dabrafenib and vemurafenib) were less than £50,000 per QALY gained. The exact ICERs are confidential and cannot be reported here.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme, in which pembrolizumab is provided with a simple discount to its list price.\n\nThe ERG presented analyses incorporating the confidential patient access schemes for pembrolizumab, ipilimumab, dabrafenib and vemurafenib. The Committee took into account all 4\xa0patient access schemes.\n\n, 3.8, 4.10\n\nEnd‑of‑life considerations\n\nThe Committee understood that the median survival for people with previously untreated melanoma is 14–20\xa0months.\n\nIt considered that the extension to life offered by pembrolizumab was somewhat uncertain, but the estimates presented were consistently greater than 3\xa0months.\n\nIt noted that the population for which pembrolizumab is indicated is small.\n\nThe Committee concluded that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified.\n\n–", 'Review of guidance': 'The guidance on this technology will be considered for review 3\xa0years after publication. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveNovember 2015'}
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Evidence-based recommendations on pembrolizumab (Keytruda) for treating advanced melanoma in adults who have not had ipilimumab.
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Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab
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Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab
Evidence-based recommendations on pembrolizumab (Keytruda) for treating advanced melanoma after disease progression with ipilimumab in adults.
# Guidance
Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in adults only:
after the disease has progressed with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor and
when the company provides pembrolizumab in line with the commercial access agreement with NHS England.# The technology
Pembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody. It acts on the programmed cell death protein‑1 immune checkpoint receptor pathway, blocking its interaction with ligand on the tumour cells. This allows reactivation of anti‑tumour immunity. It has a marketing authorisation in the UK as monotherapy 'for the treatment of advanced (unresectable or metastatic) melanoma in adults'. Previously, pembrolizumab was available in the NHS through the early access to medicines schemes from the UK Medicines and Healthcare products Regulatory Agency. Pembrolizumab is administered intravenously for 30 minutes at a dose of 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.
The most common (occurring in 1 in 10 people or more) adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue. The most serious adverse reactions were immune‑related adverse reactions and severe infusion‑related reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The acquisition cost of pembrolizumab is £1,315 per 50‑mg vial (excluding VAT; company's submission). The pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in October 2015, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.# The company's submission
The Appraisal Committee (section 7) considered evidence submitted by Merck Sharp & Dohme, and a review of this submission by the Evidence Review Group (ERG; section 8).
# Clinical effectiveness
The company's submission focused on the evidence from KEYNOTE‑002, a multicentre randomised controlled trial (including centres in Argentina, US and Europe, although not in the UK). This trial compared pembrolizumab with chemotherapy in people with advanced melanoma who had had at least 2 doses of ipilimumab and whose disease had progressed within 24 weeks of the last ipilimumab dose. People with BRAF mutation‑positive melanomas must have also had treatment with a BRAF inhibitor (vemurafenib or dabrafenib) or a MEK inhibitor (trametinib). People were randomised to chemotherapy chosen by an investigator (paclitaxel plus carboplatin, carboplatin alone, paclitaxel alone, dacarbazine or temozolomide; n=179) according to standard of care or current practice, or pembrolizumab 2 mg/kg (licensed dose; n=180) or 10 mg/kg (unlicensed dose; n=181) given every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, physician's decision to stop therapy or study sponsor's decision to stop the study. After week 12, people who had chemotherapy and whose disease progressed were allowed to switch to pembrolizumab. The company reported that people in KEYNOTE‑002 had had several previous treatments for advanced melanoma and that their baseline characteristics were generally balanced between the 3 treatment groups. Seventy seven percent of people in the trial had BRAF wild‑type disease. The company focused on the pembrolizumab 2 mg/kg dose because it was the licensed dose.
The progression‑free survival results were based on the interim analysis 2 (data cut‑off 12 May 2014). Results based on central review showed that median progression‑free survival was 2.9 months in the pembrolizumab 2 mg/kg group and 2.7 months in the chemotherapy group. The difference in progression‑free survival between the treatment groups was statistically significant (hazard ratio 0.57, 95% confidence interval 0.45 to 0.73, p<0.0001). The company noted that the Kaplan–Meier results showed that the progression‑free survival curves for both treatment groups separated from week 12 onwards and showed a substantial separation by month 6. The company also noted that progression‑free survival results based on investigator review were consistent with the results based on central review results (median progression‑free survival was 3.7 months in the pembrolizumab 2 mg/kg group and 2.6 months in the chemotherapy group, HR 0.49, 95% CI 0.38 to 0.62, p<0.0001).
The overall survival results were also based on the interim analysis 2, at which time 86 out of 179 people (48%) in the chemotherapy group had switched treatment to pembrolizumab. At this time, 215 deaths had occurred. The company reported that there was not a statistically significant difference in overall survival results between pembrolizumab 2 mg/kg and chemotherapy (HR 0.88, 95% CI 0.64 to 1.22, p=0.229). This could be attributed to confounding because people whose disease progressed on the chemotherapy group could switch to pembrolizumab when their disease progressed. The rank‑preserving structural failure time (RPSFT) adjustment method to account for treatment switching was pre‑specified in the trial protocol. Also, the company explored other adjustment methods: 2‑stage and inverse probability of censoring weighting (IPCW). The company stated that the RPSFT method is based on the assumption of a common treatment effect, so this method might not have been appropriate because there may have been a different treatment effect in people who switched to pembrolizumab after having had chemotherapy than in people who had pembrolizumab initially. It also stated that the overall survival results derived when adjusting for treatment switching with the RPSFT method were invalid because the results were similar to the ones before correction, and because the results implied that people having pembrolizumab died more quickly after progression than those having chemotherapy. Because of the small sample size and the high proportion of people switching treatment, the company noted that it was uncertain whether the IPCW method could be considered a valid method. It stated that the 2‑stage method appeared to be the most appropriate because treatment switching occurred after disease progression and the potential relevant confounders were measured until the moment of switching. The company validated the adjusted overall survival results generated with the 2‑stage method for the control group. To do this, it used the predicted overall survival using the algorithm from Korn et al. (2008; a study that evaluated historical data from different trials that included 2100 people with metastatic melanoma in an attempt to develop benchmarks for overall survival and progression‑free survival as reference points for future trials), and reported a high degree of similarity to the adjusted overall survival trial results. For the overall survival analysis, applying the 2‑stage adjustment method, the company presented the results of 2 models. One model adjusted for all relevant covariates (including Eastern Cooperative Oncology Group status, tumour size, lactate dehydrogenase level, BRAF status, melanoma stage and age). The other model only incorporated ECOG. The company noted that both models led to similar results and it focused on the model with all relevant covariates (median overall survival in pembrolizumab group 11.4 months, median overall survival in chemotherapy group 7.9 months, HR 0.63, 95% CI 0.45 to 0.88, p=0.007).
The most common adverse events in the pembrolizumab 2 mg/kg group were fatigue (38.8%), itching (23.5%), constipation (21.3%), diarrhoea (20.8%), nausea (19.7%), anaemia (17.4%), cough (17.4%), decreased appetite (16.3%) and joint pain (15.2%). The most common adverse events in the chemotherapy group were fatigue (48.0%), nausea (41.5%), anaemia (26.3%), vomiting (22.8%), decreased appetite (22.8%), constipation (20.5%), hair loss (20.5%), diarrhoea (19.9%) and cough (15.8%). The company stated that the results showed that the overall safety profile of pembrolizumab as an immune therapy for advanced melanoma was favourable compared with chemotherapy.
# Cost effectiveness
The company did a de novo economic model to assess the cost effectiveness of pembrolizumab compared with best supportive care in people with unresectable or metastatic melanoma previously treated with ipilimumab and whose disease had progressed within 24 weeks of the last dose. The population in the model differed from the scope in that people with BRAF mutation‑positive disease had also had treatment with a BRAF inhibitor (vemurafenib or dabrafenib) in line with KEYNOTE‑002. Best supportive care included systemic therapies such as dacarbazine, paclitaxel, paclitaxel plus carboplatin, carboplatin or temozolomide. The model structure was a partitioned survival model with 3 states: pre‑progression, post‑progression and death. The cycle length was 1 week, the time horizon was 30 years (assumed to be lifetime), and costs and outcomes were discounted at a 3.5% rate. Data from KEYNOTE‑002 were used to estimate the baseline characteristics, the proportion of people in the different states, the proportion experiencing adverse events, and utility values. The average age of the cohort in the model was 60 years.
The company assumed that all chemotherapy treatments had equal efficacy in terms of progression‑free survival and overall survival. The company used progression‑free survival results based on central review assessment. It applied standard parametric curve fitting using the Gompertz distribution for extrapolating progression‑free survival in the pembrolizumab group. It stated that, because progression‑free survival results were affected by the fact that the first radiological tumour response assessment was done in week 12, it applied a 2‑part curve fit: Kaplan–Meier curves were used until week 13 and parametric curves were fitted from this point onwards. The company also stated that the proportional hazard assumption could not be rejected so it incorporated it in the extrapolation of the data. For the best supportive care group, the company directly used Kaplan–Meier data until the final date when any patient was seen to still have progression‑free disease (week 62). At this point, all remaining patients were assumed to have died or have disease progression. The company highlighted that using progression‑free survival to represent disease status within the model may have underestimated pre‑progression survival and overestimated post‑progression survival. The company acknowledged that because of the relatively short‑term progression‑free survival data from KEYNOTE‑002, the extrapolation of these results added uncertainty to the cost‑effectiveness results.
The company reported that, because overall survival data from KEYNOTE‑002 were immature and standard parametric curve fitting resulted in survival estimates that were not clinically plausible, alternative methods were needed to extrapolate survival beyond the trial period. The company used the following sources for the extrapolation of overall survival in its base case:
from 0 to 1 year: KEYNOTE‑002 data
from 1 year to 10 years: ipilimumab (previously treated) survival curve (as published in Schadendorf et al. , a study that included a pooled analysis of long‑term survival data for ipilimumab in unresectable or metastatic melanoma)
from year 10 onwards: Balch et al. (2001) registry data from the American Joint Committee on Cancer registry plus general population mortality.
The company got the utility values from EQ‑5D questionnaire data from KEYNOTE‑002. The company noted that utility values decreased when patients were closer to the time of death so utility values were calculated based on time to death. The company reported that there were no statistically significant differences in utility values between the pembrolizumab and chemotherapy groups at baseline so it pooled the utility values from both treatment groups in the model. The company also calculated pooled utility values for pre‑progression and post‑progression states and used them in sensitivity analyses.
The company included costs reflecting the clinical management of unresectable or metastatic melanoma. This included costs of treatment, monitoring and follow‑up, management of complications and adverse events, and terminal care. The incidence of adverse events was based on KEYNOTE‑002, and their associated costs were taken from NICE technology appraisal guidance on ipilimumab for previously untreated advanced melanoma.
The results from the company's cost‑effectiveness analysis of pembrolizumab compared with best supportive care showed that pembrolizumab provided 1.19 additional quality‑adjusted life years (QALYs) at an additional cost of £50,995 compared with best supportive care. This led to an incremental cost‑effectiveness ratio (ICER) of £42,923 per QALY gained. The company did deterministic sensitivity analyses and found that the variables with the highest impact on the ICER were the curve fit parameters for progression‑free survival data and the HR for overall survival from the 2‑stage treatment switching adjustment method.
The company did probabilistic sensitivity analyses to assess the uncertainty around the variables included in the model. The results led to a probabilistic ICER of £67,615 per QALY gained for pembrolizumab compared with best supportive care. The company noted that these results were higher than the deterministic results because of the uncertainty in the progression‑free survival data from KEYNOTE‑002 and the fact that, in the model, many patients did not have disease progression and had treatment for life. The cost‑effectiveness acceptability curves showed that there was a probability of about 50% of pembrolizumab being cost effective at a maximum acceptable ICER of £50,000 per QALY gained.
# Evidence review group comments
The ERG considered that KEYNOTE‑002 was generalisable to UK clinical practice even though there were no participating centres in the UK. It noted that the company stated that people in KEYNOTE‑002 had more advanced disease and a worse prognosis than expected in clinical practice in England. However, the ERG considered that it could also be argued that people in KEYNOTE‑002 had a better prognosis because they had ECOG status 0–1 and were considered to be fit enough to have further immunotherapy after treatment with ipilimumab.
The ERG agreed with the company that the difference in median progression‑free survival between treatment groups in KEYNOTE‑002 could be affected by the timing of the first scheduled response assessment (week 12). The ERG also agreed that it was likely that median progression‑free survival rates underestimated the treatment effect of pembrolizumab compared with chemotherapy. It noted that the company explored different methods to adjust overall survival data from KEYNOTE‑002 for treatment switching, and agreed with the company that the 2‑stage adjustment method was the most appropriate.
The ERG considered that the exponential distribution provided a better fit to Kaplan–Meier progression‑free survival data from KEYNOTE‑002 than the Gompertz distribution used by the company in its model. The ERG also noted that the Gompertz distribution usually overestimates progression‑free survival results in the long term. It noted that assuming that all patients in the best supportive care group died or had disease progression at week 62 without any projection underestimated the progression‑free survival results in the best supportive care group. The ERG considered that this overestimated the benefit of pembrolizumab in terms of progression‑free survival compared with best supportive care by about 30%. The ERG considered that progression‑free survival by investigator assessment was more representative of clinical practice than progression‑free survival results by central review. Therefore, it applied the progression‑free survival results by investigator assessment using an alternative censoring rule in its exploratory analyses and used exponential models for extrapolating the results in both treatment groups. It found that this still led to a substantial long‑term progression‑free survival benefit for pembrolizumab compared with best supportive care (net extended progression‑free survival benefit with pembrolizumab compared with best supportive care of 4.18 months compared with the company's estimate of 5.35 months). This reduced the ICER for pembrolizumab compared with best supportive care by approximately £6900.
The ERG stated that the company's approach to modelling overall survival (using 3 different sources of data) led to clinically implausible results such as a 4‑year period of zero mortality risk and a sudden increase in mortality from zero to non‑zero at 10 years. It was concerned that the company applied the overall survival hazard ratio from the trial to the whole time horizon (including to the background mortality from all causes from UK life tables), and that this led to an indefinite overall survival gain in the pembrolizumab group compared with best supportive care from 10 years to 30 years. The ERG applied a different method for extrapolating overall survival data in the model based on a previous approach developed during NICE's technology appraisal guidance on ipilimumab for previously treated advanced (unresectable or metastatic) melanoma. The ERG's method used a mixed exponential model with 2 subgroups of people (1 subgroup had a high risk of mortality, the other subgroup had much longer survival) as seen in clinical practice. The ERG used the American Joint Committee on Cancer registry data. It generated expected survival profiles matched for the subgroups of people with stage IV melanoma (M1a, M1b and M1c) for each treatment group in KEYNOTE‑002. It used the subsequent curves in both extrapolation phases of the company's model (that is, from year 1 onwards) using the point at which the American Joint Committee on Cancer registry data matched profiles corresponded to a common mortality rate in both the KEYNOTE‑002 data and the projection model. This meant that, beyond the observed trial period, most patients having pembrolizumab stopped treatment rapidly because of disease progression or adverse events, so future survival was largely determined by the conventional treatment options covered in the registry data. Using this method for extrapolating overall survival data led to a reduction in the estimated survival gain of about 17%, and increased the ICER for pembrolizumab compared with best supportive care by approximately £8400.
The ERG applied other amendments to the company's model, including the approach used to incorporate utility values and the way the company included resources use and costs in the model. The ERG noted that, although individual amendments had substantial effects on the ICER, the net effect when implementing all the changes was small. It noted that this led to an overall change in the ICER of less than £4000, so the ICER for pembrolizumab compared with best supportive care including all of the ERG's preferred amendments was £46,662 per QALY gained.
Full details of all the evidence are in available.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of unresectable, metastatic melanoma after progression with ipilimumab, and the value placed on the benefits of pembrolizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee discussed the current clinical management of advanced (unresectable or metastatic) melanoma in the NHS and the place of pembrolizumab within the treatment pathway. It was aware of the disparity between the wording of the marketing authorisation for pembrolizumab, the definition of the population in the scope and the decision problem addressed by the company in its submission. The Committee noted the broad wording of the marketing authorisation for pembrolizumab (that is, the treatment of advanced melanoma in adults), and the narrower population in the scope (that is, people with advanced melanoma whose disease has progressed after previous treatment with ipilimumab). It further noted that the decision problem addressed by the company in its submission was even narrower, based on the population included in the clinical trial evidence available for pembrolizumab from KEYNOTE‑002 (that is, people with unresectable or metastatic melanoma whose disease has progressed after ipilimumab and, if the disease is BRAF V600 mutation positive, a BRAF or MEK inhibitor). The Committee heard from the company that, when preparing the submission, the marketing authorisation was expected to specify that pembrolizumab would be indicated after progression with ipilimumab, and if BRAF V600 mutation‑positive disease, after a BRAF or MEK inhibitor, and that this had been the approach taken when pembrolizumab was made available via the early access to medicines scheme in the NHS. The Committee questioned whether in clinical practice pembrolizumab would always be used after a BRAF or MEK inhibitor in people with BRAF V600 mutation positive disease, as in KEYNOTE‑002 and the company submission, or whether pembrolizumab would sometimes be considered as an alternative to a BRAF or MEK inhibitor. It heard from the clinical experts that, after disease progression with ipilimumab, most people with BRAF V600 mutation‑positive disease would have a BRAF or MEK inhibitor but that, in a few people, pembrolizumab might be preferred because of slow‑growing disease and the expectation of a longer survival. However, the Committee was aware that the company had not submitted any evidence for the efficacy of pembrolizumab compared with BRAF inhibitors. It considered that it could not make recommendations for a population for whom there was no evidence of the relative clinical effectiveness of pembrolizumab. Therefore, the Committee accepted the company's approach to the decision problem. It concluded that, on the basis of the evidence submitted, it could only make recommendations for pembrolizumab after treatment with ipilimumab and, for BRAF V600 mutation‑positive disease, after both ipilimumab and a BRAF or MEK inhibitor.
The Committee discussed the relevant comparators for pembrolizumab and noted that the company considered conventional chemotherapy to be the appropriate comparator for pembrolizumab. The Committee heard from the clinical experts that conventional chemotherapy, including dacarbazine, remained the only treatment option after treatment with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor. It also heard that there is no proven survival benefit associated with these therapies. The Committee concluded that conventional chemotherapy was an appropriate comparator for pembrolizumab at this stage of the disease.
The Committee discussed the clinical need of people with advanced melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor. It heard from the patient expert that metastatic melanoma is associated with severe emotional stress and anxiety about the future for the patient and their family, and a reduced quality and length of life. The patient expert and clinical experts also explained that ipilimumab, which is used earlier in the pathway, can be associated with severe side effects that affect normal activities and that these may be so severe the patient sometimes needs hospital admission. The patient expert also noted that, in contrast, pembrolizumab offers a much more manageable side effect profile that means people with metastatic melanoma can continue their normal lives and activities, including employment. The patient expert also highlighted that, once the disease progresses after ipilimumab, the lack of further therapy options that can extend survival is devastating, so having an additional option such as pembrolizumab provides hope for the future. The Committee concluded that the availability of a new treatment that slows disease progression and improves quality of life when other therapies have failed is very important to patients and their families.
The Committee considered that the key clinical evidence came from KEYNOTE‑002. The Committee noted that KEYNOTE‑002 had not included any UK sites but had included centres in the USA, Argentina, and some European countries. It heard from the clinical experts that historically there had been a difference in outcomes in people with advanced melanoma in the UK compared with some other countries, possibly related to later diagnosis. However, the clinical experts explained that, because of recent advances in managing malignant melanoma in the NHS, including earlier diagnosis and the availability of new treatments, this has changed. The Committee also noted that 23% of people in KEYNOTE‑002 had BRAF V600 mutation‑positive disease. It heard from the clinical experts that this was lower than the overall prevalence of BRAF V600 mutation‑positive disease in the UK, which is about 45%. The clinical experts noted that this difference related mainly to patient selection in the trial and that the results would still be generalisable to the BRAF V600 mutation‑positive population eligible to have pembrolizumab in clinical practice. Therefore, the Committee concluded that KEYNOTE‑002 was generalisable to clinical practice in the NHS for those people whose disease has progressed after ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.
The Committee discussed the progression‑free survival results from KEYNOTE‑002. It was aware that follow‑up in the trial was short and therefore, the results were immature. It was aware that the company presented results based on an independent central review and an investigator assessment, and that both results were based on an interim analysis. It was also aware that the median progression‑free survival for pembrolizumab was higher using the investigator assessment, which it considered could relate to the lack of blinding in the trial. However, the Committee noted that both methods showed small but statistically significant improvements in median progression‑free survival with pembrolizumab compared with conventional chemotherapy. It also noted that there was a separation of the progression‑free survival curves that began around 12 weeks, after which a larger difference in progression‑free survival was seen between chemotherapy and pembrolizumab. The Committee heard from the clinical experts that treatment response is best assessed around 12 weeks and, after this, the progression‑free survival benefit starts becoming apparent. The Committee concluded that the evidence from KEYNOTE‑002, although immature, suggested that pembrolizumab improved progression‑free survival compared with conventional chemotherapy, and that the benefit became most apparent after 12 weeks.
The Committee discussed the overall survival results and was aware that there was no statistically significant difference seen between pembrolizumab and chemotherapy. It considered that this could relate to immaturity of the data given the short follow‑up in the trial, and particularly to the fact that 48% of people in the chemotherapy group had switched to pembrolizumab. The Committee noted that the company had explored different methods of adjusting for treatment switching, and had concluded that the 2‑stage adjustment method was the most appropriate. It noted that the Evidence Review Group (ERG) had agreed with the company's approach and that, when using this method, there was a statistically significant difference in median overall survival between pembrolizumab and chemotherapy of 3.5 months. The Committee concluded that, although the results were immature and there was uncertainty about the true survival benefit associated with pembrolizumab compared with conventional chemotherapy, the best available evidence from KEYNOTE‑002, using the 2‑stage adjustment method, suggested a difference in median overall survival of 3.5 months.
The Committee discussed the adverse events associated with pembrolizumab. It noted that, in KEYNOTE‑002, pembrolizumab was associated with fewer adverse events than chemotherapy. It also recalled the comments from the clinical and patient experts that the adverse events of pembrolizumab were usually manageable and allowed people to continue with their normal activities (see section 4.3). The Committee concluded that the adverse events of pembrolizumab were manageable, and favourable when compared with chemotherapy.
# Cost effectiveness
The Committee considered the company's model, which compared pembrolizumab with best supportive care in people with advanced (unresectable or metastatic) melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor. The Committee considered that a 3‑state model structure was appropriate for decision‑making. It also accepted the company's use of data from the chemotherapy group in KEYNOTE‑002 as a proxy for best supportive care based on the Committee's previous conclusion that conventional chemotherapy was an appropriate comparator for pembrolizumab in its expected place in the treatment pathway (see section 4.2).
The Committee noted that the company's economic analysis resulted in a deterministic incremental cost‑effectiveness ratio (ICER) for pembrolizumab compared with best supportive care of about £43,000 per quality‑adjusted life year (QALY) gained, and a probabilistic ICER of about £68,000 per QALY gained. The Committee expressed concerns about the substantial difference between these figures and discussed possible reasons for the difference. It understood that the variables with the biggest impact on the results were the parameters used to extrapolate progression‑free survival and the hazard ratio for overall survival from the 2‑stage adjustment method used to extrapolate the overall survival results.
The Committee was aware that the company used a Gompertz distribution for extrapolating progression‑free survival from the time of assessment (week 12) onwards in the pembrolizumab group, and that it assumed all people having chemotherapy had progressed or died by the end of the trial (week 67). The Committee noted the comments from the ERG that the Gompertz distribution is associated with a long tail in the progression‑free survival curve and that this tends to overestimate progression‑free survival in the long‑term. It also noted that the confidence intervals were wide because there was a very small proportion of the cohort still at risk at the end of the tail in the progression‑free survival curve, which would have a particular impact on the probabilistic cost‑effectiveness estimate. The ERG also considered that the company's assumption that all people in the chemotherapy group had disease progression or died at week 67 overestimated the relative progression‑free survival benefit associated with pembrolizumab. It also noted that it was more appropriate to use exponential models for extrapolation in both treatment groups. The Committee was concerned that the progression‑free survival results were immature, and that it was uncertain how many and for how long people would have progression‑free disease. However, it accepted that, when using a Gompertz distribution, the progression‑free survival results appeared too optimistic because it was unlikely that people would have life‑long progression‑free disease.
The Committee noted that the company had used a 3‑stage approach to modelling overall survival based on different data sources. It also noted the comments from the ERG that this provided clinically implausible results such as: a 4‑year period of zero mortality risk followed by a sudden increase in the mortality risk occurring after 10 years, and an overall survival benefit of pembrolizumab compared with best supportive care that persisted indefinitely. The Committee noted that the ERG had implemented amendments to the company's model in line with its preferred assumptions. It also noted that it provided an exploratory analysis incorporating a different approach to modelling overall survival using trial results, together with a mixed‑exponential model based on registry data. The Committee expressed the view that the ERG's overall approach was generally more clinically plausible than the company's model using 3 separate sources.
The Committee noted that, even when incorporating multiple amendments such as changes to the utility values and costs, the cumulative effect of all ERG amendments on the ICER was modest, increasing the ICER for pembrolizumab compared with best supportive care by about £4000, to £47,000 per QALY gained. The Committee was aware that the ERG had not presented probabilistic cost‑effectiveness results and recalled its previous concerns about the wide difference between the company's deterministic and probabilistic results (see sections 4.9 and 4.10). The Committee heard from the ERG that, because its approach for modelling progression‑free survival used an exponential model instead of a Gompertz model, it was likely that the ERG's deterministic and probabilistic analyses would be much more similar. The Committee therefore considered that, despite the differences between the company's model and the ERG's preferred approach, the ICERs were not very different. It concluded that the most plausible ICER for pembrolizumab compared with best supportive care was likely to be less than £50,000 per QALY gained.
The Committee discussed the innovative nature of pembrolizumab. It noted that the company stated that pembrolizumab was innovative and a step‑change in the management of advanced melanoma because it treats a life‑threatening and seriously debilitating condition, meets a high unmet need and provides a significant advantage over other treatments used in the UK. The Committee agreed with the company that pembrolizumab is innovative because it meets a high unmet medical need, and because of its low toxicity and favourable adverse effects profile compared with other treatments for metastatic melanoma. However, it could not identify any specific health‑related benefit that had not been already captured in the QALY calculation.
The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
The Committee discussed whether pembrolizumab met all the criteria to be considered a life‑extending, end‑of‑life treatment and whether the evidence presented was plausible, objective and robust enough to support it. The Committee agreed that the life expectancy of people with advanced melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor, who do not have any other treatments available apart from conventional chemotherapy, is normally less than 24 months. For example, life expectancy in people with metastatic melanoma was up to 9.0 months based on data from Balch et al. (2001), Korn et al. (2008) and Thirlwell and Nathan (2008), 20.9 months in the company's base‑case analysis, and 17.2 months in the ERG's exploratory analyses. The Committee also agreed that, although the overall survival data are immature, the best available data from KEYNOTE‑002 and using the 2‑stage adjustment method for treatment switching suggested that pembrolizumab offers an extension to life compared with conventional chemotherapy of 3.5 months (see section 4.6). Finally, the Committee discussed the company's estimate for the number of people eligible to have pembrolizumab (that is, people with unresectable or metastatic melanoma whose disease has progressed after ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor), noting that this was about 600 in 2015, and about 300 annually thereafter. It heard from the clinical experts that these estimates were plausible and in line with the number of people who have had pembrolizumab through the early access to medicines scheme in the NHS. It concluded that this represents a small patient population. The Committee considered that, although the evidence for pembrolizumab in terms of progression‑free survival and overall survival is immature and based on a short follow‑up, the estimates and assumptions applied can be considered plausible, objective and robust enough to conclude that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.
Having accepted that the supplementary advice for appraising a life‑extending, end‑of‑life treatment applies, the Committee discussed whether pembrolizumab could be considered a cost‑effective use of NHS resources. The Committee recalled its previous conclusion that, despite the differences between the company's model and the ERG's amendments, the results were not very different and that it was likely that the most plausible ICER for pembrolizumab compared with best supportive care was less than £50,000 per QALY gained. Therefore, the Committee concluded that, on balance, pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic melanoma) after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.
The Committee was aware of NICE's position statement about the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism. It acknowledged 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of pembrolizumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of pembrolizumab.
# Summary of Appraisal Committee's key conclusions
TA357
Appraisal title: Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab
Section
Key conclusion
Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in adults only:
after the disease has progressed with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor and
when the company provides pembrolizumab with the discount agreed in the patient access scheme.
The Committee concluded that the evidence from KEYNOTE‑002, although immature, suggested that pembrolizumab improved progression‑free survival compared with conventional chemotherapy and that, when using the 2‑stage adjustment method, pembrolizumab was associated with an overall survival benefit of 3.5 months compared with chemotherapy.
The Committee concluded that the most plausible incremental cost‑effectiveness ratio (ICER) for pembrolizumab compared with best supportive care was likely to be less than £50,000 per quality‑adjusted life year (QALY) gained.
Having accepted that the supplementary advice for appraising a life‑extending, end‑of‑life treatment applies, the Committee concluded that pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic melanoma) after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee concluded that the availability of a new treatment which slows disease progression and improves quality of life when other therapies have failed is very important to patients and their families.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?
The Committee agreed with the company that pembrolizumab is innovative because it meets a high unmet medical need and because of its low toxicity and favourable adverse effects profile compared with other treatments for metastatic melanoma.
What is the position of the treatment in the pathway of care for the condition?
The Committee concluded that, on the basis of the evidence submitted, it could only make recommendations for pembrolizumab after treatment with ipilimumab and, for BRAF V600 mutation‑positive disease, after both ipilimumab and a BRAF or MEK inhibitor.
Adverse reactions
The Committee concluded that the adverse effects of pembrolizumab were manageable, and favourable when compared with chemotherapy.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee considered that the key clinical evidence came from KEYNOTE‑002.
Relevance to general clinical practice in the NHS
The Committee concluded that KEYNOTE‑002 was generalisable to clinical practice in the NHS for those people whose disease has progressed after ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.
Uncertainties generated by the evidence
The Committee concluded that, because the results were immature, there was uncertainty about the true survival benefit associated with pembrolizumab compared with conventional chemotherapy.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
None
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that the evidence from KEYNOTE‑002, although immature, suggested that pembrolizumab improved progression‑free survival compared with conventional chemotherapy and that, when using the 2‑stage adjustment method, pembrolizumab was associated with an overall survival benefit of 3.5 months compared with chemotherapy.
Evidence for cost effectiveness
Availability and nature of evidence
The Committee considered that the company's model, which compared pembrolizumab with best supportive care in people with advanced (unresectable or metastatic) melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor, had a 3‑state model structure that was appropriate for decision‑making.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The Committee was concerned that the progression‑free survival results were immature and that it was uncertain how many and for how long people would have progression‑free disease. However, it accepted that the company's approach to extrapolating progression‑free survival using a Gompertz distribution led to progression‑free survival results that appeared too optimistic because it was unlikely that people would have life‑long progression‑free disease.
The Committee expressed the view that the Evidence Review Group's (ERG's) approach to modelling overall survival was generally more clinically plausible than the company's model using 3 separate sources.
Incorporation of health‑related quality‑of‑life benefits and utility values
Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?
The company got the utility values from EQ‑5D questionnaire data from KEYNOTE‑002. The utility values were incorporated into the model based on time to death.
The Committee could not identify any specific health‑related benefit that had not been already captured in the QALY calculation.
Are there specific groups of people for whom the technology is particularly cost effective?
None
What are the key drivers of cost effectiveness?
The Committee understood that the variables with the biggest impact on the results were the parameters used to extrapolate progression‑free survival and the hazard ratio for overall survival from the 2‑stage adjustment method used to extrapolate the overall survival results.
Most likely cost‑effectiveness estimate (given as an ICER)
The Committee concluded that that the most plausible ICER for pembrolizumab compared with best supportive care was likely to be less than £50,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pembrolizumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.
End‑of‑life considerations
The Committee considered that, although the evidence for pembrolizumab in terms of progression‑free survival and overall survival is immature (that is, based on a short period of follow‑up), the estimates and assumptions applied can be considered plausible, objective and robust enough to conclude that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.
Equalities considerations and social value judgements
No equality issues were raised during the appraisal process.
# Review of guidance
The guidance on this technology will be considered for review 3 years after publication. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveOctober 2015
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{'Guidance': 'Pembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in adults only:\n\nafter the disease has progressed with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor and\n\nwhen the company provides pembrolizumab in line with the commercial access agreement with NHS England.', 'The technology': "Pembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody. It acts on the programmed cell death protein‑1 immune checkpoint receptor pathway, blocking its interaction with ligand on the tumour cells. This allows reactivation of anti‑tumour immunity. It has a marketing authorisation in the UK as monotherapy 'for the treatment of advanced (unresectable or metastatic) melanoma in adults'. Previously, pembrolizumab was available in the NHS through the early access to medicines schemes from the UK Medicines and Healthcare products Regulatory Agency. Pembrolizumab is administered intravenously for 30\xa0minutes at a dose of 2\xa0mg/kg every 3\xa0weeks until disease progression or unacceptable toxicity.\n\nThe most common (occurring in 1\xa0in\xa010 people or more) adverse reactions with pembrolizumab in clinical trials were diarrhoea, nausea, itching, rash, joint pain and fatigue. The most serious adverse reactions were immune‑related adverse reactions and severe infusion‑related reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nThe acquisition cost of pembrolizumab is £1,315 per 50‑mg vial (excluding VAT; company's submission). The pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in October 2015, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.", "The company's submission": "The Appraisal Committee (section\xa07) considered evidence submitted by Merck Sharp & Dohme, and a review of this submission by the Evidence Review Group (ERG; section\xa08).\n\n# Clinical effectiveness\n\nThe company's submission focused on the evidence from KEYNOTE‑002, a multicentre randomised controlled trial (including centres in Argentina, US and Europe, although not in the UK). This trial compared pembrolizumab with chemotherapy in people with advanced melanoma who had had at least 2\xa0doses of ipilimumab and whose disease had progressed within 24\xa0weeks of the last ipilimumab dose. People with BRAF mutation‑positive melanomas must have also had treatment with a BRAF inhibitor (vemurafenib or dabrafenib) or a MEK inhibitor (trametinib). People were randomised to chemotherapy chosen by an investigator (paclitaxel plus carboplatin, carboplatin alone, paclitaxel alone, dacarbazine or temozolomide; n=179) according to standard of care or current practice, or pembrolizumab 2\xa0mg/kg (licensed dose; n=180) or 10\xa0mg/kg (unlicensed dose; n=181) given every 3\xa0weeks until disease progression, unacceptable toxicity, withdrawal of consent, physician's decision to stop therapy or study sponsor's decision to stop the study. After week\xa012, people who had chemotherapy and whose disease progressed were allowed to switch to pembrolizumab. The company reported that people in KEYNOTE‑002 had had several previous treatments for advanced melanoma and that their baseline characteristics were generally balanced between the 3\xa0treatment groups. Seventy seven percent of people in the trial had BRAF wild‑type disease. The company focused on the pembrolizumab 2\xa0mg/kg dose because it was the licensed dose.\n\nThe progression‑free survival results were based on the interim analysis\xa02 (data cut‑off 12\xa0May 2014). Results based on central review showed that median progression‑free survival was 2.9\xa0months in the pembrolizumab 2\xa0mg/kg group and 2.7\xa0months in the chemotherapy group. The difference in progression‑free survival between the treatment groups was statistically significant (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.45 to 0.73, p<0.0001). The company noted that the Kaplan–Meier results showed that the progression‑free survival curves for both treatment groups separated from week\xa012 onwards and showed a substantial separation by month\xa06. The company also noted that progression‑free survival results based on investigator review were consistent with the results based on central review results (median progression‑free survival was 3.7\xa0months in the pembrolizumab 2\xa0mg/kg group and 2.6\xa0months in the chemotherapy group, HR\xa00.49, 95%\xa0CI 0.38 to 0.62, p<0.0001).\n\nThe overall survival results were also based on the interim analysis 2, at which time 86\xa0out of 179\xa0people (48%) in the chemotherapy group had switched treatment to pembrolizumab. At this time, 215\xa0deaths had occurred. The company reported that there was not a statistically significant difference in overall survival results between pembrolizumab 2\xa0mg/kg and chemotherapy (HR\xa00.88, 95%\xa0CI 0.64 to 1.22, p=0.229). This could be attributed to confounding because people whose disease progressed on the chemotherapy group could switch to pembrolizumab when their disease progressed. The rank‑preserving structural failure time (RPSFT) adjustment method to account for treatment switching was pre‑specified in the trial protocol. Also, the company explored other adjustment methods: 2‑stage and inverse probability of censoring weighting (IPCW). The company stated that the RPSFT method is based on the assumption of a common treatment effect, so this method might not have been appropriate because there may have been a different treatment effect in people who switched to pembrolizumab after having had chemotherapy than in people who had pembrolizumab initially. It also stated that the overall survival results derived when adjusting for treatment switching with the RPSFT method were invalid because the results were similar to the ones before correction, and because the results implied that people having pembrolizumab died more quickly after progression than those having chemotherapy. Because of the small sample size and the high proportion of people switching treatment, the company noted that it was uncertain whether the IPCW method could be considered a valid method. It stated that the 2‑stage method appeared to be the most appropriate because treatment switching occurred after disease progression and the potential relevant confounders were measured until the moment of switching. The company validated the adjusted overall survival results generated with the 2‑stage method for the control group. To do this, it used the predicted overall survival using the algorithm from Korn et al. (2008; a study that evaluated historical data from different trials that included 2100 people with metastatic melanoma in an attempt to develop benchmarks for overall survival and progression‑free survival as reference points for future trials), and reported a high degree of similarity to the adjusted overall survival trial results. For the overall survival analysis, applying the 2‑stage adjustment method, the company presented the results of 2\xa0models. One model adjusted for all relevant covariates (including Eastern Cooperative Oncology Group [ECOG] status, tumour size, lactate dehydrogenase level, BRAF status, melanoma stage and age). The other model only incorporated ECOG. The company noted that both models led to similar results and it focused on the model with all relevant covariates (median overall survival in pembrolizumab group 11.4\xa0months, median overall survival in chemotherapy group 7.9\xa0months, HR\xa00.63, 95%\xa0CI 0.45 to 0.88, p=0.007).\n\nThe most common adverse events in the pembrolizumab 2\xa0mg/kg group were fatigue (38.8%), itching (23.5%), constipation (21.3%), diarrhoea (20.8%), nausea (19.7%), anaemia (17.4%), cough (17.4%), decreased appetite (16.3%) and joint pain (15.2%). The most common adverse events in the chemotherapy group were fatigue (48.0%), nausea (41.5%), anaemia (26.3%), vomiting (22.8%), decreased appetite (22.8%), constipation (20.5%), hair loss (20.5%), diarrhoea (19.9%) and cough (15.8%). The company stated that the results showed that the overall safety profile of pembrolizumab as an immune therapy for advanced melanoma was favourable compared with chemotherapy.\n\n# Cost effectiveness\n\nThe company did a de novo economic model to assess the cost effectiveness of pembrolizumab compared with best supportive care in people with unresectable or metastatic melanoma previously treated with ipilimumab and whose disease had progressed within 24\xa0weeks of the last dose. The population in the model differed from the scope in that people with BRAF mutation‑positive disease had also had treatment with a BRAF inhibitor (vemurafenib or dabrafenib) in line with KEYNOTE‑002. Best supportive care included systemic therapies such as dacarbazine, paclitaxel, paclitaxel plus carboplatin, carboplatin or temozolomide. The model structure was a partitioned survival model with 3\xa0states: pre‑progression, post‑progression and death. The cycle length was 1\xa0week, the time horizon was 30\xa0years (assumed to be lifetime), and costs and outcomes were discounted at a 3.5% rate. Data from KEYNOTE‑002 were used to estimate the baseline characteristics, the proportion of people in the different states, the proportion experiencing adverse events, and utility values. The average age of the cohort in the model was 60\xa0years.\n\nThe company assumed that all chemotherapy treatments had equal efficacy in terms of progression‑free survival and overall survival. The company used progression‑free survival results based on central review assessment. It applied standard parametric curve fitting using the Gompertz distribution for extrapolating progression‑free survival in the pembrolizumab group. It stated that, because progression‑free survival results were affected by the fact that the first radiological tumour response assessment was done in week\xa012, it applied a 2‑part curve fit: Kaplan–Meier curves were used until week\xa013 and parametric curves were fitted from this point onwards. The company also stated that the proportional hazard assumption could not be rejected so it incorporated it in the extrapolation of the data. For the best supportive care group, the company directly used Kaplan–Meier data until the final date when any patient was seen to still have progression‑free disease (week\xa062). At this point, all remaining patients were assumed to have died or have disease progression. The company highlighted that using progression‑free survival to represent disease status within the model may have underestimated pre‑progression survival and overestimated post‑progression survival. The company acknowledged that because of the relatively short‑term progression‑free survival data from KEYNOTE‑002, the extrapolation of these results added uncertainty to the cost‑effectiveness results.\n\nThe company reported that, because overall survival data from KEYNOTE‑002 were immature and standard parametric curve fitting resulted in survival estimates that were not clinically plausible, alternative methods were needed to extrapolate survival beyond the trial period. The company used the following sources for the extrapolation of overall survival in its base case:\n\nfrom 0\xa0to 1\xa0year: KEYNOTE‑002 data\n\nfrom 1\xa0year to 10\xa0years: ipilimumab (previously treated) survival curve (as published in Schadendorf et al. , a study that included a pooled analysis of long‑term survival data for ipilimumab in unresectable or metastatic melanoma)\n\nfrom year\xa010 onwards: Balch et al. (2001) registry data from the American Joint Committee on Cancer registry plus general population mortality.\n\nThe company got the utility values from EQ‑5D questionnaire data from KEYNOTE‑002. The company noted that utility values decreased when patients were closer to the time of death so utility values were calculated based on time to death. The company reported that there were no statistically significant differences in utility values between the pembrolizumab and chemotherapy groups at baseline so it pooled the utility values from both treatment groups in the model. The company also calculated pooled utility values for pre‑progression and post‑progression states and used them in sensitivity analyses.\n\nThe company included costs reflecting the clinical management of unresectable or metastatic melanoma. This included costs of treatment, monitoring and follow‑up, management of complications and adverse events, and terminal care. The incidence of adverse events was based on KEYNOTE‑002, and their associated costs were taken from NICE technology appraisal guidance on ipilimumab for previously untreated advanced melanoma.\n\nThe results from the company's cost‑effectiveness analysis of pembrolizumab compared with best supportive care showed that pembrolizumab provided 1.19\xa0additional quality‑adjusted life years (QALYs) at an additional cost of £50,995 compared with best supportive care. This led to an incremental cost‑effectiveness ratio (ICER) of £42,923 per QALY gained. The company did deterministic sensitivity analyses and found that the variables with the highest impact on the ICER were the curve fit parameters for progression‑free survival data and the HR for overall survival from the 2‑stage treatment switching adjustment method.\n\nThe company did probabilistic sensitivity analyses to assess the uncertainty around the variables included in the model. The results led to a probabilistic ICER of £67,615 per QALY gained for pembrolizumab compared with best supportive care. The company noted that these results were higher than the deterministic results because of the uncertainty in the progression‑free survival data from KEYNOTE‑002 and the fact that, in the model, many patients did not have disease progression and had treatment for life. The cost‑effectiveness acceptability curves showed that there was a probability of about 50% of pembrolizumab being cost effective at a maximum acceptable ICER of £50,000 per QALY gained.\n\n# Evidence review group comments\n\nThe ERG considered that KEYNOTE‑002 was generalisable to UK clinical practice even though there were no participating centres in the UK. It noted that the company stated that people in KEYNOTE‑002 had more advanced disease and a worse prognosis than expected in clinical practice in England. However, the ERG considered that it could also be argued that people in KEYNOTE‑002 had a better prognosis because they had ECOG status 0–1 and were considered to be fit enough to have further immunotherapy after treatment with ipilimumab.\n\nThe ERG agreed with the company that the difference in median progression‑free survival between treatment groups in KEYNOTE‑002 could be affected by the timing of the first scheduled response assessment (week\xa012). The ERG also agreed that it was likely that median progression‑free survival rates underestimated the treatment effect of pembrolizumab compared with chemotherapy. It noted that the company explored different methods to adjust overall survival data from KEYNOTE‑002 for treatment switching, and agreed with the company that the 2‑stage adjustment method was the most appropriate.\n\nThe ERG considered that the exponential distribution provided a better fit to Kaplan–Meier progression‑free survival data from KEYNOTE‑002 than the Gompertz distribution used by the company in its model. The ERG also noted that the Gompertz distribution usually overestimates progression‑free survival results in the long term. It noted that assuming that all patients in the best supportive care group died or had disease progression at week\xa062 without any projection underestimated the progression‑free survival results in the best supportive care group. The ERG considered that this overestimated the benefit of pembrolizumab in terms of progression‑free survival compared with best supportive care by about 30%. The ERG considered that progression‑free survival by investigator assessment was more representative of clinical practice than progression‑free survival results by central review. Therefore, it applied the progression‑free survival results by investigator assessment using an alternative censoring rule in its exploratory analyses and used exponential models for extrapolating the results in both treatment groups. It found that this still led to a substantial long‑term progression‑free survival benefit for pembrolizumab compared with best supportive care (net extended progression‑free survival benefit with pembrolizumab compared with best supportive care of 4.18\xa0months compared with the company's estimate of 5.35\xa0months). This reduced the ICER for pembrolizumab compared with best supportive care by approximately £6900.\n\nThe ERG stated that the company's approach to modelling overall survival (using 3\xa0different sources of data) led to clinically implausible results such as a 4‑year period of zero mortality risk and a sudden increase in mortality from zero to non‑zero at 10\xa0years. It was concerned that the company applied the overall survival hazard ratio from the trial to the whole time horizon (including to the background mortality from all causes from UK life tables), and that this led to an indefinite overall survival gain in the pembrolizumab group compared with best supportive care from 10\xa0years to 30\xa0years. The ERG applied a different method for extrapolating overall survival data in the model based on a previous approach developed during NICE's technology appraisal guidance on ipilimumab for previously treated advanced (unresectable or metastatic) melanoma. The ERG's method used a mixed exponential model with 2\xa0subgroups of people (1\xa0subgroup had a high risk of mortality, the other subgroup [about 10–15% of the total population] had much longer survival) as seen in clinical practice. The ERG used the American Joint Committee on Cancer registry data. It generated expected survival profiles matched for the subgroups of people with stage\xa0IV melanoma (M1a, M1b and M1c) for each treatment group in KEYNOTE‑002. It used the subsequent curves in both extrapolation phases of the company's model (that is, from year\xa01 onwards) using the point at which the American Joint Committee on Cancer registry data matched profiles corresponded to a common mortality rate in both the KEYNOTE‑002 data and the projection model. This meant that, beyond the observed trial period, most patients having pembrolizumab stopped treatment rapidly because of disease progression or adverse events, so future survival was largely determined by the conventional treatment options covered in the registry data. Using this method for extrapolating overall survival data led to a reduction in the estimated survival gain of about 17%, and increased the ICER for pembrolizumab compared with best supportive care by approximately £8400.\n\nThe ERG applied other amendments to the company's model, including the approach used to incorporate utility values and the way the company included resources use and costs in the model. The ERG noted that, although individual amendments had substantial effects on the ICER, the net effect when implementing all the changes was small. It noted that this led to an overall change in the ICER of less than £4000, so the ICER for pembrolizumab compared with best supportive care including all of the ERG's preferred amendments was £46,662 per QALY gained.\n\nFull details of all the evidence are in available.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of unresectable, metastatic melanoma after progression with ipilimumab, and the value placed on the benefits of pembrolizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed the current clinical management of advanced (unresectable or metastatic) melanoma in the NHS and the place of pembrolizumab within the treatment pathway. It was aware of the disparity between the wording of the marketing authorisation for pembrolizumab, the definition of the population in the scope and the decision problem addressed by the company in its submission. The Committee noted the broad wording of the marketing authorisation for pembrolizumab (that is, the treatment of advanced [unresectable or metastatic] melanoma in adults), and the narrower population in the scope (that is, people with advanced [unresectable stage\xa0III or\xa0IV] melanoma whose disease has progressed after previous treatment with ipilimumab). It further noted that the decision problem addressed by the company in its submission was even narrower, based on the population included in the clinical trial evidence available for pembrolizumab from KEYNOTE‑002 (that is, people with unresectable or metastatic melanoma whose disease has progressed after ipilimumab and, if the disease is BRAF V600 mutation positive, a BRAF or MEK inhibitor). The Committee heard from the company that, when preparing the submission, the marketing authorisation was expected to specify that pembrolizumab would be indicated after progression with ipilimumab, and if BRAF V600 mutation‑positive disease, after a BRAF or MEK inhibitor, and that this had been the approach taken when pembrolizumab was made available via the early access to medicines scheme in the NHS. The Committee questioned whether in clinical practice pembrolizumab would always be used after a BRAF or MEK inhibitor in people with BRAF V600 mutation positive disease, as in KEYNOTE‑002 and the company submission, or whether pembrolizumab would sometimes be considered as an alternative to a BRAF or MEK inhibitor. It heard from the clinical experts that, after disease progression with ipilimumab, most people with BRAF V600 mutation‑positive disease would have a BRAF or MEK inhibitor but that, in a few people, pembrolizumab might be preferred because of slow‑growing disease and the expectation of a longer survival. However, the Committee was aware that the company had not submitted any evidence for the efficacy of pembrolizumab compared with BRAF inhibitors. It considered that it could not make recommendations for a population for whom there was no evidence of the relative clinical effectiveness of pembrolizumab. Therefore, the Committee accepted the company's approach to the decision problem. It concluded that, on the basis of the evidence submitted, it could only make recommendations for pembrolizumab after treatment with ipilimumab and, for BRAF V600 mutation‑positive disease, after both ipilimumab and a BRAF or MEK inhibitor.\n\nThe Committee discussed the relevant comparators for pembrolizumab and noted that the company considered conventional chemotherapy to be the appropriate comparator for pembrolizumab. The Committee heard from the clinical experts that conventional chemotherapy, including dacarbazine, remained the only treatment option after treatment with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor. It also heard that there is no proven survival benefit associated with these therapies. The Committee concluded that conventional chemotherapy was an appropriate comparator for pembrolizumab at this stage of the disease.\n\nThe Committee discussed the clinical need of people with advanced melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor. It heard from the patient expert that metastatic melanoma is associated with severe emotional stress and anxiety about the future for the patient and their family, and a reduced quality and length of life. The patient expert and clinical experts also explained that ipilimumab, which is used earlier in the pathway, can be associated with severe side effects that affect normal activities and that these may be so severe the patient sometimes needs hospital admission. The patient expert also noted that, in contrast, pembrolizumab offers a much more manageable side effect profile that means people with metastatic melanoma can continue their normal lives and activities, including employment. The patient expert also highlighted that, once the disease progresses after ipilimumab, the lack of further therapy options that can extend survival is devastating, so having an additional option such as pembrolizumab provides hope for the future. The Committee concluded that the availability of a new treatment that slows disease progression and improves quality of life when other therapies have failed is very important to patients and their families.\n\nThe Committee considered that the key clinical evidence came from KEYNOTE‑002. The Committee noted that KEYNOTE‑002 had not included any UK sites but had included centres in the USA, Argentina, and some European countries. It heard from the clinical experts that historically there had been a difference in outcomes in people with advanced melanoma in the UK compared with some other countries, possibly related to later diagnosis. However, the clinical experts explained that, because of recent advances in managing malignant melanoma in the NHS, including earlier diagnosis and the availability of new treatments, this has changed. The Committee also noted that 23% of people in KEYNOTE‑002 had BRAF V600 mutation‑positive disease. It heard from the clinical experts that this was lower than the overall prevalence of BRAF V600 mutation‑positive disease in the UK, which is about 45%. The clinical experts noted that this difference related mainly to patient selection in the trial and that the results would still be generalisable to the BRAF V600 mutation‑positive population eligible to have pembrolizumab in clinical practice. Therefore, the Committee concluded that KEYNOTE‑002 was generalisable to clinical practice in the NHS for those people whose disease has progressed after ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.\n\nThe Committee discussed the progression‑free survival results from KEYNOTE‑002. It was aware that follow‑up in the trial was short and therefore, the results were immature. It was aware that the company presented results based on an independent central review and an investigator assessment, and that both results were based on an interim analysis. It was also aware that the median progression‑free survival for pembrolizumab was higher using the investigator assessment, which it considered could relate to the lack of blinding in the trial. However, the Committee noted that both methods showed small but statistically significant improvements in median progression‑free survival with pembrolizumab compared with conventional chemotherapy. It also noted that there was a separation of the progression‑free survival curves that began around 12\xa0weeks, after which a larger difference in progression‑free survival was seen between chemotherapy and pembrolizumab. The Committee heard from the clinical experts that treatment response is best assessed around 12\xa0weeks and, after this, the progression‑free survival benefit starts becoming apparent. The Committee concluded that the evidence from KEYNOTE‑002, although immature, suggested that pembrolizumab improved progression‑free survival compared with conventional chemotherapy, and that the benefit became most apparent after 12\xa0weeks.\n\nThe Committee discussed the overall survival results and was aware that there was no statistically significant difference seen between pembrolizumab and chemotherapy. It considered that this could relate to immaturity of the data given the short follow‑up in the trial, and particularly to the fact that 48% of people in the chemotherapy group had switched to pembrolizumab. The Committee noted that the company had explored different methods of adjusting for treatment switching, and had concluded that the 2‑stage adjustment method was the most appropriate. It noted that the Evidence Review Group (ERG) had agreed with the company's approach and that, when using this method, there was a statistically significant difference in median overall survival between pembrolizumab and chemotherapy of 3.5\xa0months. The Committee concluded that, although the results were immature and there was uncertainty about the true survival benefit associated with pembrolizumab compared with conventional chemotherapy, the best available evidence from KEYNOTE‑002, using the 2‑stage adjustment method, suggested a difference in median overall survival of 3.5\xa0months.\n\nThe Committee discussed the adverse events associated with pembrolizumab. It noted that, in KEYNOTE‑002, pembrolizumab was associated with fewer adverse events than chemotherapy. It also recalled the comments from the clinical and patient experts that the adverse events of pembrolizumab were usually manageable and allowed people to continue with their normal activities (see section\xa04.3). The Committee concluded that the adverse events of pembrolizumab were manageable, and favourable when compared with chemotherapy.\n\n# Cost effectiveness\n\nThe Committee considered the company's model, which compared pembrolizumab with best supportive care in people with advanced (unresectable or metastatic) melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor. The Committee considered that a 3‑state model structure was appropriate for decision‑making. It also accepted the company's use of data from the chemotherapy group in KEYNOTE‑002 as a proxy for best supportive care based on the Committee's previous conclusion that conventional chemotherapy was an appropriate comparator for pembrolizumab in its expected place in the treatment pathway (see section\xa04.2).\n\nThe Committee noted that the company's economic analysis resulted in a deterministic incremental cost‑effectiveness ratio (ICER) for pembrolizumab compared with best supportive care of about £43,000 per quality‑adjusted life year (QALY) gained, and a probabilistic ICER of about £68,000 per QALY gained. The Committee expressed concerns about the substantial difference between these figures and discussed possible reasons for the difference. It understood that the variables with the biggest impact on the results were the parameters used to extrapolate progression‑free survival and the hazard ratio for overall survival from the 2‑stage adjustment method used to extrapolate the overall survival results.\n\nThe Committee was aware that the company used a Gompertz distribution for extrapolating progression‑free survival from the time of assessment (week\xa012) onwards in the pembrolizumab group, and that it assumed all people having chemotherapy had progressed or died by the end of the trial (week\xa067). The Committee noted the comments from the ERG that the Gompertz distribution is associated with a long tail in the progression‑free survival curve and that this tends to overestimate progression‑free survival in the long‑term. It also noted that the confidence intervals were wide because there was a very small proportion of the cohort still at risk at the end of the tail in the progression‑free survival curve, which would have a particular impact on the probabilistic cost‑effectiveness estimate. The ERG also considered that the company's assumption that all people in the chemotherapy group had disease progression or died at week\xa067 overestimated the relative progression‑free survival benefit associated with pembrolizumab. It also noted that it was more appropriate to use exponential models for extrapolation in both treatment groups. The Committee was concerned that the progression‑free survival results were immature, and that it was uncertain how many and for how long people would have progression‑free disease. However, it accepted that, when using a Gompertz distribution, the progression‑free survival results appeared too optimistic because it was unlikely that people would have life‑long progression‑free disease.\n\nThe Committee noted that the company had used a 3‑stage approach to modelling overall survival based on different data sources. It also noted the comments from the ERG that this provided clinically implausible results such as: a 4‑year period of zero mortality risk followed by a sudden increase in the mortality risk occurring after 10\xa0years, and an overall survival benefit of pembrolizumab compared with best supportive care that persisted indefinitely. The Committee noted that the ERG had implemented amendments to the company's model in line with its preferred assumptions. It also noted that it provided an exploratory analysis incorporating a different approach to modelling overall survival using trial results, together with a mixed‑exponential model based on registry data. The Committee expressed the view that the ERG's overall approach was generally more clinically plausible than the company's model using 3\xa0separate sources.\n\nThe Committee noted that, even when incorporating multiple amendments such as changes to the utility values and costs, the cumulative effect of all ERG amendments on the ICER was modest, increasing the ICER for pembrolizumab compared with best supportive care by about £4000, to £47,000 per QALY gained. The Committee was aware that the ERG had not presented probabilistic cost‑effectiveness results and recalled its previous concerns about the wide difference between the company's deterministic and probabilistic results (see sections\xa04.9 and\xa04.10). The Committee heard from the ERG that, because its approach for modelling progression‑free survival used an exponential model instead of a Gompertz model, it was likely that the ERG's deterministic and probabilistic analyses would be much more similar. The Committee therefore considered that, despite the differences between the company's model and the ERG's preferred approach, the ICERs were not very different. It concluded that the most plausible ICER for pembrolizumab compared with best supportive care was likely to be less than £50,000 per QALY gained.\n\nThe Committee discussed the innovative nature of pembrolizumab. It noted that the company stated that pembrolizumab was innovative and a step‑change in the management of advanced melanoma because it treats a life‑threatening and seriously debilitating condition, meets a high unmet need and provides a significant advantage over other treatments used in the UK. The Committee agreed with the company that pembrolizumab is innovative because it meets a high unmet medical need, and because of its low toxicity and favourable adverse effects profile compared with other treatments for metastatic melanoma. However, it could not identify any specific health‑related benefit that had not been already captured in the QALY calculation.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether pembrolizumab met all the criteria to be considered a life‑extending, end‑of‑life treatment and whether the evidence presented was plausible, objective and robust enough to support it. The Committee agreed that the life expectancy of people with advanced melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor, who do not have any other treatments available apart from conventional chemotherapy, is normally less than 24\xa0months. For example, life expectancy in people with metastatic melanoma was up to 9.0\xa0months based on data from Balch et al. (2001), Korn et al. (2008) and Thirlwell and Nathan (2008), 20.9\xa0months in the company's base‑case analysis, and 17.2\xa0months in the ERG's exploratory analyses. The Committee also agreed that, although the overall survival data are immature, the best available data from KEYNOTE‑002 and using the 2‑stage adjustment method for treatment switching suggested that pembrolizumab offers an extension to life compared with conventional chemotherapy of 3.5\xa0months (see section\xa04.6). Finally, the Committee discussed the company's estimate for the number of people eligible to have pembrolizumab (that is, people with unresectable or metastatic melanoma whose disease has progressed after ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor), noting that this was about 600 in 2015, and about 300 annually thereafter. It heard from the clinical experts that these estimates were plausible and in line with the number of people who have had pembrolizumab through the early access to medicines scheme in the NHS. It concluded that this represents a small patient population. The Committee considered that, although the evidence for pembrolizumab in terms of progression‑free survival and overall survival is immature and based on a short follow‑up, the estimates and assumptions applied can be considered plausible, objective and robust enough to conclude that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.\n\nHaving accepted that the supplementary advice for appraising a life‑extending, end‑of‑life treatment applies, the Committee discussed whether pembrolizumab could be considered a cost‑effective use of NHS resources. The Committee recalled its previous conclusion that, despite the differences between the company's model and the ERG's amendments, the results were not very different and that it was likely that the most plausible ICER for pembrolizumab compared with best supportive care was less than £50,000 per QALY gained. Therefore, the Committee concluded that, on balance, pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic melanoma) after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.\n\nThe Committee was aware of NICE's position statement about the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism. It acknowledged 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of pembrolizumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the cost effectiveness of pembrolizumab.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA357\n\nAppraisal title: Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab\n\nSection\n\nKey conclusion\n\nPembrolizumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in adults only:\n\nafter the disease has progressed with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor and\n\nwhen the company provides pembrolizumab with the discount agreed in the patient access scheme.\n\n\n\nThe Committee concluded that the evidence from KEYNOTE‑002, although immature, suggested that pembrolizumab improved progression‑free survival compared with conventional chemotherapy and that, when using the 2‑stage adjustment method, pembrolizumab was associated with an overall survival benefit of 3.5\xa0months compared with chemotherapy.\n\n, 4.6\n\nThe Committee concluded that the most plausible incremental cost‑effectiveness ratio (ICER) for pembrolizumab compared with best supportive care was likely to be less than £50,000 per quality‑adjusted life year (QALY) gained.\n\n\n\n\n\nHaving accepted that the supplementary advice for appraising a life‑extending, end‑of‑life treatment applies, the Committee concluded that pembrolizumab could be considered a cost‑effective use of NHS resources for people with advanced (unresectable or metastatic melanoma) after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe Committee concluded that the availability of a new treatment which slows disease progression and improves quality of life when other therapies have failed is very important to patients and their families.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\n\nThe Committee agreed with the company that pembrolizumab is innovative because it meets a high unmet medical need and because of its low toxicity and favourable adverse effects profile compared with other treatments for metastatic melanoma.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee concluded that, on the basis of the evidence submitted, it could only make recommendations for pembrolizumab after treatment with ipilimumab and, for BRAF V600 mutation‑positive disease, after both ipilimumab and a BRAF or MEK inhibitor.\n\n\n\nAdverse reactions\n\nThe Committee concluded that the adverse effects of pembrolizumab were manageable, and favourable when compared with chemotherapy.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe Committee considered that the key clinical evidence came from KEYNOTE‑002.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee concluded that KEYNOTE‑002 was generalisable to clinical practice in the NHS for those people whose disease has progressed after ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that, because the results were immature, there was uncertainty about the true survival benefit associated with pembrolizumab compared with conventional chemotherapy.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee concluded that the evidence from KEYNOTE‑002, although immature, suggested that pembrolizumab improved progression‑free survival compared with conventional chemotherapy and that, when using the 2‑stage adjustment method, pembrolizumab was associated with an overall survival benefit of 3.5\xa0months compared with chemotherapy.\n\n, 4.6\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered that the company's model, which compared pembrolizumab with best supportive care in people with advanced (unresectable or metastatic) melanoma after progression with ipilimumab and, for BRAF V600 mutation‑positive disease, a BRAF or MEK inhibitor, had a 3‑state model structure that was appropriate for decision‑making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was concerned that the progression‑free survival results were immature and that it was uncertain how many and for how long people would have progression‑free disease. However, it accepted that the company's approach to extrapolating progression‑free survival using a Gompertz distribution led to progression‑free survival results that appeared too optimistic because it was unlikely that people would have life‑long progression‑free disease.\n\n\n\nThe Committee expressed the view that the Evidence Review Group's (ERG's) approach to modelling overall survival was generally more clinically plausible than the company's model using 3\xa0separate sources.\n\n\n\nIncorporation of health‑related quality‑of‑life benefits and utility values\n\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe company got the utility values from EQ‑5D questionnaire data from KEYNOTE‑002. The utility values were incorporated into the model based on time to death.\n\n\n\nThe Committee could not identify any specific health‑related benefit that had not been already captured in the QALY calculation.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe Committee understood that the variables with the biggest impact on the results were the parameters used to extrapolate progression‑free survival and the hazard ratio for overall survival from the 2‑stage adjustment method used to extrapolate the overall survival results.\n\n\n\nMost likely cost‑effectiveness estimate (given as an ICER)\n\nThe Committee concluded that that the most plausible ICER for pembrolizumab compared with best supportive care was likely to be less than £50,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of pembrolizumab, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence.\n\n\n\nEnd‑of‑life considerations\n\nThe Committee considered that, although the evidence for pembrolizumab in terms of progression‑free survival and overall survival is immature (that is, based on a short period of follow‑up), the estimates and assumptions applied can be considered plausible, objective and robust enough to conclude that pembrolizumab meets all the criteria to be considered a life‑extending, end‑of‑life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were raised during the appraisal process.\n\n", 'Review of guidance': 'The guidance on this technology will be considered for review 3\xa0years after publication. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveOctober 2015'}
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Evidence-based recommendations on pembrolizumab (Keytruda) for treating advanced melanoma after disease progression with ipilimumab in adults.
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Pembrolizumab for treating PD-L1-positive non-small-cell lung cancer after chemotherapy
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Pembrolizumab for treating PD-L1-positive non-small-cell lung cancer after chemotherapy
Evidence-based recommendations on pembrolizumab (Keytruda) for treating PD-L1-positive non-small-cell lung cancer in adults who have had chemotherapy.
# Recommendations
Pembrolizumab is recommended as an option for treating locally advanced or metastatic PD‑L1‑positive non‑small‑cell lung cancer in adults who have had at least one chemotherapy (and targeted treatment if they have an epidermal growth factor receptor - or anaplastic lymphoma kinase ‑positive tumour), only if:
pembrolizumab is stopped at 2 years of uninterrupted treatment and no documented disease progression, and
the company provides pembrolizumab in line with the commercial access agreement with NHS England.
This guidance is not intended to affect the position of patients whose treatment with pembrolizumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Pembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody that acts on the 'programmed death 1' protein (PD‑1). The PD‑1 protein is part of the immune checkpoint pathway, and blocking its activity may promote an anti-tumour immune response.
Marketing authorisation
Pembrolizumab has a marketing authorisation for treating locally advanced or metastatic non‑small‑cell lung cancer (NSCLC) in adults whose tumours express PD‑L1 (that is, with a tumour proportion score ≥1%) and who have had at least 1 chemotherapy regimen. Patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)‑positive tumour mutations should also have had approved therapy for these mutations before having pembrolizumab.
Adverse reactions
The most common treatment-related adverse events associated with pembrolizumab include fatigue, decreased appetite, nausea, rash and pruritus. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
mg/kg every 3 weeks by intravenous (IV) infusion. The summary of product characteristics recommends treatment with pembrolizumab until disease progression or unacceptable toxicity.
Price
Pembrolizumab is available at a cost of £1,315.00 per 50‑mg vial (excluding VAT; 'British national formulary' online, accessed November 2016).
The pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in January 2017, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.# Evidence
The appraisal committee (section 6) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of non‑small‑cell lung cancer (NSCLC) and the value placed on the benefits of pembrolizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical management
The committee noted that people with locally advanced or metastatic NSCLC that has progressed after platinum-based chemotherapy have a poor prognosis. It is a debilitating condition with many distressing symptoms. The committee heard from clinical experts that people with this condition have limited treatment options and that existing treatments such as docetaxel can cause severe adverse effects. It heard from the experts that premedication is not needed before pembrolizumab. The committee noted that pembrolizumab was better tolerated than docetaxel although a small proportion of people have immune-related adverse effects such as rash and colitis. The committee heard from the clinical experts that some people whose disease progresses rapidly after initial treatment or who cannot tolerate docetaxel currently have best supportive care and pembrolizumab may be considered suitable for these patients. The committee was aware that in their submissions the patient experts stated that the current outlook for patients with NSCLC whose disease has relapsed after platinum-based chemotherapy is poor. It noted that improving quality of life and even small extensions in duration of life are of considerable importance to this patient group. The committee concluded that pembrolizumab is an important treatment option for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 and who have had platinum-based chemotherapy, and a targeted treatment if the person has an epidermal growth factor receptor tyrosine kinase (EGFR‑TK)- or anaplastic lymphoma kinase (ALK)‑positive tumour.
The committee noted that the marketing authorisation for pembrolizumab states that people should have treatment based on their tumour's expression of PD‑L1, confirmed by a validated test. It heard from the clinical experts that trial evidence suggested that the higher the level of PD‑L1 expression, the greater the clinical response in people with locally advanced or metastatic NSCLC. The clinical experts also noted that although PD‑L1 testing is not part of standard NHS clinical practice, it is a straightforward immunohistochemical assay. It could be standardised quickly and, with training, quickly implemented as standard practice in the NHS. The clinical experts highlighted that re-biopsy on progression is becoming standard practice in lung oncology, but that re-biopsies for analysis of PD‑L1 expression may not always be needed because testing of stored samples is possible. The committee noted that the costs of testing for PD‑L1 expression were included in the company's economic analysis. The committee concluded that PD‑L1 testing could be standardised quickly and, with training, implemented as standard clinical practice in the NHS.
The committee discussed the clinical management of locally advanced or metastatic NSCLC. It understood that platinum therapy is given as a first treatment for NSCLC in people whose tumours are not EGFR‑TK‑positive, followed by docetaxel or docetaxel plus nintedanib for people with adenocarcinoma. The committee understood that pembrolizumab would be considered as an alternative option to docetaxel or docetaxel plus nintedanib. For people with EGFR‑TK‑positive tumours, treatment starts with a tyrosine kinase inhibitor, followed by platinum therapy. For people with ALK‑positive tumours, platinum combination therapy followed by an ALK inhibitor are the standard treatment choices. The committee heard from the clinical experts that pembrolizumab would be an alternative to docetaxel or to docetaxel plus nintedanib in people who have had targeted treatment for EGFR‑TK- or ALK‑positive tumours. The committee agreed with the company's approach of not comparing pembrolizumab with nivolumab, ceritinib or ramucirumab which, at the time of committee's first discussion, were the subject of ongoing NICE appraisals. The committee noted that the company had not compared pembrolizumab with best supportive care. It concluded that for a small proportion of patients who declined docetaxel, or could not tolerate it, best supportive care could be a relevant comparator but there was no direct evidence for this comparison. The committee also concluded that pembrolizumab was appropriately positioned in the clinical pathway as a treatment option for people who have had previous chemotherapy with or without a targeted therapy and as an alternative to docetaxel or to docetaxel plus nintedanib.
# Clinical effectiveness
The committee noted that the clinical effectiveness evidence for pembrolizumab compared with docetaxel came from 2 studies:
KEYNOTE‑001 and
KEYNOTE‑010.The committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of people with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias. The committee understood from the company submission that the trial was designed to assess the efficacy and safety of pembrolizumab in patients with advanced PD‑L1‑positive NSCLC in 2 populations according to tumour proportion score (TPS), that is, the overall population with TPS 1% or greater and a population with TPS 50% or greater. The committee heard from the company that KEYNOTE‑010 was powered to detect a difference between pembrolizumab and docetaxel in the population with TPS 50% or more and in the overall TPS 1% or more population, but not for the TPS 1 to 49% population. The committee noted that inclusion criteria in KEYNOTE‑010 required patients to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The committee heard from the clinical experts that the overall population in KEYNOTE‑010 was likely to be the same as those who have pembrolizumab in clinical practice. The committee concluded that the population in KEYNOTE‑010 was generalisable to clinical practice in England.
The committee noted that the median overall survival gain from KEYNOTE‑010 was 10.5 months for pembrolizumab compared with 8.6 months for docetaxel in the intention-to-treat population. This difference was statistically significant. The committee concluded that based on the trial data, pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 compared with docetaxel.
The committee discussed the indirect treatment comparison presented by the company, which compared the relative treatment effects of pembrolizumab with nintedanib plus docetaxel in the population with adenocarcinoma. Two studies formed the basis of the indirect treatment comparison: KEYNOTE‑010 and LUME-LUNG-01. Both trials included docetaxel as a comparator. LUME-LUNG-01 included adults with advanced NSCLC whose disease had progressed on or after treatment with only 1 previous chemotherapy regimen, and stratified recruited patients by cancer histology, with both treatment arms including about 50% of patients with adenocarcinoma. The ERG highlighted that KEYNOTE‑010 included adults with PD‑L1‑positive advanced NSCLC whose disease has progressed after chemotherapy and after targeted therapy for EGFR- or ALK‑positive tumours. But in LUME-LUNG-01, neither PD‑L1 expression nor EGFR mutation status was assessed in the patients with advanced NSCLC. The committee noted that the results from the indirect treatment comparison were not directly used in the economic model. Only the hazard ratio for nintedanib plus docetaxel compared with docetaxel was applied to the docetaxel arm in the model for the adenocarcinoma subgroup. The committee concluded that the indirect treatment comparison was not robust, and that the trial populations of KEYNOTE-010 and LUME-LUNG-01 were too different. Therefore it was not appropriate for decision-making regarding the effectiveness of pembrolizumab compared with nintedanib in the population with adenocarcinoma.
# Cost effectiveness
The committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. It accepted the structure of the economic model developed by the company and considered it appropriate for decision-making. During consultation the company submitted a revised patient access scheme and updated evidence, which took into account 6 months of further follow-up data from the KEYNOTE‑010 trial.
## Treatment duration
The committee discussed the assumption in the company's model that at 2 years all patients whose disease had not progressed (the pre-progression state) would stop treatment. It understood that this assumption was based on the KEYNOTE‑010 protocol, which stated that patients could continue pembrolizumab until disease progression or unacceptable toxicity, or for 2 years without interruption. The committee recalled that the company's submission stated that the optimal duration of treatment with pembrolizumab is unknown. It was aware of the clinical experts' comments that this is because the data are immature. The committee heard from the company that, based on the latest data cut-off (31 March 2016) and additional follow-up data (to 21 July 2016), no KEYNOTE‑010 patients continued treatment after 2 years. In line with the protocol, patients discontinued treatment after 2 years of uninterrupted therapy (and no documented disease progression) or 35 doses, whichever occurred later. The committee noted that, despite being in the trial protocol, there is no 2‑year stopping rule in the pembrolizumab summary of product characteristics. The clinical experts stated that in clinical practice, the decision to stop treatment would be made between the clinician and the patient, but the number of patients likely to have treatment after 2 years would be small. The clinical experts also stated that a small proportion of patients who stopped treatment would be followed up with the possibility of restarting treatment depending on the clinical circumstances. The committee considered the company's analyses which explored the effect of varying the proportion of patients having treatment after 2 years and before disease progression. The company had resubmitted evidence during consultation assuming that 25% of patients would continue treatment at 2 years in the base-case analysis and the committee noted that the incremental cost-effectiveness ratio (ICER) increased from £44,490 to £49,063 per quality-adjusted life year (QALY) gained as the proportion of patients having treatment after 2 years increased from 25% to 100%. The committee noted that, to model implementation of a 2-year stopping rule, it should be assumed that all people having pembrolizumab would stop treatment after 2 years if their disease has not progressed, and incorporating a 2-year stopping rule would reduce the company's base-case ICER by about £2,000 per QALY gained. The committee noted the uncertainty around the optimal treatment duration and was aware that consultation comments from NHS England stated that data on the optimal treatment duration of checkpoint inhibitors such as pembrolizumab will begin to be available within the next 2 years. NHS England commented during consultation that it was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable. Also, the comments suggested that pembrolizumab could be reappraised by NICE in 2 years time to account for new evidence on optimal treatment duration. The committee concluded that implementation of a 2-year stopping rule and review of the published guidance at 2 years is appropriate.
## Treatment switching
The committee heard that crossover was not permitted in KEYNOTE-010. However, the company reported that of the patients randomised to chemotherapy, 12.5% (43 people) crossed over and had treatment with other anti‑PD‑1 or anti‑PD‑L1 treatments after treatment discontinuation. A 2‑stage adjustment method was used by the company to account for treatment switching in the base-case analyses. The rank-preserving structural failure time (RPSFT) method, a pre-specified analysis, was presented as a scenario. The committee noted that the ICER for pembrolizumab compared with docetaxel using the RPSFT method was higher than that for the 2‑stage method. The committee heard from the ERG that the RPSFT method does not have a test for a common treatment effect and it preferred the 2‑stage adjustment method to account for the effects of crossover; it also noted that this method has been used in other appraisals of immunotherapies. The committee concluded that the 2‑stage adjustment method was reasonable.
## Time on treatment and additional weeks of therapy
The committee discussed time on treatment for people enrolled in KEYNOTE‑010. The ERG highlighted that when using the individual patient level data provided by the company at clarification stage, the ERG analyses gave an estimated treatment duration of 217 days using the gamma model and 255 days with the Kaplan–Meier plus exponential model. The company also did analyses in which different parametric curves were fitted; it concluded that the generalised gamma model did not provide the best model or visual fit. The committee noted that it would have preferred to see time on treatment taken directly from KEYNOTE‑010 rather than the company's approach of using time to progression with a constant hazard adjustment to estimate time to treatment discontinuation. The committee was not clear about how many patients had scans to check for true disease progression and what proportion of these scans confirmed disease progression. The committee noted that additional weeks of therapy were sometimes needed (as stated in the KEYNOTE‑010 protocol) to distinguish between true progression and pseudo-progression. Pseudo-progression is when tumours appear to enlarge but then respond to treatment. It heard from the clinical experts that additional outpatient visits and CT scans may be needed for approximately 10% of patients in clinical practice. In response to a query from committee, the company clarified that the hazard ratio for the relationship between disease progression and time on treatment (HR=1.039) included administration costs for people who remained on pembrolizumab (needing a confirmatory scan) and people whose disease had not yet progressed. The company did not specifically adjust for pseudo-progression in their estimates of treatment costs, but the committee heard from the company that if patients remained on treatment during pseudo-progression, the time on treatment data would reflect this. The ERG stated that, overall, the adjusted progression-free survival curve appeared very similar to the time on treatment curve. However, the committee noted that after a confirmatory scan some patients remained on treatment after disease progression. It was unclear if some patients, who did not need a scan to confirm true progression, continued therapy in the progressed state. The committee concluded that there was still some uncertainty about how many people continue treatment after disease progression and noted that these treatment and administration costs may not be appropriately captured in the company's analyses.
## Extrapolation methods used for overall survival
The committee noted that, to estimate overall survival, the company used 52‑week Kaplan–Meier data from KEYNOTE‑010. After 52 weeks, for docetaxel, the company fitted an exponential model to the KEYNOTE‑010 data after a 2‑stage crossover adjustment. The company explored cut-off points of 42, 62, 72 and 82 weeks as well as 52 weeks. The committee acknowledged at the first appraisal meeting that there was marked sensitivity of the ICER to the choice of different cut-off points when using the original September data cut-off as well as the company and the ERG's approach to deriving the exponential curve.During consultation the company submitted additional evidence, which incorporated the more recent KEYNOTE-010 data from March 2016. The committee discussed the different cut-off points used when switching from trial survival data to the exponential survival modelling based on this additional evidence, and it noted that the sensitivity of the ICER to the different cut-off points was significantly reduced, and this supported the company's use of the exponential model. The company stated that their original extrapolated curves overlaid with the Kaplan–Meier data from March 2016 showed that the 42‑week and 82‑week cut-off points were implausible. The committee concluded that the 42‑week and 82‑week cut-off points could be excluded from consideration, but there was no evidence that the 52‑week cut-off chosen by the company and ERG for their base-case analyses was the most appropriate for extrapolating the Kaplan–Meier data. The committee concluded that the 52‑week, 62‑week and 72‑week cut-off points are all plausible, but noted that based on the March 2016 data submitted by the company during consultation, the ICER is no longer very sensitive to the choice of cut-off point to model overall survival.
## Long-term treatment effect
The committee understood that the company's survival estimates depend on an ongoing reduction in the risk of death with pembrolizumab (time to death was independent of previous time on treatment or disease progression), which continues after treatment has stopped and is maintained for a lifetime. The committee recalled that the original modelling projections, using the September 2015 KEYNOTE‑010 data and the company's preferred assumptions, suggested that 10.3% and 1.2% of patients in the pembrolizumab arm would be alive at 5 years and 10 years, falling to 9.6% and 1.0% respectively when incorporating the March 2016 data submitted during consultation. Consultation comments from clinical experts noted that immunotherapies are expected to maintain their effect for a subgroup of people and that these values appear reasonable from clinical experience. But the committee considered that the assumption of a constant treatment effect over 20 years, irrespective of the time spent on treatment or disease progression was unlikely based on current clinical understanding of disease progression. The additional evidence submitted by the company during consultation included scenarios in which the hazard ratio for overall survival was set to 1.0 at 3, 5, and 10 years to model stopping of the continued treatment effect. The committee noted that, using the company's preferred assumptions of an extrapolation point of 52 weeks (see section 4.11) and 25% of patients continuing treatment after 2 years (see section 4.8), the ICER ranges from £61,954 per QALY gained with a 3‑year treatment effect to £44,490 per QALY gained with a lifetime treatment effect.
The committee noted that the ERG presented data from Schadendorf (2015). This was a meta-analysis of studies in which patients received ipilimumab for treating unresectable or metastatic melanoma. The ERG based their preferred scenario that continued treatment effect stops at 3 years on the Schadendorf evidence, but it noted that these analyses are only designed to show the sensitivity of ICERs to different treatment effect durations. The committee noted in the March 2016 data submitted by the company at consultation all patients had stopped taking pembrolizumab and that the hazard ratios for both overall survival and progression-free survival were essentially unchanged from the original September 2015 data, supporting the company's preferred assumption that there is a long-term treatment effect. The committee considered that although there is evidence to support a continued benefit of pembrolizumab after stopping treatment and in the progressed state, the size of this effect and its duration is unknown for NSCLC. The committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.
## Utility values used in the pre- and post-progression states
The committee concluded that the KEYNOTE‑010 utility data were the most appropriate to inform decision-making and including a disutility for adverse events was appropriate.
# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It noted the evidence presented by the company, which showed that people with NSCLC have a life expectancy of less than 24 months. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is between 21.2 and 22.8 months, compared with 10.4 months with docetaxel. It agreed that there is significant uncertainty in the overall survival gain and that this degree of benefit is likely to be optimistic. However, the committee considered it reasonable to assume that the benefit is likely to exceed 3 months. The committee therefore concluded that pembrolizumab met the end-of-life criteria and that it can be considered a life-extending, end-of-life treatment.
# Most plausible ICER
The committee discussed the most plausible ICER for pembrolizumab compared with docetaxel. It noted comments from the clinical experts that the appropriate population is the overall population expressing PD‑L1 (see section 4.4). Also, the committee considered that the indirect comparison in the adenocarcinoma subgroup was too unreliable for decision-making and so it focused on the pembrolizumab and docetaxel comparison in the overall population (see section 4.6). The committee agreed that the KEYNOTE‑010 data were more appropriate, compared with the KEYNOTE‑001 data (see section 4.4). The committee was aware of its earlier conclusion that no patient would continue treatment after 2 years with implementation of a 2‑year stopping rule, and that this would reduce the ICER by about £2,000 per QALY gained (see section 4.8) and discussed the remaining area of uncertainty; the long-term treatment effect. It recalled that the ICERs are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of £61,954 to £44,490 per QALY gained (see section 4.12), but concluded that within the uncertainties and with implementation of a 2‑year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.
The committee discussed the uncertainty about the long-term treatment effect. It was aware of several ongoing clinical trials which could reduce this uncertainty and if pembrolizumab is recommended for routine commissioning, relevant data would be collected by the Systemic Anti-Cancer Therapy Data Set. The committee concluded that uncertainty about the long-term treatment effect would reduce as data become available on the optimal duration of treatment of PD‑1 inhibitors in the next 2 years.
The committee discussed whether, overall, pembrolizumab is a cost-effective use of NHS resources, taking into account the most plausible ICER and the uncertainty that has been identified. It was also aware that there would be a wider benefit to the NHS because the simple discount agreed in the patient access scheme would apply across all indications. It concluded that pembrolizumab should be recommended for routine use with a 2‑year stopping rule, but the guidance should be reviewed 2 years after publication to take in account more mature evidence.
The committee heard from the clinical and patient experts that pembrolizumab was innovative in its potential to make a significant and substantial effect on health-related benefits. It understood that pembrolizumab is generally well tolerated compared with docetaxel, is easy to administer and shows an improvement in overall survival benefit compared with other drugs. The committee concluded that pembrolizumab addresses an unmet need in a debilitating condition for which few treatment options are available, but there were no other benefits not captured in the QALY.
# Summary of appraisal committee's key conclusions
TA428
Appraisal title: Pembrolizumab for treating PD‑L1‑positive non‑small‑cell lung cancer after chemotherapy
Section
Key conclusion
Pembrolizumab is recommended as an option for treating locally advanced or metastatic PD‑L1‑positive non‑small‑cell lung cancer in adults who have had at least one chemotherapy (and targeted treatment if they have an epidermal growth factor receptor - or anaplastic lymphoma kinase ‑positive tumour), only if:
pembrolizumab is stopped at 2 years of uninterrupted treatment and no documented disease progression, and
the company provides pembrolizumab with the discount agreed in the patient access scheme revised in the context of this appraisal.
The committee concluded that pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 based on the KEYNOTE-010 trial data.
The committee noted the uncertainty around the optimal treatment duration and was aware that consultation comments from NHS England stated that data on the optimal treatment duration of checkpoint inhibitors such as pembrolizumab will begin to be available within the next 2 years. NHS England commented during consultation that it was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable.
It recalled that the ICERs are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of £61,954 to £44,490 per QALY gained (see section 4.12), but concluded that within the uncertainties and with implementation of a 2-year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.
The committee discussed whether, overall, pembrolizumab is a cost-effective use of NHS resources, taking into account the most plausible ICER and the uncertainty that has been identified. It was also aware and that there would be a wider benefit to the NHS because the simple discount agreed in the patient access scheme would apply across all indications. It concluded that pembrolizumab should be recommended for routine use with a 2-year stopping rule, but the guidance should be reviewed 2 years after publication to take in account more mature evidence.
Current practice
Clinical need of patients, including the availability of alternative treatments
People with locally advanced or metastatic NSCLC have a poor prognosis. It is a debilitating condition with many distressing symptoms. Improving quality of life and even small extensions in duration of life are of considerable importance to this patient group.
Platinum therapy is given as a first treatment for NSCLC in people whose disease is not EGFR‑TK‑positive, followed by docetaxel or docetaxel plus nintedanib (depending on tumour histology).
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
People with NSCLC have limited treatment options and existing treatments such as docetaxel can cause severe adverse effects. Premedication is not needed before pembrolizumab and it is generally well tolerated. Based on clinical trial data, pembrolizumab provides a statistically significant median overall survival gain compared with docetaxel and an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1.
What is the position of the treatment in the pathway of care for the condition?
The committee noted that the marketing authorisation for pembrolizumab states that people should have treatment based on their tumour's expression of PD‑L1 (that is, with a tumour proportion score ≥1%), confirmed by a validated test.
The committee understood that platinum therapy is given as a first treatment for NSCLC in people whose tumours are not EGFR‑TK‑positive, followed by docetaxel or docetaxel plus nintedanib (depending on tumour histology). For people with EGFR‑TK‑positive tumours, treatment starts with a tyrosine kinase inhibitor, followed by a platinum therapy option. For people with ALK‑positive tumours, platinum combination therapy followed by an ALK inhibitor are the standard treatment choices. The committee heard from the clinical experts that pembrolizumab would be an alternative to docetaxel or to docetaxel plus nintedanib (depending on tumour histology) in people who have had targeted treatment for EGFR‑TK- or ALK‑positive tumours.
The committee concluded that pembrolizumab was appropriately positioned in the clinical pathway as a treatment option for people who have had 2 or 3 therapies and as an alternative to docetaxel or to docetaxel plus nintedanib.
Adverse reactions
A small proportion of people have immune-related adverse effects such as rash and colitis.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The clinical evidence for treating NSCLC came from 3 studies (KEYNOTE-001, KEYNOTE-010 and LUME-LUNG-01).
The committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of people with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias. The committee concluded that pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 based on the trial data.
The committee concluded that the indirect treatment comparison of pembrolizumab compared with nintedanib plus docetaxel was not robust and was limited because of the differences between the trial populations. Therefore it was not appropriate for decision-making on the effectiveness of pembrolizumab in the population with adenocarcinoma histology.
Relevance to general clinical practice in the NHS
The committee heard from the clinical experts that the overall population in KEYNOTE-010 was likely to be the same as those who have pembrolizumab in clinical practice. The committee concluded that the population in KEYNOTE-010 was generalisable to clinical practice in England.
Uncertainties generated by the evidence
The committee noted the uncertainty around the optimal duration of treatment. It noted NHS England was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable. It concluded that implementation of a 2-year stopping rule and review of the published guidance at 2 years is appropriate.
The committee heard from the ERG that the RPSFT method to account for treatment switching does not have a test for a common treatment effect and it preferred the 2-stage adjustment method to account for the effects of crossover; it also noted that this method has been used in other appraisals of immunotherapies. The committee concluded that the 2-stage adjustment method was reasonable.
The committee concluded that there was still some uncertainty about how many people continue treatment after disease progression and noted that these treatment and administration costs would not be included in the company analyses.
The committee concluded that there was no evidence that the 52-week cut-off was the most appropriate for extrapolating the Kaplan–Meier data but noted that based on the March 2016 data submitted by the company during consultation, the ICER is no longer very sensitive to the choice of cut-off point to model overall survival.
The committee considered that although it is likely there would be some continued benefit of pembrolizumab after stopping treatment and in the progressed state, the size of this effect and its duration is unknown for NSCLC. The committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The company presented an indirect treatment comparison to compare the relative treatment effects of pembrolizumab with nintedanib plus docetaxel in the population with adenocarcinoma. Two studies formed the basis of the indirect treatment comparison: KEYNOTE-010 and LUME-LUNG-01. The committee concluded that the indirect treatment comparison was not robust, and that the trial populations of KEYNOTE-010 and LUME-LUNG-01 were too different. Therefore it was not appropriate for decision-making on the effectiveness of pembrolizumab in the population with adenocarcinoma histology.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
In the overall population in KEYNOTE-010 the median overall survival gain was 10.5 months for pembrolizumab compared with 8.6 months for docetaxel. The committee concluded that pembrolizumab had an important extension-to-life benefit compared with docetaxel.
Evidence for cost effectiveness
Availability and nature of evidence
The committee accepted the structure of the economic model developed by the company and considered it appropriate for decision-making. During consultation the company submitted a revised patient access scheme and updated evidence, which takes into account 6 months of further follow-up data from the KEYNOTE-010 trial.
The company used efficacy data for pembrolizumab and docetaxel from KEYNOTE-010.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee was not clear about how many patients had scans to check for true disease progression and what proportion of these scans confirmed disease progression. The committee noted that additional weeks of therapy were sometimes needed (as stated in the KEYNOTE-010 protocol) to distinguish between true progression and pseudo-progression. The committee concluded that there was still some uncertainty about how many people continue treatment after disease progression and noted that these treatment and administration costs would not be included in the company analyses.
The committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of people with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias.
The committee concluded that the 52-week, 62-week and 72-week cut-off points for extrapolating the Kaplan–Meier data are all plausible, but noted that based on the March 2016 data submitted by the company during consultation, the ICER is no longer very sensitive to the choice of cut-off point to model overall survival.
The committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.
The committee discussed the uncertainty about the long-term treatment effect. It was aware of several ongoing clinical trials which could reduce this uncertainty and if pembrolizumab is recommended for routine commissioning, relevant data would be collected by the Systemic Anti-Cancer Therapy Data Set. The committee concluded that uncertainty about the long-term treatment effect would reduce as data become available on the optimal duration of treatment of PD‑1 inhibitors in the next 2 years.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee concluded that the KEYNOTE-010 utility data were the most appropriate to inform decision-making and including a disutility for adverse events was appropriate.
The committee concluded that pembrolizumab addresses an unmet need in a debilitating condition, for which few treatment options are available, but there were no other health benefits not captured in the QALY.
Are there specific groups of people for whom the technology is particularly cost effective?
No evidence has been submitted that there is a group of people for whom the technology is particularly cost effective.
What are the key drivers of cost effectiveness?
The key drivers of cost-effectiveness were:
Treatment duration: the committee noted that the ICER increased from £44,490 to £49,063 per QALY gained as the proportion of patients having treatment after 2 years increased from 25% to 100%
Long-term treatment effect: The committee noted that, using the company's preferred assumptions of an extrapolation point of 52 weeks (see section 4.11) and 25% of patients continuing treatment after 2 years (see section 4.8), the ICER ranges from £61,954 per QALY gained with a 3-year treatment effect to £44,490 per QALY gained with a lifetime treatment effect.
The committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.
Most likely cost-effectiveness estimate (given as an ICER)
The committee discussed the most plausible ICER for pembrolizumab compared with docetaxel. It noted comments from the clinical experts that the appropriate population is the overall population expressing PD‑L1 (see section 4.4). Also, the committee considered that the indirect comparison in the adenocarcinoma subgroup was too unreliable for decision-making and so it focused on the pembrolizumab and docetaxel comparison in the overall population (see section 4.6). The committee agreed that the KEYNOTE-010 data were more appropriate, compared with the KEYNOTE-001 data (see section 4.4). The committee was aware of its earlier conclusion that no patient would continue treatment after 2 years with implementation of a 2-year stopping rule, and that this would reduce the ICER by about £2,000 per QALY gained (see section 4.8) and discussed the remaining area of uncertainty; the long-term treatment effect. It recalled that the ICERs are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of £61,954 to £44,490 per QALY gained (see section 4.12), but concluded that within the uncertainties and with implementation of a 2-year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.
Additional factors taken into account
Patient access schemes (PPRS)
The company has agreed a patient access scheme with the Department of Health. This scheme provides a discount to the list price of pembrolizumab applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.
End-of-life considerations
The committee heard that people with NSCLC have a life expectancy of less than 24 months. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is between 21.2 and 22.8 months, compared with 10.4 months with docetaxel. It agreed that there is significant uncertainty in the overall survival gain, and that this degree of benefit is likely to be optimistic. However it was reasonable to assume that the benefit is likely to exceed 3 months. The committee therefore concluded that pembrolizumab met the end-of-life criteria and that it can be considered a life-extending, end-of-life treatment.
Equalities considerations and social value judgements
No equalities issues were raised during this appraisal.
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{'Recommendations': 'Pembrolizumab is recommended as an option for treating locally advanced or metastatic PD‑L1‑positive non‑small‑cell lung cancer in adults who have had at least one chemotherapy (and targeted treatment if they have an epidermal growth factor receptor [EGFR]- or anaplastic lymphoma kinase [ALK]‑positive tumour), only if:\n\npembrolizumab is stopped at 2\xa0years of uninterrupted treatment and no documented disease progression, and\n\nthe company provides pembrolizumab in line with the commercial access agreement with NHS England.\n\nThis guidance is not intended to affect the position of patients whose treatment with pembrolizumab was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) is a humanised monoclonal antibody that acts on the 'programmed death\xa01' protein (PD‑1). The PD‑1 protein is part of the immune checkpoint pathway, and blocking its activity may promote an anti-tumour immune response.\n\nMarketing authorisation\n\nPembrolizumab has a marketing authorisation for treating locally advanced or metastatic non‑small‑cell lung cancer (NSCLC) in adults whose tumours express PD‑L1 (that is, with a tumour proportion score [TPS] ≥1%) and who have had at least 1\xa0chemotherapy regimen. Patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)‑positive tumour mutations should also have had approved therapy for these mutations before having pembrolizumab.\n\nAdverse reactions\n\nThe most common treatment-related adverse events associated with pembrolizumab include fatigue, decreased appetite, nausea, rash and pruritus. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nmg/kg every 3\xa0weeks by intravenous (IV) infusion. The summary of product characteristics recommends treatment with pembrolizumab until disease progression or unacceptable toxicity.\n\nPrice\n\nPembrolizumab is available at a cost of £1,315.00 per 50‑mg vial (excluding VAT; 'British national formulary' [BNF] online, accessed November 2016).\n\nThe pricing arrangement considered during guidance development was that Merck Sharp & Dohme had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of pembrolizumab with the discount applied at the point of purchase or invoice. After guidance publication in January 2017, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Merck Sharp & Dohme and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of pembrolizumab, having considered evidence on the nature of non‑small‑cell lung cancer (NSCLC) and the value placed on the benefits of pembrolizumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical management\n\nThe committee noted that people with locally advanced or metastatic NSCLC that has progressed after platinum-based chemotherapy have a poor prognosis. It is a debilitating condition with many distressing symptoms. The committee heard from clinical experts that people with this condition have limited treatment options and that existing treatments such as docetaxel can cause severe adverse effects. It heard from the experts that premedication is not needed before pembrolizumab. The committee noted that pembrolizumab was better tolerated than docetaxel although a small proportion of people have immune-related adverse effects such as rash and colitis. The committee heard from the clinical experts that some people whose disease progresses rapidly after initial treatment or who cannot tolerate docetaxel currently have best supportive care and pembrolizumab may be considered suitable for these patients. The committee was aware that in their submissions the patient experts stated that the current outlook for patients with NSCLC whose disease has relapsed after platinum-based chemotherapy is poor. It noted that improving quality of life and even small extensions in duration of life are of considerable importance to this patient group. The committee concluded that pembrolizumab is an important treatment option for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 and who have had platinum-based chemotherapy, and a targeted treatment if the person has an epidermal growth factor receptor tyrosine kinase (EGFR‑TK)- or anaplastic lymphoma kinase (ALK)‑positive tumour.\n\nThe committee noted that the marketing authorisation for pembrolizumab states that people should have treatment based on their tumour's expression of PD‑L1, confirmed by a validated test. It heard from the clinical experts that trial evidence suggested that the higher the level of PD‑L1 expression, the greater the clinical response in people with locally advanced or metastatic NSCLC. The clinical experts also noted that although PD‑L1 testing is not part of standard NHS clinical practice, it is a straightforward immunohistochemical assay. It could be standardised quickly and, with training, quickly implemented as standard practice in the NHS. The clinical experts highlighted that re-biopsy on progression is becoming standard practice in lung oncology, but that re-biopsies for analysis of PD‑L1 expression may not always be needed because testing of stored samples is possible. The committee noted that the costs of testing for PD‑L1 expression were included in the company's economic analysis. The committee concluded that PD‑L1 testing could be standardised quickly and, with training, implemented as standard clinical practice in the NHS.\n\nThe committee discussed the clinical management of locally advanced or metastatic NSCLC. It understood that platinum therapy is given as a first treatment for NSCLC in people whose tumours are not EGFR‑TK‑positive, followed by docetaxel or docetaxel plus nintedanib for people with adenocarcinoma. The committee understood that pembrolizumab would be considered as an alternative option to docetaxel or docetaxel plus nintedanib. For people with EGFR‑TK‑positive tumours, treatment starts with a tyrosine kinase inhibitor, followed by platinum therapy. For people with ALK‑positive tumours, platinum combination therapy followed by an ALK inhibitor are the standard treatment choices. The committee heard from the clinical experts that pembrolizumab would be an alternative to docetaxel or to docetaxel plus nintedanib in people who have had targeted treatment for EGFR‑TK- or ALK‑positive tumours. The committee agreed with the company's approach of not comparing pembrolizumab with nivolumab, ceritinib or ramucirumab which, at the time of committee's first discussion, were the subject of ongoing NICE appraisals. The committee noted that the company had not compared pembrolizumab with best supportive care. It concluded that for a small proportion of patients who declined docetaxel, or could not tolerate it, best supportive care could be a relevant comparator but there was no direct evidence for this comparison. The committee also concluded that pembrolizumab was appropriately positioned in the clinical pathway as a treatment option for people who have had previous chemotherapy with or without a targeted therapy and as an alternative to docetaxel or to docetaxel plus nintedanib.\n\n# Clinical effectiveness\n\nThe committee noted that the clinical effectiveness evidence for pembrolizumab compared with docetaxel came from 2\xa0studies:\n\nKEYNOTE‑001 and\n\nKEYNOTE‑010.The committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of people with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias. The committee understood from the company submission that the trial was designed to assess the efficacy and safety of pembrolizumab in patients with advanced PD‑L1‑positive NSCLC in 2\xa0populations according to tumour proportion score (TPS), that is, the overall population with TPS 1% or greater and a population with TPS 50% or greater. The committee heard from the company that KEYNOTE‑010 was powered to detect a difference between pembrolizumab and docetaxel in the population with TPS 50% or more and in the overall TPS 1% or more population, but not for the TPS 1 to 49% population. The committee noted that inclusion criteria in KEYNOTE‑010 required patients to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of\xa00 or\xa01. The committee heard from the clinical experts that the overall population in KEYNOTE‑010 was likely to be the same as those who have pembrolizumab in clinical practice. The committee concluded that the population in KEYNOTE‑010 was generalisable to clinical practice in England.\n\nThe committee noted that the median overall survival gain from KEYNOTE‑010 was 10.5\xa0months for pembrolizumab compared with 8.6\xa0months for docetaxel in the intention-to-treat population. This difference was statistically significant. The committee concluded that based on the trial data, pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 compared with docetaxel.\n\nThe committee discussed the indirect treatment comparison presented by the company, which compared the relative treatment effects of pembrolizumab with nintedanib plus docetaxel in the population with adenocarcinoma. Two studies formed the basis of the indirect treatment comparison: KEYNOTE‑010 and LUME-LUNG-01. Both trials included docetaxel as a comparator. LUME-LUNG-01 included adults with advanced NSCLC whose disease had progressed on or after treatment with only 1\xa0previous chemotherapy regimen, and stratified recruited patients by cancer histology, with both treatment arms including about 50% of patients with adenocarcinoma. The ERG highlighted that KEYNOTE‑010 included adults with PD‑L1‑positive advanced NSCLC whose disease has progressed after chemotherapy and after targeted therapy for EGFR- or ALK‑positive tumours. But in LUME-LUNG-01, neither PD‑L1 expression nor EGFR mutation status was assessed in the patients with advanced NSCLC. The committee noted that the results from the indirect treatment comparison were not directly used in the economic model. Only the hazard ratio for nintedanib plus docetaxel compared with docetaxel was applied to the docetaxel arm in the model for the adenocarcinoma subgroup. The committee concluded that the indirect treatment comparison was not robust, and that the trial populations of KEYNOTE-010 and LUME-LUNG-01 were too different. Therefore it was not appropriate for decision-making regarding the effectiveness of pembrolizumab compared with nintedanib in the population with adenocarcinoma.\n\n# Cost effectiveness\n\nThe committee discussed the cost-effectiveness evidence presented by the company and its critique by the ERG. It accepted the structure of the economic model developed by the company and considered it appropriate for decision-making. During consultation the company submitted a revised patient access scheme and updated evidence, which took into account 6\xa0months of further follow-up data from the KEYNOTE‑010 trial.\n\n## Treatment duration\n\nThe committee discussed the assumption in the company's model that at 2\xa0years all patients whose disease had not progressed (the pre-progression state) would stop treatment. It understood that this assumption was based on the KEYNOTE‑010 protocol, which stated that patients could continue pembrolizumab until disease progression or unacceptable toxicity, or for 2\xa0years without interruption. The committee recalled that the company's submission stated that the optimal duration of treatment with pembrolizumab is unknown. It was aware of the clinical experts' comments that this is because the data are immature. The committee heard from the company that, based on the latest data cut-off (31\xa0March 2016) and additional follow-up data (to 21\xa0July 2016), no KEYNOTE‑010 patients continued treatment after 2\xa0years. In line with the protocol, patients discontinued treatment after 2\xa0years of uninterrupted therapy (and no documented disease progression) or 35\xa0doses, whichever occurred later. The committee noted that, despite being in the trial protocol, there is no 2‑year stopping rule in the pembrolizumab summary of product characteristics. The clinical experts stated that in clinical practice, the decision to stop treatment would be made between the clinician and the patient, but the number of patients likely to have treatment after 2\xa0years would be small. The clinical experts also stated that a small proportion of patients who stopped treatment would be followed up with the possibility of restarting treatment depending on the clinical circumstances. The committee considered the company's analyses which explored the effect of varying the proportion of patients having treatment after 2\xa0years and before disease progression. The company had resubmitted evidence during consultation assuming that 25% of patients would continue treatment at 2\xa0years in the base-case analysis and the committee noted that the incremental cost-effectiveness ratio (ICER) increased from £44,490 to £49,063 per quality-adjusted life year (QALY) gained as the proportion of patients having treatment after 2\xa0years increased from 25% to 100%. The committee noted that, to model implementation of a 2-year stopping rule, it should be assumed that all people having pembrolizumab would stop treatment after 2\xa0years if their disease has not progressed, and incorporating a 2-year stopping rule would reduce the company's base-case ICER by about £2,000 per QALY gained. The committee noted the uncertainty around the optimal treatment duration and was aware that consultation comments from NHS England stated that data on the optimal treatment duration of checkpoint inhibitors such as pembrolizumab will begin to be available within the next 2\xa0years. NHS England commented during consultation that it was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable. Also, the comments suggested that pembrolizumab could be reappraised by NICE in 2\xa0years time to account for new evidence on optimal treatment duration. The committee concluded that implementation of a 2-year stopping rule and review of the published guidance at 2\xa0years is appropriate.\n\n## Treatment switching\n\nThe committee heard that crossover was not permitted in KEYNOTE-010. However, the company reported that of the patients randomised to chemotherapy, 12.5% (43\xa0people) crossed over and had treatment with other anti‑PD‑1 or anti‑PD‑L1 treatments after treatment discontinuation. A 2‑stage adjustment method was used by the company to account for treatment switching in the base-case analyses. The rank-preserving structural failure time (RPSFT) method, a pre-specified analysis, was presented as a scenario. The committee noted that the ICER for pembrolizumab compared with docetaxel using the RPSFT method was higher than that for the 2‑stage method. The committee heard from the ERG that the RPSFT method does not have a test for a common treatment effect and it preferred the 2‑stage adjustment method to account for the effects of crossover; it also noted that this method has been used in other appraisals of immunotherapies. The committee concluded that the 2‑stage adjustment method was reasonable.\n\n## Time on treatment and additional weeks of therapy\n\nThe committee discussed time on treatment for people enrolled in KEYNOTE‑010. The ERG highlighted that when using the individual patient level data provided by the company at clarification stage, the ERG analyses gave an estimated treatment duration of 217\xa0days using the gamma model and 255\xa0days with the Kaplan–Meier plus exponential model. The company also did analyses in which different parametric curves were fitted; it concluded that the generalised gamma model did not provide the best model or visual fit. The committee noted that it would have preferred to see time on treatment taken directly from KEYNOTE‑010 rather than the company's approach of using time to progression with a constant hazard adjustment to estimate time to treatment discontinuation. The committee was not clear about how many patients had scans to check for true disease progression and what proportion of these scans confirmed disease progression. The committee noted that additional weeks of therapy were sometimes needed (as stated in the KEYNOTE‑010 protocol) to distinguish between true progression and pseudo-progression. Pseudo-progression is when tumours appear to enlarge but then respond to treatment. It heard from the clinical experts that additional outpatient visits and CT scans may be needed for approximately 10% of patients in clinical practice. In response to a query from committee, the company clarified that the hazard ratio for the relationship between disease progression and time on treatment (HR=1.039) included administration costs for people who remained on pembrolizumab (needing a confirmatory scan) and people whose disease had not yet progressed. The company did not specifically adjust for pseudo-progression in their estimates of treatment costs, but the committee heard from the company that if patients remained on treatment during pseudo-progression, the time on treatment data would reflect this. The ERG stated that, overall, the adjusted progression-free survival curve appeared very similar to the time on treatment curve. However, the committee noted that after a confirmatory scan some patients remained on treatment after disease progression. It was unclear if some patients, who did not need a scan to confirm true progression, continued therapy in the progressed state. The committee concluded that there was still some uncertainty about how many people continue treatment after disease progression and noted that these treatment and administration costs may not be appropriately captured in the company's analyses.\n\n## Extrapolation methods used for overall survival\n\nThe committee noted that, to estimate overall survival, the company used 52‑week Kaplan–Meier data from KEYNOTE‑010. After 52\xa0weeks, for docetaxel, the company fitted an exponential model to the KEYNOTE‑010 data after a 2‑stage crossover adjustment. The company explored cut-off points of\xa042,\xa062, 72\xa0and 82\xa0weeks as well as 52\xa0weeks. The committee acknowledged at the first appraisal meeting that there was marked sensitivity of the ICER to the choice of different cut-off points when using the original September data cut-off as well as the company and the ERG's approach to deriving the exponential curve.During consultation the company submitted additional evidence, which incorporated the more recent KEYNOTE-010 data from March 2016. The committee discussed the different cut-off points used when switching from trial survival data to the exponential survival modelling based on this additional evidence, and it noted that the sensitivity of the ICER to the different cut-off points was significantly reduced, and this supported the company's use of the exponential model. The company stated that their original extrapolated curves overlaid with the Kaplan–Meier data from March 2016 showed that the 42‑week and 82‑week cut-off points were implausible. The committee concluded that the 42‑week and 82‑week cut-off points could be excluded from consideration, but there was no evidence that the 52‑week cut-off chosen by the company and ERG for their base-case analyses was the most appropriate for extrapolating the Kaplan–Meier data. The committee concluded that the 52‑week, 62‑week and 72‑week cut-off points are all plausible, but noted that based on the March 2016 data submitted by the company during consultation, the ICER is no longer very sensitive to the choice of cut-off point to model overall survival.\n\n## Long-term treatment effect\n\nThe committee understood that the company's survival estimates depend on an ongoing reduction in the risk of death with pembrolizumab (time to death was independent of previous time on treatment or disease progression), which continues after treatment has stopped and is maintained for a lifetime. The committee recalled that the original modelling projections, using the September 2015 KEYNOTE‑010 data and the company's preferred assumptions, suggested that 10.3% and 1.2% of patients in the pembrolizumab arm would be alive at 5\xa0years and 10\xa0years, falling to 9.6% and 1.0% respectively when incorporating the March 2016 data submitted during consultation. Consultation comments from clinical experts noted that immunotherapies are expected to maintain their effect for a subgroup of people and that these values appear reasonable from clinical experience. But the committee considered that the assumption of a constant treatment effect over 20\xa0years, irrespective of the time spent on treatment or disease progression was unlikely based on current clinical understanding of disease progression. The additional evidence submitted by the company during consultation included scenarios in which the hazard ratio for overall survival was set to\xa01.0 at\xa03,\xa05, and 10\xa0years to model stopping of the continued treatment effect. The committee noted that, using the company's preferred assumptions of an extrapolation point of 52\xa0weeks (see section 4.11) and 25% of patients continuing treatment after 2\xa0years (see section 4.8), the ICER ranges from £61,954 per QALY gained with a 3‑year treatment effect to £44,490 per QALY gained with a lifetime treatment effect.\n\nThe committee noted that the ERG presented data from Schadendorf (2015). This was a meta-analysis of studies in which patients received ipilimumab for treating unresectable or metastatic melanoma. The ERG based their preferred scenario that continued treatment effect stops at 3\xa0years on the Schadendorf evidence, but it noted that these analyses are only designed to show the sensitivity of ICERs to different treatment effect durations. The committee noted in the March 2016 data submitted by the company at consultation all patients had stopped taking pembrolizumab and that the hazard ratios for both overall survival and progression-free survival were essentially unchanged from the original September 2015 data, supporting the company's preferred assumption that there is a long-term treatment effect. The committee considered that although there is evidence to support a continued benefit of pembrolizumab after stopping treatment and in the progressed state, the size of this effect and its duration is unknown for NSCLC. The committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.\n\n## Utility values used in the pre- and post-progression states\n\nThe committee concluded that the KEYNOTE‑010 utility data were the most appropriate to inform decision-making and including a disutility for adverse events was appropriate.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It noted the evidence presented by the company, which showed that people with NSCLC have a life expectancy of less than 24\xa0months. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is between 21.2\xa0and 22.8\xa0months, compared with 10.4\xa0months with docetaxel. It agreed that there is significant uncertainty in the overall survival gain and that this degree of benefit is likely to be optimistic. However, the committee considered it reasonable to assume that the benefit is likely to exceed 3\xa0months. The committee therefore concluded that pembrolizumab met the end-of-life criteria and that it can be considered a life-extending, end-of-life treatment.\n\n# Most plausible ICER\n\nThe committee discussed the most plausible ICER for pembrolizumab compared with docetaxel. It noted comments from the clinical experts that the appropriate population is the overall population expressing PD‑L1 (see section 4.4). Also, the committee considered that the indirect comparison in the adenocarcinoma subgroup was too unreliable for decision-making and so it focused on the pembrolizumab and docetaxel comparison in the overall population (see section 4.6). The committee agreed that the KEYNOTE‑010 data were more appropriate, compared with the KEYNOTE‑001 data (see section\xa04.4). The committee was aware of its earlier conclusion that no patient would continue treatment after 2\xa0years with implementation of a 2‑year stopping rule, and that this would reduce the ICER by about £2,000 per QALY gained (see section 4.8) and discussed the remaining area of uncertainty; the long-term treatment effect. It recalled that the ICERs are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of £61,954 to £44,490 per QALY gained (see section 4.12), but concluded that within the uncertainties and with implementation of a 2‑year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.\n\nThe committee discussed the uncertainty about the long-term treatment effect. It was aware of several ongoing clinical trials which could reduce this uncertainty and if pembrolizumab is recommended for routine commissioning, relevant data would be collected by the Systemic Anti-Cancer Therapy Data Set. The committee concluded that uncertainty about the long-term treatment effect would reduce as data become available on the optimal duration of treatment of PD‑1 inhibitors in the next 2\xa0years.\n\nThe committee discussed whether, overall, pembrolizumab is a cost-effective use of NHS resources, taking into account the most plausible ICER and the uncertainty that has been identified. It was also aware that there would be a wider benefit to the NHS because the simple discount agreed in the patient access scheme would apply across all indications. It concluded that pembrolizumab should be recommended for routine use with a 2‑year stopping rule, but the guidance should be reviewed 2\xa0years after publication to take in account more mature evidence.\n\nThe committee heard from the clinical and patient experts that pembrolizumab was innovative in its potential to make a significant and substantial effect on health-related benefits. It understood that pembrolizumab is generally well tolerated compared with docetaxel, is easy to administer and shows an improvement in overall survival benefit compared with other drugs. The committee concluded that pembrolizumab addresses an unmet need in a debilitating condition for which few treatment options are available, but there were no other benefits not captured in the QALY.\n\n# Summary of appraisal committee's key conclusions\n\nTA428\n\nAppraisal title: Pembrolizumab for treating PD‑L1‑positive non‑small‑cell lung cancer after chemotherapy\n\nSection\n\nKey conclusion\n\nPembrolizumab is recommended as an option for treating locally advanced or metastatic PD‑L1‑positive non‑small‑cell lung cancer in adults who have had at least one chemotherapy (and targeted treatment if they have an epidermal growth factor receptor [EGFR]- or anaplastic lymphoma kinase [ALK]‑positive tumour), only if:\n\npembrolizumab is stopped at 2\xa0years of uninterrupted treatment and no documented disease progression, and\n\nthe company provides pembrolizumab with the discount agreed in the patient access scheme revised in the context of this appraisal.\n\n\n\nThe committee concluded that pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 based on the KEYNOTE-010 trial data.\n\n\n\nThe committee noted the uncertainty around the optimal treatment duration and was aware that consultation comments from NHS England stated that data on the optimal treatment duration of checkpoint inhibitors such as pembrolizumab will begin to be available within the next 2\xa0years. NHS England commented during consultation that it was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable.\n\n\n\nIt recalled that the ICERs are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of £61,954 to £44,490 per QALY gained (see section\xa04.12), but concluded that within the uncertainties and with implementation of a 2-year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.\n\n\n\nThe committee discussed whether, overall, pembrolizumab is a cost-effective use of NHS resources, taking into account the most plausible ICER and the uncertainty that has been identified. It was also aware and that there would be a wider benefit to the NHS because the simple discount agreed in the patient access scheme would apply across all indications. It concluded that pembrolizumab should be recommended for routine use with a 2-year stopping rule, but the guidance should be reviewed 2\xa0years after publication to take in account more mature evidence.\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nPeople with locally advanced or metastatic NSCLC have a poor prognosis. It is a debilitating condition with many distressing symptoms. Improving quality of life and even small extensions in duration of life are of considerable importance to this patient group.\n\n\n\nPlatinum therapy is given as a first treatment for NSCLC in people whose disease is not EGFR‑TK‑positive, followed by docetaxel or docetaxel plus nintedanib (depending on tumour histology).\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nPeople with NSCLC have limited treatment options and existing treatments such as docetaxel can cause severe adverse effects. Premedication is not needed before pembrolizumab and it is generally well tolerated. Based on clinical trial data, pembrolizumab provides a statistically significant median overall survival gain compared with docetaxel and an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1.\n\n, 4.5\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee noted that the marketing authorisation for pembrolizumab states that people should have treatment based on their tumour's expression of PD‑L1 (that is, with a tumour proportion score [TPS] ≥1%), confirmed by a validated test.\n\n\n\nThe committee understood that platinum therapy is given as a first treatment for NSCLC in people whose tumours are not EGFR‑TK‑positive, followed by docetaxel or docetaxel plus nintedanib (depending on tumour histology). For people with EGFR‑TK‑positive tumours, treatment starts with a tyrosine kinase inhibitor, followed by a platinum therapy option. For people with ALK‑positive tumours, platinum combination therapy followed by an ALK inhibitor are the standard treatment choices. The committee heard from the clinical experts that pembrolizumab would be an alternative to docetaxel or to docetaxel plus nintedanib (depending on tumour histology) in people who have had targeted treatment for EGFR‑TK- or ALK‑positive tumours.\n\nThe committee concluded that pembrolizumab was appropriately positioned in the clinical pathway as a treatment option for people who have had 2 or 3\xa0therapies and as an alternative to docetaxel or to docetaxel plus nintedanib.\n\n\n\nAdverse reactions\n\nA small proportion of people have immune-related adverse effects such as rash and colitis.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe clinical evidence for treating NSCLC came from 3\xa0studies (KEYNOTE-001, KEYNOTE-010 and LUME-LUNG-01).\n\n\n\nThe committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of people with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias. The committee concluded that pembrolizumab had an important extension-to-life benefit for people with locally advanced or metastatic NSCLC whose tumours express PD‑L1 based on the trial data.\n\n\n\nThe committee concluded that the indirect treatment comparison of pembrolizumab compared with nintedanib plus docetaxel was not robust and was limited because of the differences between the trial populations. Therefore it was not appropriate for decision-making on the effectiveness of pembrolizumab in the population with adenocarcinoma histology.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee heard from the clinical experts that the overall population in KEYNOTE-010 was likely to be the same as those who have pembrolizumab in clinical practice. The committee concluded that the population in KEYNOTE-010 was generalisable to clinical practice in England.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted the uncertainty around the optimal duration of treatment. It noted NHS England was confident that a 2-year stopping rule would be acceptable to both patients and clinicians and would be implementable. It concluded that implementation of a 2-year stopping rule and review of the published guidance at 2\xa0years is appropriate.\n\n\n\nThe committee heard from the ERG that the RPSFT method to account for treatment switching does not have a test for a common treatment effect and it preferred the 2-stage adjustment method to account for the effects of crossover; it also noted that this method has been used in other appraisals of immunotherapies. The committee concluded that the 2-stage adjustment method was reasonable.\n\n\n\nThe committee concluded that there was still some uncertainty about how many people continue treatment after disease progression and noted that these treatment and administration costs would not be included in the company analyses.\n\n\n\nThe committee concluded that there was no evidence that the 52-week cut-off was the most appropriate for extrapolating the Kaplan–Meier data but noted that based on the March 2016 data submitted by the company during consultation, the ICER is no longer very sensitive to the choice of cut-off point to model overall survival.\n\n\n\nThe committee considered that although it is likely there would be some continued benefit of pembrolizumab after stopping treatment and in the progressed state, the size of this effect and its duration is unknown for NSCLC. The committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe company presented an indirect treatment comparison to compare the relative treatment effects of pembrolizumab with nintedanib plus docetaxel in the population with adenocarcinoma. Two studies formed the basis of the indirect treatment comparison: KEYNOTE-010 and LUME-LUNG-01. The committee concluded that the indirect treatment comparison was not robust, and that the trial populations of KEYNOTE-010 and LUME-LUNG-01 were too different. Therefore it was not appropriate for decision-making on the effectiveness of pembrolizumab in the population with adenocarcinoma histology.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nIn the overall population in KEYNOTE-010 the median overall survival gain was 10.5\xa0months for pembrolizumab compared with 8.6\xa0months for docetaxel. The committee concluded that pembrolizumab had an important extension-to-life benefit compared with docetaxel.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee accepted the structure of the economic model developed by the company and considered it appropriate for decision-making. During consultation the company submitted a revised patient access scheme and updated evidence, which takes into account 6\xa0months of further follow-up data from the KEYNOTE-010 trial.\n\n\n\nThe company used efficacy data for pembrolizumab and docetaxel from KEYNOTE-010.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee was not clear about how many patients had scans to check for true disease progression and what proportion of these scans confirmed disease progression. The committee noted that additional weeks of therapy were sometimes needed (as stated in the KEYNOTE-010 protocol) to distinguish between true progression and pseudo-progression. The committee concluded that there was still some uncertainty about how many people continue treatment after disease progression and noted that these treatment and administration costs would not be included in the company analyses.\n\n\n\n\n\nThe committee considered that the KEYNOTE-010 evidence was the most applicable to the decision problem because the KEYNOTE-010 population consisted only of people with PD‑L1‑positive NSCLC, whereas KEYNOTE-001 is a non-randomised cohort study of pembrolizumab which retrospectively identified PD‑L1 status and used the docetaxel arm of KEYNOTE-010 as a comparator; this can lead to a greater risk of bias.\n\n\n\nThe committee concluded that the 52-week, 62-week and 72-week cut-off points for extrapolating the Kaplan–Meier data are all plausible, but noted that based on the March 2016 data submitted by the company during consultation, the ICER is no longer very sensitive to the choice of cut-off point to model overall survival.\n\n\n\nThe committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.\n\n\n\nThe committee discussed the uncertainty about the long-term treatment effect. It was aware of several ongoing clinical trials which could reduce this uncertainty and if pembrolizumab is recommended for routine commissioning, relevant data would be collected by the Systemic Anti-Cancer Therapy Data Set. The committee concluded that uncertainty about the long-term treatment effect would reduce as data become available on the optimal duration of treatment of PD‑1 inhibitors in the next 2 years.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee concluded that the KEYNOTE-010 utility data were the most appropriate to inform decision-making and including a disutility for adverse events was appropriate.\n\n\n\nThe committee concluded that pembrolizumab addresses an unmet need in a debilitating condition, for which few treatment options are available, but there were no other health benefits not captured in the QALY.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo evidence has been submitted that there is a group of people for whom the technology is particularly cost effective.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe key drivers of cost-effectiveness were:\n\nTreatment duration: the committee noted that the ICER increased from £44,490 to £49,063 per QALY gained as the proportion of patients having treatment after 2 years increased from 25% to 100%\n\n\n\nLong-term treatment effect: The committee noted that, using the company's preferred assumptions of an extrapolation point of 52\xa0weeks (see section\xa04.11) and 25% of patients continuing treatment after 2 years (see section\xa04.8), the ICER ranges from £61,954 per QALY gained with a 3-year treatment effect to £44,490 per QALY gained with a lifetime treatment effect.\n\n\n\nThe committee concluded that the ICERs were sensitive to a continued treatment effect after stopping treatment, and although it considered the company's preferred scenario of a lifetime treatment effect to be implausible, it had not been presented with any evidence on which it could agree a single clinically plausible scenario.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee discussed the most plausible ICER for pembrolizumab compared with docetaxel. It noted comments from the clinical experts that the appropriate population is the overall population expressing PD‑L1 (see section\xa04.4). Also, the committee considered that the indirect comparison in the adenocarcinoma subgroup was too unreliable for decision-making and so it focused on the pembrolizumab and docetaxel comparison in the overall population (see section\xa04.6). The committee agreed that the KEYNOTE-010 data were more appropriate, compared with the KEYNOTE-001 data (see section\xa04.4). The committee was aware of its earlier conclusion that no patient would continue treatment after 2 years with implementation of a 2-year stopping rule, and that this would reduce the ICER by about £2,000 per QALY gained (see section\xa04.8) and discussed the remaining area of uncertainty; the long-term treatment effect. It recalled that the ICERs are sensitive to a continued treatment effect after stopping treatment, with a range when using the company's preferred assumptions of £61,954 to £44,490 per QALY gained (see section\xa04.12), but concluded that within the uncertainties and with implementation of a 2-year stopping rule, the majority of plausible ICERs are below the range usually considered to be a cost-effective use of NHS resources.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a discount to the list price of pembrolizumab applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.\n\n\n\nEnd-of-life considerations\n\nThe committee heard that people with NSCLC have a life expectancy of less than 24\xa0months. The committee heard that the average number of months of life gained with pembrolizumab, as estimated by the company's economic model, is between 21.2 and 22.8\xa0months, compared with 10.4\xa0months with docetaxel. It agreed that there is significant uncertainty in the overall survival gain, and that this degree of benefit is likely to be optimistic. However it was reasonable to assume that the benefit is likely to exceed 3\xa0months. The committee therefore concluded that pembrolizumab met the end-of-life criteria and that it can be considered a life-extending, end-of-life treatment.\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were raised during this appraisal.\n\n–"}
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https://www.nice.org.uk/guidance/ta428
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Evidence-based recommendations on pembrolizumab (Keytruda) for treating PD-L1-positive non-small-cell lung cancer in adults who have had chemotherapy.
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89219f75dd4ba67df0915a07150f6dbdc7e69e23
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nice
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Fertility problems: assessment and treatment
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Fertility problems: assessment and treatment
This guideline covers diagnosing and treating fertility problems. It aims to reduce variation in practice and improve the way fertility problems are investigated and managed.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Principles of care
## Providing information
Couples who experience problems in conceiving should be seen together because both partners are affected by decisions surrounding investigation and treatment.
People should have the opportunity to make informed decisions regarding their care and treatment via access to evidence-based information. These choices should be recognised as an integral part of the decision-making process. Verbal information should be supplemented with written information or audio-visual media.
Information regarding care and treatment options should be provided in a form that is accessible to people who have additional needs, such as people with physical, cognitive or sensory disabilities, and people who do not speak or read English.
## Psychological effects of fertility problems
When couples have fertility problems, both partners should be informed that stress in the male and/or female partner can affect the couple's relationship and is likely to reduce libido and frequency of intercourse, which can contribute to the fertility problems.
People who experience fertility problems should be informed that they may find it helpful to contact a fertility support group.
People who experience fertility problems should be offered counselling because fertility problems themselves, and the investigation and treatment of fertility problems, can cause psychological stress.
Counselling should be offered before, during and after investigation and treatment, irrespective of the outcome of these procedures.
Counselling should be provided by someone who is not directly involved in the management of the individual's and/or couple's fertility problems.
## Generalist and specialist care
People who experience fertility problems should be treated by a specialist team because this is likely to improve the effectiveness and efficiency of treatment and is known to improve people's satisfaction with treatment.
# Initial advice to people concerned about delays in conception
## Chance of conception
People who are concerned about their fertility should be informed that over 80% of couples in the general population will conceive within 1 year if:
the woman is aged under 40 years and
they do not use contraception and have regular sexual intercourse.Of those who do not conceive in the first year, about half will do so in the second year (cumulative pregnancy rate over 90%).
Inform people who are using artificial insemination to conceive and who are concerned about their fertility that:
-ver 50% of women aged under 40 years will conceive within 6 cycles of intrauterine insemination (IUI)
-f those who do not conceive within 6 cycles of intrauterine insemination, about half will do so with a further 6 cycles (cumulative pregnancy rate over 75%).
Inform people who are using artificial insemination to conceive and who are concerned about their fertility that using fresh sperm is associated with higher conception rates than frozen–thawed sperm. However, intrauterine insemination, even using frozen–thawed sperm, is associated with higher conception rates than intracervical insemination.
Inform people who are concerned about their fertility, that female fertility (and to a lesser extent) male fertility declines with age.
Discuss chances of conception with people concerned about their fertility who are:
having sexual intercourse (see table 1) or
using artificial insemination (see table 2).
## Frequency and timing of sexual intercourse or artificial insemination
People who are concerned about their fertility should be informed that vaginal sexual intercourse every 2 to 3 days optimises the chance of pregnancy.
People who are using artificial insemination to conceive should have their insemination timed around ovulation.
## Alcohol
Women who are trying to become pregnant should be informed that drinking no more than 1 or 2 units of alcohol once or twice per week and avoiding episodes of intoxication reduces the risk of harming a developing fetus.
Men should be informed that alcohol consumption within the Department of Health and Social Care's recommendations of 3 to 4 units per day for men is unlikely to affect their semen quality.
Men should be informed that excessive alcohol intake is detrimental to semen quality.
## Smoking
Women who smoke should be informed that this is likely to reduce their fertility.
Women who smoke should be offered referral to a smoking cessation programme to support their efforts in stopping smoking.
Women should be informed that passive smoking is likely to affect their chance of conceiving.
Men who smoke should be informed that there is an association between smoking and reduced semen quality (although the impact of this on male fertility is uncertain), and that stopping smoking will improve their general health.
## Caffeinated beverages
People who are concerned about their fertility should be informed that there is no consistent evidence of an association between consumption of caffeinated beverages (tea, coffee and colas) and fertility problems. Also see recommendation 1.10.5.3 about caffeine intake and in vitro fertilisation (IVF) treatment.
## Obesity
Women who have a body mass index (BMI) of 30 or over should be informed that they are likely to take longer to conceive.
Women who have a BMI of 30 or over and who are not ovulating should be informed that losing weight is likely to increase their chance of conception.
Women should be informed that participating in a group programme involving exercise and dietary advice leads to more pregnancies than weight loss advice alone.
Men who have a BMI of 30 or over should be informed that they are likely to have reduced fertility.
## Low body weight
Women who have a BMI of less than 19 and who have irregular menstruation or are not menstruating should be advised that increasing body weight is likely to improve their chance of conception.
## Tight underwear
Men should be informed that there is an association between elevated scrotal temperature and reduced semen quality, but that it is uncertain whether wearing loose-fitting underwear improves fertility.
## Occupation
Some occupations involve exposure to hazards that can reduce male or female fertility and therefore a specific enquiry about occupation should be made to people who are concerned about their fertility, and appropriate advice should be offered.
## Prescribed, over-the-counter and recreational drug use
A number of prescription, over-the-counter and recreational drugs interfere with male and female fertility, and therefore a specific enquiry about these should be made to people who are concerned about their fertility, and appropriate advice should be offered.
## Complementary therapy
People who are concerned about their fertility should be informed that the effectiveness of complementary therapies for fertility problems has not been properly evaluated and that further research is needed before such interventions can be recommended.
## Folic acid supplementation
Women intending to become pregnant should be informed that dietary supplementation with folic acid before conception and up to 12 weeks' gestation reduces the risk of having a baby with neural tube defects. The recommended dose is 0.4 mg per day. For women who have previously had an infant with a neural tube defect or who are receiving anti-epileptic medication or who have diabetes (see the NICE guideline on diabetes in pregnancy), a higher dose of 5 mg per day is recommended.
## Defining infertility
People who are concerned about delays in conception should be offered an initial assessment. A specific enquiry about lifestyle and sexual history should be taken to identify people who are less likely to conceive.
Offer an initial consultation to discuss the options for attempting conception to people who are unable to, or would find it very difficult to, have vaginal intercourse.
The environment in which investigation of fertility problems takes place should enable people to discuss sensitive issues such as sexual abuse.
Healthcare professionals should define infertility in practice as the period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented.
A woman of reproductive age who has not conceived after 1 year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner.
A woman of reproductive age who is using artificial insemination to conceive (with either partner or donor sperm) should be offered further clinical assessment and investigation if she has not conceived after 6 cycles of treatment, in the absence of any known cause of infertility. Where this is using partner sperm, the referral for clinical assessment and investigation should include her partner.
Offer an earlier referral for specialist consultation to discuss the options for attempting conception, further assessment and appropriate treatment where:
the woman is aged 36 years or over
there is a known clinical cause of infertility or a history of predisposing factors for infertility.
Where treatment is planned that may result in infertility (such as treatment for cancer), early fertility specialist referral should be offered.
People who are concerned about their fertility and who are known to have chronic viral infections such as hepatitis B, hepatitis C or HIV, should be referred to centres that have appropriate expertise and facilities to provide safe risk-reduction investigation and treatment.
# Investigation of fertility problems and management strategies
## Semen analysis
The results of semen analysis conducted as part of an initial assessment should be compared with the following World Health Organization reference values:
semen volume: 1.5 ml or more
pH: 7.2 or more
sperm concentration: 15 million spermatozoa per ml or more
total sperm number: 39 million spermatozoa per ejaculate or more
total motility (percentage of progressive motility and non-progressive motility): 40% or more motile or 32% or more with progressive motility
vitality: 58% or more live spermatozoa
sperm morphology (percentage of normal forms): 4% or more. Please note the reference ranges are only valid for the semen analysis tests outlined by the World Health Organization.
Screening for antisperm antibodies should not be offered because there is no evidence of effective treatment to improve fertility.
If the result of the first semen analysis is abnormal, a repeat confirmatory test should be offered.
Repeat confirmatory tests should ideally be undertaken 3 months after the initial analysis to allow time for the cycle of spermatozoa formation to be completed. However, if a gross spermatozoa deficiency (azoospermia or severe oligozoospermia) has been detected, the repeat test should be undertaken as soon as possible.
## Post-coital testing of cervical mucus
The routine use of post-coital testing of cervical mucus in the investigation of fertility problems is not recommended because it has no predictive value on pregnancy rate.
## Ovarian reserve testing
Use a woman's age as an initial predictor of her overall chance of success through natural conception (see figure 1) or with IVF (see figure 2).
Use 1 of the following measures to predict the likely ovarian response to gonadotrophin stimulation in IVF:
total antral follicle count of less than or equal to 4 for a low response (follicles of less than or equal to 5 mm measured by transvaginal ultrasound on day 3 of cycle: low response was less than 4 oocytes) , and greater than 16 for a high response (follicles of 2 to 10 mm measured by transvaginal ultrasound on day 3 of cycle: high response was more than or equal to 15 oocytes or more than or equal to 20 oocytes)
anti-Müllerian hormone of less than or equal to 5.4 pmol/l for a low response (Beckman–Coulter assay: poor response defined as less than 4 oocytes or cancellation), and greater than or equal to 25.0 pmol/l for a high response (Beckman–Coulter or DSL assays: defined high response as more than or equal to 15 oocytes to more than 21 oocytes)
follicle-stimulating hormone greater than 8.9 IU/l for a low response, and less than 4 IU/l for a high response (long protocol of down-regulation: low response defined as less than 4 oocytes or cancellation; high response defined as more than 20 oocytes).
Do not use any of the following tests individually to predict any outcome of fertility treatment:
-varian volume
-varian blood flow
inhibin B
-estradiol (E2).
## Regularity of menstrual cycles
Women who are concerned about their fertility should be asked about the frequency and regularity of their menstrual cycles. Women with regular monthly menstrual cycles should be informed that they are likely to be ovulating.
Women who are undergoing investigations for infertility should be offered a blood test to measure serum progesterone in the mid-luteal phase of their cycle (day 21 of a 28‑day cycle) to confirm ovulation even if they have regular menstrual cycles.
Women with prolonged irregular menstrual cycles should be offered a blood test to measure serum progesterone. Depending on the timing of menstrual periods, this test may need to be conducted later in the cycle (for example, day 28 of a 35‑day cycle) and repeated weekly thereafter until the next menstrual cycle starts.
The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
Women with irregular menstrual cycles should be offered a blood test to measure serum gonadotrophins (follicle-stimulating hormone and luteinising hormone).
## Prolactin measurement
Women who are concerned about their fertility should not be offered a blood test to measure prolactin. This test should only be offered to women who have an ovulatory disorder, galactorrhoea or a pituitary tumour.
## Thyroid function tests
Women with possible fertility problems are no more likely than the general population to have thyroid disease and the routine measurement of thyroid function should not be offered. Estimation of thyroid function should be confined to women with symptoms of thyroid disease.
## Endometrial biopsy
Women should not be offered an endometrial biopsy to evaluate the luteal phase as part of the investigation of fertility problems because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
## Investigation of suspected tubal and uterine abnormalities
Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy or endometriosis) should be offered hysterosalpingography (HSG) to screen for tubal occlusion because this is a reliable test for ruling out tubal occlusion, and it is less invasive and makes more efficient use of resources than laparoscopy.
Where appropriate expertise is available, screening for tubal occlusion using hysterosalpingo-contrast-ultrasonography should be considered because it is an effective alternative to HSG for women who are not known to have comorbidities.
Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.
Women should not be offered hysteroscopy on its own as part of the initial investigation unless clinically indicated because the effectiveness of surgical treatment of uterine abnormalities on improving pregnancy rates has not been established.
## Testing for viral status
People undergoing IVF treatment should be offered testing for HIV, hepatitis B and hepatitis C (for donor insemination, see recommendation 1.14.3.1).
People found to test positive for 1 or more of HIV, hepatitis B or hepatitis C should be offered specialist advice and counselling and appropriate clinical management.
## Viral transmission
For couples where the man is HIV positive, any decision about fertility management should be the result of discussions between the couple, a fertility specialist and an HIV specialist.
Advise couples where the man is HIV positive that the risk of HIV transmission to the female partner is negligible through unprotected sexual intercourse when all of the following criteria are met:
the man is compliant with highly active antiretroviral therapy (HAART)
the man has had a plasma viral load of less than 50 copies/ml for more than 6 months
there are no other infections present
unprotected intercourse is limited to the time of ovulation.
Advise couples that if all the criteria in recommendation 1.3.10.2 are met, sperm washing may not further reduce the risk of infection and may reduce the likelihood of pregnancy.
For couples where the man is HIV positive and either he is not compliant with HAART or his plasma viral load is 50 copies/ml or greater, offer sperm washing.
Inform couples that sperm washing reduces, but does not eliminate, the risk of HIV transmission.
If couples who meet all the criteria in recommendation 1.3.10.2 still perceive an unacceptable risk of HIV transmission after discussion with their HIV specialist, consider sperm washing.
Inform couples that there is insufficient evidence to recommend that HIV-negative women use pre-exposure prophylaxis, when all the criteria in recommendation 1.3.10.2 are met.
For partners of people with hepatitis B, offer vaccination before starting fertility treatment.
Do not offer sperm washing as part of fertility treatment for men with hepatitis B.
For couples where the man has hepatitis C, any decision about fertility management should be the result of discussions between the couple, a fertility specialist and a hepatitis specialist.
Advise couples who want to conceive and where the man has hepatitis C that the risk of transmission through unprotected sexual intercourse is thought to be low.
Men with hepatitis C should discuss treatment options to eradicate the hepatitis C with their appropriate specialist before conception is considered.
## Susceptibility to rubella
Women who are concerned about their fertility should be offered testing for their rubella status so that those who are susceptible to rubella can be offered vaccination. Women who are susceptible to rubella should be offered vaccination and advised not to become pregnant for at least 1 month following vaccination.
## Cervical cancer screening
To avoid delay in fertility treatment, a specific enquiry about the timing and result of the most recent cervical smear test should be made to women who are concerned about their fertility. Cervical screening should be offered in accordance with the national cervical screening programme guidance.
## Screening for Chlamydia trachomatis
Before undergoing uterine instrumentation, women should be offered screening for Chlamydia trachomatis using an appropriately sensitive technique.
If the result of a test for Chlamydia trachomatis is positive, women and their sexual partners should be referred for appropriate management with treatment and contact tracing.
Prophylactic antibiotics should be considered before uterine instrumentation if screening has not been carried out.
# Medical and surgical management of male factor fertility problems
## Medical management (male factor infertility)
Men with hypogonadotrophic hypogonadism should be offered gonadotrophin drugs because these are effective in improving fertility.
Men with idiopathic semen abnormalities should not be offered anti-oestrogens, gonadotrophins, androgens, bromocriptine or kinin-enhancing drugs because they have not been shown to be effective.
Men should be informed that the significance of antisperm antibodies is unclear and the effectiveness of systemic corticosteroids is uncertain.
Men with leucocytes in their semen should not be offered antibiotic treatment unless there is an identified infection because there is no evidence that this improves pregnancy rates.
## Surgical management (male factor infertility)
Where appropriate expertise is available, men with obstructive azoospermia should be offered surgical correction of epididymal blockage because it is likely to restore patency of the duct and improve fertility. Surgical correction should be considered as an alternative to surgical sperm recovery and IVF.
Men should not be offered surgery for varicoceles as a form of fertility treatment because it does not improve pregnancy rates.
## Management of ejaculatory failure
Treatment of ejaculatory failure can restore fertility without the need for invasive methods of sperm retrieval or the use of assisted reproduction procedures. However, further evaluation of different treatment options is needed.
# Ovulation disorders
## Classification of ovulatory disorders
The World Health Organization (WHO) classifies ovulation disorders into 3 groups:
Group 1: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism)
Group 2: hypothalamic-pituitary-ovarian dysfunction (predominately polycystic ovary syndrome)
Group 3: ovarian failure.
## WHO Group 1 ovulation disorders
Advise women with WHO Group 1 anovulatory infertility that they can improve their chance of regular ovulation, conception and an uncomplicated pregnancy by:
increasing their body weight if they have a BMI of less than 19 and/or
moderating their exercise levels if they undertake high levels of exercise.
Offer women with WHO Group 1 ovulation disorders pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinising hormone activity to induce ovulation.
## WHO Group 2 ovulation disorders
At the time of publication (February 2013), metformin did not have a UK marketing authorisation for the indications in this section. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing medicines – guidance for doctors for further information.
Women with WHO Group 2 ovulation disorders receiving first-line treatment for ovarian stimulation
Advise women with WHO Group 2 anovulatory infertility who have a BMI of 30 or over to lose weight (see recommendation 1.2.6.3). Inform them that this alone may restore ovulation, improve their response to ovulation induction agents, and have a positive impact on pregnancy outcomes.
Offer women with WHO Group 2 anovulatory infertility 1 of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman's BMI, and monitoring needed:
clomifene citrate or
metformin or
a combination of the above.
For women who are taking clomifene citrate, offer ultrasound monitoring during at least the first cycle of treatment to ensure that they are taking a dose that minimises the risk of multiple pregnancy.
For women who are taking clomifene citrate, do not continue treatment for longer than 6 months.
Women prescribed metformin should be informed of the side effects associated with its use (such as nausea, vomiting and other gastrointestinal disturbances).
Women with WHO Group 3 ovulation disorders who are known to be resistant to clomifene citrate
For women with WHO Group 3 ovulation disorders who are known to be resistant to clomifene citrate, consider 1 of the following second-line treatments, depending on clinical circumstances and the woman's preference:
laparoscopic ovarian drilling or
combined treatment with clomifene citrate and metformin if not already offered as first-line treatment or
gonadotrophins.
Women with polycystic ovary syndrome who are being treated with gonadotrophins should not be offered treatment with gonadotrophin-releasing hormone agonist concomitantly because it does not improve pregnancy rates, and it is associated with an increased risk of ovarian hyperstimulation.
The use of adjuvant growth hormone treatment with gonadotrophin-releasing hormone agonist and/or human menopausal gonadotrophin during ovulation induction in women with polycystic ovary syndrome who do not respond to clomifene citrate is not recommended because it does not improve pregnancy rates.
The effectiveness of pulsatile gonadotrophin-releasing hormone in women with clomifene citrate-resistant polycystic ovary syndrome is uncertain and is therefore not recommended outside a research context.
## Hyperprolactinaemic amenorrhoea – dopamine agonists
Women with ovulatory disorders due to hyperprolactinaemia should be offered treatment with dopamine agonists such as bromocriptine. Consideration should be given to safety for use in pregnancy and minimising cost when prescribing.
## Monitoring ovulation induction during gonadotrophin therapy
Women who are offered ovulation induction with gonadotrophins should be informed about the risk of multiple pregnancy and ovarian hyperstimulation before starting treatment.
Ovarian ultrasound monitoring to measure follicular size and number should be an integral part of gonadotrophin therapy to reduce the risk of multiple pregnancy and ovarian hyperstimulation.
# Tubal and uterine surgery
## Tubal microsurgery and laparoscopic tubal surgery
For women with mild tubal disease, tubal surgery may be more effective than no treatment. In centres where appropriate expertise is available, it may be considered as a treatment option.
## Tubal catheterisation or cannulation
For women with proximal tubal obstruction, selective salpingography plus tubal catheterisation, or hysteroscopic tubal cannulation, may be treatment options because these treatments improve the chance of pregnancy.
## Surgery for hydrosalpinges before IVF treatment
Women with hydrosalpinges should be offered salpingectomy, preferably by laparoscopy, before IVF treatment because this improves the chance of a live birth.
## Uterine surgery
Women with amenorrhoea who are found to have intrauterine adhesions should be offered hysteroscopic adhesiolysis because this is likely to restore menstruation and improve the chance of pregnancy.
# Medical and surgical management of endometriosis
This section has been stood down as it has been superseded by publication of the NICE guideline on endometriosis.
# Unexplained infertility
## Ovarian stimulation for unexplained infertility
Do not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) to women with unexplained infertility.
Inform women with unexplained infertility that clomifene citrate as a stand-alone treatment does not increase the chances of a pregnancy or a live birth.
Advise women with unexplained infertility who are having regular unprotected sexual intercourse to try to conceive for a total of 2 years (this can include up to 1 year before their fertility investigations) before IVF will be considered.
Offer IVF treatment (see recommendations 1.11.1.3 and 1.11.1.4) to women with unexplained infertility who have not conceived after 2 years (this can include up to 1 year before their fertility investigations) of regular unprotected sexual intercourse.
# Intrauterine insemination
## Intrauterine insemination
Consider unstimulated intrauterine insemination as a treatment option in the following groups as an alternative to vaginal sexual intercourse:
people who are unable to, or would find it very difficult to, have vaginal intercourse because of a clinically diagnosed physical disability or psychosexual problem who are using partner or donor sperm
people with conditions that require specific consideration in relation to methods of conception (for example, after sperm washing where the man is HIV positive)
people in same-sex relationships.
For people in recommendation 1.9.1.1 who have not conceived after 6 cycles of donor or partner insemination, despite evidence of normal ovulation, tubal patency and semen analysis, offer a further 6 cycles of unstimulated intrauterine insemination before IVF is considered.
For people with unexplained infertility, mild endometriosis or mild male factor infertility, who are having regular unprotected sexual intercourse:
do not routinely offer intrauterine insemination, either with or without ovarian stimulation (exceptional circumstances include, for example, when people have social, cultural or religious objections to IVF)
advise them to try to conceive for a total of 2 years (this can include up to 1 year before their fertility investigations) before IVF will be considered.
# Prediction of IVF success
## Female age
Inform women that the chance of a live birth following IVF treatment falls with rising female age (see figure 2).
## Number of previous treatment cycles
Inform people that the overall chance of a live birth following IVF treatment falls as the number of unsuccessful cycles increases.
## Previous pregnancy history
People should be informed that IVF treatment is more effective in women who have previously been pregnant and/or had a live birth.
## Body mass index
Women should be informed that female BMI should ideally be in the range 19 to 30 before commencing assisted reproduction, and that a female BMI outside this range is likely to reduce the success of assisted reproduction procedures.
## Lifestyle factors
People should be informed that the consumption of more than 1 unit of alcohol per day reduces the effectiveness of assisted reproduction procedures, including IVF.
People should be informed that maternal and paternal smoking can adversely affect the success rates of assisted reproduction procedures, including IVF treatment.
People should be informed that maternal caffeine consumption has adverse effects on the success rates of assisted reproduction procedures, including IVF treatment.
# Access criteria for IVF
## Criteria for referral for IVF
When considering IVF as a treatment option for people with fertility problems, discuss the risks and benefits of IVF in accordance with the current Human Fertilisation and Embryology Authority (HFEA) Code of Practice.
Inform people that normally a full cycle of IVF treatment, with or without intracytoplasmic sperm injection (ICSI), should comprise 1 episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s).
In women aged under 40 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (where 6 or more are by intrauterine insemination), offer 3 full cycles of IVF, with or without ICSI. If the woman reaches the age of 40 during treatment, complete the current full cycle but do not offer further full cycles.
In women aged 40 to 42 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (where 6 or more are by intrauterine insemination), offer 1 full cycle of IVF, with or without ICSI, provided the following 3 criteria are fulfilled:
they have never previously had IVF treatment
there is no evidence of low ovarian reserve (see recommendation 1.3.3.2)
there has been a discussion of the additional implications of IVF and pregnancy at this age.
Where investigations show there is no chance of pregnancy with expectant management and where IVF is the only effective treatment, refer the woman directly to a specialist team for IVF treatment.
In women aged under 40 years, any previous full IVF cycle, whether self- or NHS-funded, should count towards the total of 3 full cycles that should be offered by the NHS.
Take into account the outcome of previous IVF treatment when assessing the likely effectiveness and safety of any further IVF treatment.
Healthcare providers should define a cancelled IVF cycle as one where an egg collection procedure is not undertaken. However, cancelled cycles due to low ovarian reserve should be taken into account when considering suitability for further IVF treatment.
# Procedures used during IVF treatment
## Pre-treatment in IVF
Advise women that using pre-treatment (with either the oral contraceptive pill or a progestogen) as part of IVF does not affect the chances of having a live birth.
Consider pre-treatment in order to schedule IVF treatment for women who are not undergoing long down-regulation protocols.
## Down regulation and other regimens to avoid premature luteinising hormone surges in IVF
Use regimens to avoid premature luteinising hormone surges in gonadotrophin-stimulated IVF treatment cycles.
Use either gonadotrophin-releasing hormone agonist down-regulation or gonadotrophin-releasing hormone antagonists as part of gonadotrophin-stimulated IVF treatment cycles.
Only offer gonadotrophin-releasing hormone agonists to women who have a low risk of ovarian hyperstimulation syndrome.
When using gonadotrophin-releasing hormone agonists as part of IVF treatment, use a long down-regulation protocol.
## Controlled ovarian stimulation in IVF
Use ovarian stimulation as part of IVF treatment.
Use either urinary or recombinant gonadotrophins for ovarian stimulation as part of IVF treatment.
When using gonadotrophins for ovarian stimulation in IVF treatment:
use an individualised starting dose of follicle-stimulating hormone, based on factors that predict success, such as:
age
BMI
presence of polycystic ovaries
-varian reserve
do not use a dosage of follicle-stimulating hormone of more than 450 IU/day.
Offer women ultrasound monitoring (with or without oestradiol levels) for efficacy and safety throughout ovarian stimulation.
Inform women that clomifene citrate-stimulated and gonadotrophin-stimulated IVF cycles have higher pregnancy rates per cycle than natural cycle IVF.
Do not offer women natural cycle IVF treatment.
Do not use growth hormone or dehydroepiandrosterone (DHEA) as adjuvant treatment in IVF protocols.
## Triggering ovulation in IVF
Offer women human chorionic gonadotrophin (urinary or recombinant) to trigger ovulation in IVF treatment.
Offer ultrasound monitoring of ovarian response as an integral part of the IVF treatment cycle.
Clinics providing ovarian stimulation with gonadotrophins should have protocols in place for preventing, diagnosing and managing ovarian hyperstimulation syndrome.
## Oocyte and sperm retrieval in IVF
Women undergoing transvaginal retrieval of oocytes should be offered conscious sedation because it is a safe and acceptable method of providing analgesia.
The safe practice of administering sedative drugs published by the Academy of Medical Royal Colleges should be followed.
Women who have developed at least 3 follicles before oocyte retrieval should not be offered follicle flushing because this procedure does not increase the numbers of oocytes retrieved or pregnancy rates, and it increases the duration of oocyte retrieval and associated pain.
Surgical sperm recovery before ICSI may be performed using several different techniques depending on the pathology and wishes of the man. In all cases, facilities for cryopreservation of spermatozoa should be available.
Assisted hatching is not recommended because it has not been shown to improve pregnancy rates.
## Embryo transfer strategies in IVF
Women undergoing IVF treatment should be offered ultrasound-guided embryo transfer because this improves pregnancy rates.
Replacement of embryos into a uterine cavity with an endometrium of less than 5 mm thickness is unlikely to result in a pregnancy and is therefore not recommended.
Women should be informed that bed rest of more than 20 minutes' duration following embryo transfer does not improve the outcome of IVF treatment.
Evaluate embryo quality, at both cleavage and blastocyst stages, according to the Association of Clinical Embryologists (ACE) and UK National External Quality Assessment Service (UK NEQAS) for Reproductive Science Embryo and Blastocyst Grading schematic (see figure 3).
When considering the number of fresh or frozen embryos to transfer in IVF treatment:
For women aged under 37 years:
In the first full IVF cycle, use single embryo transfer.
In the second full IVF cycle, use single embryo transfer if 1 or more top-quality embryos are available. Consider using 2 embryos if no top-quality embryos are available.
In the third full IVF cycle, transfer no more than 2 embryos.
For women aged 37 to 39 years:
In the first and second full IVF cycles, use single embryo transfer if there are 1 or more top-quality embryos. Consider double embryo transfer if there are no top-quality embryos.
In the third full IVF cycle, transfer no more than 2 embryos.
For women aged 40 to 42 years, consider double embryo transfer.
For women undergoing IVF treatment with donor eggs, use an embryo transfer strategy that is based on the age of the donor.
No more than 2 embryos should be transferred during any 1 cycle of IVF treatment.
Where a top-quality blastocyst is available, use single embryo transfer.
When considering double embryo transfer, advise people of the risks of multiple pregnancy associated with this strategy.
Offer cryopreservation to store any remaining good-quality embryos after embryo transfer.
Advise women who have regular ovulatory cycles that the likelihood of a live birth after replacement of frozen–thawed embryos is similar for embryos replaced during natural cycles and hormone-supplemented cycles.
## Luteal phase support after IVF
Offer women progesterone for luteal phase support after IVF treatment.
Do not routinely offer women human chorionic gonadotrophin for luteal phase support after IVF treatment because of the increased likelihood of ovarian hyperstimulation syndrome.
Inform women undergoing IVF treatment that the evidence does not support continuing any form of treatment for luteal phase support beyond 8 weeks' gestation.
## Gamete intrafallopian transfer and zygote intrafallopian transfer
There is insufficient evidence to recommend the use of gamete intrafallopian transfer or zygote intrafallopian transfer in preference to IVF in couples with unexplained fertility problems or male factor fertility problems.
# Intracytoplasmic sperm injection
## Indications for intracytoplasmic sperm injection
The recognised indications for treatment by intracytoplasmic sperm injection (ICSI) include:
severe deficits in semen quality
-bstructive azoospermia
non-obstructive azoospermia. In addition, treatment by ICSI should be considered for couples in whom a previous IVF treatment cycle has resulted in failed or very poor fertilisation.
## Genetic issues and counselling
Before considering treatment by ICSI, people should undergo appropriate investigations, both to establish a diagnosis and to enable informed discussion about the implications of treatment.
Before treatment by ICSI, consideration should be given to relevant genetic issues.
Where a specific genetic defect associated with male infertility is known or suspected, couples should be offered appropriate genetic counselling and testing.
Where the indication for ICSI is a severe deficit of semen quality or non-obstructive azoospermia, the man's karyotype should be established.
Men who are undergoing karyotype testing should be offered genetic counselling regarding the genetic abnormalities that may be detected.
Testing for Y chromosome microdeletions should not be regarded as a routine investigation before ICSI. However, it is likely that a significant proportion of male infertility results from abnormalities of genes on the Y chromosome involved in the regulation of spermatogenesis, and couples should be informed of this.
## ICSI versus IVF
Couples should be informed that ICSI improves fertilisation rates compared with IVF alone, but once fertilisation is achieved, the pregnancy rate is no better than with IVF.
# Donor insemination
## Indications for donor insemination
The use of donor insemination is considered effective in managing fertility problems associated with the following conditions:
-bstructive azoospermia
non-obstructive azoospermia
severe deficits in semen quality in couples who do not wish to undergo intracytoplasmic sperm injection (ICSI).
Donor insemination should be considered in conditions such as:
where there is a high risk of transmitting a genetic disorder to the offspring
where there is a high risk of transmitting infectious disease to the offspring or woman from the man
severe rhesus isoimmunisation.
## Information and counselling
Couples should be offered information about the relative merits of ICSI and donor insemination in a context that allows equal access to both treatment options.
Couples considering donor insemination should be offered counselling from someone who is independent of the treatment unit regarding all the physical and psychological implications of treatment for themselves and potential children.
## Screening of sperm donors
Units undertaking semen donor recruitment and the cryopreservation of donor spermatozoa for treatment purposes should follow the UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors (2008) describing the selection and screening of donors. This recommendation has been updated to reflect a new guideline issued by the joint working party of Association of Biomedical Andrologists (ABA), Association of Clinical Embryologists (ACE), British Andrology Society (BAS), British Fertility Society (BFS) and Royal College of Obstetricians and Gynaecologists (RCOG).
All potential semen donors should be offered counselling from someone who is independent of the treatment unit regarding the implications for themselves and their genetic children, including any potential children resulting from donated semen.
## Assessments to offer the woman
Before starting treatment by donor insemination (for conditions listed in recommendations 1.14.1.1 and 1.14.1.2), it is important to confirm that the woman is ovulating. Women with a history that is suggestive of tubal damage should be offered tubal assessment before treatment.
Women with no risk factors in their history should be offered tubal assessment after 3 cycles if treatment by donor insemination (for conditions listed in recommendations 1.14.1.1 and 1.14.1.2) has been unsuccessful.
## Intrauterine insemination versus intracervical insemination
Couples using donor sperm should be offered intrauterine insemination in preference to intracervical insemination because it improves pregnancy rates.
## Unstimulated versus stimulated donor insemination
Women who are ovulating regularly should be offered a minimum of 6 cycles of donor insemination (for conditions listed in recommendations 1.14.1.1 and 1.14.1.2) without ovarian stimulation to reduce the risk of multiple pregnancy and its consequences.
# Oocyte donation
## Indications for oocyte donation
The use of donor oocytes is considered effective in managing fertility problems associated with the following conditions:
premature ovarian failure
gonadal dysgenesis, including Turner syndrome
bilateral oophorectomy
-varian failure following chemotherapy or radiotherapy
certain cases of IVF treatment failure.Oocyte donation should also be considered in certain cases where there is a high risk of transmitting a genetic disorder to the offspring.
## Screening of oocyte donors
Before donation is undertaken, oocyte donors should be screened for both infectious and genetic diseases in accordance with the UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors (2008). This recommendation has been updated to reflect a new guideline issued by the joint working party of Association of Biomedical Andrologists (ABA), Association of Clinical Embryologists (ACE), British Andrology Society (BAS), British Fertility Society (BFS) and Royal College of Obstetricians and Gynaecologists (RCOG).
## Oocyte donation and 'egg sharing'
Oocyte donors should be offered information regarding the potential risks of ovarian stimulation and oocyte collection.
Oocyte recipients and donors should be offered counselling from someone who is independent of the treatment unit regarding the physical and psychological implications of treatment for themselves and their genetic children, including any potential children resulting from donated oocytes.
All people considering participation in an 'egg-sharing' scheme should be counselled about its particular implications.
# People with cancer who wish to preserve fertility
## Cryopreservation of semen, oocytes and embryos
When considering and using cryopreservation for people before starting chemotherapy or radiotherapy that is likely to affect their fertility, follow recommendations in the guidance on management on the effects of cancer treatment on reproductive functions (2007) by the Royal College of Physicians, the Royal College of Radiologists, the Royal College of Obstetricians and Gynaecologists.
At diagnosis, the impact of the cancer and its treatment on future fertility should be discussed between the person diagnosed with cancer and their cancer team.
When deciding to offer fertility preservation to people diagnosed with cancer, take into account the following factors:
diagnosis
treatment plan
expected outcome of subsequent fertility treatment
prognosis of the cancer treatment
viability of stored or post-thawed material.
For cancer-related fertility preservation, do not apply the eligibility criteria used for conventional infertility treatment.
Do not use a lower age limit for cryopreservation for fertility preservation in people diagnosed with cancer.
Inform people diagnosed with cancer that the eligibility criteria used in conventional infertility treatment do not apply in the case of fertility cryopreservation provided by the NHS. However, those criteria will apply when it comes to using stored material for assisted conception in an NHS setting.
When using cryopreservation to preserve fertility in people diagnosed with cancer, use sperm, embryos or oocytes.
Offer sperm cryopreservation to men and adolescent boys who are preparing for medical treatment for cancer that is likely to make them infertile.
Use freezing in liquid nitrogen vapour as the preferred cryopreservation technique for sperm.
Offer oocyte or embryo cryopreservation as appropriate to women of reproductive age (including adolescent girls) who are preparing for medical treatment for cancer that is likely to make them infertile if:
they are well enough to undergo ovarian stimulation and egg collection and
this will not worsen their condition and
enough time is available before the start of their cancer treatment.
In cryopreservation of oocytes and embryos, use vitrification instead of controlled-rate freezing if the necessary equipment and expertise is available.
Store cryopreserved material for an initial period of 10 years.
Offer continued storage of cryopreserved sperm, beyond 10 years, to men who remain at risk of significant infertility.
# Long-term safety of assisted reproductive technologies for women with infertility and their children
## Long-term health outcomes of ovulation induction and ovarian stimulation
Give people who are considering ovulation induction or ovarian stimulation up-to-date information about the long-term health outcomes of these treatments.
Inform women who are offered ovulation induction or ovarian stimulation that:
no direct association has been found between these treatments and invasive cancer and
no association has been found in the short- to medium-term between these treatments and adverse outcomes (including cancer) in children born from ovulation induction and
information about long-term health outcomes in women and children is still awaited.
Limit the use of ovulation induction or ovarian stimulation agents to the lowest effective dose and duration of use.
## Long-term health outcomes and safety of IVF
Give people who are considering IVF treatment, with or without intracytoplasmic sperm injection (ICSI), up-to-date information about the long-term health outcomes (including the consequences of multiple pregnancy) of these treatments.
Inform women that while the absolute risks of long-term adverse outcomes of IVF treatment, with or without ICSI, are low, a small increased risk of borderline ovarian tumours cannot be excluded.
Inform people who are considering IVF treatment that the absolute risks of long-term adverse outcomes in children born as result of IVF are low.
Limit drugs used for controlled ovarian stimulation in IVF treatment to the lowest effective dose and duration of use. # Terms used in this guideline
# Expectant management
A formal approach that encourages conception through unprotected vaginal intercourse. It involves supportively offering an individual or couple information and advice about the regularity and timing of intercourse and any lifestyle changes which might improve their chances of conceiving. It does not involve active clinical or therapeutic interventions.
# Full cycle
This term is used to define a full in vitro fertilisation (IVF) treatment, which should include 1 episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s).
# Mild male factor infertility
This term is used extensively in practice and in the literature. However, no formally recognised definition is currently available. For the purpose of this guideline, it is defined as when 2 or more semen analyses have 1 or more variables below the 5th centile (as defined by the World Health Organization, 2010). The effect on the chance of pregnancy occurring naturally through vaginal intercourse within 2 years would then be similar to people with unexplained infertility or mild endometriosis.
# Natural cycle IVF
An IVF procedure in which 1 or more oocytes are collected from the ovaries during a spontaneous menstrual cycle without the use of drugs.# Recommendations for research
In 2013, the guideline committee made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Expectant management before IVF
What is the optimum period of expectant management for women of different age groups before invasive treatment such as in vitro fertilisation (IVF) is considered?
## Why this is important
Where there is no known cause for infertility, expectant management increases the cumulative chances of successful conception. However, the chances of a live birth both by natural conception and by using assisted reproductive technology decline with advancing age because of a woman's decreasing ovarian reserve. The guideline currently recommends a shorter period of expectant management for women who are 36 years or older. This is a very crude cut‑off. If there were better evidence, it might be possible to customise the period of expectant management based on a woman's age, including longer periods of expectant management for younger women.
# Embryo selection for single embryo transfer
Further research is needed to improve embryo selection to facilitate single embryo transfers.
## Why this is important
In current IVF practice, it is common to transfer more than 1 embryo in order to maximise the chance of pregnancy. As detailed in the guideline, this practice has inherent risks, especially of multiple pregnancy. Embryo selection is based on the assessment of developmental stage and morphological grading criteria in the laboratory. These features are indicative of implantation potential, though the predictive accuracy is relatively poor. However, if prediction of implantation potential could be improved, this would facilitate embryo selection for single rather than double embryo transfer.
# Adjuvant luteal phase support treatments in IVF
Further research is needed to assess the efficacy of adjuvant luteal phase support treatments such as low-dose aspirin, heparin, prednisolone, immunoglobulins and/or fat emulsions.
## Why this is important
These interventions are starting to be used in clinical practice in the absence of any randomised controlled trial (RCT) evidence of benefit, and even where there is RCT evidence of no benefit. Their use has potential dangers to the treated women. In cases where women are advised to continue taking the preparations until the end of the first trimester, there is the additional potential for teratogenicity. Immunoglobulins are also very expensive. It is important that the clinical efficacy of these agents is formally established so that clear statements about whether they should be recommended or are contraindicated can be made.
# Long-term safety of ovarian stimulation and ovulation induction for women
Is there an association between ovulation induction or ovarian stimulation and adverse long-term (over 20 years) effects in women in the UK?
## Why this is important
Women need to be reassured that it is safe to undergo ovulation induction and ovarian stimulation and that these interventions will not lead to significant long-term health issues, especially ovarian malignancy. Both treatments are common in managing infertility in women. The use of ovarian stimulation in IVF is particularly important as IVF is the final treatment option for most causes of infertility. During the course of the review for this guideline update, the guideline development group commented on the paucity of long-term research on the subject, despite the fact that the treatments have been established practice for over 30 years. The longest length of follow-up in the studies reviewed was 20 years, and the larger studies had shorter follow-up periods.
# Long-term effects of IVF with or without intracytoplasmic sperm injection in children
What are the long-term (over 20 years) effects of IVF with or without intracytoplasmic sperm injection (ICSI) in children in the UK?
## Why this is important
This topic is important in informing patients, service providers and society at large about the potential long-term safety of assisted reproduction. Both IVF and ICSI involve manipulation of egg and sperm in the laboratory, with impacts on the development of the subsequent embryo. However, while the first successful live birth following IVF was over 30 years ago, there is relatively little long-term research on the subject. In the review undertaken in this guideline update, the longest length of follow-up in the studies reviewed was 20 years, and the larger studies had shorter follow-up periods.# Figures and tables to support chances of conception and embryo quality recommendations
Age category (years)
Pregnant after 1 year (12 cycles; %)
Pregnant after 2 years (24 cycles; %)
to 26
to 29
to 34
to 39
Cumulative probability of conceiving a clinical pregnancy by the number of menstrual cycles attempting to conceive in different age categories (assuming vaginal intercourse occurs twice per week; reproduced with permission: Dunson DB, Baird DD, Colombo B . Increased infertility with age in men and women. Obstetrics and Gynecology 103: 51–6).
Woman's age (years)
ICI using thawed semen
(Schwartz et al. 1982) – 6 cycles
ICI using thawed semen
(Schwartz et al. 1982) – 12 cycles
Woman's age (years)
ICI using fresh semen (van Noord-Zaadstra, 1991) – 6 cycles
ICI using fresh semen (van Noord-Zaadstra, 1991) – 12 cycles
Woman's age (years)
IUI using thawed semen (HFEA data and personal communication) – 6 cycles
IUI using thawed semen (HFEA data and personal communication) – 12 cycles
to 34
to 35
to 39
Cumulative probability of conceiving a clinical pregnancy by the number of cycles of insemination in different age categories and according to the method and sperm status where assisted reproduction technology is used (see the full guideline for full references).
Abbreviations: ICI, intracervical insemination; IUI, intrauterine insemination; HFEA, Human Fertilisation and Embryology Authority.
Calculated on the basis of studies in 10 different populations that did not use contraceptives (Heffner 2004, based on 2 reviews by Menken et al. 1986 and Anderson et al. 2000).
The vertical axis shows embryo transfers; the horizontal axis shows age of woman (based on all 52,996 embryo transfers using the woman's own eggs undertaken in the UK between 1 October 2007 and 30 June 2009; HFEA, personal communication; note: small numbers of women aged under 24 years in the HFEA database).
Abbreviations: HFEA, Human Fertilisation and Embryology Authority.
Abbreviations: NEQAS, National External Quality Assessment Service.# Context
It is estimated that infertility affects 1 in 7 heterosexual couples in the UK. Since the original NICE guideline on fertility published in 2004, there has been a small increase in the prevalence of fertility problems, and a greater proportion of people now seeking help for such problems.
The main causes of infertility in the UK are (per cent figures indicate approximate prevalence):
unexplained infertility (no identified male or female cause; 25%)
-vulatory disorders (25%)
tubal damage (20%)
factors in the male causing infertility (30%)
uterine or peritoneal disorders (10%).
In about 40% of cases, disorders are found in both the man and the woman. Uterine or endometrial factors, gamete or embryo defects, and pelvic conditions such as endometriosis may also play a role.
Given the range of causes of fertility problems, the provision of appropriate investigations is critical. These investigations include semen analysis; assessment of ovulation, tubal damage and uterine abnormalities; and screening for infections such as Chlamydia trachomatis and susceptibility to rubella.
Once a diagnosis has been established, treatment falls into 3 main types:
medical treatment to restore fertility (for example, the use of drugs for ovulation induction)
surgical treatment to restore fertility (for example, laparoscopy for ablation of endometriosis)
assisted reproduction techniques (ART) – any treatment that deals with means of conception other than vaginal intercourse. It frequently involves the handling of gametes or embryos.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles of care\n\n## Providing information\n\nCouples who experience problems in conceiving should be seen together because both partners are affected by decisions surrounding investigation and treatment. \n\nPeople should have the opportunity to make informed decisions regarding their care and treatment via access to evidence-based information. These choices should be recognised as an integral part of the decision-making process. Verbal information should be supplemented with written information or audio-visual media. \n\nInformation regarding care and treatment options should be provided in a form that is accessible to people who have additional needs, such as people with physical, cognitive or sensory disabilities, and people who do not speak or read English. \n\n## Psychological effects of fertility problems\n\nWhen couples have fertility problems, both partners should be informed that stress in the male and/or female partner can affect the couple's relationship and is likely to reduce libido and frequency of intercourse, which can contribute to the fertility problems. [2004, amended 2013]\n\nPeople who experience fertility problems should be informed that they may find it helpful to contact a fertility support group. \n\nPeople who experience fertility problems should be offered counselling because fertility problems themselves, and the investigation and treatment of fertility problems, can cause psychological stress. \n\nCounselling should be offered before, during and after investigation and treatment, irrespective of the outcome of these procedures. \n\nCounselling should be provided by someone who is not directly involved in the management of the individual's and/or couple's fertility problems. [2004, amended 2013]\n\n## Generalist and specialist care\n\nPeople who experience fertility problems should be treated by a specialist team because this is likely to improve the effectiveness and efficiency of treatment and is known to improve people's satisfaction with treatment. [2004, amended 2013]\n\n# Initial advice to people concerned about delays in conception\n\n## Chance of conception\n\nPeople who are concerned about their fertility should be informed that over 80% of couples in the general population will conceive within 1\xa0year if:\n\nthe woman is aged under 40\xa0years and\n\nthey do not use contraception and have regular sexual intercourse.Of those who do not conceive in the first year, about half will do so in the second year (cumulative pregnancy rate over\xa090%). [2004, amended 2013]\n\nInform people who are using artificial insemination to conceive and who are concerned about their fertility that:\n\nover 50% of women aged under 40\xa0years will conceive within 6\xa0cycles of intrauterine insemination (IUI)\n\nof those who do not conceive within 6\xa0cycles of intrauterine insemination, about half will do so with a further 6\xa0cycles (cumulative pregnancy rate over\xa075%). [new 2013]\n\nInform people who are using artificial insemination to conceive and who are concerned about their fertility that using fresh sperm is associated with higher conception rates than frozen–thawed sperm. However, intrauterine insemination, even using frozen–thawed sperm, is associated with higher conception rates than intracervical insemination. [new 2013]\n\nInform people who are concerned about their fertility, that female fertility (and to a lesser extent) male fertility declines with age. [new 2013]\n\nDiscuss chances of conception with people concerned about their fertility who are:\n\nhaving sexual intercourse (see table\xa01) or\n\nusing artificial insemination (see table\xa02). [new 2013]\n\n## Frequency and timing of sexual intercourse or artificial insemination\n\nPeople who are concerned about their fertility should be informed that vaginal sexual intercourse every 2\xa0to 3\xa0days optimises the chance of pregnancy. [2004, amended 2013]\n\nPeople who are using artificial insemination to conceive should have their insemination timed around ovulation. [new 2013]\n\n## Alcohol\n\nWomen who are trying to become pregnant should be informed that drinking no more than 1\xa0or 2\xa0units of alcohol once or twice per week and avoiding episodes of intoxication reduces the risk of harming a developing fetus. \n\nMen should be informed that alcohol consumption within the Department of Health and Social Care's recommendations of 3\xa0to 4\xa0units per day for men is unlikely to affect their semen quality. [2004, amended 2013]\n\nMen should be informed that excessive alcohol intake is detrimental to semen quality. \n\n## Smoking\n\nWomen who smoke should be informed that this is likely to reduce their fertility. \n\nWomen who smoke should be offered referral to a smoking cessation programme to support their efforts in stopping smoking. \n\nWomen should be informed that passive smoking is likely to affect their chance of conceiving. \n\nMen who smoke should be informed that there is an association between smoking and reduced semen quality (although the impact of this on male fertility is uncertain), and that stopping smoking will improve their general health. \n\n## Caffeinated beverages\n\nPeople who are concerned about their fertility should be informed that there is no consistent evidence of an association between consumption of caffeinated beverages (tea, coffee and colas) and fertility problems. Also see recommendation\xa01.10.5.3 about caffeine intake and in vitro fertilisation (IVF) treatment. \n\n## Obesity\n\nWomen who have a body mass index (BMI) of 30\xa0or over should be informed that they are likely to take longer to conceive. [2004, amended 2013]\n\nWomen who have a BMI of 30\xa0or over and who are not ovulating should be informed that losing weight is likely to increase their chance of conception. [2004, amended 2013]\n\nWomen should be informed that participating in a group programme involving exercise and dietary advice leads to more pregnancies than weight loss advice alone. \n\nMen who have a BMI of 30\xa0or over should be informed that they are likely to have reduced fertility. [2004, amended 2013]\n\n## Low body weight\n\nWomen who have a BMI of less than\xa019 and who have irregular menstruation or are not menstruating should be advised that increasing body weight is likely to improve their chance of conception. \n\n## Tight underwear\n\nMen should be informed that there is an association between elevated scrotal temperature and reduced semen quality, but that it is uncertain whether wearing loose-fitting underwear improves fertility. \n\n## Occupation\n\nSome occupations involve exposure to hazards that can reduce male or female fertility and therefore a specific enquiry about occupation should be made to people who are concerned about their fertility, and appropriate advice should be offered. \n\n## Prescribed, over-the-counter and recreational drug use\n\nA number of prescription, over-the-counter and recreational drugs interfere with male and female fertility, and therefore a specific enquiry about these should be made to people who are concerned about their fertility, and appropriate advice should be offered. \n\n## Complementary therapy\n\nPeople who are concerned about their fertility should be informed that the effectiveness of complementary therapies for fertility problems has not been properly evaluated and that further research is needed before such interventions can be recommended. \n\n## Folic acid supplementation\n\nWomen intending to become pregnant should be informed that dietary supplementation with folic acid before conception and up to 12\xa0weeks' gestation reduces the risk of having a baby with neural tube defects. The recommended dose is 0.4\xa0mg per day. For women who have previously had an infant with a neural tube defect or who are receiving anti-epileptic medication or who have diabetes (see the NICE guideline on diabetes in pregnancy), a higher dose of 5\xa0mg per day is recommended. [2004, amended 2013]\n\n## Defining infertility\n\nPeople who are concerned about delays in conception should be offered an initial assessment. A specific enquiry about lifestyle and sexual history should be taken to identify people who are less likely to conceive. \n\nOffer an initial consultation to discuss the options for attempting conception to people who are unable to, or would find it very difficult to, have vaginal intercourse. [new 2013]\n\nThe environment in which investigation of fertility problems takes place should enable people to discuss sensitive issues such as sexual abuse. \n\nHealthcare professionals should define infertility in practice as the period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented. [new 2013]\n\nA woman of reproductive age who has not conceived after 1\xa0year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner. [new 2013]\n\nA woman of reproductive age who is using artificial insemination to conceive (with either partner or donor sperm) should be offered further clinical assessment and investigation if she has not conceived after 6\xa0cycles of treatment, in the absence of any known cause of infertility. Where this is using partner sperm, the referral for clinical assessment and investigation should include her partner. [new 2013]\n\nOffer an earlier referral for specialist consultation to discuss the options for attempting conception, further assessment and appropriate treatment where:\n\nthe woman is aged 36\xa0years or over\n\nthere is a known clinical cause of infertility or a history of predisposing factors for infertility. [new 2013]\n\nWhere treatment is planned that may result in infertility (such as treatment for cancer), early fertility specialist referral should be offered. [2004, amended 2013]\n\nPeople who are concerned about their fertility and who are known to have chronic viral infections such as hepatitis\xa0B, hepatitis\xa0C or HIV, should be referred to centres that have appropriate expertise and facilities to provide safe risk-reduction investigation and treatment. \n\n# Investigation of fertility problems and management strategies\n\n## Semen analysis\n\nThe results of semen analysis conducted as part of an initial assessment should be compared with the following World Health Organization reference values:\n\nsemen volume: 1.5\xa0ml or more\n\npH: 7.2\xa0or more\n\nsperm concentration: 15\xa0million spermatozoa per ml or more\n\ntotal sperm number: 39\xa0million spermatozoa per ejaculate or more\n\ntotal motility (percentage of progressive motility and non-progressive motility): 40% or more motile or 32% or more with progressive motility\n\nvitality: 58% or more live spermatozoa\n\nsperm morphology (percentage of normal forms): 4% or more. [2004, amended 2013]Please note the reference ranges are only valid for the semen analysis tests outlined by the World Health Organization.\n\nScreening for antisperm antibodies should not be offered because there is no evidence of effective treatment to improve fertility. \n\nIf the result of the first semen analysis is abnormal, a repeat confirmatory test should be offered. \n\nRepeat confirmatory tests should ideally be undertaken 3\xa0months after the initial analysis to allow time for the cycle of spermatozoa formation to be completed. However, if a gross spermatozoa deficiency (azoospermia or severe oligozoospermia) has been detected, the repeat test should be undertaken as soon as possible. \n\n## Post-coital testing of cervical mucus\n\nThe routine use of post-coital testing of cervical mucus in the investigation of fertility problems is not recommended because it has no predictive value on pregnancy rate. \n\n## Ovarian reserve testing\n\nUse a woman's age as an initial predictor of her overall chance of success through natural conception (see figure\xa01) or with IVF (see figure\xa02). [new 2013]\n\nUse 1 of the following measures to predict the likely ovarian response to gonadotrophin stimulation in IVF:\n\ntotal antral follicle count of less than or equal to\xa04 for a low response (follicles of less than or equal to 5\xa0mm measured by transvaginal ultrasound on day\xa03 of cycle: low response was less than 4\xa0oocytes) , and greater than\xa016 for a high response (follicles of 2\xa0to 10\xa0mm measured by transvaginal ultrasound on day\xa03 of cycle: high response was more than or equal to 15\xa0oocytes or more than or equal to 20\xa0oocytes)\n\nanti-Müllerian hormone of less than or equal to 5.4\xa0pmol/l for a low response (Beckman–Coulter assay: poor response defined as less than 4\xa0oocytes or cancellation), and greater than or equal to 25.0\xa0pmol/l for a high response (Beckman–Coulter or DSL assays: defined high response as more than or equal to 15\xa0oocytes to more than 21\xa0oocytes)\n\nfollicle-stimulating hormone greater than 8.9\xa0IU/l for a low response, and less than 4\xa0IU/l for a high response (long protocol of down-regulation: low response defined as less than 4\xa0oocytes or cancellation; high response defined as more than 20\xa0oocytes). [new 2013]\n\nDo not use any of the following tests individually to predict any outcome of fertility treatment:\n\novarian volume\n\novarian blood flow\n\ninhibin\xa0B\n\noestradiol (E2). [new 2013]\n\n## Regularity of menstrual cycles\n\nWomen who are concerned about their fertility should be asked about the frequency and regularity of their menstrual cycles. Women with regular monthly menstrual cycles should be informed that they are likely to be ovulating. \n\nWomen who are undergoing investigations for infertility should be offered a blood test to measure serum progesterone in the mid-luteal phase of their cycle (day\xa021 of a 28‑day cycle) to confirm ovulation even if they have regular menstrual cycles. [2004, amended 2013]\n\nWomen with prolonged irregular menstrual cycles should be offered a blood test to measure serum progesterone. Depending on the timing of menstrual periods, this test may need to be conducted later in the cycle (for example, day\xa028 of a 35‑day cycle) and repeated weekly thereafter until the next menstrual cycle starts. \n\nThe use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended. \n\nWomen with irregular menstrual cycles should be offered a blood test to measure serum gonadotrophins (follicle-stimulating hormone and luteinising hormone). \n\n## Prolactin measurement\n\nWomen who are concerned about their fertility should not be offered a blood test to measure prolactin. This test should only be offered to women who have an ovulatory disorder, galactorrhoea or a pituitary tumour. \n\n## Thyroid function tests\n\nWomen with possible fertility problems are no more likely than the general population to have thyroid disease and the routine measurement of thyroid function should not be offered. Estimation of thyroid function should be confined to women with symptoms of thyroid disease. \n\n## Endometrial biopsy\n\nWomen should not be offered an endometrial biopsy to evaluate the luteal phase as part of the investigation of fertility problems because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates. \n\n## Investigation of suspected tubal and uterine abnormalities\n\nWomen who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy or endometriosis) should be offered hysterosalpingography (HSG) to screen for tubal occlusion because this is a reliable test for ruling out tubal occlusion, and it is less invasive and makes more efficient use of resources than laparoscopy. \n\nWhere appropriate expertise is available, screening for tubal occlusion using hysterosalpingo-contrast-ultrasonography should be considered because it is an effective alternative to HSG for women who are not known to have comorbidities. \n\nWomen who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time. \n\nWomen should not be offered hysteroscopy on its own as part of the initial investigation unless clinically indicated because the effectiveness of surgical treatment of uterine abnormalities on improving pregnancy rates has not been established. \n\n## Testing for viral status\n\nPeople undergoing IVF treatment should be offered testing for HIV, hepatitis\xa0B and hepatitis\xa0C (for donor insemination, see recommendation\xa01.14.3.1). [2004, amended 2013]\n\nPeople found to test positive for 1 or more of HIV, hepatitis\xa0B or hepatitis\xa0C should be offered specialist advice and counselling and appropriate clinical management. [2004, amended 2013]\n\n## Viral transmission\n\nFor couples where the man is HIV positive, any decision about fertility management should be the result of discussions between the couple, a fertility specialist and an HIV specialist. [new 2013]\n\nAdvise couples where the man is HIV positive that the risk of HIV transmission to the female partner is negligible through unprotected sexual intercourse when all of the following criteria are met:\n\nthe man is compliant with highly active antiretroviral therapy (HAART)\n\nthe man has had a plasma viral load of less than 50\xa0copies/ml for more than 6\xa0months\n\nthere are no other infections present\n\nunprotected intercourse is limited to the time of ovulation. [new 2013]\n\nAdvise couples that if all the criteria in recommendation\xa01.3.10.2 are met, sperm washing may not further reduce the risk of infection and may reduce the likelihood of pregnancy. [new 2013]\n\nFor couples where the man is HIV positive and either he is not compliant with HAART or his plasma viral load is 50\xa0copies/ml or greater, offer sperm washing. [new 2013]\n\nInform couples that sperm washing reduces, but does not eliminate, the risk of HIV transmission. [new 2013]\n\nIf couples who meet all the criteria in recommendation\xa01.3.10.2 still perceive an unacceptable risk of HIV transmission after discussion with their HIV specialist, consider sperm washing. [new 2013]\n\nInform couples that there is insufficient evidence to recommend that HIV-negative women use pre-exposure prophylaxis, when all the criteria in recommendation\xa01.3.10.2 are met. [new 2013]\n\nFor partners of people with hepatitis\xa0B, offer vaccination before starting fertility treatment. [new 2013]\n\nDo not offer sperm washing as part of fertility treatment for men with hepatitis\xa0B. [new 2013]\n\nFor couples where the man has hepatitis\xa0C, any decision about fertility management should be the result of discussions between the couple, a fertility specialist and a hepatitis specialist. [new 2013]\n\nAdvise couples who want to conceive and where the man has hepatitis\xa0C that the risk of transmission through unprotected sexual intercourse is thought to be low. [new 2013]\n\nMen with hepatitis\xa0C should discuss treatment options to eradicate the hepatitis\xa0C with their appropriate specialist before conception is considered. [new 2013]\n\n## Susceptibility to rubella\n\nWomen who are concerned about their fertility should be offered testing for their rubella status so that those who are susceptible to rubella can be offered vaccination. Women who are susceptible to rubella should be offered vaccination and advised not to become pregnant for at least 1\xa0month following vaccination. [2004, amended 2013]\n\n## Cervical cancer screening\n\nTo avoid delay in fertility treatment, a specific enquiry about the timing and result of the most recent cervical smear test should be made to women who are concerned about their fertility. Cervical screening should be offered in accordance with the national cervical screening programme guidance. \n\n## Screening for Chlamydia trachomatis\n\nBefore undergoing uterine instrumentation, women should be offered screening for Chlamydia trachomatis using an appropriately sensitive technique. \n\nIf the result of a test for Chlamydia trachomatis is positive, women and their sexual partners should be referred for appropriate management with treatment and contact tracing. \n\nProphylactic antibiotics should be considered before uterine instrumentation if screening has not been carried out. \n\n# Medical and surgical management of male factor fertility problems\n\n## Medical management (male factor infertility)\n\nMen with hypogonadotrophic hypogonadism should be offered gonadotrophin drugs because these are effective in improving fertility. \n\nMen with idiopathic semen abnormalities should not be offered anti-oestrogens, gonadotrophins, androgens, bromocriptine or kinin-enhancing drugs because they have not been shown to be effective. \n\nMen should be informed that the significance of antisperm antibodies is unclear and the effectiveness of systemic corticosteroids is uncertain. \n\nMen with leucocytes in their semen should not be offered antibiotic treatment unless there is an identified infection because there is no evidence that this improves pregnancy rates. \n\n## Surgical management (male factor infertility)\n\nWhere appropriate expertise is available, men with obstructive azoospermia should be offered surgical correction of epididymal blockage because it is likely to restore patency of the duct and improve fertility. Surgical correction should be considered as an alternative to surgical sperm recovery and IVF. \n\nMen should not be offered surgery for varicoceles as a form of fertility treatment because it does not improve pregnancy rates. \n\n## Management of ejaculatory failure\n\nTreatment of ejaculatory failure can restore fertility without the need for invasive methods of sperm retrieval or the use of assisted reproduction procedures. However, further evaluation of different treatment options is needed. \n\n# Ovulation disorders\n\n## Classification of ovulatory disorders\n\nThe World Health Organization (WHO) classifies ovulation disorders into 3\xa0groups:\n\nGroup\xa01: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism)\n\nGroup\xa02: hypothalamic-pituitary-ovarian dysfunction (predominately polycystic ovary syndrome)\n\nGroup\xa03: ovarian failure.\n\n## WHO Group\xa01 ovulation disorders\n\nAdvise women with WHO Group\xa01 anovulatory infertility that they can improve their chance of regular ovulation, conception and an uncomplicated pregnancy by:\n\nincreasing their body weight if they have a BMI of less than\xa019 and/or\n\nmoderating their exercise levels if they undertake high levels of exercise. [new 2013]\n\nOffer women with WHO Group\xa01 ovulation disorders pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinising hormone activity to induce ovulation. \n\n## WHO Group\xa02 ovulation disorders\n\nAt the time of publication (February\xa02013), metformin did not have a UK marketing authorisation for the indications in this section. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. The patient should provide informed consent, which should be documented. See the General Medical Council's Good practice in prescribing medicines – guidance for doctors for further information.\n\nWomen with WHO Group\xa02 ovulation disorders receiving first-line treatment for ovarian stimulation\n\nAdvise women with WHO Group\xa02 anovulatory infertility who have a BMI of 30\xa0or over to lose weight (see recommendation\xa01.2.6.3). Inform them that this alone may restore ovulation, improve their response to ovulation induction agents, and have a positive impact on pregnancy outcomes. [new 2013]\n\nOffer women with WHO Group\xa02 anovulatory infertility 1\xa0of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman's BMI, and monitoring needed:\n\nclomifene citrate or\n\nmetformin or\n\na combination of the above. [new 2013]\n\nFor women who are taking clomifene citrate, offer ultrasound monitoring during at least the first cycle of treatment to ensure that they are taking a dose that minimises the risk of multiple pregnancy. \n\nFor women who are taking clomifene citrate, do not continue treatment for longer than 6\xa0months. [new 2013]\n\nWomen prescribed metformin should be informed of the side effects associated with its use (such as nausea, vomiting and other gastrointestinal disturbances). \n\nWomen with WHO Group\xa03 ovulation disorders who are known to be resistant to clomifene citrate\n\nFor women with WHO Group\xa03 ovulation disorders who are known to be resistant to clomifene citrate, consider 1\xa0of the following second-line treatments, depending on clinical circumstances and the woman's preference:\n\nlaparoscopic ovarian drilling or\n\ncombined treatment with clomifene citrate and metformin if not already offered as first-line treatment or\n\ngonadotrophins. [new 2013]\n\nWomen with polycystic ovary syndrome who are being treated with gonadotrophins should not be offered treatment with gonadotrophin-releasing hormone agonist concomitantly because it does not improve pregnancy rates, and it is associated with an increased risk of ovarian hyperstimulation. \n\nThe use of adjuvant growth hormone treatment with gonadotrophin-releasing hormone agonist and/or human menopausal gonadotrophin during ovulation induction in women with polycystic ovary syndrome who do not respond to clomifene citrate is not recommended because it does not improve pregnancy rates. \n\nThe effectiveness of pulsatile gonadotrophin-releasing hormone in women with clomifene citrate-resistant polycystic ovary syndrome is uncertain and is therefore not recommended outside a research context. \n\n## Hyperprolactinaemic amenorrhoea – dopamine agonists\n\nWomen with ovulatory disorders due to hyperprolactinaemia should be offered treatment with dopamine agonists such as bromocriptine. Consideration should be given to safety for use in pregnancy and minimising cost when prescribing. \n\n## Monitoring ovulation induction during gonadotrophin therapy\n\nWomen who are offered ovulation induction with gonadotrophins should be informed about the risk of multiple pregnancy and ovarian hyperstimulation before starting treatment. \n\nOvarian ultrasound monitoring to measure follicular size and number should be an integral part of gonadotrophin therapy to reduce the risk of multiple pregnancy and ovarian hyperstimulation. \n\n# Tubal and uterine surgery\n\n## Tubal microsurgery and laparoscopic tubal surgery\n\nFor women with mild tubal disease, tubal surgery may be more effective than no treatment. In centres where appropriate expertise is available, it may be considered as a treatment option. \n\n## Tubal catheterisation or cannulation\n\nFor women with proximal tubal obstruction, selective salpingography plus tubal catheterisation, or hysteroscopic tubal cannulation, may be treatment options because these treatments improve the chance of pregnancy. \n\n## Surgery for hydrosalpinges before IVF treatment\n\nWomen with hydrosalpinges should be offered salpingectomy, preferably by laparoscopy, before IVF treatment because this improves the chance of a live birth. \n\n## Uterine surgery\n\nWomen with amenorrhoea who are found to have intrauterine adhesions should be offered hysteroscopic adhesiolysis because this is likely to restore menstruation and improve the chance of pregnancy. \n\n# Medical and surgical management of endometriosis\n\nThis section has been stood down as it has been superseded by publication of the NICE guideline on endometriosis.\n\n# Unexplained infertility\n\n## Ovarian stimulation for unexplained infertility\n\nDo not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) to women with unexplained infertility. [new 2013]\n\nInform women with unexplained infertility that clomifene citrate as a stand-alone treatment does not increase the chances of a pregnancy or a live birth. [new 2013]\n\nAdvise women with unexplained infertility who are having regular unprotected sexual intercourse to try to conceive for a total of 2\xa0years (this can include up to 1\xa0year before their fertility investigations) before IVF will be considered. [new 2013]\n\nOffer IVF treatment (see recommendations 1.11.1.3 and 1.11.1.4) to women with unexplained infertility who have not conceived after 2\xa0years (this can include up to 1\xa0year before their fertility investigations) of regular unprotected sexual intercourse. [new 2013]\n\n# Intrauterine insemination\n\n## Intrauterine insemination\n\nConsider unstimulated intrauterine insemination as a treatment option in the following groups as an alternative to vaginal sexual intercourse:\n\npeople who are unable to, or would find it very difficult to, have vaginal intercourse because of a clinically diagnosed physical disability or psychosexual problem who are using partner or donor sperm\n\npeople with conditions that require specific consideration in relation to methods of conception (for example, after sperm washing where the man is HIV\xa0positive)\n\npeople in same-sex relationships. [new 2013]\n\nFor people in recommendation\xa01.9.1.1 who have not conceived after 6\xa0cycles of donor or partner insemination, despite evidence of normal ovulation, tubal patency and semen analysis, offer a further 6\xa0cycles of unstimulated intrauterine insemination before IVF is considered. [new 2013]\n\nFor people with unexplained infertility, mild endometriosis or mild male factor infertility, who are having regular unprotected sexual intercourse:\n\ndo not routinely offer intrauterine insemination, either with or without ovarian stimulation (exceptional circumstances include, for example, when people have social, cultural or religious objections to IVF)\n\nadvise them to try to conceive for a total of 2\xa0years (this can include up to 1\xa0year before their fertility investigations) before IVF will be considered. \n\n# Prediction of IVF success\n\n## Female age\n\nInform women that the chance of a live birth following IVF treatment falls with rising female age (see figure\xa02). \n\n## Number of previous treatment cycles\n\nInform people that the overall chance of a live birth following IVF treatment falls as the number of unsuccessful cycles increases. [new 2013]\n\n## Previous pregnancy history\n\nPeople should be informed that IVF treatment is more effective in women who have previously been pregnant and/or had a live birth. [2004, amended 2013]\n\n## Body mass index\n\nWomen should be informed that female BMI should ideally be in the range 19\xa0to\xa030 before commencing assisted reproduction, and that a female BMI outside this range is likely to reduce the success of assisted reproduction procedures. \n\n## Lifestyle factors\n\nPeople should be informed that the consumption of more than 1\xa0unit of alcohol per day reduces the effectiveness of assisted reproduction procedures, including IVF. [2004, amended 2013]\n\nPeople should be informed that maternal and paternal smoking can adversely affect the success rates of assisted reproduction procedures, including IVF treatment. [2004, amended 2013]\n\nPeople should be informed that maternal caffeine consumption has adverse effects on the success rates of assisted reproduction procedures, including IVF treatment. [2004, amended 2013]\n\n# Access criteria for IVF\n\n## Criteria for referral for IVF\n\nWhen considering IVF as a treatment option for people with fertility problems, discuss the risks and benefits of IVF in accordance with the current Human Fertilisation and Embryology Authority (HFEA) Code of Practice. [new 2013]\n\nInform people that normally a full cycle of IVF treatment, with or without intracytoplasmic sperm injection (ICSI), should comprise 1\xa0episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s). [new 2013]\n\nIn women aged under 40\xa0years who have not conceived after 2\xa0years of regular unprotected intercourse or 12\xa0cycles of artificial insemination (where 6\xa0or more are by intrauterine insemination), offer 3\xa0full cycles of IVF, with or without ICSI. If the woman reaches the age of\xa040 during treatment, complete the current full cycle but do not offer further full cycles. [new 2013]\n\nIn women aged 40\xa0to 42\xa0years who have not conceived after 2\xa0years of regular unprotected intercourse or 12\xa0cycles of artificial insemination (where 6\xa0or more are by intrauterine insemination), offer 1\xa0full cycle of IVF, with or without ICSI, provided the following 3\xa0criteria are fulfilled:\n\nthey have never previously had IVF treatment\n\nthere is no evidence of low ovarian reserve (see recommendation\xa01.3.3.2)\n\nthere has been a discussion of the additional implications of IVF and pregnancy at this age. [new 2013]\n\nWhere investigations show there is no chance of pregnancy with expectant management and where IVF is the only effective treatment, refer the woman directly to a specialist team for IVF treatment. [new 2013]\n\nIn women aged under 40\xa0years, any previous full IVF cycle, whether self- or NHS-funded, should count towards the total of 3\xa0full cycles that should be offered by the NHS. [new 2013]\n\nTake into account the outcome of previous IVF treatment when assessing the likely effectiveness and safety of any further IVF treatment. [new 2013]\n\nHealthcare providers should define a cancelled IVF cycle as one where an egg collection procedure is not undertaken. However, cancelled cycles due to low ovarian reserve should be taken into account when considering suitability for further IVF treatment. [new 2013]\n\n# Procedures used during IVF treatment\n\n## Pre-treatment in IVF\n\nAdvise women that using pre-treatment (with either the oral contraceptive pill or a progestogen) as part of IVF does not affect the chances of having a live birth. [new 2013]\n\nConsider pre-treatment in order to schedule IVF treatment for women who are not undergoing long down-regulation protocols. [new 2013]\n\n## Down regulation and other regimens to avoid premature luteinising hormone surges in IVF\n\nUse regimens to avoid premature luteinising hormone surges in gonadotrophin-stimulated IVF treatment cycles. [new 2013]\n\nUse either gonadotrophin-releasing hormone agonist down-regulation or gonadotrophin-releasing hormone antagonists as part of gonadotrophin-stimulated IVF treatment cycles. [new 2013]\n\nOnly offer gonadotrophin-releasing hormone agonists to women who have a low risk of ovarian hyperstimulation syndrome. [new 2013]\n\nWhen using gonadotrophin-releasing hormone agonists as part of IVF treatment, use a long down-regulation protocol. [new 2013]\n\n## Controlled ovarian stimulation in IVF\n\nUse ovarian stimulation as part of IVF treatment. [new 2013]\n\nUse either urinary or recombinant gonadotrophins for ovarian stimulation as part of IVF treatment. [new 2013]\n\nWhen using gonadotrophins for ovarian stimulation in IVF treatment:\n\nuse an individualised starting dose of follicle-stimulating hormone, based on factors that predict success, such as:\n\n\n\nage\n\nBMI\n\npresence of polycystic ovaries\n\novarian reserve\n\n\n\ndo not use a dosage of follicle-stimulating hormone of more than 450\xa0IU/day. [new 2013]\n\nOffer women ultrasound monitoring (with or without oestradiol levels) for efficacy and safety throughout ovarian stimulation. [new 2013]\n\nInform women that clomifene citrate-stimulated and gonadotrophin-stimulated IVF cycles have higher pregnancy rates per cycle than natural cycle IVF. \n\nDo not offer women natural cycle IVF treatment. \n\nDo not use growth hormone or dehydroepiandrosterone (DHEA) as adjuvant treatment in IVF protocols. [new 2013]\n\n## Triggering ovulation in IVF\n\nOffer women human chorionic gonadotrophin (urinary or recombinant) to trigger ovulation in IVF treatment. [new 2013]\n\nOffer ultrasound monitoring of ovarian response as an integral part of the IVF treatment cycle. \n\nClinics providing ovarian stimulation with gonadotrophins should have protocols in place for preventing, diagnosing and managing ovarian hyperstimulation syndrome. \n\n## Oocyte and sperm retrieval in IVF\n\nWomen undergoing transvaginal retrieval of oocytes should be offered conscious sedation because it is a safe and acceptable method of providing analgesia. \n\nThe safe practice of administering sedative drugs published by the Academy of Medical Royal Colleges should be followed. \n\nWomen who have developed at least 3\xa0follicles before oocyte retrieval should not be offered follicle flushing because this procedure does not increase the numbers of oocytes retrieved or pregnancy rates, and it increases the duration of oocyte retrieval and associated pain. \n\nSurgical sperm recovery before ICSI may be performed using several different techniques depending on the pathology and wishes of the man. In all cases, facilities for cryopreservation of spermatozoa should be available. \n\nAssisted hatching is not recommended because it has not been shown to improve pregnancy rates. \n\n## Embryo transfer strategies in IVF\n\nWomen undergoing IVF treatment should be offered ultrasound-guided embryo transfer because this improves pregnancy rates. \n\nReplacement of embryos into a uterine cavity with an endometrium of less than 5\xa0mm thickness is unlikely to result in a pregnancy and is therefore not recommended. \n\nWomen should be informed that bed rest of more than 20\xa0minutes' duration following embryo transfer does not improve the outcome of IVF treatment. \n\nEvaluate embryo quality, at both cleavage and blastocyst stages, according to the Association of Clinical Embryologists (ACE) and UK National External Quality Assessment Service (UK NEQAS) for Reproductive Science Embryo and Blastocyst Grading schematic (see figure\xa03). [new 2013]\n\nWhen considering the number of fresh or frozen embryos to transfer in IVF treatment:\n\nFor women aged under 37\xa0years:\n\n\n\nIn the first full IVF cycle, use single embryo transfer.\n\nIn the second full IVF cycle, use single embryo transfer if 1\xa0or more top-quality embryos are available. Consider using 2\xa0embryos if no top-quality embryos are available.\n\nIn the third full IVF cycle, transfer no more than 2\xa0embryos.\n\n\n\nFor women aged 37\xa0to 39\xa0years:\n\n\n\nIn the first and second full IVF cycles, use single embryo transfer if there are 1\xa0or more top-quality embryos. Consider double embryo transfer if there are no top-quality embryos.\n\nIn the third full IVF cycle, transfer no more than 2\xa0embryos.\n\n\n\nFor women aged 40\xa0to 42\xa0years, consider double embryo transfer. [new 2013]\n\nFor women undergoing IVF treatment with donor eggs, use an embryo transfer strategy that is based on the age of the donor. [new 2013]\n\nNo more than 2\xa0embryos should be transferred during any 1\xa0cycle of IVF treatment. \n\nWhere a top-quality blastocyst is available, use single embryo transfer. [new 2013]\n\nWhen considering double embryo transfer, advise people of the risks of multiple pregnancy associated with this strategy. [new 2013]\n\nOffer cryopreservation to store any remaining good-quality embryos after embryo transfer. [new 2013]\n\nAdvise women who have regular ovulatory cycles that the likelihood of a live birth after replacement of frozen–thawed embryos is similar for embryos replaced during natural cycles and hormone-supplemented cycles. \n\n## Luteal phase support after IVF\n\nOffer women progesterone for luteal phase support after IVF treatment. [new 2013]\n\nDo not routinely offer women human chorionic gonadotrophin for luteal phase support after IVF treatment because of the increased likelihood of ovarian hyperstimulation syndrome. \n\nInform women undergoing IVF treatment that the evidence does not support continuing any form of treatment for luteal phase support beyond 8\xa0weeks' gestation. [new 2013]\n\n## Gamete intrafallopian transfer and zygote intrafallopian transfer\n\nThere is insufficient evidence to recommend the use of gamete intrafallopian transfer or zygote intrafallopian transfer in preference to IVF in couples with unexplained fertility problems or male factor fertility problems. \n\n# Intracytoplasmic sperm injection\n\n## Indications for intracytoplasmic sperm injection\n\nThe recognised indications for treatment by intracytoplasmic sperm injection (ICSI) include:\n\nsevere deficits in semen quality\n\nobstructive azoospermia\n\nnon-obstructive azoospermia. In addition, treatment by ICSI should be considered for couples in whom a previous IVF treatment cycle has resulted in failed or very poor fertilisation. \n\n## Genetic issues and counselling\n\nBefore considering treatment by ICSI, people should undergo appropriate investigations, both to establish a diagnosis and to enable informed discussion about the implications of treatment. [2004, amended 2013]\n\nBefore treatment by ICSI, consideration should be given to relevant genetic issues. \n\nWhere a specific genetic defect associated with male infertility is known or suspected, couples should be offered appropriate genetic counselling and testing. \n\nWhere the indication for ICSI is a severe deficit of semen quality or non-obstructive azoospermia, the man's karyotype should be established. \n\nMen who are undergoing karyotype testing should be offered genetic counselling regarding the genetic abnormalities that may be detected. \n\nTesting for Y\xa0chromosome microdeletions should not be regarded as a routine investigation before ICSI. However, it is likely that a significant proportion of male infertility results from abnormalities of genes on the Y\xa0chromosome involved in the regulation of spermatogenesis, and couples should be informed of this. \n\n## ICSI versus IVF\n\nCouples should be informed that ICSI improves fertilisation rates compared with IVF alone, but once fertilisation is achieved, the pregnancy rate is no better than with IVF. \n\n# Donor insemination\n\n## Indications for donor insemination\n\nThe use of donor insemination is considered effective in managing fertility problems associated with the following conditions:\n\nobstructive azoospermia\n\nnon-obstructive azoospermia\n\nsevere deficits in semen quality in couples who do not wish to undergo intracytoplasmic sperm injection (ICSI). [2004, amended 2013]\n\nDonor insemination should be considered in conditions such as:\n\nwhere there is a high risk of transmitting a genetic disorder to the offspring\n\nwhere there is a high risk of transmitting infectious disease to the offspring or woman from the man\n\nsevere rhesus isoimmunisation. [2004, amended 2013]\n\n## Information and counselling\n\nCouples should be offered information about the relative merits of ICSI and donor insemination in a context that allows equal access to both treatment options. \n\nCouples considering donor insemination should be offered counselling from someone who is independent of the treatment unit regarding all the physical and psychological implications of treatment for themselves and potential children. \n\n## Screening of sperm donors\n\nUnits undertaking semen donor recruitment and the cryopreservation of donor spermatozoa for treatment purposes should follow the UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors (2008) describing the selection and screening of donors. This recommendation has been updated to reflect a new guideline issued by the joint working party of Association of Biomedical Andrologists (ABA), Association of Clinical Embryologists (ACE), British Andrology Society (BAS), British Fertility Society (BFS) and Royal College of Obstetricians and Gynaecologists (RCOG). [2004, amended 2013]\n\nAll potential semen donors should be offered counselling from someone who is independent of the treatment unit regarding the implications for themselves and their genetic children, including any potential children resulting from donated semen. \n\n## Assessments to offer the woman\n\nBefore starting treatment by donor insemination (for conditions listed in recommendations\xa01.14.1.1 and 1.14.1.2), it is important to confirm that the woman is ovulating. Women with a history that is suggestive of tubal damage should be offered tubal assessment before treatment. [2004, amended 2013]\n\nWomen with no risk factors in their history should be offered tubal assessment after 3\xa0cycles if treatment by donor insemination (for conditions listed in recommendations\xa01.14.1.1 and 1.14.1.2) has been unsuccessful. [2004, amended 2013]\n\n## Intrauterine insemination versus intracervical insemination\n\nCouples using donor sperm should be offered intrauterine insemination in preference to intracervical insemination because it improves pregnancy rates. \n\n## Unstimulated versus stimulated donor insemination\n\nWomen who are ovulating regularly should be offered a minimum of 6\xa0cycles of donor insemination (for conditions listed in recommendations\xa01.14.1.1 and 1.14.1.2) without ovarian stimulation to reduce the risk of multiple pregnancy and its consequences. [2004, amended 2013]\n\n# Oocyte donation\n\n## Indications for oocyte donation\n\nThe use of donor oocytes is considered effective in managing fertility problems associated with the following conditions:\n\npremature ovarian failure\n\ngonadal dysgenesis, including Turner syndrome\n\nbilateral oophorectomy\n\novarian failure following chemotherapy or radiotherapy\n\ncertain cases of IVF treatment failure.Oocyte donation should also be considered in certain cases where there is a high risk of transmitting a genetic disorder to the offspring. \n\n## Screening of oocyte donors\n\nBefore donation is undertaken, oocyte donors should be screened for both infectious and genetic diseases in accordance with the UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors (2008). This recommendation has been updated to reflect a new guideline issued by the joint working party of Association of Biomedical Andrologists (ABA), Association of Clinical Embryologists (ACE), British Andrology Society (BAS), British Fertility Society (BFS) and Royal College of Obstetricians and Gynaecologists (RCOG). [2004, amended 2013]\n\n## Oocyte donation and 'egg sharing'\n\nOocyte donors should be offered information regarding the potential risks of ovarian stimulation and oocyte collection. \n\nOocyte recipients and donors should be offered counselling from someone who is independent of the treatment unit regarding the physical and psychological implications of treatment for themselves and their genetic children, including any potential children resulting from donated oocytes. \n\nAll people considering participation in an 'egg-sharing' scheme should be counselled about its particular implications. \n\n# People with cancer who wish to preserve fertility\n\n## Cryopreservation of semen, oocytes and embryos\n\nWhen considering and using cryopreservation for people before starting chemotherapy or radiotherapy that is likely to affect their fertility, follow recommendations in the guidance on management on the effects of cancer treatment on reproductive functions (2007) by the Royal College of Physicians, the Royal College of Radiologists, the Royal College of Obstetricians and Gynaecologists. \n\nAt diagnosis, the impact of the cancer and its treatment on future fertility should be discussed between the person diagnosed with cancer and their cancer team. [new 2013]\n\nWhen deciding to offer fertility preservation to people diagnosed with cancer, take into account the following factors:\n\ndiagnosis\n\ntreatment plan\n\nexpected outcome of subsequent fertility treatment\n\nprognosis of the cancer treatment\n\nviability of stored or post-thawed material. [new 2013]\n\nFor cancer-related fertility preservation, do not apply the eligibility criteria used for conventional infertility treatment. [new 2013]\n\nDo not use a lower age limit for cryopreservation for fertility preservation in people diagnosed with cancer. [new 2013]\n\nInform people diagnosed with cancer that the eligibility criteria used in conventional infertility treatment do not apply in the case of fertility cryopreservation provided by the NHS. However, those criteria will apply when it comes to using stored material for assisted conception in an NHS setting. [new 2013]\n\nWhen using cryopreservation to preserve fertility in people diagnosed with cancer, use sperm, embryos or oocytes. [new 2013]\n\nOffer sperm cryopreservation to men and adolescent boys who are preparing for medical treatment for cancer that is likely to make them infertile. [new 2013]\n\nUse freezing in liquid nitrogen vapour as the preferred cryopreservation technique for sperm. [new 2013]\n\nOffer oocyte or embryo cryopreservation as appropriate to women of reproductive age (including adolescent girls) who are preparing for medical treatment for cancer that is likely to make them infertile if:\n\nthey are well enough to undergo ovarian stimulation and egg collection and\n\nthis will not worsen their condition and\n\nenough time is available before the start of their cancer treatment. [new 2013]\n\nIn cryopreservation of oocytes and embryos, use vitrification instead of controlled-rate freezing if the necessary equipment and expertise is available. [new 2013]\n\nStore cryopreserved material for an initial period of 10\xa0years. [new 2013]\n\nOffer continued storage of cryopreserved sperm, beyond 10\xa0years, to men who remain at risk of significant infertility. [new 2013]\n\n# Long-term safety of assisted reproductive technologies for women with infertility and their children\n\n## Long-term health outcomes of ovulation induction and ovarian stimulation\n\nGive people who are considering ovulation induction or ovarian stimulation up-to-date information about the long-term health outcomes of these treatments. [new 2013]\n\nInform women who are offered ovulation induction or ovarian stimulation that:\n\nno direct association has been found between these treatments and invasive cancer and\n\nno association has been found in the short- to medium-term between these treatments and adverse outcomes (including cancer) in children born from ovulation induction and\n\ninformation about long-term health outcomes in women and children is still awaited. [new 2013]\n\nLimit the use of ovulation induction or ovarian stimulation agents to the lowest effective dose and duration of use. [new 2013]\n\n## Long-term health outcomes and safety of IVF\n\nGive people who are considering IVF treatment, with or without intracytoplasmic sperm injection (ICSI), up-to-date information about the long-term health outcomes (including the consequences of multiple pregnancy) of these treatments. [new 2013]\n\nInform women that while the absolute risks of long-term adverse outcomes of IVF treatment, with or without ICSI, are low, a small increased risk of borderline ovarian tumours cannot be excluded. [new 2013]\n\nInform people who are considering IVF treatment that the absolute risks of long-term adverse outcomes in children born as result of IVF are low. [new 2013]\n\nLimit drugs used for controlled ovarian stimulation in IVF treatment to the lowest effective dose and duration of use. [new 2013]", 'Terms used in this guideline': '# Expectant management\n\nA formal approach that encourages conception through unprotected vaginal intercourse. It involves supportively offering an individual or couple information and advice about the regularity and timing of intercourse and any lifestyle changes which might improve their chances of conceiving. It does not involve active clinical or therapeutic interventions.\n\n# Full cycle\n\nThis term is used to define a full in vitro fertilisation (IVF) treatment, which should include 1\xa0episode of ovarian stimulation and the transfer of any resultant fresh and frozen embryo(s).\n\n# Mild male factor infertility\n\nThis term is used extensively in practice and in the literature. However, no formally recognised definition is currently available. For the purpose of this guideline, it is defined as when 2\xa0or more semen analyses have 1\xa0or more variables below the 5th centile (as defined by the World Health Organization, 2010). The effect on the chance of pregnancy occurring naturally through vaginal intercourse within 2\xa0years would then be similar to people with unexplained infertility or mild endometriosis.\n\n# Natural cycle IVF\n\nAn IVF procedure in which 1\xa0or more oocytes are collected from the ovaries during a spontaneous menstrual cycle without the use of drugs.', 'Recommendations for research': "In 2013, the guideline committee made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Expectant management before IVF\n\nWhat is the optimum period of expectant management for women of different age groups before invasive treatment such as in vitro fertilisation (IVF) is considered?\n\n## Why this is important\n\nWhere there is no known cause for infertility, expectant management increases the cumulative chances of successful conception. However, the chances of a live birth both by natural conception and by using assisted reproductive technology decline with advancing age because of a woman's decreasing ovarian reserve. The guideline currently recommends a shorter period of expectant management for women who are 36\xa0years or older. This is a very crude cut‑off. If there were better evidence, it might be possible to customise the period of expectant management based on a woman's age, including longer periods of expectant management for younger women.\n\n# Embryo selection for single embryo transfer\n\nFurther research is needed to improve embryo selection to facilitate single embryo transfers.\n\n## Why this is important\n\nIn current IVF practice, it is common to transfer more than 1\xa0embryo in order to maximise the chance of pregnancy. As detailed in the guideline, this practice has inherent risks, especially of multiple pregnancy. Embryo selection is based on the assessment of developmental stage and morphological grading criteria in the laboratory. These features are indicative of implantation potential, though the predictive accuracy is relatively poor. However, if prediction of implantation potential could be improved, this would facilitate embryo selection for single rather than double embryo transfer.\n\n# Adjuvant luteal phase support treatments in IVF\n\nFurther research is needed to assess the efficacy of adjuvant luteal phase support treatments such as low-dose aspirin, heparin, prednisolone, immunoglobulins and/or fat emulsions.\n\n## Why this is important\n\nThese interventions are starting to be used in clinical practice in the absence of any randomised controlled trial (RCT) evidence of benefit, and even where there is RCT evidence of no benefit. Their use has potential dangers to the treated women. In cases where women are advised to continue taking the preparations until the end of the first trimester, there is the additional potential for teratogenicity. Immunoglobulins are also very expensive. It is important that the clinical efficacy of these agents is formally established so that clear statements about whether they should be recommended or are contraindicated can be made.\n\n# Long-term safety of ovarian stimulation and ovulation induction for women\n\nIs there an association between ovulation induction or ovarian stimulation and adverse long-term (over 20\xa0years) effects in women in the UK?\n\n## Why this is important\n\nWomen need to be reassured that it is safe to undergo ovulation induction and ovarian stimulation and that these interventions will not lead to significant long-term health issues, especially ovarian malignancy. Both treatments are common in managing infertility in women. The use of ovarian stimulation in IVF is particularly important as IVF is the final treatment option for most causes of infertility. During the course of the review for this guideline update, the guideline development group commented on the paucity of long-term research on the subject, despite the fact that the treatments have been established practice for over 30\xa0years. The longest length of follow-up in the studies reviewed was 20\xa0years, and the larger studies had shorter follow-up periods.\n\n# Long-term effects of IVF with or without intracytoplasmic sperm injection in children\n\nWhat are the long-term (over 20\xa0years) effects of IVF with or without intracytoplasmic sperm injection (ICSI) in children in the UK?\n\n## Why this is important\n\nThis topic is important in informing patients, service providers and society at large about the potential long-term safety of assisted reproduction. Both IVF and ICSI involve manipulation of egg and sperm in the laboratory, with impacts on the development of the subsequent embryo. However, while the first successful live birth following IVF was over 30\xa0years ago, there is relatively little long-term research on the subject. In the review undertaken in this guideline update, the longest length of follow-up in the studies reviewed was 20\xa0years, and the larger studies had shorter follow-up periods.", 'Figures and tables to support chances of conception and embryo quality recommendations': "Age category (years)\n\nPregnant after 1\xa0year (12\xa0cycles; %)\n\nPregnant after 2\xa0years (24\xa0cycles; %)\n\nto 26\n\n\n\n\n\nto 29\n\n\n\n\n\nto 34\n\n\n\n\n\nto 39\n\n\n\n\n\nCumulative probability of conceiving a clinical pregnancy by the number of menstrual cycles attempting to conceive in different age categories (assuming vaginal intercourse occurs twice per week; reproduced with permission: Dunson DB, Baird DD, Colombo B . Increased infertility with age in men and women. Obstetrics and Gynecology 103: 51–6).\n\nWoman's age (years)\n\nICI using thawed semen\n\n(Schwartz et al. 1982) – 6 cycles\n\nICI using thawed semen\n\n(Schwartz et al. 1982) – 12 cycles\n\nWoman's age (years)\n\nICI using fresh semen (van Noord-Zaadstra, 1991) – 6 cycles\n\nICI using fresh semen (van Noord-Zaadstra, 1991) – 12 cycles\n\nWoman's age (years)\n\nIUI using thawed semen (HFEA data and personal communication) – 6 cycles\n\nIUI using thawed semen (HFEA data and personal communication) – 12 cycles\n\n<30\n\n%\n\n%\n\n<31\n\n%\n\n%\n\n–\n\n–\n\n–\n\nto 34\n\n%\n\n%\n\nto 35\n\n%\n\n%\n\n<35\n\n%\n\n%\n\n>34\n\n%\n\n%\n\n>35\n\n%\n\n%\n\nto 39\n\n%\n\n%\n\nCumulative probability of conceiving a clinical pregnancy by the number of cycles of insemination in different age categories and according to the method and sperm status where assisted reproduction technology is used (see the full guideline for full references).\n\nAbbreviations: ICI, intracervical insemination; IUI, intrauterine insemination; HFEA, Human Fertilisation and Embryology Authority.\n\nCalculated on the basis of studies in 10\xa0different populations that did not use contraceptives (Heffner 2004, based on 2\xa0reviews by Menken et al. 1986 and Anderson et al. 2000).\n\nThe vertical axis shows embryo transfers; the horizontal axis shows age of woman (based on all 52,996\xa0embryo transfers using the woman's own eggs undertaken in the UK between 1\xa0October 2007 and 30\xa0June 2009; HFEA, personal communication; note: small numbers of women aged under 24\xa0years in the HFEA database).\n\nAbbreviations: HFEA, Human Fertilisation and Embryology Authority.\n\nAbbreviations: NEQAS, National External Quality Assessment Service.", 'Context': 'It is estimated that infertility affects 1\xa0in 7\xa0heterosexual couples in the UK. Since the original NICE guideline on fertility published in 2004, there has been a small increase in the prevalence of fertility problems, and a greater proportion of people now seeking help for such problems.\n\nThe main causes of infertility in the UK are (per cent figures indicate approximate prevalence):\n\nunexplained infertility (no identified male or female cause; 25%)\n\novulatory disorders (25%)\n\ntubal damage (20%)\n\nfactors in the male causing infertility (30%)\n\nuterine or peritoneal disorders (10%).\n\nIn about 40% of cases, disorders are found in both the man and the woman. Uterine or endometrial factors, gamete or embryo defects, and pelvic conditions such as endometriosis may also play a role.\n\nGiven the range of causes of fertility problems, the provision of appropriate investigations is critical. These investigations include semen analysis; assessment of ovulation, tubal damage and uterine abnormalities; and screening for infections such as Chlamydia trachomatis and susceptibility to rubella.\n\nOnce a diagnosis has been established, treatment falls into 3\xa0main types:\n\nmedical treatment to restore fertility (for example, the use of drugs for ovulation induction)\n\nsurgical treatment to restore fertility (for example, laparoscopy for ablation of endometriosis)\n\nassisted reproduction techniques (ART) – any treatment that deals with means of conception other than vaginal intercourse. It frequently involves the handling of gametes or embryos.'}
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https://www.nice.org.uk/guidance/cg156
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This guideline covers diagnosing and treating fertility problems. It aims to reduce variation in practice and improve the way fertility problems are investigated and managed.
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951ea30b34806f91ea8ed4ed087a50e70bf92137
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nice
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Endometriosis: diagnosis and management
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Endometriosis: diagnosis and management
This guideline covers diagnosing and managing endometriosis. It aims to raise awareness of the symptoms of endometriosis, and to provide clear advice on what action to take when women with signs and symptoms first present in healthcare settings. It also provides advice on the range of treatments available.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
NICE has also produced a patient decision aid on hormonal treatment for endometriosis.
# Organisation of care
Set up a managed clinical network for women with suspected or confirmed endometriosis, consisting of community services (including GPs, practice nurses, school nurses and sexual health services), gynaecology services (see the recommendation on gynaecology services) and specialist endometriosis services (see the recommendation on specialist endometriosis services ).
Community, gynaecology and specialist endometriosis services (endometriosis centres) should:
provide coordinated care for women with suspected or confirmed endometriosis
have processes in place for prompt diagnosis and treatment of endometriosis, because delays can affect quality of life and result in disease progression.
## Gynaecology services for women with suspected or confirmed endometriosis
Gynaecology services for women with suspected or confirmed endometriosis should have access to:
a gynaecologist with expertise in diagnosing and managing endometriosis, including training and skills in laparoscopic surgery
a gynaecology specialist nurse with expertise in endometriosis
a multidisciplinary pain management service
a healthcare professional with an interest in gynaecological imaging
fertility services.
## Specialist endometriosis services (endometriosis centres)
Specialist endometriosis services (endometriosis centres) should have access to:
gynaecologists with expertise in diagnosing and managing endometriosis, including advanced laparoscopic surgical skills
a colorectal surgeon with an interest in endometriosis
a urologist with an interest in endometriosis
an endometriosis specialist nurse
a multidisciplinary pain management service with expertise in pelvic pain
a healthcare professional with specialist expertise in gynaecological imaging of endometriosis
advanced diagnostic facilities (for example, radiology and histopathology)
fertility services.
# Endometriosis information and support
Be aware that endometriosis can be a long-term condition, and can have a significant physical, sexual, psychological and social impact. Women may have complex needs and require long-term support.
Assess the individual information and support needs of women with suspected or confirmed endometriosis, taking into account their circumstances, symptoms, priorities, desire for fertility, aspects of daily living, work and study, cultural background, and their physical, psychosexual and emotional needs.
Provide information and support for women with suspected or confirmed endometriosis, which should include:
what endometriosis is
endometriosis symptoms and signs
how endometriosis is diagnosed
treatment options
local support groups, online forums and national charities, and how to access them.
If women agree, involve their partner (and/or other family members or people important to them) and include them in discussions. For more guidance on providing information to people and involving family members and carers, see the NICE guideline on patient experience in adult NHS services.
# Endometriosis symptoms and signs
Suspect endometriosis in women (including young women aged 17 and under) presenting with 1 or more of the following symptoms or signs:
chronic pelvic pain
period-related pain (dysmenorrhoea) affecting daily activities and quality of life
deep pain during or after sexual intercourse
period-related or cyclical gastrointestinal symptoms, in particular, painful bowel movements
period-related or cyclical urinary symptoms, in particular, blood in the urine or pain passing urine
infertility in association with 1 or more of the above.
Inform women with suspected or confirmed endometriosis that keeping a pain and symptom diary can aid discussions.
Offer an abdominal and pelvic examination to women with suspected endometriosis to identify abdominal masses and pelvic signs, such as reduced organ mobility and enlargement, tender nodularity in the posterior vaginal fornix, and visible vaginal endometriotic lesions.
If a pelvic examination is not appropriate, offer an abdominal examination to exclude abdominal masses.
# Referral for women with suspected or confirmed endometriosis
Consider referring women to a gynaecology service (see the recommendation on gynaecology services) for an ultrasound or gynaecology opinion if:
they have severe, persistent or recurrent symptoms of endometriosis
they have pelvic signs of endometriosis or
initial management is not effective, not tolerated or is contraindicated.
Refer women to a specialist endometriosis service (see the recommendation on specialist endometriosis services ) if they have suspected or confirmed:
deep endometriosis involving the bowel, bladder or ureter, or
endometriosis outside the pelvic cavity.
Consider referring young women (aged 17 and under) with suspected or confirmed endometriosis to a paediatric and adolescent gynaecology service, gynaecology service or specialist endometriosis service (endometriosis centre), depending on local service provision.
# Diagnosing endometriosis
Do not exclude the possibility of endometriosis if the abdominal or pelvic examination, ultrasound or MRI are normal. If clinical suspicion remains or symptoms persist, consider referral for further assessment and investigation.
## Ultrasound
Consider transvaginal ultrasound:
to investigate suspected endometriosis even if the pelvic and/or abdominal examination is normal
to identify endometriomas and deep endometriosis involving the bowel, bladder or ureter.
If a transvaginal scan is not appropriate, consider a transabdominal ultrasound scan of the pelvis.
## Serum CA125
Do not use serum CA125 to diagnose endometriosis.
If a coincidentally reported serum CA125 level is available, be aware that:
a raised serum CA125 (that is, 35 IU/ml or more) may be consistent with having endometriosis
endometriosis may be present despite a normal serum CA125 (less than 35 IU/ml).
## MRI
Do not use pelvic MRI as the primary investigation to diagnose endometriosis in women with symptoms or signs suggestive of endometriosis.
Consider pelvic MRI to assess the extent of deep endometriosis involving the bowel, bladder or ureter.
Ensure that pelvic MRI scans are interpreted by a healthcare professional with specialist expertise in gynaecological imaging.
## Diagnostic laparoscopy
Also refer to the section on surgical management and the section on surgical management if fertility is a priority.
Consider laparoscopy to diagnose endometriosis in women with suspected endometriosis, even if the ultrasound was normal.
For women with suspected deep endometriosis involving the bowel, bladder or ureter, consider a pelvic ultrasound or MRI before an operative laparoscopy.
During a diagnostic laparoscopy, a gynaecologist with training and skills in laparoscopic surgery for endometriosis should perform a systematic inspection of the pelvis.
During a diagnostic laparoscopy, consider taking a biopsy of suspected endometriosis:
to confirm the diagnosis of endometriosis (be aware that a negative histological result does not exclude endometriosis)
to exclude malignancy if an endometrioma is treated but not excised.
If a full, systematic laparoscopy is performed and is normal, explain to the woman that she does not have endometriosis, and offer alternative management.
# Staging systems
Offer endometriosis treatment according to the woman's symptoms, preferences and priorities, rather than the stage of the endometriosis.
When endometriosis is diagnosed, the gynaecologist should document a detailed description of the appearance and site of endometriosis.
# Monitoring for women with confirmed endometriosis
Consider outpatient follow‑up (with or without examination and pelvic imaging) for women with confirmed endometriosis, particularly women who choose not to have surgery, if they have:
deep endometriosis involving the bowel, bladder or ureter or
-r more endometrioma that is larger than 3 cm.
# Pharmacological pain management
## Analgesics
For women with endometriosis-related pain, discuss the benefits and risks of analgesics, taking into account any comorbidities and the woman's preferences.
Consider a short trial (for example, 3 months) of paracetamol or a non-steroidal anti-inflammatory drug (NSAID) alone or in combination for first-line management of endometriosis-related pain.
If a trial of paracetamol or an NSAID (alone or in combination) does not provide adequate pain relief, consider other forms of pain management and referral for further assessment.
## Neuromodulators and neuropathic pain treatments
For recommendations on using neuromodulators to treat neuropathic pain, see the NICE guideline on neuropathic pain.
## Hormonal treatments
NICE has produced a patient decision aid on hormonal treatment for endometriosis.
Explain to women with suspected or confirmed endometriosis that hormonal treatment for endometriosis can reduce pain and has no permanent negative effect on subsequent fertility.
Offer hormonal treatment (for example, the combined oral contraceptive pill or a progestogen) to women with suspected, confirmed or recurrent endometriosis. In September 2017, this was off-label use for some combined oral contraceptive pills or progestogens. See NICE's information on prescribing medicines.
If initial hormonal treatment for endometriosis is not effective, not tolerated or is contraindicated, refer the woman to a gynaecology service (see the recommendation on gynaecology services), specialist endometriosis service (see the recommendation on specialist endometriosis services ) or paediatric and adolescent gynaecology service for investigation and treatment options.
# Non-pharmacological management
Advise women that the available evidence does not support the use of traditional Chinese medicine or other Chinese herbal medicines or supplements for treating endometriosis.
# Surgical management
Ask women with suspected or confirmed endometriosis about their symptoms, preferences and priorities with respect to pain and fertility, to guide surgical decision-making.
Discuss surgical management options with women with suspected or confirmed endometriosis. Discussions may include:
what a laparoscopy involves
that laparoscopy may include surgical treatment (with prior patient consent)
how laparoscopic surgery could affect endometriosis symptoms
the possible benefits and risks of laparoscopic surgery
the possible need for further surgery (for example, for recurrent endometriosis or if complications arise)
the possible need for further planned surgery for deep endometriosis involving the bowel, bladder or ureter.
Perform surgery for endometriosis laparoscopically unless there are contraindications.
During a laparoscopy to diagnose endometriosis, consider laparoscopic treatment of the following, if present:
peritoneal endometriosis not involving the bowel, bladder or ureter
uncomplicated ovarian endometriomas.
As an adjunct to surgery for deep endometriosis involving the bowel, bladder or ureter, consider 3 months of gonadotrophin-releasing hormone agonists before surgery. In September 2017, this was off-label use for some gonadotrophin-releasing hormone agonists. See NICE's information on prescribing medicines.
Consider excision rather than ablation to treat endometriomas, taking into account the woman's desire for fertility and her ovarian reserve. Also see the section on ovarian reserve testing in the NICE guideline on fertility problems.
## Combination treatments
After laparoscopic excision or ablation of endometriosis, consider hormonal treatment (with, for example, the combined oral contraceptive pill), to prolong the benefits of surgery and manage symptoms. In September 2017, this was off-label use for some hormonal treatments (including some combined oral contraceptive pills). See NICE's information on prescribing medicines.
## Hysterectomy in combination with surgical management
If hysterectomy is indicated (for example, if the woman has adenomyosis or heavy menstrual bleeding that has not responded to other treatments), excise all visible endometriotic lesions at the time of the hysterectomy.
Perform hysterectomy (with or without oophorectomy) laparoscopically when combined with surgical treatment of endometriosis, unless there are contraindications.
For women thinking about having a hysterectomy, discuss:
what a hysterectomy involves and when it may be needed
the possible benefits and risks of hysterectomy
the possible benefits and risks of having oophorectomy at the same time
how a hysterectomy (with or without oophorectomy) could affect endometriosis symptoms
that hysterectomy should be combined with excision of all visible endometriotic lesions
endometriosis recurrence and the possible need for further surgery
the possible benefits and risks of hormone replacement therapy after hysterectomy with oophorectomy (also see the NICE guideline on menopause).
# Surgical management if fertility is a priority
The recommendations in this section should be interpreted within the context of NICE's guideline on fertility problems. The management of endometriosis-related subfertility should have multidisciplinary team involvement with input from a fertility specialist. This should include the recommended diagnostic fertility tests or preoperative tests, as well as other recommended fertility treatments such as assisted reproduction that are included in the NICE guideline on fertility problems.
Offer excision or ablation of endometriosis plus adhesiolysis for endometriosis not involving the bowel, bladder or ureter, because this improves the chance of spontaneous pregnancy.
Offer laparoscopic ovarian cystectomy with excision of the cyst wall to women with endometriomas, because this improves the chance of spontaneous pregnancy and reduces recurrence. Take into account the woman's ovarian reserve. (Also see the section on ovarian reserve testing in the NICE guideline on fertility problems.)
Discuss the benefits and risks of laparoscopic surgery as a treatment option for women who have deep endometriosis involving the bowel, bladder or ureter and who are trying to conceive (working with a fertility specialist). Topics to discuss may include:
whether laparoscopic surgery may alter the chance of future pregnancy
the possible impact on ovarian reserve (also see the section on ovarian reserve testing in the NICE guideline on fertility problems)
the possible impact on fertility if complications arise
alternatives to surgery
-ther fertility factors.
Do not offer hormonal treatment to women with endometriosis who are trying to conceive, because it does not improve spontaneous pregnancy rates.
# Terms used in this guideline
## Chronic pelvic pain
Defined as pelvic pain lasting for 6 months or longer.
## Paediatric and adolescent gynaecology service
Paediatric and adolescent gynaecology services are hospital-based, multidisciplinary specialist services for girls and young women (usually aged under 18).
## Ovarian cystectomy
Ovarian cystectomy is a surgical excision of an ovarian endometriotic cyst. An ovarian endometrioma is a cystic mass arising from ectopic endometrial tissue within the ovary.
## Managed clinical networks
Linked groups of healthcare professionals from primary, secondary and tertiary care providing a coordinated patient pathway. Responsibility for setting up these networks will depend on existing service provision and location.
# Endometriosis algorithm
# Context
Endometriosis is one of the most common gynaecological diseases needing treatment. It is defined as the growth of endometrial-like tissue (the womb lining) outside the uterus (womb). Endometriosis is mainly a disease of the reproductive years and, although its exact cause is unknown, it is hormone mediated and is associated with menstruation.
Endometriosis is typically associated with symptoms such as pelvic pain, painful periods and subfertility. Endometriosis is also associated with a lower quality of life. Women with endometriosis report pain, which can be frequent, chronic and/or severe, as well as tiredness, more sick days, and a significant physical, sexual, psychological and social impact. Endometriosis is an important cause of subfertility and this can also have a significant effect on quality of life.
Women may also have endometriosis without symptoms, so it is difficult to know how common the disease is in the population. It is also unclear whether endometriosis is always progressive or can remain stable or improve with time.
Delayed diagnosis is a significant problem for women with endometriosis. Patient self-help groups emphasise that healthcare professionals often do not recognise the importance of symptoms or consider endometriosis as a possibility. In addition, women can delay seeking help because of a perception that pelvic pain is normal. Delays of 4 to 10 years can occur between first reporting symptoms and confirming the diagnosis. Many women report that the delay in diagnosis leads to increased personal suffering, prolonged ill health and a disease state that is more difficult to treat.
Diagnosis can only be made definitively by laparoscopic visualisation of the pelvis, but other, less invasive methods may be useful in assisting diagnosis, including ultrasound. Management options for endometriosis include pharmacological, non-pharmacological and surgical treatments. Endometriosis is an oestrogen-dependent condition. Most drug treatments for endometriosis work by suppressing ovarian function, and are contraceptive. Surgical treatment aims to remove or destroy endometriotic lesions. The choice of treatment depends on the woman's preferences and priorities in terms of pain management and/or fertility.
Endometriosis can be a chronic condition affecting women throughout their reproductive lives (and sometimes beyond). Women's priorities and preferences may change over time, and management strategies should change to reflect this.
Women with endometriosis typically present to community services (including GPs, practice nurses, school nurses and sexual health services) with pain, and may then be referred to gynaecology services for diagnosis and management. Some women may present to fertility services. Complex surgical treatment is carried out in specialist endometriosis services (endometriosis centres), which incorporate a multidisciplinary team.
This guideline makes recommendations for the diagnosis and management of endometriosis in community services, gynaecology services and specialist endometriosis services (endometriosis centres).
The guideline also covers the care of women with confirmed or suspected endometriosis, including recurrent endometriosis. It includes women who do not have symptoms but have endometriosis discovered incidentally. Special consideration was given to young women (aged 17 and under). The guideline does not cover the investigation of fertility problems related to endometriosis, care of women with endometriosis occurring outside the pelvis, nor postmenopausal women.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Pain management programmes
Are pain management programmes a clinically and cost-effective intervention for women with endometriosis?
## Why this is important
Pain is one of the most debilitating symptoms of endometriosis. Endometriosis-related pain can be acute or chronic, and can adversely affect the woman's quality of life, ability to work, and can affect partners and their families.
Pain management programmes have been found to be effective in managing chronic pelvic pain, and can improve quality of life. However, it is unclear how much of this small evidence base can be generalised to women with endometriosis for which evidence is lacking. Furthermore, pain management programmes have not been compared with other treatments available for endometriosis. Pain management programmes promote self-management and are often provided in the community.
If found to be effective for endometriosis, pain management programmes would provide an additional or alternative treatment option for women experiencing endometriosis-related pain. Groups of particular interest are women for whom hormonal and surgical options have been exhausted, women who would prefer an alternative to a pharmacological or surgical approach, and women who may be prioritising trying to conceive.
# Laparoscopic treatment of peritoneal endometriosis (excision or ablation)
Is laparoscopic treatment (excision or ablation) of peritoneal disease in isolation effective for managing endometriosis-related pain?
## Why this is important
Isolated peritoneal endometriosis can be an incidental finding in women who may or may not experience pain or other symptoms.
Research is needed to determine whether laparoscopic treatment of isolated peritoneal endometriosis in women with endometriosis-related pain results in a clinical and cost-effective improvement in symptoms.
The current literature does not provide a clear answer because the stage of endometriosis is often not sufficiently clearly defined in research studies, and the treatment modalities used are multiple and varied. The resultant amalgamation of various stages of endometriosis and variable treatment modalities leads to loss of certainty of outcome in this specific group of women.
Establishing whether treating isolated peritoneal endometriosis is cost effective is important, because this forms a large part of the workload in general gynaecology, and uses considerable resources.
# Lifestyle interventions (diet and exercise)
Are specialist lifestyle interventions (diet and exercise) effective, compared with no specialist lifestyle interventions, for women with endometriosis?
## Why this is important
Endometriosis is a long-term condition that can cause acute and chronic pain, and fatigue. It has a significant and sometimes severe impact on the woman's quality of life and activities of daily living, including relationships and sexuality, ability to work, fertility, fitness and mental health.
Supporting self-management is critical to improving quality of life for women living with endometriosis. In order to successfully self-manage the condition, women need evidence-based, easily accessible information about the condition and ways of managing it that support surgical and medical treatment. However, no high-quality research was identified on the effectiveness of lifestyle interventions such as diet or exercise and other non-medical treatments in reducing pain, fatigue and other symptoms.
Studies should aim to provide evidence-based options to support self-management of endometriosis. This would improve the quality of life of women with endometriosis, enabling them to manage pain and fatigue, and reducing the negative impact on their career, relationships, sex lives, fertility, and physical and emotional wellbeing.
# Information and support
What information and support interventions are effective to help women with endometriosis deal with their symptoms and improve their quality of lives?
## Why this is important
This guideline has identified that women with endometriosis and their partners feel that information and support is not always provided in the way that best meet their needs. However, the direct effectiveness of different types or formats of information and support interventions on measurable outcomes such as health-related quality of life and level of function (for example, activities of daily living) have not been tested. Good practice in this area in non-specialist and specialist settings can improve satisfaction with the care provided. It may also improve quality of life and positively affect relationships between healthcare professionals and the woman with endometriosis, as well as the woman's personal family relationships.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nNICE has also produced a patient decision aid on hormonal treatment for endometriosis.\n\n# Organisation of care\n\nSet up a managed clinical network for women with suspected or confirmed endometriosis, consisting of community services (including GPs, practice nurses, school nurses and sexual health services), gynaecology services (see the recommendation on gynaecology services) and specialist endometriosis services (see the recommendation on specialist endometriosis services [endometriosis centres]).\n\nCommunity, gynaecology and specialist endometriosis services (endometriosis centres) should:\n\nprovide coordinated care for women with suspected or confirmed endometriosis\n\nhave processes in place for prompt diagnosis and treatment of endometriosis, because delays can affect quality of life and result in disease progression.\n\n## Gynaecology services for women with suspected or confirmed endometriosis\n\nGynaecology services for women with suspected or confirmed endometriosis should have access to:\n\na gynaecologist with expertise in diagnosing and managing endometriosis, including training and skills in laparoscopic surgery\n\na gynaecology specialist nurse with expertise in endometriosis\n\na multidisciplinary pain management service\n\na healthcare professional with an interest in gynaecological imaging\n\nfertility services.\n\n## Specialist endometriosis services (endometriosis centres)\n\nSpecialist endometriosis services (endometriosis centres) should have access to:\n\ngynaecologists with expertise in diagnosing and managing endometriosis, including advanced laparoscopic surgical skills\n\na colorectal surgeon with an interest in endometriosis\n\na urologist with an interest in endometriosis\n\nan endometriosis specialist nurse\n\na multidisciplinary pain management service with expertise in pelvic pain\n\na healthcare professional with specialist expertise in gynaecological imaging of endometriosis\n\nadvanced diagnostic facilities (for example, radiology and histopathology)\n\nfertility services.\n\n# Endometriosis information and support\n\nBe aware that endometriosis can be a long-term condition, and can have a significant physical, sexual, psychological and social impact. Women may have complex needs and require long-term support.\n\nAssess the individual information and support needs of women with suspected or confirmed endometriosis, taking into account their circumstances, symptoms, priorities, desire for fertility, aspects of daily living, work and study, cultural background, and their physical, psychosexual and emotional needs.\n\nProvide information and support for women with suspected or confirmed endometriosis, which should include:\n\nwhat endometriosis is\n\nendometriosis symptoms and signs\n\nhow endometriosis is diagnosed\n\ntreatment options\n\nlocal support groups, online forums and national charities, and how to access them.\n\nIf women agree, involve their partner (and/or other family members or people important to them) and include them in discussions. For more guidance on providing information to people and involving family members and carers, see the NICE guideline on patient experience in adult NHS services.\n\n# Endometriosis symptoms and signs\n\nSuspect endometriosis in women (including young women aged 17\xa0and under) presenting with 1\xa0or more of the following symptoms or signs:\n\nchronic pelvic pain\n\nperiod-related pain (dysmenorrhoea) affecting daily activities and quality of life\n\ndeep pain during or after sexual intercourse\n\nperiod-related or cyclical gastrointestinal symptoms, in particular, painful bowel movements\n\nperiod-related or cyclical urinary symptoms, in particular, blood in the urine or pain passing urine\n\ninfertility in association with 1\xa0or more of the above.\n\nInform women with suspected or confirmed endometriosis that keeping a pain and symptom diary can aid discussions.\n\nOffer an abdominal and pelvic examination to women with suspected endometriosis to identify abdominal masses and pelvic signs, such as reduced organ mobility and enlargement, tender nodularity in the posterior vaginal fornix, and visible vaginal endometriotic lesions.\n\nIf a pelvic examination is not appropriate, offer an abdominal examination to exclude abdominal masses.\n\n# Referral for women with suspected or confirmed endometriosis\n\nConsider referring women to a gynaecology service (see the recommendation on gynaecology services) for an ultrasound or gynaecology opinion if:\n\nthey have severe, persistent or recurrent symptoms of endometriosis\n\nthey have pelvic signs of endometriosis or\n\ninitial management is not effective, not tolerated or is contraindicated.\n\nRefer women to a specialist endometriosis service (see the recommendation on specialist endometriosis services [endometriosis centre]) if they have suspected or confirmed:\n\ndeep endometriosis involving the bowel, bladder or ureter, or\n\nendometriosis outside the pelvic cavity.\n\nConsider referring young women (aged 17\xa0and under) with suspected or confirmed endometriosis to a paediatric and adolescent gynaecology service, gynaecology service or specialist endometriosis service (endometriosis centre), depending on local service provision.\n\n# Diagnosing endometriosis\n\nDo not exclude the possibility of endometriosis if the abdominal or pelvic examination, ultrasound or MRI are normal. If clinical suspicion remains or symptoms persist, consider referral for further assessment and investigation.\n\n## Ultrasound\n\nConsider transvaginal ultrasound:\n\nto investigate suspected endometriosis even if the pelvic and/or abdominal examination is normal\n\nto identify endometriomas and deep endometriosis involving the bowel, bladder or ureter.\n\nIf a transvaginal scan is not appropriate, consider a transabdominal ultrasound scan of the pelvis.\n\n## Serum CA125\n\nDo not use serum CA125 to diagnose endometriosis.\n\nIf a coincidentally reported serum CA125 level is available, be aware that:\n\na raised serum CA125 (that is, 35\xa0IU/ml or more) may be consistent with having endometriosis\n\nendometriosis may be present despite a normal serum CA125 (less than 35\xa0IU/ml).\n\n## MRI\n\nDo not use pelvic MRI as the primary investigation to diagnose endometriosis in women with symptoms or signs suggestive of endometriosis.\n\nConsider pelvic MRI to assess the extent of deep endometriosis involving the bowel, bladder or ureter.\n\nEnsure that pelvic MRI scans are interpreted by a healthcare professional with specialist expertise in gynaecological imaging.\n\n## Diagnostic laparoscopy\n\nAlso refer to the section on surgical management and the section on surgical management if fertility is a priority.\n\nConsider laparoscopy to diagnose endometriosis in women with suspected endometriosis, even if the ultrasound was normal.\n\nFor women with suspected deep endometriosis involving the bowel, bladder or ureter, consider a pelvic ultrasound or MRI before an operative laparoscopy.\n\nDuring a diagnostic laparoscopy, a gynaecologist with training and skills in laparoscopic surgery for endometriosis should perform a systematic inspection of the pelvis.\n\nDuring a diagnostic laparoscopy, consider taking a biopsy of suspected endometriosis:\n\nto confirm the diagnosis of endometriosis (be aware that a negative histological result does not exclude endometriosis)\n\nto exclude malignancy if an endometrioma is treated but not excised.\n\nIf a full, systematic laparoscopy is performed and is normal, explain to the woman that she does not have endometriosis, and offer alternative management.\n\n# Staging systems\n\nOffer endometriosis treatment according to the woman's symptoms, preferences and priorities, rather than the stage of the endometriosis.\n\nWhen endometriosis is diagnosed, the gynaecologist should document a detailed description of the appearance and site of endometriosis.\n\n# Monitoring for women with confirmed endometriosis\n\nConsider outpatient follow‑up (with or without examination and pelvic imaging) for women with confirmed endometriosis, particularly women who choose not to have surgery, if they have:\n\ndeep endometriosis involving the bowel, bladder or ureter or\n\nor more endometrioma that is larger than 3\xa0cm.\n\n# Pharmacological pain management\n\n## Analgesics\n\nFor women with endometriosis-related pain, discuss the benefits and risks of analgesics, taking into account any comorbidities and the woman's preferences.\n\nConsider a short trial (for example, 3\xa0months) of paracetamol or a non-steroidal anti-inflammatory drug (NSAID) alone or in combination for first-line management of endometriosis-related pain.\n\nIf a trial of paracetamol or an NSAID (alone or in combination) does not provide adequate pain relief, consider other forms of pain management and referral for further assessment.\n\n## Neuromodulators and neuropathic pain treatments\n\nFor recommendations on using neuromodulators to treat neuropathic pain, see the NICE guideline on neuropathic pain.\n\n## Hormonal treatments\n\nNICE has produced a patient decision aid on hormonal treatment for endometriosis.\n\nExplain to women with suspected or confirmed endometriosis that hormonal treatment for endometriosis can reduce pain and has no permanent negative effect on subsequent fertility.\n\nOffer hormonal treatment (for example, the combined oral contraceptive pill or a progestogen) to women with suspected, confirmed or recurrent endometriosis. In September 2017, this was off-label use for some combined oral contraceptive pills or progestogens. See NICE's information on prescribing medicines.\n\nIf initial hormonal treatment for endometriosis is not effective, not tolerated or is contraindicated, refer the woman to a gynaecology service (see the recommendation on gynaecology services), specialist endometriosis service (see the recommendation on specialist endometriosis services [endometriosis centres]) or paediatric and adolescent gynaecology service for investigation and treatment options.\n\n# Non-pharmacological management\n\nAdvise women that the available evidence does not support the use of traditional Chinese medicine or other Chinese herbal medicines or supplements for treating endometriosis.\n\n# Surgical management\n\nAsk women with suspected or confirmed endometriosis about their symptoms, preferences and priorities with respect to pain and fertility, to guide surgical decision-making.\n\nDiscuss surgical management options with women with suspected or confirmed endometriosis. Discussions may include:\n\nwhat a laparoscopy involves\n\nthat laparoscopy may include surgical treatment (with prior patient consent)\n\nhow laparoscopic surgery could affect endometriosis symptoms\n\nthe possible benefits and risks of laparoscopic surgery\n\nthe possible need for further surgery (for example, for recurrent endometriosis or if complications arise)\n\nthe possible need for further planned surgery for deep endometriosis involving the bowel, bladder or ureter.\n\nPerform surgery for endometriosis laparoscopically unless there are contraindications.\n\nDuring a laparoscopy to diagnose endometriosis, consider laparoscopic treatment of the following, if present:\n\nperitoneal endometriosis not involving the bowel, bladder or ureter\n\nuncomplicated ovarian endometriomas.\n\nAs an adjunct to surgery for deep endometriosis involving the bowel, bladder or ureter, consider 3\xa0months of gonadotrophin-releasing hormone agonists before surgery. In September 2017, this was off-label use for some gonadotrophin-releasing hormone agonists. See NICE's information on prescribing medicines.\n\nConsider excision rather than ablation to treat endometriomas, taking into account the woman's desire for fertility and her ovarian reserve. Also see the section on ovarian reserve testing in the NICE guideline on fertility problems.\n\n## Combination treatments\n\nAfter laparoscopic excision or ablation of endometriosis, consider hormonal treatment (with, for example, the combined oral contraceptive pill), to prolong the benefits of surgery and manage symptoms. In September 2017, this was off-label use for some hormonal treatments (including some combined oral contraceptive pills). See NICE's information on prescribing medicines.\n\n## Hysterectomy in combination with surgical management\n\nIf hysterectomy is indicated (for example, if the woman has adenomyosis or heavy menstrual bleeding that has not responded to other treatments), excise all visible endometriotic lesions at the time of the hysterectomy.\n\nPerform hysterectomy (with or without oophorectomy) laparoscopically when combined with surgical treatment of endometriosis, unless there are contraindications.\n\nFor women thinking about having a hysterectomy, discuss:\n\nwhat a hysterectomy involves and when it may be needed\n\nthe possible benefits and risks of hysterectomy\n\nthe possible benefits and risks of having oophorectomy at the same time\n\nhow a hysterectomy (with or without oophorectomy) could affect endometriosis symptoms\n\nthat hysterectomy should be combined with excision of all visible endometriotic lesions\n\nendometriosis recurrence and the possible need for further surgery\n\nthe possible benefits and risks of hormone replacement therapy after hysterectomy with oophorectomy (also see the NICE guideline on menopause).\n\n# Surgical management if fertility is a priority\n\nThe recommendations in this section should be interpreted within the context of NICE's guideline on fertility problems. The management of endometriosis-related subfertility should have multidisciplinary team involvement with input from a fertility specialist. This should include the recommended diagnostic fertility tests or preoperative tests, as well as other recommended fertility treatments such as assisted reproduction that are included in the NICE guideline on fertility problems.\n\nOffer excision or ablation of endometriosis plus adhesiolysis for endometriosis not involving the bowel, bladder or ureter, because this improves the chance of spontaneous pregnancy.\n\nOffer laparoscopic ovarian cystectomy with excision of the cyst wall to women with endometriomas, because this improves the chance of spontaneous pregnancy and reduces recurrence. Take into account the woman's ovarian reserve. (Also see the section on ovarian reserve testing in the NICE guideline on fertility problems.)\n\nDiscuss the benefits and risks of laparoscopic surgery as a treatment option for women who have deep endometriosis involving the bowel, bladder or ureter and who are trying to conceive (working with a fertility specialist). Topics to discuss may include:\n\nwhether laparoscopic surgery may alter the chance of future pregnancy\n\nthe possible impact on ovarian reserve (also see the section on ovarian reserve testing in the NICE guideline on fertility problems)\n\nthe possible impact on fertility if complications arise\n\nalternatives to surgery\n\nother fertility factors.\n\nDo not offer hormonal treatment to women with endometriosis who are trying to conceive, because it does not improve spontaneous pregnancy rates.\n\n# Terms used in this guideline\n\n## Chronic pelvic pain\n\nDefined as pelvic pain lasting for 6\xa0months or longer.\n\n## Paediatric and adolescent gynaecology service\n\nPaediatric and adolescent gynaecology services are hospital-based, multidisciplinary specialist services for girls and young women (usually aged under\xa018).\n\n## Ovarian cystectomy\n\nOvarian cystectomy is a surgical excision of an ovarian endometriotic cyst. An ovarian endometrioma is a cystic mass arising from ectopic endometrial tissue within the ovary.\n\n## Managed clinical networks\n\nLinked groups of healthcare professionals from primary, secondary and tertiary care providing a coordinated patient pathway. Responsibility for setting up these networks will depend on existing service provision and location.\n\n# Endometriosis algorithm\n\n", 'Context': "Endometriosis is one of the most common gynaecological diseases needing treatment. It is defined as the growth of endometrial-like tissue (the womb lining) outside the uterus (womb). Endometriosis is mainly a disease of the reproductive years and, although its exact cause is unknown, it is hormone mediated and is associated with menstruation.\n\nEndometriosis is typically associated with symptoms such as pelvic pain, painful periods and subfertility. Endometriosis is also associated with a lower quality of life. Women with endometriosis report pain, which can be frequent, chronic and/or severe, as well as tiredness, more sick days, and a significant physical, sexual, psychological and social impact. Endometriosis is an important cause of subfertility and this can also have a significant effect on quality of life.\n\nWomen may also have endometriosis without symptoms, so it is difficult to know how common the disease is in the population. It is also unclear whether endometriosis is always progressive or can remain stable or improve with time.\n\nDelayed diagnosis is a significant problem for women with endometriosis. Patient self-help groups emphasise that healthcare professionals often do not recognise the importance of symptoms or consider endometriosis as a possibility. In addition, women can delay seeking help because of a perception that pelvic pain is normal. Delays of 4\xa0to 10\xa0years can occur between first reporting symptoms and confirming the diagnosis. Many women report that the delay in diagnosis leads to increased personal suffering, prolonged ill health and a disease state that is more difficult to treat.\n\nDiagnosis can only be made definitively by laparoscopic visualisation of the pelvis, but other, less invasive methods may be useful in assisting diagnosis, including ultrasound. Management options for endometriosis include pharmacological, non-pharmacological and surgical treatments. Endometriosis is an oestrogen-dependent condition. Most drug treatments for endometriosis work by suppressing ovarian function, and are contraceptive. Surgical treatment aims to remove or destroy endometriotic lesions. The choice of treatment depends on the woman's preferences and priorities in terms of pain management and/or fertility.\n\nEndometriosis can be a chronic condition affecting women throughout their reproductive lives (and sometimes beyond). Women's priorities and preferences may change over time, and management strategies should change to reflect this.\n\nWomen with endometriosis typically present to community services (including GPs, practice nurses, school nurses and sexual health services) with pain, and may then be referred to gynaecology services for diagnosis and management. Some women may present to fertility services. Complex surgical treatment is carried out in specialist endometriosis services (endometriosis centres), which incorporate a multidisciplinary team.\n\nThis guideline makes recommendations for the diagnosis and management of endometriosis in community services, gynaecology services and specialist endometriosis services (endometriosis centres).\n\nThe guideline also covers the care of women with confirmed or suspected endometriosis, including recurrent endometriosis. It includes women who do not have symptoms but have endometriosis discovered incidentally. Special consideration was given to young women (aged 17\xa0and under). The guideline does not cover the investigation of fertility problems related to endometriosis, care of women with endometriosis occurring outside the pelvis, nor postmenopausal women.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Pain management programmes\n\nAre pain management programmes a clinically and cost-effective intervention for women with endometriosis?\n\n## Why this is important\n\nPain is one of the most debilitating symptoms of endometriosis. Endometriosis-related pain can be acute or chronic, and can adversely affect the woman's quality of life, ability to work, and can affect partners and their families.\n\nPain management programmes have been found to be effective in managing chronic pelvic pain, and can improve quality of life. However, it is unclear how much of this small evidence base can be generalised to women with endometriosis for which evidence is lacking. Furthermore, pain management programmes have not been compared with other treatments available for endometriosis. Pain management programmes promote self-management and are often provided in the community.\n\nIf found to be effective for endometriosis, pain management programmes would provide an additional or alternative treatment option for women experiencing endometriosis-related pain. Groups of particular interest are women for whom hormonal and surgical options have been exhausted, women who would prefer an alternative to a pharmacological or surgical approach, and women who may be prioritising trying to conceive.\n\n# Laparoscopic treatment of peritoneal endometriosis (excision or ablation)\n\nIs laparoscopic treatment (excision or ablation) of peritoneal disease in isolation effective for managing endometriosis-related pain?\n\n## Why this is important\n\nIsolated peritoneal endometriosis can be an incidental finding in women who may or may not experience pain or other symptoms.\n\nResearch is needed to determine whether laparoscopic treatment of isolated peritoneal endometriosis in women with endometriosis-related pain results in a clinical and cost-effective improvement in symptoms.\n\nThe current literature does not provide a clear answer because the stage of endometriosis is often not sufficiently clearly defined in research studies, and the treatment modalities used are multiple and varied. The resultant amalgamation of various stages of endometriosis and variable treatment modalities leads to loss of certainty of outcome in this specific group of women.\n\nEstablishing whether treating isolated peritoneal endometriosis is cost effective is important, because this forms a large part of the workload in general gynaecology, and uses considerable resources.\n\n# Lifestyle interventions (diet and exercise)\n\nAre specialist lifestyle interventions (diet and exercise) effective, compared with no specialist lifestyle interventions, for women with endometriosis?\n\n## Why this is important\n\nEndometriosis is a long-term condition that can cause acute and chronic pain, and fatigue. It has a significant and sometimes severe impact on the woman's quality of life and activities of daily living, including relationships and sexuality, ability to work, fertility, fitness and mental health.\n\nSupporting self-management is critical to improving quality of life for women living with endometriosis. In order to successfully self-manage the condition, women need evidence-based, easily accessible information about the condition and ways of managing it that support surgical and medical treatment. However, no high-quality research was identified on the effectiveness of lifestyle interventions such as diet or exercise and other non-medical treatments in reducing pain, fatigue and other symptoms.\n\nStudies should aim to provide evidence-based options to support self-management of endometriosis. This would improve the quality of life of women with endometriosis, enabling them to manage pain and fatigue, and reducing the negative impact on their career, relationships, sex lives, fertility, and physical and emotional wellbeing.\n\n# Information and support\n\nWhat information and support interventions are effective to help women with endometriosis deal with their symptoms and improve their quality of lives?\n\n## Why this is important\n\nThis guideline has identified that women with endometriosis and their partners feel that information and support is not always provided in the way that best meet their needs. However, the direct effectiveness of different types or formats of information and support interventions on measurable outcomes such as health-related quality of life and level of function (for example, activities of daily living) have not been tested. Good practice in this area in non-specialist and specialist settings can improve satisfaction with the care provided. It may also improve quality of life and positively affect relationships between healthcare professionals and the woman with endometriosis, as well as the woman's personal family relationships."}
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https://www.nice.org.uk/guidance/ng73
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This guideline covers diagnosing and managing endometriosis. It aims to raise awareness of the symptoms of endometriosis, and to provide clear advice on what action to take when women with signs and symptoms first present in healthcare settings. It also provides advice on the range of treatments available.
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daa78c26ae4c7fb27f89d7df36a332dd260ed799
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nice
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Sorafenib for treating advanced hepatocellular carcinoma
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Sorafenib for treating advanced hepatocellular carcinoma
Evidence-based recommendations on sorafenib (Nexavar) for treating advanced hepatocellular carcinoma in adults.
# Recommendations
Sorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade A liver impairment, only if the company provides sorafenib within the agreed commercial access arrangement.
This recommendation is not intended to affect treatment with sorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Sorafenib (Nexavar, Bayer) is a multikinase inhibitor that inhibits tumour blood vessel development and tumour cell proliferation. It does this by inhibiting the Raf cascade, vascular endothelial growth factor and platelet-derived growth factor receptors of tumour cells, vascular endothelial cells and pericytes.
Marketing authorisation
Sorafenib has a marketing authorisation in the UK for treating hepatocellular carcinoma.
Adverse reactions
The summary of product characteristics includes the following conditions that may be associated with sorafenib treatment: dermatological toxicities, hypertension, haemorrhage, cardiac ischaemia and/or infarction, gastrointestinal perforation, hepatic impairment and wound healing complications. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Sorafenib is administered orally as 200-mg film-coated tablets. The recommended dosage is 400 mg twice daily (a total daily dose of 800 mg). The dosage may be adjusted to 2×200-mg tablets once daily if adverse drug reactions are suspected. The summary of product characteristics recommends that treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.
Price
The price for a pack of 200-mg tablets (112 tablets per pack) is £3,575.56.
The company agreed a nationally available price reduction for sorafenib with the Commercial Medicines Unit. The pricing agreement considered during guidance development was that the company (Bayer) had agreed a commercial access agreement with NHS England inclusive of the reduction for sorafenib agreed with the Commercial Medicines Unit. The commercial access agreement replaces the Commercial Medicines Unit price used during the Cancer Drugs Fund reconsideration of technology appraisal guidance 189. The details of this commercial access agreement are commercial in confidence.# Evidence
The appraisal committee (section 6) considered evidence submitted by Bayer and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma.
The company's original submission presented clinical effectiveness data from the SHARP study. SHARP was a multicentre, double-blind, placebo-controlled, randomised trial in patients with advanced hepatocellular carcinoma who had not received previous systemic treatment. The study included 602 patients and assessed the effect of sorafenib plus best supportive care (n=299) compared with placebo plus best supportive care (n=303). The primary outcomes in SHARP were overall survival and time to symptomatic progression.
Sections 4.1 to 4.17 reflect the committee's discussion of the evidence submitted in the original appraisal. Section 4.18 onwards reflects the committee's discussion of the additional evidence submitted for the Cancer Drugs Fund reconsideration, which focused on:
data from the key source of evidence, SHARP
-bservational data from Palmer et al. (2013) and the GIDEON study to validate survival extrapolations from the company's original submission
estimates of treatment duration using individual patient data for time on treatment from SHARP and GIDEON
updated resource use data
cost-effectiveness analyses using a new Commercial Medicines Unit price, providing sorafenib at a reduced cost (commercial in confidence)
estimates of how much sorafenib is wasted.
See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of sorafenib, having considered evidence on the nature of hepatocellular carcinoma and the value placed on the benefits of sorafenib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee considered the UK treatment pathway for patients with hepatocellular carcinoma. The clinical experts described that in UK clinical practice one third of patients with hepatocellular carcinoma would be eligible for procedures such as local resection, radiofrequency ablation or chemoembolisation. They noted that these procedures are not considered clinically effective for approximately 50% of patients, who would progress to further locoregional therapy or systemic treatment. The committee accepted that the scope of this technology appraisal was restricted to these patients. The committee further reviewed the treatment pathway consistent with the Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule as presented by Llovet et al. (2008). The clinical experts agreed that the BCLC staging system is used in UK clinical practice.
The committee was aware that the licensed indication for sorafenib is hepatocellular carcinoma without specific restrictions. However, the clinical effectiveness evidence from the SHARP study was for patients with advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable. This population was consistent with UK clinical practice and clinical guidelines as outlined in the company's decision problem. The committee noted that the company presented evidence from SHARP in which patients had predominantly BCLC stage C (that is, advanced stage) disease (82.4%). They also had predominantly good liver function (that is, Child-Pugh grade A liver function; 96.5%), and good Eastern Cooperative Oncology Group (ECOG) performance status (0 to 2). The committee considered how the clinical effectiveness evidence from SHARP related to the total UK population with advanced hepatocellular carcinoma, particularly for patients with Child-Pugh grade B liver function. The committee heard from the clinical experts that systemic therapy with sorafenib would be considered for patients with Child-Pugh grade B liver function although this type of therapy may be less clinically effective than for patients with Child-Pugh grade A liver function. The committee accepted that patients with advanced hepatocellular carcinoma with either Child-Pugh grade A or B liver function may benefit from systemic therapy, although not necessarily to the same degree. The committee accepted that the company's decision problem focused on advanced hepatocellular carcinoma and was in accordance with the scope.
The committee then discussed possible comparators used in the UK for advanced hepatocellular carcinoma in clinical practice. The committee accepted that in UK clinical practice, treatment with conventional chemotherapy (such as doxorubicin) would be recommended only for a minority of patients who are able to tolerate it. The committee noted that usual treatment for patients with intermediate hepatocellular carcinoma (defined as asymptomatic tumours without vascular invasion or hepatic spread) is transarterial chemoembolisation, in line with current clinical guidelines. The committee was aware that this subgroup was outside the decision problem presented by the company. Therefore best supportive care was accepted as an appropriate comparator for most patients with advanced hepatocellular carcinoma.
# Clinical effectiveness (NICE technology appraisal guidance 189)
The committee considered the clinical effectiveness data presented by the company. It noted that evidence from the clinical studies of sorafenib plus best supportive care suggested that it increased median survival by more than 2.8 months compared with placebo plus best supportive care. The committee also noted that there was a statistically significant difference in median time to radiological disease progression for patients in the sorafenib group compared with the placebo group. The committee was aware that there was an extension in time to disease progression of 11.7 weeks according to independent assessment or 5.1 weeks according to investigator assessment, compared with placebo. The committee accepted the evidence from SHARP, but was aware that the study was stopped early, potentially underestimating the survival benefit attributable to sorafenib. The committee heard from clinical experts and patient experts that the observed benefits in overall survival and time to radiological disease progression were clinically meaningful. It noted that a statistically significant difference was not seen for time to symptomatic disease progression for sorafenib compared with placebo. However, the committee accepted the company's and evidence review group's (ERG's) view that the questionnaire used to measure time to symptomatic disease progression (FHSI-8) may not have been able to distinguish between the toxicity of sorafenib, symptoms of the underlying liver disease, and the symptoms of advanced hepatocellular carcinoma.
The committee heard from a patient expert that severe adverse events (such as diarrhoea and hand-foot skin reaction) had been experienced during 15 months of treatment with sorafenib, and occasionally it was necessary to stop treatment temporarily. The clinical experts confirmed that similar adverse events have been seen in clinical practice, but no patients in their experience had completely stopped treatment with sorafenib for this reason. The patient experts agreed that although the adverse events experienced were unpredictable and affected health-related quality of life, they could be tolerated because of the benefits in terms of extension to life.
Based on the clinical effectiveness evidence and the testimony from clinical experts and patient experts, the committee concluded that sorafenib is a clinically effective treatment for advanced hepatocellular carcinoma when surgical or locoregional therapy had failed or was not suitable.
# Cost effectiveness (NICE technology appraisal guidance 189)
The committee discussed the cost effectiveness of sorafenib for patients with advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable. The committee noted that the base-case incremental cost-effectiveness ratio (ICER) presented by the company was originally £64,800 per quality-adjusted life year (QALY) gained. When the patient access scheme was included this went down to £51,900 per QALY gained. Both ICERs were substantially higher than those normally considered to be an acceptable use of NHS resources.
The committee noted that the ICER presented in the company's base case depended on the extrapolation of overall survival beyond the SHARP study timeframe by fitting a log normal probability distribution. Several alternative probability distributions were considered and fitted the data well, and the committee was aware that although the log normal curve provided a slightly better fit, particularly for the early trial data, alternatives also fitted the data well. The main differences were in the shape of the curves at the tail of the distribution where, for example, a Weibull curve with a heavier tail was a good fit. The committee concluded that, although the log normal curve provided a slightly better fit to the observed data, it could not be accepted as the definitive function to extrapolate beyond the study data. The Weibull distribution, which also provided an acceptable fit, should also be considered in any consideration of uncertainty. The base-case log normal extrapolation produced an ICER for sorafenib of £51,900 per QALY gained, which was at the lowest end of the range. The Weibull extrapolation of survival data produced an ICER that was substantially higher (commercial in confidence) than the log normal base case.
The committee then discussed the ERG's critique of the company's patient access scheme submission. The committee noted concerns about the discrepancies in the dosage of sorafenib and the length of time a pack would last between the patient access scheme as modelled and as described in the summary of product characteristics. It agreed that the description in the summary of product characteristics did not account for dose reductions or stopping treatment temporarily, and that the treatment intensity modelled in the company's submission (based on SHARP) was more appropriate. The committee considered that the cost of post-progression sorafenib treatment was removed from the model but that the benefits were not adjusted. It agreed that, because in clinical practice the benefit from post-progression treatment is likely to be small, retaining the benefits in the model would have a minimal effect on the ICER.
The committee also noted the inconsistencies in costs associated with treatment duration and agreed that the treatment costs should be based on the actual length of the model cycle. This increased the ICER derived using the log normal extrapolation from £51,900 to £52,600 per QALY gained. It also increased the corresponding (commercial in confidence) ICER using the Weibull extrapolation of survival data. The committee also noted that the company's model did not take into account the administration costs to the NHS of the patient access scheme but concluded that this would only increase the ICERs marginally.
The committee was aware of the concerns raised by the ERG about inconsistencies in the utilities used in the company's model. However, it noted that when alternative utility values from a previous renal cell carcinoma assessment report (used to develop NICE's technology appraisal guidance on sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma and bevacizumab , sorafenib , sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma) were used in a sensitivity analysis, the log normal base-case ICER was not significantly affected.
The committee considered the additional work by the ERG on the independent and investigator assessments of time to radiological disease progression. It noted that the ICER presented in the company's base case depended on investigator assessment (rather than independent assessment, which was the primary analysis in SHARP). The committee noted that the ERG's analyses demonstrated that the original log normal base case increased to £76,000 per QALY gained (not including the patient access scheme) when using the independent assessment of time to radiological disease progression. The corresponding (commercial in confidence) ICER derived using the Weibull extrapolation of survival data would also be substantially higher. Therefore it concluded that sorafenib, as a treatment for advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable, would not be a cost-effective use of NHS resources.
The committee then considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.
The committee discussed whether the benefit provided by sorafenib in hepatocellular carcinoma fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It noted from the clinical studies that life expectancy without sorafenib was unlikely to be greater than 24 months and was potentially as low as 7.9 months, although the latter was based on SHARP, which was stopped early. The committee considered that evidence from the clinical studies of sorafenib plus best supportive care suggested that it increased median survival by more than 2.8 months compared with placebo plus best supportive care, and the company's economic model predicted a mean gain in overall survival of 6.1 months, although this depended on the method of extrapolation. Although the committee noted that sorafenib is licensed for indications other than hepatocellular carcinoma, the committee considered sorafenib to fulfil the small population criterion for an end-of life treatment. In summary, the committee was satisfied that sorafenib for advanced hepatocellular carcinoma met the criteria for an appraisal of a life-extending, end-of-life treatment, and that the evidence presented was supported by robust data.
The committee then discussed the range of cost-effectiveness estimates for sorafenib (with the lowest being the ICER of £52,600 per QALY gained and the highest being substantially greater), in light of the end-of-life considerations. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. Therefore the committee concluded that sorafenib as a treatment for advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable would not be a cost-effective use of NHS resources.
The committee considered whether there were any subgroups of people for whom sorafenib would be considered a cost-effective use of NHS resources. The committee noted that the subgroups presented by the company were based on a small number of patients, and because the clinical study was not powered to assess differential patient response to treatment, the subgroups were intended to be descriptive only. Also, no adjustments were made for multiple comparisons. The committee was aware that there was limited evidence of clinical effectiveness in these subgroups and that the ICERs would be based on a weak evidence base. Therefore the committee was not satisfied that the estimates of extension to life were robust or that the resulting subgroup ICERs were plausible. It concluded that it would not be appropriate to recommend sorafenib for specific subgroups of patients with advanced hepatocellular carcinoma.
# Cancer Drugs Fund reconsideration of NICE technology appraisal guidance 189
This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on sorafenib for the treatment of advanced hepatocellular carcinoma. At its first reconsideration meeting, the committee considered the company's submission, including:
a Commercial Medicines Unit price that was lower than the price used in the original appraisal
data from 2 observational studies:
GIDEON, unmatched to the characteristics of the SHARP population, and Palmer et al. (2013), also unmatched to SHARP, which the company used to validate the log normal curve it chose in the original appraisal to extrapolate overall survival beyond the end of SHARP (see section 4.9)
an estimate of the duration of treatment using data from SHARP on time to disease progression
the committee's preferred assumptions on costs from the original appraisal (see section 4.11)
updated unit cost and resource use estimates.
At its second meeting, the committee considered the company's responses to the appraisal consultation document, including:
evidence from GIDEON, now matched to the SHARP population for the baseline characteristics of patients that might influence mortality, to validate the log normal curve extrapolating overall survival beyond the end of SHARP
further explanation about Palmer et al.
an estimate of the duration of treatment using individual patient data on time to treatment discontinuation from SHARP (the committee's preferred assumption)
justification for using only recent data on resource use in the economic model
a cost-effectiveness analysis calculated using a lower Commercial Medicines Unit price of sorafenib than considered at the first meeting.The committee also considered the ERG's review of the company's submission, the ERG's review of the company's response to the appraisal consultation document and the ERG's exploratory analyses.
At its third meeting, the committee considered the responses to the appraisal consultation document, including:
UK audit data from King et al. (2016)
an estimate of the duration of treatment using individual patient data on time to treatment discontinuation from GIDEON (matched to the SHARP population)
a cost-effectiveness analysis calculated using a lower Commercial Medicines Unit price of sorafenib than considered at the second meeting.
## Population
The committee noted that SHARP's inclusion criteria specified people with Child-Pugh grade A liver function and an ECOG performance status of 0 to 2, but that a very small proportion of people with Child-Pugh grade B liver function were enrolled (approximately 3%). The committee noted consultation comments from professional groups that suggested sorafenib may be more clinically effective in people with Child-Pugh grade A liver function and good performance status. It was aware that results from the King et al. study showed median overall survival in people with Child-Pugh grade A liver function was 9.5 months, compared with 4.6 months in people with Child-Pugh grade B liver function and that the Gideon study demonstrated median overall survival of 6.2 months in people with Child-Pugh grade B7 liver function. The committee highlighted that the majority of people contributing data to the observational studies submitted by the company for the Cancer Drugs Fund reconsideration meetings had Child-Pugh grade A liver function. The committee acknowledged the comments from clinical experts and NHS England that current clinical experience suggests that patients need both adequate liver function and performance status to have sorafenib in clinical practice in England. On this basis, they also commented that treatment should be restricted to people with Child-Pugh grade A liver function and performance status of 0 to 2. Taking all the evidence into account, the committee concluded that people with Child-Pugh grade A liver function are the appropriate population for its recommendations for treating advanced hepatocellular carcinoma with sorafenib in England.
## Validating the overall survival extrapolation
The committee understood that the final draft guidance issued during the original appraisal went to an appeal panel. It was aware that the appeal panel concluded that there was opportunity to comment on overall survival modelling and dismissed all appeal points. In the final guidance the committee therefore concluded that the Weibull distribution should be taken into account in any consideration of uncertainty.
The committee discussed the 3 longitudinal observational studies; Palmer et al., GIDEON and King et al. It recognised that Palmer et al. was a published retrospective cohort study comparing patients with hepatocellular carcinoma in 2 hepatobiliary oncology units in the UK who either received funding for sorafenib (n=57) or did not receive funding (n=76) before the existence of the Cancer Drugs Fund. The committee heard from the company that the decision to fund sorafenib was not based on clinical variables. The committee was aware that there was a higher proportion of patients with metastatic disease in the unfunded group. The committee noted that patients who did not receive funding for sorafenib did not live as long as patients who did have funding. It also considered that the association between funding and death may be confounded, that is, patients with better prognoses might be more likely to receive funding and treatment than patients with poorer prognoses. It noted the ERG's comment that the study was not suitable for decision-making. However, the committee could not exclude the possibility of residual confounding and concluded that the data from Palmer were a less robust source of evidence than the GIDEON data, now matched to SHARP. It further noted that the parametric curves to extrapolate overall survival using the Palmer data did not favour a log normal or Weibull distribution over the other. The committee then discussed the King et al. audit of mainly Cancer Drugs Fund patients in England, noting that it describes the experience of 448 people with hepatocellular carcinoma who had sorafenib. However, the committee noted that the population did not match that of SHARP because of the higher proportion of patients with Child-Pugh B liver function in King et al. The committee concluded that the matched GIDEON data were more appropriate than Palmer or King et al. for validating the extrapolation of overall survival beyond SHARP.
The committee discussed the GIDEON data, noting that the company responded to the appraisal consultation document by adjusting the data to match the characteristics of the SHARP population, particularly for risk factors for death. The company chose a propensity score, a method of statistical matching, to do this for baseline characteristics reported across both SHARP and GIDEON. The committee recognised that the ERG considered this statistical approach satisfactory but some baseline characteristics likely to affect the risk of death (such as viral hepatitis) could not be matched because of a lack of reporting. The committee also noted that the matched GIDEON sample (n=895) resulted in longer median overall survival than SHARP. The committee noted that this longer median overall survival was associated with a shorter mean treatment duration and dosage compared with SHARP. The committee considered this relationship seemed counterintuitive (that is, it would have expected a shorter treatment duration and dosage to result in a shorter overall survival), and considered that there may be residual confounding. It concluded that there was some uncertainty around the comparability of the matched GIDEON population and the SHARP population.
The committee then considered the most appropriate parametric curve to extrapolate overall survival in SHARP to fit the matched GIDEON data, which provided a longer period of follow-up. The company fitted log normal and Weibull curves to the Kaplan–Meier data for the matched GIDEON population and stated that the log normal curve provided a better statistical fit to the observed data than the Weibull curve; the committee agreed with this based on standard statistical criteria using the Bayesian information criterion described in Kass et al. (1995). The committee considered that beyond about 600 days, the Weibull curve fitted the data better than the log normal curve. However, the committee was aware that the uncertainty was greater in the tail of the curve where limited or no data existed. The committee understood from the ERG that the log normal function would overestimate overall survival whereas the Weibull function would underestimate it. Therefore, the ERG advised that both curves should be considered when extrapolating overall survival, and to estimate the ICER for sorafenib compared with best supportive care. The committee acknowledged that it would not use statistical goodness of fit alone to choose the most appropriate survival function. It noted that in general the log normal function used by the company to extrapolate survival beyond SHARP fitted GIDEON better than the Weibull function, but that the Weibull function was still plausible. The committee was also aware that the 3 data sets the company had presented (SHARP, GIDEON, and Palmer et al.) for informing the choice of survival distribution did not conclusively favour 1 single distribution. For example, the Bayesian information criterion statistics provided evidence that the log normal function fitted the data better than the Weibull function in the SHARP analysis based on Kass et al., but this was not considered a statistically strong difference and therefore the committee considered that the Weibull function remained plausible. The committee reiterated that SHARP was among the most robust source of evidence it had seen for sorafenib during the Cancer Drugs Fund reconsideration committee meetings. Therefore, the committee concluded that the true estimate of life expectancy with sorafenib compared with best supportive care was likely to lie between the estimates from the log normal and the Weibull distributions, but agreed it was closer to the log normal estimates than the Weibull estimates.
## Duration of treatment
The committee discussed whether the estimates of treatment duration should come from SHARP (the source of the clinical effectiveness data) or from another source. At its first and second meetings, the committee agreed that the effectiveness and costs should ideally come from the same study; this approach was supported by the ERG and by NHS England. The committee noted that in King et al. people with Child-Pugh grade A liver function did not live as long as people in SHARP (9.5 months compared with 10.7 months). The committee considered that this may have been partly explained by the reduction in treatment duration (3.6 months in King et al. compared with 5.3 months in SHARP) and daily dose (590 mg in King et al. compared with 711 mg in SHARP) between the studies. The committee was also aware that people with Child-Pugh grade A liver function in GIDEON had a median overall survival of 13.6 months and a median treatment duration of 4.1 months, which the committee stated seemed counterintuitive when compared with King et al. and SHARP. The committee appreciated that clinical experience with sorafenib had improved over time and adverse events may now be managed better, partly by shorter duration of treatment. The committee heard from NHS England that patients now have treatment for a shorter period of time than was standard in 2007, trading a sizeable decrease in adverse events for a small drop in effectiveness. But taking all the observational evidence into account, the committee noted it had concerns about the generalisability of these results to the SHARP randomised controlled trial. The committee discussed the company's analysis of the individual patient level data on the time to treatment discontinuation from the matched GIDEON analysis. The committee understood from the company that everyone in GIDEON stopped treatment so the company provided only an unrestricted mean and a Kaplan–Meier analysis (rather than a parametric model). But the committee highlighted that it would have preferred the company to also fit parametric curves to the data because of the differences in the GIDEON and SHARP populations, and the small number of events towards the end of the Kaplan–Meier curves of time to treatment discontinuation, which leads to uncertainty. The committee concluded that data from SHARP should be used to estimate duration of treatment, and the total cost of treatment.
The committee discussed at its first 2 meetings which data from SHARP best reflected the duration of treatment. It understood that the company and the ERG preferred different methods; the company preferred time to disease progression as a proxy for duration of treatment, whereas the ERG and the committee preferred the actual data on duration of treatment. The committee acknowledged the debate in the original appraisal about using either investigator assessment or independent assessment of disease progression as a surrogate for time on treatment. The company continued to use time to disease progression for treatment duration in its base-case analysis despite the committee's stated preference in the appraisal consultation document. This was because the company considered that the treatment duration in SHARP was longer than seen in UK clinical practice. The committee understood that the ERG considered that the estimates of mean and median treatment duration reported by the Cancer Drugs Fund, King et al., GIDEON and Palmer et al. were inconclusive and therefore did not support the company's claim that SHARP overestimated the treatment duration of sorafenib in clinical practice. The ERG noted that time to progression based on independent assessment (the primary means of assessment in the SHARP protocol) and treatment duration were similar and also noted the committee's preference in the original appraisal for including treatment costs for patients who had treatment after progression. The committee concluded that treatment duration estimates should be based on data directly reflecting the time on treatment.
The committee discussed the company's methods for extrapolating time on treatment data from SHARP. The company presented a survival analysis of the time from the date of randomisation to the date of discontinuation of treatment from any cause. To extrapolate beyond the end of the trial, the company applied 5 parametric models: exponential, Gompertz, log logistic, log normal and Weibull, plus a hybrid analysis that the company considered the most robust. The committee understood that the ERG preferred the fully parametric log normal model because a hybrid approach was only appropriate when there was a strong rationale for not using all of the available data to inform the extrapolated curve. The committee stated that the log normal distribution was the best statistical fit of the 5 distributions explored by the company. The committee noted that based on the Kass et al. criteria, the Bayesian information criterion statistics strongly indicated that the log normal distribution was a better fit to the observed data than the Weibull. The committee also heard from the clinical expert that approximately 10% of patients are still having sorafenib treatment at 3 years, which supported using the log normal distribution. The committee concluded that the company's fully parametric method using the log normal distribution was the most robust estimate of treatment duration.
## Cost and resource use estimates
The committee was aware that the company updated the unit cost data in its reconsideration submission. It was also aware that in clinical practice, the company charges the NHS for a full pack of sorafenib at the start of each treatment cycle. Some patients do not complete the treatment cycle. Therefore the company may have underestimated the cost of treatment in its economic modelling for the first reconsideration meeting. In its response to the appraisal consultation document, the company presented cost-effectiveness results for analyses including the wastage of up to 7 days of treatment. The committee concluded that it was appropriate for the company to use updated unit cost data and account for 7 days of drug wastage because this reflected the price relevant to the NHS.
The committee was aware that in the original appraisal the company based its estimates of resource use, for example, number of hospitalisations, on the opinion of 4 clinicians. But in this reconsideration, the company provided recent resource use estimates based on the opinion of 3 different clinicians. At the first Cancer Drugs Fund reconsideration meeting the committee noted that the revised resource use data estimates varied widely and therefore it was better to pool the original and revised estimates. In its response to the appraisal consultation document, the company claimed that resource estimates from the original appraisal were no longer accurate because of significant changes in clinical practice. Specifically, patients now had treatment in oncology rather than hepatology clinics and had palliative care in the community. The committee noted that the company did not provide any more evidence in its response to the appraisal consultation document. The committee heard from the ERG that the parameters affecting the ICER most when using the updated resource use estimates compared with the pooled resource use estimates were in the best supportive care group, particularly those for admission and frequency of hospitalisation. Also, the committee understood from the ERG that the ICER was extremely sensitive to changes in these parameters. The committee concluded that the company's revised resource use data were not robust and preferred to pool the original and revised estimates.
The company provided information that sorafenib would come off patent in approximately 5 years. The committee discussed the implications of this, but also noted that it had no information on the future price of sorafenib. The committee concluded that it could only take into account the company's current price for sorafenib.
## End-of-life considerations
The committee considered the advice about life-extending treatments in NICE's final Cancer Drugs Fund technology appraisal process and methods. It noted the committee's conclusion in the original appraisal that sorafenib in hepatocellular carcinoma met the end-of-life criteria (see section 4.15). The committee agreed that sorafenib was indicated for patients with a short life expectancy and offered an extension to life of at least 3 months compared with current NHS treatment. The committee concluded that sorafenib could plausibly meet the criteria to be considered a life-extending, end-of-life treatment.
## Conclusion
The committee discussed the most plausible ICER for sorafenib compared with best supportive care for treating advanced hepatocellular carcinoma. It considered that there was still uncertainty associated with extrapolating overall survival from SHARP (see section 4.25). The committee agreed that the most plausible ICER should:
be based on the ERG's exploratory analyses using the company's fully parametric method (log normal distribution) to estimate treatment duration (see section 4.28)
account for drug wastage for up to 7 days and
use the pooled resource use data in the absence of more robust updated resource use data.The committee was aware that after its third meeting the company proposed a new commercial access agreement to NHS England, and the committee was aware of the revised estimates of cost effectiveness. The committee appreciated that the most plausible ICER was below £50,000 per QALY gained for sorafenib compared with best supportive care (based on the ERG's weighted average results; 75% log normal and 25% Weibull distribution to extrapolate overall survival), including the new Commercial Medicines Unit price and the commercial access agreement (the details of the commercial access agreement are confidential and therefore cannot be published). The committee was aware that the most plausible ICER was within the range normally considered a cost-effective use of NHS resources taking into account the extra weight applied to QALYs at the end of life. The committee recalled its conclusion that patients with grade A Child-Pugh liver function are the appropriate population. The committee concluded that sorafenib could be recommended as an option for use in the NHS only for people with Child-Pugh grade A liver function, and only if the company provides sorafenib within the agreed commercial access arrangement.
# Cancer Drugs Fund considerations
Before the commercial access agreement, which was made after the committee's third meeting, the committee had concluded that sorafenib could not be recommended, and considered if sorafenib could be recommended for use within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee was aware that in considering this, the following criteria must be met:
The ICERs have plausible potential for satisfying the criteria for routine use.
It is possible that the uncertainty can be addressed through collecting outcome data from patients treated in the NHS.
It is possible that the data could inform a subsequent update of the guidance (normally within 24 months).At its second meeting the committee asked the company whether it wanted to include sorafenib in the Cancer Drugs Fund; sorafenib would be funded while collecting data in the Cancer Drugs Fund. At the third meeting, the committee noted that the company had not submitted a proposal for sorafenib to be included in the Cancer Drugs Fund because the GIDEON data were better than those the Cancer Drugs Fund could collect, and that it would seek a recommendation in routine commissioning.
# Summary of appraisal committee's key conclusions
TA474
Appraisal title: Sorafenib for treating advanced hepatocellular carcinoma
Section
Key conclusions: Cancer Drugs Fund reconsideration of TA189
Sorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade A liver impairment, only if the company provides sorafenib within the agreed commercial access arrangement.
The committee agreed that the most plausible ICER was below £50,000 per QALY gained for sorafenib compared with best supportive care, including the new Commercial Medicines Unit price and the commercial access agreement.
Additional factors taken into account
Equalities considerations and social value judgements
In response to the appraisal consultation document a consultee noted that the prevalence of liver cancer deaths is higher in socially deprived areas. Differences in the prevalence or incidence of a disease cannot be addressed in technology appraisal committee recommendations.
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{'Recommendations': 'Sorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade\xa0A liver impairment, only if the company provides sorafenib within the agreed commercial access arrangement.\n\nThis recommendation is not intended to affect treatment with sorafenib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': 'Description of the technology\n\nSorafenib (Nexavar, Bayer) is a multikinase inhibitor that inhibits tumour blood vessel development and tumour cell proliferation. It does this by inhibiting the Raf cascade, vascular endothelial growth factor and platelet-derived growth factor receptors of tumour cells, vascular endothelial cells and pericytes.\n\nMarketing authorisation\n\nSorafenib has a marketing authorisation in the UK for treating hepatocellular carcinoma.\n\nAdverse reactions\n\nThe summary of product characteristics includes the following conditions that may be associated with sorafenib treatment: dermatological toxicities, hypertension, haemorrhage, cardiac ischaemia and/or infarction, gastrointestinal perforation, hepatic impairment and wound healing complications. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nSorafenib is administered orally as 200-mg film-coated tablets. The recommended dosage is 400\xa0mg twice daily (a total daily dose of 800\xa0mg). The dosage may be adjusted to 2×200-mg tablets once daily if adverse drug reactions are suspected. The summary of product characteristics recommends that treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.\n\nPrice\n\nThe price for a pack of 200-mg tablets (112\xa0tablets per pack) is £3,575.56.\n\nThe company agreed a nationally available price reduction for sorafenib with the Commercial Medicines Unit. The pricing agreement considered during guidance development was that the company (Bayer) had agreed a commercial access agreement with NHS England inclusive of the reduction for sorafenib agreed with the Commercial Medicines Unit. The commercial access agreement replaces the Commercial Medicines Unit price used during the Cancer Drugs Fund reconsideration of technology appraisal guidance 189. The details of this commercial access agreement are commercial in confidence.', 'Evidence': "The appraisal committee (section 6) considered evidence submitted by Bayer and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma.\n\nThe company's original submission presented clinical effectiveness data from the SHARP study. SHARP was a multicentre, double-blind, placebo-controlled, randomised trial in patients with advanced hepatocellular carcinoma who had not received previous systemic treatment. The study included 602\xa0patients and assessed the effect of sorafenib plus best supportive care (n=299) compared with placebo plus best supportive care (n=303). The primary outcomes in SHARP were overall survival and time to symptomatic progression.\n\nSections\xa04.1 to 4.17 reflect the committee's discussion of the evidence submitted in the original appraisal. Section\xa04.18 onwards reflects the committee's discussion of the additional evidence submitted for the Cancer Drugs Fund reconsideration, which focused on:\n\ndata from the key source of evidence, SHARP\n\nobservational data from Palmer et al. (2013) and the GIDEON study to validate survival extrapolations from the company's original submission\n\nestimates of treatment duration using individual patient data for time on treatment from SHARP and GIDEON\n\nupdated resource use data\n\ncost-effectiveness analyses using a new Commercial Medicines Unit price, providing sorafenib at a reduced cost (commercial in confidence)\n\nestimates of how much sorafenib is wasted.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence and the history for full details of the evidence used for NICE's original technology appraisal guidance on sorafenib for treating advanced hepatocellular carcinoma.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of sorafenib, having considered evidence on the nature of hepatocellular carcinoma and the value placed on the benefits of sorafenib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee considered the UK treatment pathway for patients with hepatocellular carcinoma. The clinical experts described that in UK clinical practice one third of patients with hepatocellular carcinoma would be eligible for procedures such as local resection, radiofrequency ablation or chemoembolisation. They noted that these procedures are not considered clinically effective for approximately 50% of patients, who would progress to further locoregional therapy or systemic treatment. The committee accepted that the scope of this technology appraisal was restricted to these patients. The committee further reviewed the treatment pathway consistent with the Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule as presented by Llovet et al. (2008). The clinical experts agreed that the BCLC staging system is used in UK clinical practice.\n\nThe committee was aware that the licensed indication for sorafenib is hepatocellular carcinoma without specific restrictions. However, the clinical effectiveness evidence from the SHARP study was for patients with advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable. This population was consistent with UK clinical practice and clinical guidelines as outlined in the company's decision problem. The committee noted that the company presented evidence from SHARP in which patients had predominantly BCLC stage\xa0C (that is, advanced stage) disease (82.4%). They also had predominantly good liver function (that is, Child-Pugh grade\xa0A liver function; 96.5%), and good Eastern Cooperative Oncology Group (ECOG) performance status (0\xa0to\xa02). The committee considered how the clinical effectiveness evidence from SHARP related to the total UK population with advanced hepatocellular carcinoma, particularly for patients with Child-Pugh grade\xa0B liver function. The committee heard from the clinical experts that systemic therapy with sorafenib would be considered for patients with Child-Pugh grade\xa0B liver function although this type of therapy may be less clinically effective than for patients with Child-Pugh grade\xa0A liver function. The committee accepted that patients with advanced hepatocellular carcinoma with either Child-Pugh grade A\xa0or\xa0B liver function may benefit from systemic therapy, although not necessarily to the same degree. The committee accepted that the company's decision problem focused on advanced hepatocellular carcinoma and was in accordance with the scope.\n\nThe committee then discussed possible comparators used in the UK for advanced hepatocellular carcinoma in clinical practice. The committee accepted that in UK clinical practice, treatment with conventional chemotherapy (such as doxorubicin) would be recommended only for a minority of patients who are able to tolerate it. The committee noted that usual treatment for patients with intermediate hepatocellular carcinoma (defined as asymptomatic tumours without vascular invasion or hepatic spread) is transarterial chemoembolisation, in line with current clinical guidelines. The committee was aware that this subgroup was outside the decision problem presented by the company. Therefore best supportive care was accepted as an appropriate comparator for most patients with advanced hepatocellular carcinoma.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0189)\n\nThe committee considered the clinical effectiveness data presented by the company. It noted that evidence from the clinical studies of sorafenib plus best supportive care suggested that it increased median survival by more than 2.8\xa0months compared with placebo plus best supportive care. The committee also noted that there was a statistically significant difference in median time to radiological disease progression for patients in the sorafenib group compared with the placebo group. The committee was aware that there was an extension in time to disease progression of 11.7\xa0weeks according to independent assessment or 5.1\xa0weeks according to investigator assessment, compared with placebo. The committee accepted the evidence from SHARP, but was aware that the study was stopped early, potentially underestimating the survival benefit attributable to sorafenib. The committee heard from clinical experts and patient experts that the observed benefits in overall survival and time to radiological disease progression were clinically meaningful. It noted that a statistically significant difference was not seen for time to symptomatic disease progression for sorafenib compared with placebo. However, the committee accepted the company's and evidence review group's (ERG's) view that the questionnaire used to measure time to symptomatic disease progression (FHSI-8) may not have been able to distinguish between the toxicity of sorafenib, symptoms of the underlying liver disease, and the symptoms of advanced hepatocellular carcinoma.\n\nThe committee heard from a patient expert that severe adverse events (such as diarrhoea and hand-foot skin reaction) had been experienced during 15\xa0months of treatment with sorafenib, and occasionally it was necessary to stop treatment temporarily. The clinical experts confirmed that similar adverse events have been seen in clinical practice, but no patients in their experience had completely stopped treatment with sorafenib for this reason. The patient experts agreed that although the adverse events experienced were unpredictable and affected health-related quality of life, they could be tolerated because of the benefits in terms of extension to life.\n\nBased on the clinical effectiveness evidence and the testimony from clinical experts and patient experts, the committee concluded that sorafenib is a clinically effective treatment for advanced hepatocellular carcinoma when surgical or locoregional therapy had failed or was not suitable.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0189)\n\nThe committee discussed the cost effectiveness of sorafenib for patients with advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable. The committee noted that the base-case incremental cost-effectiveness ratio (ICER) presented by the company was originally £64,800 per quality-adjusted life year (QALY) gained. When the patient access scheme was included this went down to £51,900 per QALY gained. Both ICERs were substantially higher than those normally considered to be an acceptable use of NHS resources.\n\nThe committee noted that the ICER presented in the company's base case depended on the extrapolation of overall survival beyond the SHARP study timeframe by fitting a log normal probability distribution. Several alternative probability distributions were considered and fitted the data well, and the committee was aware that although the log normal curve provided a slightly better fit, particularly for the early trial data, alternatives also fitted the data well. The main differences were in the shape of the curves at the tail of the distribution where, for example, a Weibull curve with a heavier tail was a good fit. The committee concluded that, although the log normal curve provided a slightly better fit to the observed data, it could not be accepted as the definitive function to extrapolate beyond the study data. The Weibull distribution, which also provided an acceptable fit, should also be considered in any consideration of uncertainty. The base-case log normal extrapolation produced an ICER for sorafenib of £51,900 per QALY gained, which was at the lowest end of the range. The Weibull extrapolation of survival data produced an ICER that was substantially higher (commercial in confidence) than the log normal base case.\n\nThe committee then discussed the ERG's critique of the company's patient access scheme submission. The committee noted concerns about the discrepancies in the dosage of sorafenib and the length of time a pack would last between the patient access scheme as modelled and as described in the summary of product characteristics. It agreed that the description in the summary of product characteristics did not account for dose reductions or stopping treatment temporarily, and that the treatment intensity modelled in the company's submission (based on SHARP) was more appropriate. The committee considered that the cost of post-progression sorafenib treatment was removed from the model but that the benefits were not adjusted. It agreed that, because in clinical practice the benefit from post-progression treatment is likely to be small, retaining the benefits in the model would have a minimal effect on the ICER.\n\nThe committee also noted the inconsistencies in costs associated with treatment duration and agreed that the treatment costs should be based on the actual length of the model cycle. This increased the ICER derived using the log normal extrapolation from £51,900 to £52,600 per QALY gained. It also increased the corresponding (commercial in confidence) ICER using the Weibull extrapolation of survival data. The committee also noted that the company's model did not take into account the administration costs to the NHS of the patient access scheme but concluded that this would only increase the ICERs marginally.\n\nThe committee was aware of the concerns raised by the ERG about inconsistencies in the utilities used in the company's model. However, it noted that when alternative utility values from a previous renal cell carcinoma assessment report (used to develop NICE's technology appraisal guidance on sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma and bevacizumab [first-line], sorafenib [first- and second-line], sunitinib [second-line] and temsirolimus [first-line] for the treatment of advanced and/or metastatic renal cell carcinoma) were used in a sensitivity analysis, the log normal base-case ICER was not significantly affected.\n\nThe committee considered the additional work by the ERG on the independent and investigator assessments of time to radiological disease progression. It noted that the ICER presented in the company's base case depended on investigator assessment (rather than independent assessment, which was the primary analysis in SHARP). The committee noted that the ERG's analyses demonstrated that the original log normal base case increased to £76,000 per QALY gained (not including the patient access scheme) when using the independent assessment of time to radiological disease progression. The corresponding (commercial in confidence) ICER derived using the Weibull extrapolation of survival data would also be substantially higher. Therefore it concluded that sorafenib, as a treatment for advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable, would not be a cost-effective use of NHS resources.\n\nThe committee then considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe committee discussed whether the benefit provided by sorafenib in hepatocellular carcinoma fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It noted from the clinical studies that life expectancy without sorafenib was unlikely to be greater than 24\xa0months and was potentially as low as 7.9\xa0months, although the latter was based on SHARP, which was stopped early. The committee considered that evidence from the clinical studies of sorafenib plus best supportive care suggested that it increased median survival by more than 2.8\xa0months compared with placebo plus best supportive care, and the company's economic model predicted a mean gain in overall survival of 6.1\xa0months, although this depended on the method of extrapolation. Although the committee noted that sorafenib is licensed for indications other than hepatocellular carcinoma, the committee considered sorafenib to fulfil the small population criterion for an end-of life treatment. In summary, the committee was satisfied that sorafenib for advanced hepatocellular carcinoma met the criteria for an appraisal of a life-extending, end-of-life treatment, and that the evidence presented was supported by robust data.\n\nThe committee then discussed the range of cost-effectiveness estimates for sorafenib (with the lowest being the ICER of £52,600 per QALY gained and the highest being substantially greater), in light of the end-of-life considerations. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. Therefore the committee concluded that sorafenib as a treatment for advanced hepatocellular carcinoma when surgical or locoregional therapies had failed or were not suitable would not be a cost-effective use of NHS resources.\n\nThe committee considered whether there were any subgroups of people for whom sorafenib would be considered a cost-effective use of NHS resources. The committee noted that the subgroups presented by the company were based on a small number of patients, and because the clinical study was not powered to assess differential patient response to treatment, the subgroups were intended to be descriptive only. Also, no adjustments were made for multiple comparisons. The committee was aware that there was limited evidence of clinical effectiveness in these subgroups and that the ICERs would be based on a weak evidence base. Therefore the committee was not satisfied that the estimates of extension to life were robust or that the resulting subgroup ICERs were plausible. It concluded that it would not be appropriate to recommend sorafenib for specific subgroups of patients with advanced hepatocellular carcinoma.\n\n# Cancer Drugs Fund reconsideration of NICE technology appraisal guidance\xa0189\n\nThis appraisal was a Cancer Drugs Fund reconsideration of the published NICE technology appraisal guidance on sorafenib for the treatment of advanced hepatocellular carcinoma. At its first reconsideration meeting, the committee considered the company's submission, including:\n\na Commercial Medicines Unit price that was lower than the price used in the original appraisal\n\ndata from 2\xa0observational studies:\n\n\n\nGIDEON, unmatched to the characteristics of the SHARP population, and Palmer et al. (2013), also unmatched to SHARP, which the company used to validate the log normal curve it chose in the original appraisal to extrapolate overall survival beyond the end of SHARP (see section\xa04.9)\n\n\n\nan estimate of the duration of treatment using data from SHARP on time to disease progression\n\nthe committee's preferred assumptions on costs from the original appraisal (see section\xa04.11)\n\nupdated unit cost and resource use estimates.\n\nAt its second meeting, the committee considered the company's responses to the appraisal consultation document, including:\n\nevidence from GIDEON, now matched to the SHARP population for the baseline characteristics of patients that might influence mortality, to validate the log normal curve extrapolating overall survival beyond the end of SHARP\n\nfurther explanation about Palmer et al.\n\nan estimate of the duration of treatment using individual patient data on time to treatment discontinuation from SHARP (the committee's preferred assumption)\n\njustification for using only recent data on resource use in the economic model\n\na cost-effectiveness analysis calculated using a lower Commercial Medicines Unit price of sorafenib than considered at the first meeting.The committee also considered the ERG's review of the company's submission, the ERG's review of the company's response to the appraisal consultation document and the ERG's exploratory analyses.\n\nAt its third meeting, the committee considered the responses to the appraisal consultation document, including:\n\nUK audit data from King et al. (2016)\n\nan estimate of the duration of treatment using individual patient data on time to treatment discontinuation from GIDEON (matched to the SHARP population)\n\na cost-effectiveness analysis calculated using a lower Commercial Medicines Unit price of sorafenib than considered at the second meeting.\n\n## Population\n\nThe committee noted that SHARP's inclusion criteria specified people with Child-Pugh grade\xa0A liver function and an ECOG performance status of 0\xa0to\xa02, but that a very small proportion of people with Child-Pugh grade\xa0B liver function were enrolled (approximately 3%). The committee noted consultation comments from professional groups that suggested sorafenib may be more clinically effective in people with Child-Pugh grade\xa0A liver function and good performance status. It was aware that results from the King et al. study showed median overall survival in people with Child-Pugh grade\xa0A liver function was 9.5\xa0months, compared with 4.6\xa0months in people with Child-Pugh grade\xa0B liver function and that the Gideon study demonstrated median overall survival of 6.2\xa0months in people with Child-Pugh grade\xa0B7 liver function. The committee highlighted that the majority of people contributing data to the observational studies submitted by the company for the Cancer Drugs Fund reconsideration meetings had Child-Pugh grade\xa0A liver function. The committee acknowledged the comments from clinical experts and NHS England that current clinical experience suggests that patients need both adequate liver function and performance status to have sorafenib in clinical practice in England. On this basis, they also commented that treatment should be restricted to people with Child-Pugh grade\xa0A liver function and performance status of 0\xa0to\xa02. Taking all the evidence into account, the committee concluded that people with Child-Pugh grade\xa0A liver function are the appropriate population for its recommendations for treating advanced hepatocellular carcinoma with sorafenib in England.\n\n## Validating the overall survival extrapolation\n\nThe committee understood that the final draft guidance issued during the original appraisal went to an appeal panel. It was aware that the appeal panel concluded that there was opportunity to comment on overall survival modelling and dismissed all appeal points. In the final guidance the committee therefore concluded that the Weibull distribution should be taken into account in any consideration of uncertainty.\n\nThe committee discussed the 3\xa0longitudinal observational studies; Palmer et al., GIDEON and King et al. It recognised that Palmer et al. was a published retrospective cohort study comparing patients with hepatocellular carcinoma in 2\xa0hepatobiliary oncology units in the UK who either received funding for sorafenib (n=57) or did not receive funding (n=76) before the existence of the Cancer Drugs Fund. The committee heard from the company that the decision to fund sorafenib was not based on clinical variables. The committee was aware that there was a higher proportion of patients with metastatic disease in the unfunded group. The committee noted that patients who did not receive funding for sorafenib did not live as long as patients who did have funding. It also considered that the association between funding and death may be confounded, that is, patients with better prognoses might be more likely to receive funding and treatment than patients with poorer prognoses. It noted the ERG's comment that the study was not suitable for decision-making. However, the committee could not exclude the possibility of residual confounding and concluded that the data from Palmer were a less robust source of evidence than the GIDEON data, now matched to SHARP. It further noted that the parametric curves to extrapolate overall survival using the Palmer data did not favour a log normal or Weibull distribution over the other. The committee then discussed the King et al. audit of mainly Cancer Drugs Fund patients in England, noting that it describes the experience of 448\xa0people with hepatocellular carcinoma who had sorafenib. However, the committee noted that the population did not match that of SHARP because of the higher proportion of patients with Child-Pugh\xa0B liver function in King et al. The committee concluded that the matched GIDEON data were more appropriate than Palmer or King et al. for validating the extrapolation of overall survival beyond SHARP.\n\nThe committee discussed the GIDEON data, noting that the company responded to the appraisal consultation document by adjusting the data to match the characteristics of the SHARP population, particularly for risk factors for death. The company chose a propensity score, a method of statistical matching, to do this for baseline characteristics reported across both SHARP and GIDEON. The committee recognised that the ERG considered this statistical approach satisfactory but some baseline characteristics likely to affect the risk of death (such as viral hepatitis) could not be matched because of a lack of reporting. The committee also noted that the matched GIDEON sample (n=895) resulted in longer median overall survival than SHARP. The committee noted that this longer median overall survival was associated with a shorter mean treatment duration and dosage compared with SHARP. The committee considered this relationship seemed counterintuitive (that is, it would have expected a shorter treatment duration and dosage to result in a shorter overall survival), and considered that there may be residual confounding. It concluded that there was some uncertainty around the comparability of the matched GIDEON population and the SHARP population.\n\nThe committee then considered the most appropriate parametric curve to extrapolate overall survival in SHARP to fit the matched GIDEON data, which provided a longer period of follow-up. The company fitted log normal and Weibull curves to the Kaplan–Meier data for the matched GIDEON population and stated that the log normal curve provided a better statistical fit to the observed data than the Weibull curve; the committee agreed with this based on standard statistical criteria using the Bayesian information criterion described in Kass et al. (1995). The committee considered that beyond about 600\xa0days, the Weibull curve fitted the data better than the log normal curve. However, the committee was aware that the uncertainty was greater in the tail of the curve where limited or no data existed. The committee understood from the ERG that the log normal function would overestimate overall survival whereas the Weibull function would underestimate it. Therefore, the ERG advised that both curves should be considered when extrapolating overall survival, and to estimate the ICER for sorafenib compared with best supportive care. The committee acknowledged that it would not use statistical goodness of fit alone to choose the most appropriate survival function. It noted that in general the log normal function used by the company to extrapolate survival beyond SHARP fitted GIDEON better than the Weibull function, but that the Weibull function was still plausible. The committee was also aware that the 3\xa0data sets the company had presented (SHARP, GIDEON, and Palmer et al.) for informing the choice of survival distribution did not conclusively favour 1\xa0single distribution. For example, the Bayesian information criterion statistics provided evidence that the log normal function fitted the data better than the Weibull function in the SHARP analysis based on Kass et al., but this was not considered a statistically strong difference and therefore the committee considered that the Weibull function remained plausible. The committee reiterated that SHARP was among the most robust source of evidence it had seen for sorafenib during the Cancer Drugs Fund reconsideration committee meetings. Therefore, the committee concluded that the true estimate of life expectancy with sorafenib compared with best supportive care was likely to lie between the estimates from the log normal and the Weibull distributions, but agreed it was closer to the log normal estimates than the Weibull estimates.\n\n## Duration of treatment\n\nThe committee discussed whether the estimates of treatment duration should come from SHARP (the source of the clinical effectiveness data) or from another source. At its first and second meetings, the committee agreed that the effectiveness and costs should ideally come from the same study; this approach was supported by the ERG and by NHS England. The committee noted that in King et al. people with Child-Pugh grade\xa0A liver function did not live as long as people in SHARP (9.5\xa0months compared with 10.7\xa0months). The committee considered that this may have been partly explained by the reduction in treatment duration (3.6\xa0months in King et al. compared with 5.3\xa0months in SHARP) and daily dose (590\xa0mg in King et al. compared with 711\xa0mg in SHARP) between the studies. The committee was also aware that people with Child-Pugh grade\xa0A liver function in GIDEON had a median overall survival of 13.6\xa0months and a median treatment duration of 4.1\xa0months, which the committee stated seemed counterintuitive when compared with King et al. and SHARP. The committee appreciated that clinical experience with sorafenib had improved over time and adverse events may now be managed better, partly by shorter duration of treatment. The committee heard from NHS England that patients now have treatment for a shorter period of time than was standard in 2007, trading a sizeable decrease in adverse events for a small drop in effectiveness. But taking all the observational evidence into account, the committee noted it had concerns about the generalisability of these results to the SHARP randomised controlled trial. The committee discussed the company's analysis of the individual patient level data on the time to treatment discontinuation from the matched GIDEON analysis. The committee understood from the company that everyone in GIDEON stopped treatment so the company provided only an unrestricted mean and a Kaplan–Meier analysis (rather than a parametric model). But the committee highlighted that it would have preferred the company to also fit parametric curves to the data because of the differences in the GIDEON and SHARP populations, and the small number of events towards the end of the Kaplan–Meier curves of time to treatment discontinuation, which leads to uncertainty. The committee concluded that data from SHARP should be used to estimate duration of treatment, and the total cost of treatment.\n\nThe committee discussed at its first 2\xa0meetings which data from SHARP best reflected the duration of treatment. It understood that the company and the ERG preferred different methods; the company preferred time to disease progression as a proxy for duration of treatment, whereas the ERG and the committee preferred the actual data on duration of treatment. The committee acknowledged the debate in the original appraisal about using either investigator assessment or independent assessment of disease progression as a surrogate for time on treatment. The company continued to use time to disease progression for treatment duration in its base-case analysis despite the committee's stated preference in the appraisal consultation document. This was because the company considered that the treatment duration in SHARP was longer than seen in UK clinical practice. The committee understood that the ERG considered that the estimates of mean and median treatment duration reported by the Cancer Drugs Fund, King et al., GIDEON and Palmer et al. were inconclusive and therefore did not support the company's claim that SHARP overestimated the treatment duration of sorafenib in clinical practice. The ERG noted that time to progression based on independent assessment (the primary means of assessment in the SHARP protocol) and treatment duration were similar and also noted the committee's preference in the original appraisal for including treatment costs for patients who had treatment after progression. The committee concluded that treatment duration estimates should be based on data directly reflecting the time on treatment.\n\nThe committee discussed the company's methods for extrapolating time on treatment data from SHARP. The company presented a survival analysis of the time from the date of randomisation to the date of discontinuation of treatment from any cause. To extrapolate beyond the end of the trial, the company applied 5\xa0parametric models: exponential, Gompertz, log logistic, log normal and Weibull, plus a hybrid analysis that the company considered the most robust. The committee understood that the ERG preferred the fully parametric log normal model because a hybrid approach was only appropriate when there was a strong rationale for not using all of the available data to inform the extrapolated curve. The committee stated that the log normal distribution was the best statistical fit of the 5\xa0distributions explored by the company. The committee noted that based on the Kass et al. criteria, the Bayesian information criterion statistics strongly indicated that the log normal distribution was a better fit to the observed data than the Weibull. The committee also heard from the clinical expert that approximately 10% of patients are still having sorafenib treatment at 3\xa0years, which supported using the log normal distribution. The committee concluded that the company's fully parametric method using the log normal distribution was the most robust estimate of treatment duration.\n\n## Cost and resource use estimates\n\nThe committee was aware that the company updated the unit cost data in its reconsideration submission. It was also aware that in clinical practice, the company charges the NHS for a full pack of sorafenib at the start of each treatment cycle. Some patients do not complete the treatment cycle. Therefore the company may have underestimated the cost of treatment in its economic modelling for the first reconsideration meeting. In its response to the appraisal consultation document, the company presented cost-effectiveness results for analyses including the wastage of up to 7\xa0days of treatment. The committee concluded that it was appropriate for the company to use updated unit cost data and account for 7\xa0days of drug wastage because this reflected the price relevant to the NHS.\n\nThe committee was aware that in the original appraisal the company based its estimates of resource use, for example, number of hospitalisations, on the opinion of 4\xa0clinicians. But in this reconsideration, the company provided recent resource use estimates based on the opinion of 3\xa0different clinicians. At the first Cancer Drugs Fund reconsideration meeting the committee noted that the revised resource use data estimates varied widely and therefore it was better to pool the original and revised estimates. In its response to the appraisal consultation document, the company claimed that resource estimates from the original appraisal were no longer accurate because of significant changes in clinical practice. Specifically, patients now had treatment in oncology rather than hepatology clinics and had palliative care in the community. The committee noted that the company did not provide any more evidence in its response to the appraisal consultation document. The committee heard from the ERG that the parameters affecting the ICER most when using the updated resource use estimates compared with the pooled resource use estimates were in the best supportive care group, particularly those for admission and frequency of hospitalisation. Also, the committee understood from the ERG that the ICER was extremely sensitive to changes in these parameters. The committee concluded that the company's revised resource use data were not robust and preferred to pool the original and revised estimates.\n\nThe company provided information that sorafenib would come off patent in approximately 5\xa0years. The committee discussed the implications of this, but also noted that it had no information on the future price of sorafenib. The committee concluded that it could only take into account the company's current price for sorafenib.\n\n## End-of-life considerations\n\nThe committee considered the advice about life-extending treatments in NICE's final Cancer Drugs Fund technology appraisal process and methods. It noted the committee's conclusion in the original appraisal that sorafenib in hepatocellular carcinoma met the end-of-life criteria (see section\xa04.15). The committee agreed that sorafenib was indicated for patients with a short life expectancy and offered an extension to life of at least 3\xa0months compared with current NHS treatment. The committee concluded that sorafenib could plausibly meet the criteria to be considered a life-extending, end-of-life treatment.\n\n## Conclusion\n\nThe committee discussed the most plausible ICER for sorafenib compared with best supportive care for treating advanced hepatocellular carcinoma. It considered that there was still uncertainty associated with extrapolating overall survival from SHARP (see section\xa04.25). The committee agreed that the most plausible ICER should:\n\nbe based on the ERG's exploratory analyses using the company's fully parametric method (log normal distribution) to estimate treatment duration (see section\xa04.28)\n\naccount for drug wastage for up to 7\xa0days and\n\nuse the pooled resource use data in the absence of more robust updated resource use data.The committee was aware that after its third meeting the company proposed a new commercial access agreement to NHS England, and the committee was aware of the revised estimates of cost effectiveness. The committee appreciated that the most plausible ICER was below £50,000 per QALY gained for sorafenib compared with best supportive care (based on the ERG's weighted average results; 75% log normal and 25% Weibull distribution to extrapolate overall survival), including the new Commercial Medicines Unit price and the commercial access agreement (the details of the commercial access agreement are confidential and therefore cannot be published). The committee was aware that the most plausible ICER was within the range normally considered a cost-effective use of NHS resources taking into account the extra weight applied to QALYs at the end of life. The committee recalled its conclusion that patients with grade\xa0A Child-Pugh liver function are the appropriate population. The committee concluded that sorafenib could be recommended as an option for use in the NHS only for people with Child-Pugh grade\xa0A liver function, and only if the company provides sorafenib within the agreed commercial access arrangement.\n\n# Cancer Drugs Fund considerations\n\nBefore the commercial access agreement, which was made after the committee's third meeting, the committee had concluded that sorafenib could not be recommended, and considered if sorafenib could be recommended for use within the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England, noting the addendum to the NICE process and methods guides. The committee was aware that in considering this, the following criteria must be met:\n\nThe ICERs have plausible potential for satisfying the criteria for routine use.\n\nIt is possible that the uncertainty can be addressed through collecting outcome data from patients treated in the NHS.\n\nIt is possible that the data could inform a subsequent update of the guidance (normally within 24\xa0months).At its second meeting the committee asked the company whether it wanted to include sorafenib in the Cancer Drugs Fund; sorafenib would be funded while collecting data in the Cancer Drugs Fund. At the third meeting, the committee noted that the company had not submitted a proposal for sorafenib to be included in the Cancer Drugs Fund because the GIDEON data were better than those the Cancer Drugs Fund could collect, and that it would seek a recommendation in routine commissioning.\n\n# Summary of appraisal committee's key conclusions\n\nTA474\n\nAppraisal title: Sorafenib for treating advanced hepatocellular carcinoma\n\nSection\n\nKey conclusions: Cancer Drugs Fund reconsideration of TA189\n\nSorafenib is recommended as an option for treating advanced hepatocellular carcinoma only for people with Child-Pugh grade\xa0A liver impairment, only if the company provides sorafenib within the agreed commercial access arrangement.\n\nThe committee agreed that the most plausible ICER was below £50,000 per QALY gained for sorafenib compared with best supportive care, including the new Commercial Medicines Unit price and the commercial access agreement.\n\n, 4.33\n\nAdditional factors taken into account\n\nEqualities considerations and social value judgements\n\nIn response to the appraisal consultation document a consultee noted that the prevalence of liver cancer deaths is higher in socially deprived areas. Differences in the prevalence or incidence of a disease cannot be addressed in technology appraisal committee recommendations.\n\n–"}
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https://www.nice.org.uk/guidance/ta474
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Evidence-based recommendations on sorafenib (Nexavar) for treating advanced hepatocellular carcinoma in adults.
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679710682625c6a1ba9ef4013753f31fd83f2a66
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nice
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Dimethyl fumarate for treating moderate to severe plaque psoriasis
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Dimethyl fumarate for treating moderate to severe plaque psoriasis
Evidence-based recommendations on dimethyl fumarate (Skilarence) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Dimethyl fumarate is recommended as an option for treating plaque psoriasis in adults, only if the disease:
is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
has not responded to other systemic therapies, including, ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet A radiation), or these options are contraindicated or not tolerated.
Stop dimethyl fumarate treatment at 16 weeks if the psoriasis has not responded adequately. An adequate response is defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
When using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with dimethyl fumarate that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trial results showed that dimethyl fumarate improves severe psoriasis more than placebo but, when compared indirectly, it is less effective than systemic biological therapies and apremilast. The modelling of treatment sequences was not considered reliable enough for decision-making. However, the cost effectiveness of dimethyl fumarate followed by best supportive care compared with best supportive care alone was comparable with the respective cost-effectiveness estimates in previously published appraisals of the biologicals and apremilast. Also, dimethyl fumarate is less costly than biologicals and apremilast, and would likely provide sufficient savings per quality-adjusted life years lost when compared with these treatments. Some patients might chose to have dimethyl fumarate. Dimethyl fumarate should be used when the psoriasis is severe and has not responded to other systemic non-biological therapies, or when these treatments cannot be taken.# The technology
Dimethyl fumarate (Skilarence, Almirall)
Marketing authorisation
Dimethyl fumarate is indicated 'for the treatment of moderate to severe plaque psoriasis in adults in need of systemic medicinal therapy'.
Recommended dose and schedule
The maximum dosage is 240 mg 3 times daily given orally, after an initial titration schedule. In the first week, 30 mg is taken once daily. In the second week, 30 mg is taken twice daily. In the third week, 30 mg is taken 3 times daily. From the fourth week, a single 120‑mg daily dose is given and increased weekly for 5 weeks, until the maximum daily dose is reached.
Price
The list price is £89.04 (excluding VAT) for a titration pack (that is, 42 x 30‑mg tablets) and £190.80 (excluding VAT) for a pack of 90 x 120‑mg tablets. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (see section 5) considered evidence submitted by Almirall and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Experience of people with psoriasis
## Psoriasis can negatively affect all aspects of a person's life
The committee appreciated that psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological and social). The committee noted that having treatments that improve the disease and are associated with few or manageable side effects is important to people with psoriasis, as is having a choice of treatments.
# Clinical management
## Psoriasis can be treated with topical therapies, phototherapy, systemic non-biological therapies and systemic biological therapies
The committee was aware that people with plaque psoriasis have topical therapies as first-line treatment, followed by phototherapy (second line). If these treatments do not adequately control the psoriasis, people may have systemic conventional non‑biological therapies third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to therapy, people may have systemic biological therapies or apremilast (fourth line), which they continue as long as the drugs work. The committee understood that if the disease no longer responds to a biological therapy, people will be offered another biological therapy. This pattern is likely to be repeated over their lifetime. The committee heard that, for people whose disease does not respond to multiple biological agents or apremilast, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.
# Position of dimethyl fumarate in the treatment pathway
## Dimethyl fumarate is considered an alternative to systemic biological therapies and apremilast, and best supportive care
The committee noted that the marketing authorisation for dimethyl fumarate is for 'adults in need of systemic medicinal therapy'. It was aware that fumaric acid esters (such as fumaderm) are already used as 'off-label' treatments for psoriasis in the NHS. The committee understood that the marketing authorisation allows dimethyl fumarate to be used at different positions in the treatment pathway:
As an alternative to systemic non-biological therapies (third-line therapy): the committee heard from the clinical expert that dimethyl fumarate is unlikely to displace non-biologicals (such as methotrexate) because they are well-established, standard treatments. The company did not submit any evidence for dimethyl fumarate compared with these non-biologicals, and therefore the committee did not consider this position further.
After systemic non-biologicals, but before systemic biologicals and apremilast (between third- and fourth-line therapy): the committee heard from the clinical expert that dimethyl fumarate could be used when a patient's psoriasis does not meet NICE's technology appraisal criteria for severe disease, defined as a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10. However, the committee understood from the clinical expert that the baseline characteristics of people in the key clinical trial, BRIDGE, were broadly consistent with the severe population as defined in previous NICE technology appraisals for psoriasis (see section 3.6). The committee concluded that the company's evidence did not reflect the use of dimethyl fumarate for moderate disease at this position and did not consider this further.
As an alternative to biological therapies and apremilast (fourth-line therapy): the committee heard from the clinical expert and the company that the most likely position for dimethyl fumarate is as an alternative to biologicals and apremilast. The committee agreed that it was appropriate to consider dimethyl fumarate at this position.
After biologicals or apremilast, as an alternative to best supportive care. The committee understood from the ERG that dimethyl fumarate could be used in this position, although it heard from the clinical expert that it is unlikely to be used after biologicals because these agents are more clinically effective (see section 3.8). While the committee noted that the evidence from BRIDGE did not reflect a population who had exhausted treatment options with biologicals or apremilast, it understood that there are limited options available to patients at this point in the pathway. Therefore, the committee agreed that it was appropriate to consider dimethyl fumarate at this position.
# Comparators
## Appropriate comparators for the positioning of dimethyl fumarate are systemic biological therapies, apremilast and fumaderm
The committee was aware that the company's clinical evidence and economic model compared dimethyl fumarate with biologicals (adalimumab, etanercept, ixekizumab, secukinumab and ustekinumab), apremilast and fumaderm. The committee considered that this was appropriate because it agreed with the company that, in clinical practice, dimethyl fumarate would be offered at the same place in the treatment pathway as the existing biologicals or apremilast (see section 3.3). The committee therefore concluded that the most appropriate comparators for dimethyl fumarate were biologicals, apremilast and fumaderm.
# Clinical evidence
## Key clinical evidence for dimethyl fumarate came from the BRIDGE trial
The committee noted that the evidence for dimethyl fumarate came from the BRIDGE trial, a randomised double-blind study of 704 people with chronic plaque psoriasis that compared dimethyl fumarate with fumaderm and placebo. The co-primary outcomes were a 75% reduction in the PASI score from when treatment started (PASI 75) and a rating of 'clear' (score of 0) or 'almost clear' (score of 1) on the Physician Global Assessment (PGA), measured at 16 weeks (the end of induction period).
## The population in BRIDGE is generalisable to both patients with previously treated and with untreated severe psoriasis in the NHS
The committee considered the generalisability of the BRIDGE trial to clinical practice in the NHS:
Severity of disease: the committee acknowledged that BRIDGE included people with a PASI score of 10 or more, an affected body surface area of more than 10% and a rating of at least moderate (score of 3) on the PGA. The committee noted that the study eligibility criteria did not include the DLQI. The committee acknowledged that the definitions of severe and very severe psoriasis used in previous NICE technology appraisals (based on PASI and DLQI) were different to the European Medicines Agency's definition of severity. The committee heard from the clinical expert that the population in BRIDGE is generally aligned to NICE's technology appraisals definition of 'severe'. The committee agreed to consider dimethyl fumarate in the population with a severity similar to those in previous technology appraisals for psoriasis.
Previous treatment: the committee noted that a post-hoc subgroup analysis of BRIDGE showed differences in treatment responses in PASI 75 and PGA 0 or 1 between patients whose psoriasis had been previously treated with systemic therapy compared with those who had not. Although the company did not test for heterogeneity of treatment effects between the subgroups (see section 3.7), the committee considered that a test for interaction would not have been powered to detect real differences (n=101 not previously treated with systemic therapy compared with n=30 previously treated with systemic therapy). The committee heard from the clinical expert that similar responses in psoriasis regardless of previous systemic therapy were seen in other published research on fumaric acid esters. The committee agreed that it was reasonable to assume a similar treatment response from dimethyl fumarate in psoriasis that had and had not previously been treated with systemic therapy.
## Dimethyl fumarate is as effective as fumaderm and more clinically effective than placebo
The committee noted that, in patients randomised to dimethyl fumarate, there were clinically and statistically significantly higher PASI 75, and PGA 0 or 1 response rates at week 16 compared with placebo. It noted that PASI 75 and PGA response rates were comparable to fumaderm. The risk differences are detailed in table 1. The committee heard from the clinical expert that fumaric acid esters were effective at reducing the symptoms of psoriasis. The committee concluded that dimethyl fumarate was as effective as fumaderm and more clinically effective than placebo.
## Table 1 Risk differences for dimethyl fumarate for PASI 75, and PGA 0 or 1 at week 16
Outcome
Compared with placebo
Compared with fumaderm
PASI 75
%(99.24% CI 10.7 to 33.7)
−2.8%(99.24% CI −14.0 to 8.4)
PGA 0 or 1
%(99.24% CI 8.0 to 30.0)
-4.0%(99.24% CI −15.0 to 7.0)
Abbreviations: CI, Confidence interval; PASI, Psoriasis Area and Severity Index; PGA, Physician Global Assessment.
## The network meta-analysis may have underestimated the clinical effectiveness of dimethyl fumarate
The committee discussed the company's network meta-analysis, which indirectly compared dimethyl fumarate with fumaderm, apremilast, adalimumab, etanercept, ixekizumab, secukinumab and ustekinumab. The results showed that dimethyl fumarate had the lowest probability of achieving a PASI 75 response compared with all the other active treatments, but was better than placebo. The committee was concerned that the estimated absolute probability of achieving a PASI 75 response in the company's network meta-analysis for dimethyl fumarate (18%) was almost half that seen in BRIDGE (38%). The company explained that this could be because the analysis used estimates of the placebo response from other trials. The committee agreed that the company's network meta-analysis was conservative and likely to underestimate the relative effectiveness of dimethyl fumarate. Although it was concerned by the company's network meta-analysis, the committee concluded that it was likely that dimethyl fumarate was less effective than apremilast and other biologicals.
# Adverse events
## Short-term safety and tolerability of dimethyl fumarate and fumaderm are similar
The committee heard that the most common side effects that lead patients to stop treatment with dimethyl fumarate are gastrointestinal. It noted that the adverse effects leading to treatment being stopped were similar in type and frequency for dimethyl fumarate compared with fumaderm. The committee was aware that cases of progressive multifocal leukoencephalopathy have been reported in people who have psoriasis and prolonged lymphopenia and are taking dimethyl fumarate. It noted that the company did not provide long-term adverse-event data for dimethyl fumarate compared with other biologicals and apremilast. The committee concluded that the safety and tolerability of dimethyl fumarate were similar to that of fumaderm, and that the long-term safety of dimethyl fumarate compared with biologicals and apremilast was uncertain.
# Company's economic model
## Model structure
The committee considered the Markov state transition model that the company used to assess the cost effectiveness of dimethyl fumarate. It modelled treatments in sequence, with each sequence having up to 4 active treatments and induction periods. The model contained 4 health states:
Induction: all patients started in this health state and had treatment in the induction period. Moving from induction to maintenance occurred when the patient's condition responded to treatment if they had a PASI 75 at the end of induction. Patients who did not have a PASI 75 moved onto the next treatment in the sequence.
Maintenance: this state was only for patients whose condition responded to treatment in the induction period. The company assumed in its model that 20% of patients would stop treatment every year for any reason and move onto the next treatment in the sequence.
Best supportive care: patients moved into this health state in between trialling new treatments in the sequence and when their psoriasis did not respond to the last active treatment in the sequence.
Death: all patients could move into this state at any time. The company used age-specific mortality rates from the general UK population.
## The company modelled 6 treatment sequences
The committee noted that the company presented 6 pairwise comparisons of different treatment sequences:
Dimethyl fumarate before biologicals compared with no dimethyl fumarate before biologicals in the following sequences:
adalimumab, ustekinumab, best supportive care (base case)
etanercept, adalimumab, ustekinumab, best supportive care
adalimumab, secukinumab, best supportive care.
Dimethyl fumaratecompared with apremilast before biologicals in the following sequences:
adalimumab, ustekinumab, best supportive care
adalimumab, secukinumab, best supportive care.
Dimethyl fumarate before biologicals compared with dimethyl fumarate after biologicals:
dimethyl fumarate, adalimumab, ustekinumab, best supportive care compared with adalimumab, ustekinumab, dimethyl fumarate, best supportive care.
## Modelling all plausible sequences in a fully incremental analysis is preferred
The committee understood that the company chose its base-case treatment sequence based on clinical advice. However, it heard from the clinical expert that, although the sequence was reasonable, clinical practice and guidance constantly change and biologicals are likely to be used interchangeably. The committee appreciated that the company tried to model the most clinically relevant comparisons for the base case and scenario analyses, but was concerned that the limited number of selected treatment sequences modelled in pairwise comparisons provided narrow and potentially misleading estimates of the cost effectiveness of dimethyl fumarate. It understood that the cost effectiveness of any new treatment included early in a sequence would likely be driven by avoiding more expensive (and apparently cost-ineffective) subsequent treatments and best supportive care (see section 3.19). The committee noted that it would have preferred it if the company had modelled all plausible sequences in a fully incremental analysis taking into account the different treatment lengths and positions.
# Assumptions in the economic model
## A lifetime horizon captures all resource use and costs
The committee was aware that the company applied a 10‑year time horizon in its modelled base case, similar to some previous NICE technology appraisals on psoriasis. It heard from the ERG that a longer time horizon is necessary to allow the model to estimate the full impact of treatment sequences and that a 10‑year horizon improves the cost effectiveness of dimethyl fumarate. The committee agreed that a lifetime horizon was appropriate.
## Treatment-specific stopping rates are preferred to a 20% constant yearly rate
The committee was aware that the company model applied a constant 20% yearly treatment stopping rate (for adverse events, patient choice and lack of effectiveness) similar to previous NICE technology appraisals on psoriasis. The committee was concerned that the same rate was applied for all treatments given that 24% of patients having dimethyl fumarate in BRIDGE had stopped treatment because of adverse effects over 16 weeks. The committee heard from the company that a sensitivity analysis was done using treatment-specific stopping rates from Arnold et al. (2016). The committee noted that the annual stopping rate for dimethyl fumarate was lower in this analysis, at 14%, which it considered too low to reflect NHS clinical practice. The committee agreed that different treatment-specific stopping rates were preferable for modelling, but was concerned that the values the company derived from Arnold et al. were not valid. In the absence of other evidence, the committee agreed that the company's approach was acceptable for decision-making.
# Utility values in the economic model
## Generic preference-based quality-of-life evidence comparing dimethyl fumarate with biologicals and apremilast is not available
The committee understood that the company used the quality-of-life increments from all patients regardless of disease severity from the previous NICE technology appraisal guidance on etanercept and the PASI response rates from its network meta-analyses to estimate utility benefit. The committee was concerned that the company took the quality-of-life increments from data for a biological (etanercept) and that these values may not reflect those for dimethyl fumarate. The committee heard from the company that the increments in quality of life mapped from DLQI values taken in BRIDGE were similar to those in the NICE technology appraisal guidance on etanercept. The committee was also concerned that there was no data on quality of life for dimethyl fumarate from direct comparisons between dimethyl fumarate and biologicals or apremilast. In the absence of generic preference-based quality-of-life evidence from BRIDGE, the committee concluded that the evidence submitted by the company was sufficient for decision-making.
## Assuming that the same quality-of-life increment is applied regardless of the position of the treatment in a sequence is appropriate
The committee was aware that, in its model, the company did not apply a quality-of-life increment for a treatment if it was first in the sequence, but applied the increment if the treatment was later in the sequence. It noted the ERG's concern that this would result in greater quality-of-life gains for longer treatment sequences. The committee noted that, in its exploratory analyses, the ERG assumed that all treatments during the induction period have the same baseline quality-of-life values, irrespective of position in a sequence. The committee agreed that the ERG's exploratory analysis was appropriate.
# Costs in the economic model
## The ERG's estimate of costs for 'non-responders' during induction of £121 is more appropriate than the company's estimate of £225
The committee was aware that the company used the cost estimates from NICE's technology appraisal guidance on apremilast for people whose disease does not respond to treatment and who then go on to get another treatment during induction ('non-responder' costs). The committee understood from the ERG that this was a significant driver of cost-effectiveness results because the company had not considered that the model in the apremilast appraisal applied a 28‑day cycle compared with the company's 14‑day cycle in this appraisal. The committee agreed that the ERG's £121 was more appropriate than the company's £225 estimate for 'non-responder' costs.
# Cost-effectiveness estimate
## The ERG's base case and sensitivity analysis are preferred for decision-making
The committee had concluded that a lifetime horizon was appropriate (see section 3.13), that the same quality-of-life increment should be applied to treatments during the induction period (see section 3.16) and that the 'non-responder' cost estimates should be corrected to account for the company's 14‑day cycle (see section 3.17); the ERG included all these assumptions in its base-case analysis. The ERG also made additional adjustments in the company's model. It:
applied a cost for an apremilast induction pack (cost £10 less)
used low doses for etanercept and ustekinumab
assumed indivisible vials for infliximab and applied administrative costs
updated best supportive care costs (£4 more)
applied 14 days of drug wastage for dimethyl fumarate, fumaderm and apremilast
applied additional GP monitoring costs for blood tests for people having dimethyl fumarate (cost £36 more).The committee agreed that these changes were appropriate. In addition, the company had confirmed that, in the summary of product characteristics for dimethyl fumarate, the recommended frequency of monitoring was 4 full blood counts per year rather than 12 per year, as in its base case. The ERG used 4 full blood counts per year in its sensitivity analysis. The committee concluded that the most plausible analysis was the ERG's exploratory analysis including the lower monitoring frequency.
## Treatment sequences with comparators that are not cost effective may result in biased ICERs that are not appropriate for decision-making
The committee noted that the ERG's incremental cost-effectiveness ratios (ICERs) for each biological and apremilast alone (that is, not in a sequence with other treatments) compared with best supportive care were more than £30,000 per quality-adjusted life-year (QALY) gained. The committee was aware that previous NICE technology appraisals considered biologicals and apremilast to be a cost-effective use of NHS resources. The committee was concerned that a model with apparently cost-ineffective comparators within treatment sequences could result in misleading ICERs. It understood that this was because the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding more expensive (and apparently cost-ineffective) subsequent treatments and best supportive care. In addition, it recalled that the company's and ERG's approach included a limited number of selected treatment sequences (see section 3.11). Therefore, the committee agreed that the most reliable ICER for decision-making in this appraisal was from the comparison of dimethyl fumarate with best supportive care without a treatment sequence.
## Dimethyl fumarate is cost effective in people for whom best supportive care is the only option
The ICER for dimethyl fumarate followed by best supportive care compared with best supportive care alone was £23,115 per QALY gained. The committee agreed that dimethyl fumarate followed by best supportive care is cost effective compared with best supportive care alone. It concluded that dimethyl fumarate is a cost-effective use of NHS resources for people for whom best supportive care is the only option, that is, if biologicals and apremilast are not effective or not tolerated.
## Dimethyl fumarate is cost effective for people with severe psoriasis
The committee considered whether dimethyl fumarate was a cost-effective use of NHS resources for people with severe psoriasis for whom treatment with biologicals or apremilast is an option. It considered that the analyses including treatment sequences of biologicals or apremilast were potentially misleading (see section 3.19). However, it appreciated that the cost effectiveness of dimethyl fumarate followed by best supportive care compared with best supportive care alone was comparable with the respective cost-effectiveness estimates in the previously published appraisals of the biologicals and apremilast. These drugs are currently recommended as options for treating severe chronic plaque psoriasis that has not responded to other systemic therapies, or when systemic therapy is contraindicated or not tolerated. The committee was also aware that dimethyl fumarate was less costly than biologicals and apremilast, and considered that dimethyl fumarate would likely provide sufficient savings per QALY lost compared with biologicals and apremilast. The committee appreciated that the positioning of dimethyl fumarate would be driven largely by patient choice and understood that patients value having a range of treatment options. The committee concluded that it could recommend dimethyl fumarate as an option for treating severe chronic plaque psoriasis that has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet A radiation), or when these options are contraindicated or not tolerated.
## Stopping rule
The committee was aware that previous NICE technology appraisals for treating psoriasis recommended stopping treatment if there was an inadequate response; an adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that if there was no response to dimethyl fumarate, the patient should not continue treatment. It noted that PASI 75 was the primary outcome in the trial data used to model the cost effectiveness of dimethyl fumarate. The committee therefore concluded that, for consistency with previous appraisals for treatments in psoriasis, dimethyl fumarate should be stopped if there is an inadequate response at 16 weeks, with an adequate response as defined in previous NICE technology appraisals.
# Other factors
## Equality issues
The committee noted, as in previous NICE technology appraisals on psoriasis, the potential equality issues, that:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people, and may also miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.
## Innovation
The committee heard differing views about whether dimethyl fumarate was innovative in its potential to make a significant and substantial impact on health-related benefits. It agreed that dimethyl fumarate uses an existing mechanism of action in a new formulation, and agreed that it provided an additional oral therapy. However, the committee appreciated that some people with psoriasis prefer less frequent injectable treatments to more frequent oral ones and therefore concluded that, in this respect, there were no additional gains in health-related quality of life over those already included in the QALY calculations.
## Pharmaceutical Price Regulation Scheme
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of this technology.
|
{'Recommendations': 'Dimethyl fumarate is recommended as an option for treating plaque psoriasis in adults, only if the disease:\n\nis severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nhas not responded to other systemic therapies, including, ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet\xa0A radiation), or these options are contraindicated or not tolerated.\n\nStop dimethyl fumarate treatment at 16\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with dimethyl fumarate that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trial results showed that dimethyl fumarate improves severe psoriasis more than placebo but, when compared indirectly, it is less effective than systemic biological therapies and apremilast. The modelling of treatment sequences was not considered reliable enough for decision-making. However, the cost effectiveness of dimethyl fumarate followed by best supportive care compared with best supportive care alone was comparable with the respective cost-effectiveness estimates in previously published appraisals of the biologicals and apremilast. Also, dimethyl fumarate is less costly than biologicals and apremilast, and would likely provide sufficient savings per quality-adjusted life years lost when compared with these treatments. Some patients might chose to have dimethyl fumarate. Dimethyl fumarate should be used when the psoriasis is severe and has not responded to other systemic non-biological therapies, or when these treatments cannot be taken.', 'The technology': "Dimethyl fumarate (Skilarence, Almirall)\n\nMarketing authorisation\n\nDimethyl fumarate is indicated 'for the treatment of moderate to severe plaque psoriasis in adults in need of systemic medicinal therapy'.\n\nRecommended dose and schedule\n\nThe maximum dosage is 240\xa0mg 3\xa0times daily given orally, after an initial titration schedule. In the first week, 30\xa0mg is taken once daily. In the second week, 30\xa0mg is taken twice daily. In the third week, 30\xa0mg is taken 3\xa0times daily. From the fourth week, a single 120‑mg daily dose is given and increased weekly for 5\xa0weeks, until the maximum daily dose is reached.\n\nPrice\n\nThe list price is £89.04 (excluding VAT) for a titration pack (that is, 42 x 30‑mg tablets) and £190.80 (excluding VAT) for a pack of 90\xa0x\xa0120‑mg tablets. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (see section\xa05) considered evidence submitted by Almirall and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Experience of people with psoriasis\n\n## Psoriasis can negatively affect all aspects of a person's life\n\nThe committee appreciated that psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological and social). The committee noted that having treatments that improve the disease and are associated with few or manageable side effects is important to people with psoriasis, as is having a choice of treatments.\n\n# Clinical management\n\n## Psoriasis can be treated with topical therapies, phototherapy, systemic non-biological therapies and systemic biological therapies\n\nThe committee was aware that people with plaque psoriasis have topical therapies as first-line treatment, followed by phototherapy (second line). If these treatments do not adequately control the psoriasis, people may have systemic conventional non‑biological therapies third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to therapy, people may have systemic biological therapies or apremilast (fourth line), which they continue as long as the drugs work. The committee understood that if the disease no longer responds to a biological therapy, people will be offered another biological therapy. This pattern is likely to be repeated over their lifetime. The committee heard that, for people whose disease does not respond to multiple biological agents or apremilast, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.\n\n# Position of dimethyl fumarate in the treatment pathway\n\n## Dimethyl fumarate is considered an alternative to systemic biological therapies and apremilast, and best supportive care\n\nThe committee noted that the marketing authorisation for dimethyl fumarate is for 'adults in need of systemic medicinal therapy'. It was aware that fumaric acid esters (such as fumaderm) are already used as 'off-label' treatments for psoriasis in the NHS. The committee understood that the marketing authorisation allows dimethyl fumarate to be used at different positions in the treatment pathway:\n\nAs an alternative to systemic non-biological therapies (third-line therapy): the committee heard from the clinical expert that dimethyl fumarate is unlikely to displace non-biologicals (such as methotrexate) because they are well-established, standard treatments. The company did not submit any evidence for dimethyl fumarate compared with these non-biologicals, and therefore the committee did not consider this position further.\n\nAfter systemic non-biologicals, but before systemic biologicals and apremilast (between third- and fourth-line therapy): the committee heard from the clinical expert that dimethyl fumarate could be used when a patient's psoriasis does not meet NICE's technology appraisal criteria for severe disease, defined as a total Psoriasis Area and Severity Index (PASI) of 10\xa0or more and a Dermatology Life Quality Index (DLQI) of more than\xa010. However, the committee understood from the clinical expert that the baseline characteristics of people in the key clinical trial, BRIDGE, were broadly consistent with the severe population as defined in previous NICE technology appraisals for psoriasis (see section\xa03.6). The committee concluded that the company's evidence did not reflect the use of dimethyl fumarate for moderate disease at this position and did not consider this further.\n\nAs an alternative to biological therapies and apremilast (fourth-line therapy): the committee heard from the clinical expert and the company that the most likely position for dimethyl fumarate is as an alternative to biologicals and apremilast. The committee agreed that it was appropriate to consider dimethyl fumarate at this position.\n\nAfter biologicals or apremilast, as an alternative to best supportive care. The committee understood from the ERG that dimethyl fumarate could be used in this position, although it heard from the clinical expert that it is unlikely to be used after biologicals because these agents are more clinically effective (see section\xa03.8). While the committee noted that the evidence from BRIDGE did not reflect a population who had exhausted treatment options with biologicals or apremilast, it understood that there are limited options available to patients at this point in the pathway. Therefore, the committee agreed that it was appropriate to consider dimethyl fumarate at this position.\n\n# Comparators\n\n## Appropriate comparators for the positioning of dimethyl fumarate are systemic biological therapies, apremilast and fumaderm\n\nThe committee was aware that the company's clinical evidence and economic model compared dimethyl fumarate with biologicals (adalimumab, etanercept, ixekizumab, secukinumab and ustekinumab), apremilast and fumaderm. The committee considered that this was appropriate because it agreed with the company that, in clinical practice, dimethyl fumarate would be offered at the same place in the treatment pathway as the existing biologicals or apremilast (see section\xa03.3). The committee therefore concluded that the most appropriate comparators for dimethyl fumarate were biologicals, apremilast and fumaderm.\n\n# Clinical evidence\n\n## Key clinical evidence for dimethyl fumarate came from the BRIDGE trial\n\nThe committee noted that the evidence for dimethyl fumarate came from the BRIDGE trial, a randomised double-blind study of 704\xa0people with chronic plaque psoriasis that compared dimethyl fumarate with fumaderm and placebo. The co-primary outcomes were a 75% reduction in the PASI score from when treatment started (PASI\xa075) and a rating of 'clear' (score of\xa00) or 'almost clear' (score of\xa01) on the Physician Global Assessment (PGA), measured at 16\xa0weeks (the end of induction period).\n\n## The population in BRIDGE is generalisable to both patients with previously treated and with untreated severe psoriasis in the NHS\n\nThe committee considered the generalisability of the BRIDGE trial to clinical practice in the NHS:\n\nSeverity of disease: the committee acknowledged that BRIDGE included people with a PASI score of 10\xa0or more, an affected body surface area of more than 10% and a rating of at least moderate (score of\xa03) on the PGA. The committee noted that the study eligibility criteria did not include the DLQI. The committee acknowledged that the definitions of severe and very severe psoriasis used in previous NICE technology appraisals (based on PASI and DLQI) were different to the European Medicines Agency's definition of severity. The committee heard from the clinical expert that the population in BRIDGE is generally aligned to NICE's technology appraisals definition of 'severe'. The committee agreed to consider dimethyl fumarate in the population with a severity similar to those in previous technology appraisals for psoriasis.\n\nPrevious treatment: the committee noted that a post-hoc subgroup analysis of BRIDGE showed differences in treatment responses in PASI\xa075 and PGA\xa00 or\xa01 between patients whose psoriasis had been previously treated with systemic therapy compared with those who had not. Although the company did not test for heterogeneity of treatment effects between the subgroups (see section\xa03.7), the committee considered that a test for interaction would not have been powered to detect real differences (n=101 not previously treated with systemic therapy compared with n=30 previously treated with systemic therapy). The committee heard from the clinical expert that similar responses in psoriasis regardless of previous systemic therapy were seen in other published research on fumaric acid esters. The committee agreed that it was reasonable to assume a similar treatment response from dimethyl fumarate in psoriasis that had and had not previously been treated with systemic therapy.\n\n## Dimethyl fumarate is as effective as fumaderm and more clinically effective than placebo\n\nThe committee noted that, in patients randomised to dimethyl fumarate, there were clinically and statistically significantly higher PASI\xa075, and PGA\xa00 or 1\xa0response rates at week\xa016 compared with placebo. It noted that PASI\xa075 and PGA response rates were comparable to fumaderm. The risk differences are detailed in table 1. The committee heard from the clinical expert that fumaric acid esters were effective at reducing the symptoms of psoriasis. The committee concluded that dimethyl fumarate was as effective as fumaderm and more clinically effective than placebo.\n\n## Table 1 Risk differences for dimethyl fumarate for PASI\xa075, and PGA\xa00 or\xa01 at week\xa016\n\nOutcome\n\nCompared with placebo\n\nCompared with fumaderm\n\nPASI 75\n\n%(99.24% CI 10.7 to 33.7)\n\n−2.8%(99.24% CI −14.0 to 8.4)\n\nPGA 0 or 1\n\n%(99.24% CI 8.0 to 30.0)\n\n-4.0%(99.24% CI −15.0 to 7.0)\n\nAbbreviations: CI, Confidence interval; PASI, Psoriasis Area and Severity Index; PGA, Physician Global Assessment.\n\n## The network meta-analysis may have underestimated the clinical effectiveness of dimethyl fumarate\n\nThe committee discussed the company's network meta-analysis, which indirectly compared dimethyl fumarate with fumaderm, apremilast, adalimumab, etanercept, ixekizumab, secukinumab and ustekinumab. The results showed that dimethyl fumarate had the lowest probability of achieving a PASI\xa075 response compared with all the other active treatments, but was better than placebo. The committee was concerned that the estimated absolute probability of achieving a PASI\xa075 response in the company's network meta-analysis for dimethyl fumarate (18%) was almost half that seen in BRIDGE (38%). The company explained that this could be because the analysis used estimates of the placebo response from other trials. The committee agreed that the company's network meta-analysis was conservative and likely to underestimate the relative effectiveness of dimethyl fumarate. Although it was concerned by the company's network meta-analysis, the committee concluded that it was likely that dimethyl fumarate was less effective than apremilast and other biologicals.\n\n# Adverse events\n\n## Short-term safety and tolerability of dimethyl fumarate and fumaderm are similar\n\nThe committee heard that the most common side effects that lead patients to stop treatment with dimethyl fumarate are gastrointestinal. It noted that the adverse effects leading to treatment being stopped were similar in type and frequency for dimethyl fumarate compared with fumaderm. The committee was aware that cases of progressive multifocal leukoencephalopathy have been reported in people who have psoriasis and prolonged lymphopenia and are taking dimethyl fumarate. It noted that the company did not provide long-term adverse-event data for dimethyl fumarate compared with other biologicals and apremilast. The committee concluded that the safety and tolerability of dimethyl fumarate were similar to that of fumaderm, and that the long-term safety of dimethyl fumarate compared with biologicals and apremilast was uncertain.\n\n# Company's economic model\n\n## Model structure\n\nThe committee considered the Markov state transition model that the company used to assess the cost effectiveness of dimethyl fumarate. It modelled treatments in sequence, with each sequence having up to 4\xa0active treatments and induction periods. The model contained 4\xa0health states:\n\nInduction: all patients started in this health state and had treatment in the induction period. Moving from induction to maintenance occurred when the patient's condition responded to treatment if they had a PASI\xa075 at the end of induction. Patients who did not have a PASI\xa075 moved onto the next treatment in the sequence.\n\nMaintenance: this state was only for patients whose condition responded to treatment in the induction period. The company assumed in its model that 20% of patients would stop treatment every year for any reason and move onto the next treatment in the sequence.\n\nBest supportive care: patients moved into this health state in between trialling new treatments in the sequence and when their psoriasis did not respond to the last active treatment in the sequence.\n\nDeath: all patients could move into this state at any time. The company used age-specific mortality rates from the general UK population.\n\n## The company modelled 6\xa0treatment sequences\n\nThe committee noted that the company presented 6\xa0pairwise comparisons of different treatment sequences:\n\nDimethyl fumarate before biologicals compared with no dimethyl fumarate before biologicals in the following sequences:\n\n\n\nadalimumab, ustekinumab, best supportive care (base case)\n\netanercept, adalimumab, ustekinumab, best supportive care\n\nadalimumab, secukinumab, best supportive care.\n\n\n\nDimethyl fumaratecompared with apremilast before biologicals in the following sequences:\n\n\n\nadalimumab, ustekinumab, best supportive care\n\nadalimumab, secukinumab, best supportive care.\n\n\n\nDimethyl fumarate before biologicals compared with dimethyl fumarate after biologicals:\n\n\n\ndimethyl fumarate, adalimumab, ustekinumab, best supportive care compared with adalimumab, ustekinumab, dimethyl fumarate, best supportive care.\n\n\n\n## Modelling all plausible sequences in a fully incremental analysis is preferred\n\nThe committee understood that the company chose its base-case treatment sequence based on clinical advice. However, it heard from the clinical expert that, although the sequence was reasonable, clinical practice and guidance constantly change and biologicals are likely to be used interchangeably. The committee appreciated that the company tried to model the most clinically relevant comparisons for the base case and scenario analyses, but was concerned that the limited number of selected treatment sequences modelled in pairwise comparisons provided narrow and potentially misleading estimates of the cost effectiveness of dimethyl fumarate. It understood that the cost effectiveness of any new treatment included early in a sequence would likely be driven by avoiding more expensive (and apparently cost-ineffective) subsequent treatments and best supportive care (see section\xa03.19). The committee noted that it would have preferred it if the company had modelled all plausible sequences in a fully incremental analysis taking into account the different treatment lengths and positions.\n\n# Assumptions in the economic model\n\n## A lifetime horizon captures all resource use and costs\n\nThe committee was aware that the company applied a 10‑year time horizon in its modelled base case, similar to some previous NICE technology appraisals on psoriasis. It heard from the ERG that a longer time horizon is necessary to allow the model to estimate the full impact of treatment sequences and that a 10‑year horizon improves the cost effectiveness of dimethyl fumarate. The committee agreed that a lifetime horizon was appropriate.\n\n## Treatment-specific stopping rates are preferred to a 20% constant yearly rate\n\nThe committee was aware that the company model applied a constant 20% yearly treatment stopping rate (for adverse events, patient choice and lack of effectiveness) similar to previous NICE technology appraisals on psoriasis. The committee was concerned that the same rate was applied for all treatments given that 24% of patients having dimethyl fumarate in BRIDGE had stopped treatment because of adverse effects over 16\xa0weeks. The committee heard from the company that a sensitivity analysis was done using treatment-specific stopping rates from Arnold et al. (2016). The committee noted that the annual stopping rate for dimethyl fumarate was lower in this analysis, at 14%, which it considered too low to reflect NHS clinical practice. The committee agreed that different treatment-specific stopping rates were preferable for modelling, but was concerned that the values the company derived from Arnold et al. were not valid. In the absence of other evidence, the committee agreed that the company's approach was acceptable for decision-making.\n\n# Utility values in the economic model\n\n## Generic preference-based quality-of-life evidence comparing dimethyl fumarate with biologicals and apremilast is not available\n\nThe committee understood that the company used the quality-of-life increments from all patients regardless of disease severity from the previous NICE technology appraisal guidance on etanercept and the PASI response rates from its network meta-analyses to estimate utility benefit. The committee was concerned that the company took the quality-of-life increments from data for a biological (etanercept) and that these values may not reflect those for dimethyl fumarate. The committee heard from the company that the increments in quality of life mapped from DLQI values taken in BRIDGE were similar to those in the NICE technology appraisal guidance on etanercept. The committee was also concerned that there was no data on quality of life for dimethyl fumarate from direct comparisons between dimethyl fumarate and biologicals or apremilast. In the absence of generic preference-based quality-of-life evidence from BRIDGE, the committee concluded that the evidence submitted by the company was sufficient for decision-making.\n\n## Assuming that the same quality-of-life increment is applied regardless of the position of the treatment in a sequence is appropriate\n\nThe committee was aware that, in its model, the company did not apply a quality-of-life increment for a treatment if it was first in the sequence, but applied the increment if the treatment was later in the sequence. It noted the ERG's concern that this would result in greater quality-of-life gains for longer treatment sequences. The committee noted that, in its exploratory analyses, the ERG assumed that all treatments during the induction period have the same baseline quality-of-life values, irrespective of position in a sequence. The committee agreed that the ERG's exploratory analysis was appropriate.\n\n# Costs in the economic model\n\n## The ERG's estimate of costs for 'non-responders' during induction of £121 is more appropriate than the company's estimate of £225\n\nThe committee was aware that the company used the cost estimates from NICE's technology appraisal guidance on apremilast for people whose disease does not respond to treatment and who then go on to get another treatment during induction ('non-responder' costs). The committee understood from the ERG that this was a significant driver of cost-effectiveness results because the company had not considered that the model in the apremilast appraisal applied a 28‑day cycle compared with the company's 14‑day cycle in this appraisal. The committee agreed that the ERG's £121 was more appropriate than the company's £225 estimate for 'non-responder' costs.\n\n# Cost-effectiveness estimate\n\n## The ERG's base case and sensitivity analysis are preferred for decision-making\n\nThe committee had concluded that a lifetime horizon was appropriate (see section\xa03.13), that the same quality-of-life increment should be applied to treatments during the induction period (see section\xa03.16) and that the 'non-responder' cost estimates should be corrected to account for the company's 14‑day cycle (see section\xa03.17); the ERG included all these assumptions in its base-case analysis. The ERG also made additional adjustments in the company's model. It:\n\napplied a cost for an apremilast induction pack (cost £10 less)\n\nused low doses for etanercept and ustekinumab\n\nassumed indivisible vials for infliximab and applied administrative costs\n\nupdated best supportive care costs (£4 more)\n\napplied 14\xa0days of drug wastage for dimethyl fumarate, fumaderm and apremilast\n\napplied additional GP monitoring costs for blood tests for people having dimethyl fumarate (cost £36 more).The committee agreed that these changes were appropriate. In addition, the company had confirmed that, in the summary of product characteristics for dimethyl fumarate, the recommended frequency of monitoring was 4\xa0full blood counts per year rather than 12\xa0per year, as in its base case. The ERG used 4\xa0full blood counts per year in its sensitivity analysis. The committee concluded that the most plausible analysis was the ERG's exploratory analysis including the lower monitoring frequency.\n\n## Treatment sequences with comparators that are not cost effective may result in biased ICERs that are not appropriate for decision-making\n\nThe committee noted that the ERG's incremental cost-effectiveness ratios (ICERs) for each biological and apremilast alone (that is, not in a sequence with other treatments) compared with best supportive care were more than £30,000 per quality-adjusted life-year (QALY) gained. The committee was aware that previous NICE technology appraisals considered biologicals and apremilast to be a cost-effective use of NHS resources. The committee was concerned that a model with apparently cost-ineffective comparators within treatment sequences could result in misleading ICERs. It understood that this was because the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding more expensive (and apparently cost-ineffective) subsequent treatments and best supportive care. In addition, it recalled that the company's and ERG's approach included a limited number of selected treatment sequences (see section\xa03.11). Therefore, the committee agreed that the most reliable ICER for decision-making in this appraisal was from the comparison of dimethyl fumarate with best supportive care without a treatment sequence.\n\n## Dimethyl fumarate is cost effective in people for whom best supportive care is the only option\n\nThe ICER for dimethyl fumarate followed by best supportive care compared with best supportive care alone was £23,115 per QALY gained. The committee agreed that dimethyl fumarate followed by best supportive care is cost effective compared with best supportive care alone. It concluded that dimethyl fumarate is a cost-effective use of NHS resources for people for whom best supportive care is the only option, that is, if biologicals and apremilast are not effective or not tolerated.\n\n## Dimethyl fumarate is cost effective for people with severe psoriasis\n\nThe committee considered whether dimethyl fumarate was a cost-effective use of NHS resources for people with severe psoriasis for whom treatment with biologicals or apremilast is an option. It considered that the analyses including treatment sequences of biologicals or apremilast were potentially misleading (see section\xa03.19). However, it appreciated that the cost effectiveness of dimethyl fumarate followed by best supportive care compared with best supportive care alone was comparable with the respective cost-effectiveness estimates in the previously published appraisals of the biologicals and apremilast. These drugs are currently recommended as options for treating severe chronic plaque psoriasis that has not responded to other systemic therapies, or when systemic therapy is contraindicated or not tolerated. The committee was also aware that dimethyl fumarate was less costly than biologicals and apremilast, and considered that dimethyl fumarate would likely provide sufficient savings per QALY lost compared with biologicals and apremilast. The committee appreciated that the positioning of dimethyl fumarate would be driven largely by patient choice and understood that patients value having a range of treatment options. The committee concluded that it could recommend dimethyl fumarate as an option for treating severe chronic plaque psoriasis that has not responded to other systemic therapies, including ciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet\xa0A radiation), or when these options are contraindicated or not tolerated.\n\n## Stopping rule\n\nThe committee was aware that previous NICE technology appraisals for treating psoriasis recommended stopping treatment if there was an inadequate response; an adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that if there was no response to dimethyl fumarate, the patient should not continue treatment. It noted that PASI\xa075 was the primary outcome in the trial data used to model the cost effectiveness of dimethyl fumarate. The committee therefore concluded that, for consistency with previous appraisals for treatments in psoriasis, dimethyl fumarate should be stopped if there is an inadequate response at 16\xa0weeks, with an adequate response as defined in previous NICE technology appraisals.\n\n# Other factors\n\n## Equality issues\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, the potential equality issues, that:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people, and may also miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\n## Innovation\n\nThe committee heard differing views about whether dimethyl fumarate was innovative in its potential to make a significant and substantial impact on health-related benefits. It agreed that dimethyl fumarate uses an existing mechanism of action in a new formulation, and agreed that it provided an additional oral therapy. However, the committee appreciated that some people with psoriasis prefer less frequent injectable treatments to more frequent oral ones and therefore concluded that, in this respect, there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n## Pharmaceutical Price Regulation Scheme\n\nThe Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of this technology."}
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https://www.nice.org.uk/guidance/ta475
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Evidence-based recommendations on dimethyl fumarate (Skilarence) for treating moderate to severe plaque psoriasis in adults.
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f7470cf68024a938e22175f613af76ce67e85219
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nice
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Paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer
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Paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer
Evidence-based recommendations on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel; Abraxane) for untreated metastatic pancreatic cancer in adults.
# Recommendations
Paclitaxel as albumin-bound nanoparticles (nab‑paclitaxel) with gemcitabine is recommended as an option for untreated metastatic adenocarcinoma of the pancreas in adults, only if:
-ther combination chemotherapies are unsuitable and they would otherwise have gemcitabine monotherapy and
the company provides nab‑paclitaxel with the discount agreed in the patient access scheme.
This recommendation is not intended to affect treatment with nab‑paclitaxel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
NICE reviewed its technology appraisal guidance on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel) in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA360) because the company submitted more evidence and proposed a patient access scheme that would make nab‑paclitaxel available with a confidential price discount.
Nab‑paclitaxel plus gemcitabine would normally be considered for people with metastatic adenocarcinoma of the pancreas who would otherwise have gemcitabine.
Evidence shows that nab-paclitaxel plus gemcitabine is more effective in increasing survival than gemcitabine monotherapy, but is less effective than FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) and similarly effective to gemcitabine plus capecitabine (although the results were uncertain).
Nab‑paclitaxel plus gemcitabine met NICE's end-of-life criteria when compared with gemcitabine monotherapy, but not when compared with gemcitabine plus capecitabine or FOLFIRINOX because it did not improve survival.
The most likely estimate of cost effectiveness compared with gemcitabine monotherapy is £41,000 to £46,000 per quality-adjusted life year (QALY) gained. Nab‑paclitaxel plus gemcitabine is not cost effective compared with gemcitabine plus capecitabine or FOLFIRINOX.
Nab‑paclitaxel plus gemcitabine can therefore be recommended for people with metastatic pancreatic cancer only if other combination chemotherapies are not suitable, and they would otherwise have gemcitabine monotherapy.# The technology
Paclitaxel as albumin-bound nanoparticles (nab-paclitaxel; Abraxane, Celgene)
Marketing authorisation
Paclitaxel as albumin-bound nanoparticles with gemcitabine is indicated 'for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas'.
Recommended dose and schedule
Dosage
Nab-paclitaxel: 125 mg/m2 intravenous infusion on days 1, 8 and 15 of a 28‑day cycle.
Gemcitabine: 1,000 mg/m2 intravenous infusion immediately after each nab-paclitaxel administration.
Average length of a course of treatment
Treatment should be continued until disease progression or unacceptable toxicity (median time in pivotal trial 15 weeks).
Price
The UK list price is £246.00 per 100‑mg vial.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nab-paclitaxel, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Celgene and a review of this submission by the evidence review group (ERG). It took into account the evidence and committee considerations in NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel) in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA360) and the new evidence submitted as part of this review of that guidance. See the committee papers for full details of the evidence.
# Clinical need and patient perspective
## Clinicians and patients would value additional options for pancreatic cancer
The committee understood that untreated metastatic adenocarcinoma of the pancreas is associated with a poor prognosis because many people are not diagnosed until the cancer is very advanced, and survival may be only 2 to 6 months. The patient expert explained that a diagnosis of pancreatic cancer can have a devastating effect on patients and their families. The committee recognised that extension to life is therefore very important to people with this condition and their families. The committee understood that current treatment options for pancreatic cancer have a number of limitations. In particular, FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) can be associated with serious adverse effects. Some people are unable to take FOLFIRINOX or choose not to do so, whereas gemcitabine monotherapy is better tolerated but less effective. The patient expert explained that many patients would be willing to accept some additional side effects if it resulted in longer life expectancy. The committee acknowledged that the prognosis for people with untreated metastatic pancreatic cancer is poor and that current treatments are limited in efficacy or associated with significant adverse events. It therefore recognised the value of additional treatment options in this area.
# Current practice and comparators
## FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy are potentially relevant comparators for nab-paclitaxel
The clinical experts explained that FOLFIRINOX is the preferred choice in clinical practice for untreated pancreatic cancer, because it has the most favourable survival compared with the other available treatments. The committee heard that patients for whom FOLFIRINOX is unsuitable would normally be offered gemcitabine monotherapy, which, although more tolerable, is associated with poorer overall survival than FOLFIRINOX. The clinical experts explained that there is a group of patients in clinical practice for whom FOLFIRINOX is unsuitable but who would be fit enough to tolerate a doublet therapy such as nab‑paclitaxel plus gemcitabine. The committee understood that the suitability of FOLFIRINOX could not be defined by specific criteria, and would depend on a number of factors, including age, performance status, comorbidities and patient choice. It understood that some patients for whom FOLFIRINOX is otherwise suitable would choose not to have this treatment because of its considerable toxicity. The clinical experts explained that gemcitabine plus capecitabine is rarely used in practice, but the committee was aware of evidence that showed there is some use of gemcitabine doublet chemotherapy for pancreatic cancer in the NHS in England. The committee was also aware that the NICE scope and company decision problem listed FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy as comparators, and considered that all 3 were options in the NHS for the population covered by this appraisal. The committee took into account its decision in TA360. It concluded that FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy were all potentially relevant comparators for nab‑paclitaxel plus gemcitabine.
## Gemcitabine monotherapy is the most appropriate comparator if other combination chemotherapies are unsuitable
The committee acknowledged that the company considered gemcitabine monotherapy to be the most relevant comparator, because nab‑paclitaxel plus gemcitabine would not displace FOLFIRINOX or gemcitabine plus capecitabine in clinical practice.
The company stated that FOLFIRINOX is an intensive and toxic therapy that is only suitable for a clinically defined group of patients, for whom nab‑paclitaxel would not be considered and who would continue to have this regimen despite the availability of nab‑paclitaxel. However, the committee recalled that the suitability of FOLFIRINOX could not be defined by specific criteria, and would depend on a number of factors including patient choice (see section 3.2). It therefore considered that there may be some people for whom nab‑paclitaxel plus gemcitabine is an option who would otherwise have had FOLFIRINOX.
The company also stated that gemcitabine plus capecitabine has not shown a significant survival benefit over gemcitabine monotherapy and is only used in a few UK centres. The committee heard that the clinical experts did not consider gemcitabine plus capecitabine to be an alternative to nab‑paclitaxel plus gemcitabine. However, the committee did not hear how patients who would be offered gemcitabine plus capecitabine or nab‑paclitaxel were distinct.The committee heard from the clinical experts that nab‑paclitaxel plus gemcitabine would be considered for people for whom other combination chemotherapies are unsuitable (and hence would otherwise have gemcitabine monotherapy) but who would be fit enough to tolerate nab‑paclitaxel plus gemcitabine. It recalled that such patients could be identified in clinical practice (see section 3.2). The committee concluded that although all 3 currently used treatments are potentially relevant comparators, gemcitabine monotherapy is the most appropriate comparator in people for whom other combination chemotherapies are unsuitable.
# Nab-paclitaxel compared with gemcitabine
## Nab-paclitaxel plus gemcitabine is more effective than gemcitabine monotherapy
The committee noted that study CA046 showed that nab‑paclitaxel plus gemcitabine had statistically significantly longer overall survival and progression-free survival, and higher response rates, than gemcitabine monotherapy. In the most recent data cut (May 2013), median overall survival increased by 2.1 months (the mean increase was 2.4 months) with nab‑paclitaxel plus gemcitabine compared with gemcitabine monotherapy (median overall survival: 8.7 months compared with 6.6 months; hazard ratio 0.72; 95% confidence interval 0.62 to 0.83, p<0.0001). Data from the September 2012 data cut showed that progression-free survival increased by 1.8 months with nab‑paclitaxel plus gemcitabine compared with gemcitabine monotherapy (median progression-free survival: 5.5 months compared with 3.7 months; HR 0.69; 95% CI 0.58 to 0.82, p<0.001). The committee noted that the ERG expressed concerns about the generalisability of CA046 to UK clinical practice, because older patients were under-represented. The committee was aware that the summary of product characteristics states that for patients aged 75 years and older, no benefit for nab‑paclitaxel plus gemcitabine compared with gemcitabine monotherapy has been shown, but there were more serious adverse reactions and adverse reactions that led to stopping treatment. However, the committee understood that this was based on a small subgroup. The committee understood that clinicians would be cautious about using nab‑paclitaxel plus gemcitabine in older patients, and considered that the evidence from CA046 was suitable for decision-making. The committee concluded that nab‑paclitaxel plus gemcitabine was more clinically effective than gemcitabine monotherapy.
# Nab-paclitaxel compared with gemcitabine plus capecitabine and FOLFIRINOX
## The indirect comparison is uncertain but suitable for decision-making
The company presented a mixed treatment comparison using a fixed-effects model to compare nab‑paclitaxel plus gemcitabine with FOLFIRINOX and with gemcitabine plus capecitabine. The committee noted that this model was updated from that used in TA360, including 2 more trials and focusing only on the population with metastatic pancreatic cancer (consistent with the committee's preference in TA360). It also noted that the updated results were very similar to the results of the mixed treatment comparison in TA360. It noted the ERG's comments that the validity of the results relied on the overall survival and progression-free survival hazards being proportional for all the trials included in the mixed treatment comparison, and that the ERG stated this was not true for CA046. The ERG also noted that the base-case mixed treatment comparison included a number of additional comparators, and stated that restricting the comparators to those in the decision problem would be more appropriate. The committee agreed that, taking into account the uncertainty from the proportional hazards assumption not being met, the mixed treatment comparison was preferable to having no data on which to make a decision. The committee, although recognising the uncertainty, concluded that the mixed treatment comparison could be used to compare nab‑paclitaxel plus gemcitabine with gemcitabine plus capecitabine and with FOLFIRINOX.
## Nab-paclitaxel plus gemcitabine is less effective than FOLFIRINOX and similarly effective to gemcitabine plus capecitabine
The committee noted that the results of the mixed treatment comparison showed that FOLFIRINOX improved overall survival compared with nab‑paclitaxel plus gemcitabine, although this result was not statistically significant (company base case: HR 0.77; 95% credible interval 0.58 to 1.01). It also noted that the results of the mixed treatment comparison showed there was no evidence to suggest a difference in overall survival between nab‑paclitaxel plus gemcitabine and gemcitabine plus capecitabine (company base case: HR 0.97; 95% CrI: 0.64 to 1.47). The committee concluded that nab‑paclitaxel plus gemcitabine was likely to be less clinically effective than FOLFIRINOX, and similarly effective to gemcitabine plus capecitabine.
# Adverse events
## Nab-paclitaxel plus gemcitabine may cause more adverse events than gemcitabine monotherapy or gemcitabine plus capecitabine
The company presented adverse event data from CA046 and the SIEGE trial. The committee understood that combining therapies was likely to increase the rate of adverse events, and noted that nab‑paclitaxel plus gemcitabine was associated with more adverse events than gemcitabine monotherapy, including higher rates of peripheral neuropathy, neutropenia and fatigue. It noted that the company had presented adverse event data from the mixed treatment comparison analysis in TA360, which showed that the rates of neutropenia, febrile neutropenia, fatigue, peripheral neuropathy and leukopenia were higher for people who had nab‑paclitaxel plus gemcitabine than for people who had gemcitabine plus capecitabine. It recognised that it was difficult from the data available to draw firm conclusions about the rates of adverse events between nab‑paclitaxel plus gemcitabine and gemcitabine plus capecitabine. The committee recalled its consideration in TA360 that, based on the adverse event profiles in the pivotal studies, both nab‑paclitaxel plus gemcitabine and FOLFIRINOX were associated with considerable toxicity, and that a difference in their adverse event profiles could not be reliably determined from the data available. The committee recognised that in clinical practice the dosage and administration schedules of combination therapies are modified to maintain efficacy but minimise adverse events. The clinical expert explained that the adverse effects associated with nab‑paclitaxel, although serious, were mainly manageable. The committee concluded that nab‑paclitaxel plus gemcitabine may be associated with more adverse events than gemcitabine or gemcitabine plus capecitabine.
# Cost-effectiveness evidence
## The model structure is appropriate for decision-making
The committee considered the company's model, the associated assumptions and the ERG's critique. It noted that the company had updated the model in TA360. It also noted its conclusions in TA360 that the model structure was largely appropriate. The committee therefore agreed that the structure of the company's model appropriately captured the aspects of untreated metastatic pancreatic cancer and was appropriate to use for decision-making.
# Model assumptions
## The assumptions in the economic model are generally reasonable, and the committee accepts the ERG's amendments
The committee discussed the company's assumptions for survival estimates, utilities and costs. It noted that the revised model incorporated the confidential discount for nab‑paclitaxel proposed in the company's patient access scheme. The committee heard from the company that it had aimed to keep its base case as close as possible to NICE's preferred base case from TA360. The committee noted that the company had modelled overall survival, progression-free survival and time on treatment using parametric distributions, but the ERG proposed to use the Kaplan–Meier data where available and extrapolate the 'tails' of the curves only. The committee recalled its consideration in TA360 that neither method could be considered more appropriate, but recognised that the choice of method made very little difference to the cost-effectiveness estimates.
The committee noted that the company had used utility estimates from the Romanus study (with UK adjustment) in its base-case analysis, and the company and ERG had used estimates based on EQ-5D-5L from SIEGE in scenario analyses. The committee also noted that the ERG had disputed some of the company's costing assumptions, in particular that drug costs were based on a single average body surface area for all patients (rather than a different body surface area estimate for men and women) and that not all available vial and pack sizes were included. The committee noted that the ERG amended these assumptions in its exploratory analysis, and considered this amendment reasonable. The ERG also explored the costs associated with adverse events (diarrhoea, dehydration and vomiting of grade 3 or higher) in a scenario analysis. The ERG noted that the company base-case analysis includes adverse event disutilities (decreases in utility values because of adverse events) alongside health-state utility values from a clinical trial. The ERG considered this to be double counting and therefore proposed removing the disutilities; the committee accepted this approach. The committee concluded that the assumptions in the economic model were generally reasonable, and accepted the ERG's amendments to the company's assumptions.
# Cost-effectiveness estimates
## The most plausible ICER for nab-paclitaxel plus gemcitabine compared with gemcitabine is between £41,000 and £46,000 per QALY gained
The committee noted that in the company's base case, the incremental cost-effectiveness ratio (ICER) for nab‑paclitaxel plus gemcitabine compared with gemcitabine was £46,657 per quality-adjusted life year (QALY) gained. It noted that in the ERG's preferred exploratory analysis the ICER was £41,250 per QALY gained. This analysis included the ERG's proposed changes:
to the modelling of overall survival, progression-free survival and time on treatment
to the costs, to use all available vial and pack sizes
to use different body surface areas for men and women and
to remove adverse event disutilities (see section 3.9).The committee also noted that the results of the ERG scenario analyses, which adjusted the costs of adverse events and used alternative utility values, increased the ICER to £45,571 per QALY gained. The committee was aware that the ICER remained below £50,000 per QALY gained in all of the ERG's scenarios, and almost all of the company's scenarios. Recalling that it accepted the ERG's amendments to the company's assumptions (see section 3.9), the committee it concluded that the most plausible ICER compared with gemcitabine was in the range of £41,000 to £46,000 per QALY gained.
## Nab-paclitaxel plus gemcitabine is not cost effective compared with FOLFIRINOX or gemcitabine plus capecitabine
The committee noted that the company's base case showed that nab‑paclitaxel plus gemcitabine was dominated by FOLFIRINOX (that is, nab‑paclitaxel plus gemcitabine was less effective and more costly). Nab‑paclitaxel plus gemcitabine remained dominated by FOLFIRINOX in the ERG's exploratory analysis and scenario analyses. The company's base case also showed that nab‑paclitaxel plus gemcitabine was dominated by gemcitabine plus capecitabine. The committee noted that the ERG's preferred exploratory analysis (in which the model was amended as outlined in sections 3.9 and 3.10) for nab‑paclitaxel plus gemcitabine compared with gemcitabine plus capecitabine had an ICER of £99,837 per QALY gained. This increased to £107,898 per QALY gained in the scenario analyses that adjusted the costs of adverse events and used alternative utility values. The committee recognised the uncertainty associated with these ICERs, particularly given that they were based on the results of the mixed treatment comparison. The committee concluded that although the analyses comparing nab‑paclitaxel plus gemcitabine with gemcitabine plus capecitabine and with FOLFIRINOX were subject to uncertainty, it was confident that nab‑paclitaxel plus gemcitabine would not be considered a cost-effective use of NHS resources compared with these treatments.
# End of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.
## Nab-paclitaxel plus gemcitabine meets the end-of-life criteria compared with gemcitabine monotherapy
The committee noted that the average life expectancy of people with pancreatic cancer was up to 6 months and therefore concluded that the short life expectancy criterion was met. It also noted that, compared with gemcitabine monotherapy, nab‑paclitaxel plus gemcitabine had been shown to increase overall survival by a mean of 2.4 months in CA046. The committee noted that the survival data were mature and therefore considered that the survival gain estimate was robust. It recognised that this survival gain should be considered in the context of the very poor prognosis for metastatic pancreatic cancer. The committee noted that the survival gain was below what is normally considered appropriate for the extension-to-life criterion to be met (that is, it was less than 3 months). However, it agreed that the survival gain was particularly important relative to the average survival of people with this condition, and therefore this criterion could be accepted as met in this circumstance. The committee concluded that, for the comparison with gemcitabine monotherapy, nab‑paclitaxel plus gemcitabine met the criteria to be considered a life-extending end-of-life treatment.
## Nab-paclitaxel plus gemcitabine does not meet the end-of-life criteria compared with FOLFIRINOX or gemcitabine plus capecitabine
The committee understood that both end-of-life criteria had to be met for the advice to be applied. The committee recalled that the mixed treatment comparison showed that FOLFIRINOX had a greater survival benefit than nab‑paclitaxel plus gemcitabine and there was no difference in survival between nab‑paclitaxel plus gemcitabine and gemcitabine plus capecitabine (see section 3.6). It concluded that the extension-to-life criterion had not been met for the comparison of nab‑paclitaxel plus gemcitabine with FOLFIRINOX or gemcitabine plus capecitabine, because there was no survival benefit with nab‑paclitaxel compared with these comparators. It further concluded that nab‑paclitaxel plus gemcitabine did not meet the criteria to be considered a life-extending end-of-life treatment compared with gemcitabine plus capecitabine or with FOLFIRINOX.
# Other factors
No equalities issues were identified.
The Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of nab‑paclitaxel.
The committee discussed how innovative nab‑paclitaxel plus gemcitabine is in its potential to have a significant and substantial effect on health-related benefits. It understood that nab‑paclitaxel is a novel formulation of paclitaxel and there is a high level of unmet need in terms of clinically effective treatment options for metastatic pancreatic cancer. The committee concluded that all health-related benefits had been adequately captured by the QALYs in the model.
# Conclusion
## Nab-paclitaxel is recommended when other combination chemotherapies are unsuitable
The committee recognised that, although gemcitabine and combination chemotherapies were appropriate comparators, clinicians could identify patients for whom combination chemotherapies were unsuitable (and who would otherwise have gemcitabine) but for whom nab‑paclitaxel plus gemcitabine could be considered. It is this population who would have treatment with nab‑paclitaxel plus gemcitabine in clinical practice. The committee noted that nab‑paclitaxel plus gemcitabine was more effective than gemcitabine monotherapy. Taking into account the patient access scheme, the most plausible ICER was between £41,000 and £46,000 per QALY gained. The committee considered that the end-of-life criteria were met, because the survival gain of 2.4 months was particularly important relative to the average survival of people with this condition. Therefore, nab‑paclitaxel plus gemcitabine could be considered a cost-effective use of NHS resources. Compared with combination chemotherapies (FOLFIRINOX and gemcitabine plus capecitabine), nab‑paclitaxel plus gemcitabine did not provide a survival benefit, and could not be considered cost effective. The committee therefore concluded that nab‑paclitaxel plus gemcitabine was recommended for people with adenocarcinoma of the pancreas for whom other combination chemotherapies were unsuitable and who would otherwise have gemcitabine monotherapy.
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{'Recommendations': "Paclitaxel as albumin-bound nanoparticles (nab‑paclitaxel) with gemcitabine is recommended as an option for untreated metastatic adenocarcinoma of the pancreas in adults, only if:\n\nother combination chemotherapies are unsuitable and they would otherwise have gemcitabine monotherapy and\n\nthe company provides nab‑paclitaxel with the discount agreed in the patient access scheme.\n\nThis recommendation is not intended to affect treatment with nab‑paclitaxel that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nNICE reviewed its technology appraisal guidance on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel) in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA360) because the company submitted more evidence and proposed a patient access scheme that would make nab‑paclitaxel available with a confidential price discount.\n\nNab‑paclitaxel plus gemcitabine would normally be considered for people with metastatic adenocarcinoma of the pancreas who would otherwise have gemcitabine.\n\nEvidence shows that nab-paclitaxel plus gemcitabine is more effective in increasing survival than gemcitabine monotherapy, but is less effective than FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) and similarly effective to gemcitabine plus capecitabine (although the results were uncertain).\n\nNab‑paclitaxel plus gemcitabine met NICE's end-of-life criteria when compared with gemcitabine monotherapy, but not when compared with gemcitabine plus capecitabine or FOLFIRINOX because it did not improve survival.\n\nThe most likely estimate of cost effectiveness compared with gemcitabine monotherapy is £41,000 to £46,000 per quality-adjusted life year (QALY) gained. Nab‑paclitaxel plus gemcitabine is not cost effective compared with gemcitabine plus capecitabine or FOLFIRINOX.\n\nNab‑paclitaxel plus gemcitabine can therefore be recommended for people with metastatic pancreatic cancer only if other combination chemotherapies are not suitable, and they would otherwise have gemcitabine monotherapy.", 'The technology': "Paclitaxel as albumin-bound nanoparticles (nab-paclitaxel; Abraxane, Celgene)\n\nMarketing authorisation\n\nPaclitaxel as albumin-bound nanoparticles with gemcitabine is indicated 'for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas'.\n\nRecommended dose and schedule\n\nDosage\n\nNab-paclitaxel: 125\xa0mg/m2 intravenous infusion on days\xa01, 8\xa0and\xa015 of a 28‑day cycle.\n\nGemcitabine: 1,000\xa0mg/m2 intravenous infusion immediately after each nab-paclitaxel administration.\n\nAverage length of a course of treatment\n\nTreatment should be continued until disease progression or unacceptable toxicity (median time in pivotal trial 15\xa0weeks).\n\nPrice\n\nThe UK list price is £246.00 per 100‑mg vial.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of nab-paclitaxel, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section\xa05) considered evidence submitted by Celgene and a review of this submission by the evidence review group (ERG). It took into account the evidence and committee considerations in NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel) in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA360) and the new evidence submitted as part of this review of that guidance. See the committee papers for full details of the evidence.\n\n# Clinical need and patient perspective\n\n## Clinicians and patients would value additional options for pancreatic cancer\n\nThe committee understood that untreated metastatic adenocarcinoma of the pancreas is associated with a poor prognosis because many people are not diagnosed until the cancer is very advanced, and survival may be only 2\xa0to 6\xa0months. The patient expert explained that a diagnosis of pancreatic cancer can have a devastating effect on patients and their families. The committee recognised that extension to life is therefore very important to people with this condition and their families. The committee understood that current treatment options for pancreatic cancer have a number of limitations. In particular, FOLFIRINOX (a combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) can be associated with serious adverse effects. Some people are unable to take FOLFIRINOX or choose not to do so, whereas gemcitabine monotherapy is better tolerated but less effective. The patient expert explained that many patients would be willing to accept some additional side effects if it resulted in longer life expectancy. The committee acknowledged that the prognosis for people with untreated metastatic pancreatic cancer is poor and that current treatments are limited in efficacy or associated with significant adverse events. It therefore recognised the value of additional treatment options in this area.\n\n# Current practice and comparators\n\n## FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy are potentially relevant comparators for nab-paclitaxel\n\nThe clinical experts explained that FOLFIRINOX is the preferred choice in clinical practice for untreated pancreatic cancer, because it has the most favourable survival compared with the other available treatments. The committee heard that patients for whom FOLFIRINOX is unsuitable would normally be offered gemcitabine monotherapy, which, although more tolerable, is associated with poorer overall survival than FOLFIRINOX. The clinical experts explained that there is a group of patients in clinical practice for whom FOLFIRINOX is unsuitable but who would be fit enough to tolerate a doublet therapy such as nab‑paclitaxel plus gemcitabine. The committee understood that the suitability of FOLFIRINOX could not be defined by specific criteria, and would depend on a number of factors, including age, performance status, comorbidities and patient choice. It understood that some patients for whom FOLFIRINOX is otherwise suitable would choose not to have this treatment because of its considerable toxicity. The clinical experts explained that gemcitabine plus capecitabine is rarely used in practice, but the committee was aware of evidence that showed there is some use of gemcitabine doublet chemotherapy for pancreatic cancer in the NHS in England. The committee was also aware that the NICE scope and company decision problem listed FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy as comparators, and considered that all\xa03 were options in the NHS for the population covered by this appraisal. The committee took into account its decision in TA360. It concluded that FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine monotherapy were all potentially relevant comparators for nab‑paclitaxel plus gemcitabine.\n\n## Gemcitabine monotherapy is the most appropriate comparator if other combination chemotherapies are unsuitable\n\nThe committee acknowledged that the company considered gemcitabine monotherapy to be the most relevant comparator, because nab‑paclitaxel plus gemcitabine would not displace FOLFIRINOX or gemcitabine plus capecitabine in clinical practice.\n\nThe company stated that FOLFIRINOX is an intensive and toxic therapy that is only suitable for a clinically defined group of patients, for whom nab‑paclitaxel would not be considered and who would continue to have this regimen despite the availability of nab‑paclitaxel. However, the committee recalled that the suitability of FOLFIRINOX could not be defined by specific criteria, and would depend on a number of factors including patient choice (see section\xa03.2). It therefore considered that there may be some people for whom nab‑paclitaxel plus gemcitabine is an option who would otherwise have had FOLFIRINOX.\n\nThe company also stated that gemcitabine plus capecitabine has not shown a significant survival benefit over gemcitabine monotherapy and is only used in a few UK centres. The committee heard that the clinical experts did not consider gemcitabine plus capecitabine to be an alternative to nab‑paclitaxel plus gemcitabine. However, the committee did not hear how patients who would be offered gemcitabine plus capecitabine or nab‑paclitaxel were distinct.The committee heard from the clinical experts that nab‑paclitaxel plus gemcitabine would be considered for people for whom other combination chemotherapies are unsuitable (and hence would otherwise have gemcitabine monotherapy) but who would be fit enough to tolerate nab‑paclitaxel plus gemcitabine. It recalled that such patients could be identified in clinical practice (see section\xa03.2). The committee concluded that although all\xa03 currently used treatments are potentially relevant comparators, gemcitabine monotherapy is the most appropriate comparator in people for whom other combination chemotherapies are unsuitable.\n\n# Nab-paclitaxel compared with gemcitabine\n\n## Nab-paclitaxel plus gemcitabine is more effective than gemcitabine monotherapy\n\nThe committee noted that study CA046 showed that nab‑paclitaxel plus gemcitabine had statistically significantly longer overall survival and progression-free survival, and higher response rates, than gemcitabine monotherapy. In the most recent data cut (May 2013), median overall survival increased by 2.1\xa0months (the mean increase was 2.4\xa0months) with nab‑paclitaxel plus gemcitabine compared with gemcitabine monotherapy (median overall survival: 8.7\xa0months compared with 6.6\xa0months; hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.62 to 0.83, p<0.0001). Data from the September 2012 data cut showed that progression-free survival increased by 1.8\xa0months with nab‑paclitaxel plus gemcitabine compared with gemcitabine monotherapy (median progression-free survival: 5.5\xa0months compared with 3.7\xa0months; HR 0.69; 95% CI 0.58 to 0.82, p<0.001). The committee noted that the ERG expressed concerns about the generalisability of CA046 to UK clinical practice, because older patients were under-represented. The committee was aware that the summary of product characteristics states that for patients aged 75\xa0years and older, no benefit for nab‑paclitaxel plus gemcitabine compared with gemcitabine monotherapy has been shown, but there were more serious adverse reactions and adverse reactions that led to stopping treatment. However, the committee understood that this was based on a small subgroup. The committee understood that clinicians would be cautious about using nab‑paclitaxel plus gemcitabine in older patients, and considered that the evidence from CA046 was suitable for decision-making. The committee concluded that nab‑paclitaxel plus gemcitabine was more clinically effective than gemcitabine monotherapy.\n\n# Nab-paclitaxel compared with gemcitabine plus capecitabine and FOLFIRINOX\n\n## The indirect comparison is uncertain but suitable for decision-making\n\nThe company presented a mixed treatment comparison using a fixed-effects model to compare nab‑paclitaxel plus gemcitabine with FOLFIRINOX and with gemcitabine plus capecitabine. The committee noted that this model was updated from that used in TA360, including 2\xa0more trials and focusing only on the population with metastatic pancreatic cancer (consistent with the committee's preference in TA360). It also noted that the updated results were very similar to the results of the mixed treatment comparison in TA360. It noted the ERG's comments that the validity of the results relied on the overall survival and progression-free survival hazards being proportional for all the trials included in the mixed treatment comparison, and that the ERG stated this was not true for CA046. The ERG also noted that the base-case mixed treatment comparison included a number of additional comparators, and stated that restricting the comparators to those in the decision problem would be more appropriate. The committee agreed that, taking into account the uncertainty from the proportional hazards assumption not being met, the mixed treatment comparison was preferable to having no data on which to make a decision. The committee, although recognising the uncertainty, concluded that the mixed treatment comparison could be used to compare nab‑paclitaxel plus gemcitabine with gemcitabine plus capecitabine and with FOLFIRINOX.\n\n## Nab-paclitaxel plus gemcitabine is less effective than FOLFIRINOX and similarly effective to gemcitabine plus capecitabine\n\nThe committee noted that the results of the mixed treatment comparison showed that FOLFIRINOX improved overall survival compared with nab‑paclitaxel plus gemcitabine, although this result was not statistically significant (company base case: HR 0.77; 95% credible interval [CrI] 0.58 to 1.01). It also noted that the results of the mixed treatment comparison showed there was no evidence to suggest a difference in overall survival between nab‑paclitaxel plus gemcitabine and gemcitabine plus capecitabine (company base case: HR 0.97; 95% CrI: 0.64 to 1.47). The committee concluded that nab‑paclitaxel plus gemcitabine was likely to be less clinically effective than FOLFIRINOX, and similarly effective to gemcitabine plus capecitabine.\n\n# Adverse events\n\n## Nab-paclitaxel plus gemcitabine may cause more adverse events than gemcitabine monotherapy or gemcitabine plus capecitabine\n\nThe company presented adverse event data from CA046 and the SIEGE trial. The committee understood that combining therapies was likely to increase the rate of adverse events, and noted that nab‑paclitaxel plus gemcitabine was associated with more adverse events than gemcitabine monotherapy, including higher rates of peripheral neuropathy, neutropenia and fatigue. It noted that the company had presented adverse event data from the mixed treatment comparison analysis in TA360, which showed that the rates of neutropenia, febrile neutropenia, fatigue, peripheral neuropathy and leukopenia were higher for people who had nab‑paclitaxel plus gemcitabine than for people who had gemcitabine plus capecitabine. It recognised that it was difficult from the data available to draw firm conclusions about the rates of adverse events between nab‑paclitaxel plus gemcitabine and gemcitabine plus capecitabine. The committee recalled its consideration in TA360 that, based on the adverse event profiles in the pivotal studies, both nab‑paclitaxel plus gemcitabine and FOLFIRINOX were associated with considerable toxicity, and that a difference in their adverse event profiles could not be reliably determined from the data available. The committee recognised that in clinical practice the dosage and administration schedules of combination therapies are modified to maintain efficacy but minimise adverse events. The clinical expert explained that the adverse effects associated with nab‑paclitaxel, although serious, were mainly manageable. The committee concluded that nab‑paclitaxel plus gemcitabine may be associated with more adverse events than gemcitabine or gemcitabine plus capecitabine.\n\n# Cost-effectiveness evidence\n\n## The model structure is appropriate for decision-making\n\nThe committee considered the company's model, the associated assumptions and the ERG's critique. It noted that the company had updated the model in TA360. It also noted its conclusions in TA360 that the model structure was largely appropriate. The committee therefore agreed that the structure of the company's model appropriately captured the aspects of untreated metastatic pancreatic cancer and was appropriate to use for decision-making.\n\n# Model assumptions\n\n## The assumptions in the economic model are generally reasonable, and the committee accepts the ERG's amendments\n\nThe committee discussed the company's assumptions for survival estimates, utilities and costs. It noted that the revised model incorporated the confidential discount for nab‑paclitaxel proposed in the company's patient access scheme. The committee heard from the company that it had aimed to keep its base case as close as possible to NICE's preferred base case from TA360. The committee noted that the company had modelled overall survival, progression-free survival and time on treatment using parametric distributions, but the ERG proposed to use the Kaplan–Meier data where available and extrapolate the 'tails' of the curves only. The committee recalled its consideration in TA360 that neither method could be considered more appropriate, but recognised that the choice of method made very little difference to the cost-effectiveness estimates.\n\nThe committee noted that the company had used utility estimates from the Romanus study (with UK adjustment) in its base-case analysis, and the company and ERG had used estimates based on EQ-5D-5L from SIEGE in scenario analyses. The committee also noted that the ERG had disputed some of the company's costing assumptions, in particular that drug costs were based on a single average body surface area for all patients (rather than a different body surface area estimate for men and women) and that not all available vial and pack sizes were included. The committee noted that the ERG amended these assumptions in its exploratory analysis, and considered this amendment reasonable. The ERG also explored the costs associated with adverse events (diarrhoea, dehydration and vomiting of grade\xa03 or higher) in a scenario analysis. The ERG noted that the company base-case analysis includes adverse event disutilities (decreases in utility values because of adverse events) alongside health-state utility values from a clinical trial. The ERG considered this to be double counting and therefore proposed removing the disutilities; the committee accepted this approach. The committee concluded that the assumptions in the economic model were generally reasonable, and accepted the ERG's amendments to the company's assumptions.\n\n# Cost-effectiveness estimates\n\n## The most plausible ICER for nab-paclitaxel plus gemcitabine compared with gemcitabine is between £41,000 and £46,000 per QALY gained\n\nThe committee noted that in the company's base case, the incremental cost-effectiveness ratio (ICER) for nab‑paclitaxel plus gemcitabine compared with gemcitabine was £46,657 per quality-adjusted life year (QALY) gained. It noted that in the ERG's preferred exploratory analysis the ICER was £41,250 per QALY gained. This analysis included the ERG's proposed changes:\n\nto the modelling of overall survival, progression-free survival and time on treatment\n\nto the costs, to use all available vial and pack sizes\n\nto use different body surface areas for men and women and\n\nto remove adverse event disutilities (see section\xa03.9).The committee also noted that the results of the ERG scenario analyses, which adjusted the costs of adverse events and used alternative utility values, increased the ICER to £45,571 per QALY gained. The committee was aware that the ICER remained below £50,000 per QALY gained in all of the ERG's scenarios, and almost all of the company's scenarios. Recalling that it accepted the ERG's amendments to the company's assumptions (see section\xa03.9), the committee it concluded that the most plausible ICER compared with gemcitabine was in the range of £41,000 to £46,000 per QALY gained.\n\n## Nab-paclitaxel plus gemcitabine is not cost effective compared with FOLFIRINOX or gemcitabine plus capecitabine\n\nThe committee noted that the company's base case showed that nab‑paclitaxel plus gemcitabine was dominated by FOLFIRINOX (that is, nab‑paclitaxel plus gemcitabine was less effective and more costly). Nab‑paclitaxel plus gemcitabine remained dominated by FOLFIRINOX in the ERG's exploratory analysis and scenario analyses. The company's base case also showed that nab‑paclitaxel plus gemcitabine was dominated by gemcitabine plus capecitabine. The committee noted that the ERG's preferred exploratory analysis (in which the model was amended as outlined in sections\xa03.9 and 3.10) for nab‑paclitaxel plus gemcitabine compared with gemcitabine plus capecitabine had an ICER of £99,837 per QALY gained. This increased to £107,898 per QALY gained in the scenario analyses that adjusted the costs of adverse events and used alternative utility values. The committee recognised the uncertainty associated with these ICERs, particularly given that they were based on the results of the mixed treatment comparison. The committee concluded that although the analyses comparing nab‑paclitaxel plus gemcitabine with gemcitabine plus capecitabine and with FOLFIRINOX were subject to uncertainty, it was confident that nab‑paclitaxel plus gemcitabine would not be considered a cost-effective use of NHS resources compared with these treatments.\n\n# End of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's Cancer Drugs Fund technology appraisal process and methods.\n\n## Nab-paclitaxel plus gemcitabine meets the end-of-life criteria compared with gemcitabine monotherapy\n\nThe committee noted that the average life expectancy of people with pancreatic cancer was up to 6\xa0months and therefore concluded that the short life expectancy criterion was met. It also noted that, compared with gemcitabine monotherapy, nab‑paclitaxel plus gemcitabine had been shown to increase overall survival by a mean of\xa02.4 months in CA046. The committee noted that the survival data were mature and therefore considered that the survival gain estimate was robust. It recognised that this survival gain should be considered in the context of the very poor prognosis for metastatic pancreatic cancer. The committee noted that the survival gain was below what is normally considered appropriate for the extension-to-life criterion to be met (that is, it was less than 3\xa0months). However, it agreed that the survival gain was particularly important relative to the average survival of people with this condition, and therefore this criterion could be accepted as met in this circumstance. The committee concluded that, for the comparison with gemcitabine monotherapy, nab‑paclitaxel plus gemcitabine met the criteria to be considered a life-extending end-of-life treatment.\n\n## Nab-paclitaxel plus gemcitabine does not meet the end-of-life criteria compared with FOLFIRINOX or gemcitabine plus capecitabine\n\nThe committee understood that both end-of-life criteria had to be met for the advice to be applied. The committee recalled that the mixed treatment comparison showed that FOLFIRINOX had a greater survival benefit than nab‑paclitaxel plus gemcitabine and there was no difference in survival between nab‑paclitaxel plus gemcitabine and gemcitabine plus capecitabine (see section\xa03.6). It concluded that the extension-to-life criterion had not been met for the comparison of nab‑paclitaxel plus gemcitabine with FOLFIRINOX or gemcitabine plus capecitabine, because there was no survival benefit with nab‑paclitaxel compared with these comparators. It further concluded that nab‑paclitaxel plus gemcitabine did not meet the criteria to be considered a life-extending end-of-life treatment compared with gemcitabine plus capecitabine or with FOLFIRINOX.\n\n# Other factors\n\nNo equalities issues were identified.\n\nThe Pharmaceutical Price Regulation Scheme (2014) payment mechanism was not relevant in considering the cost effectiveness of nab‑paclitaxel.\n\nThe committee discussed how innovative nab‑paclitaxel plus gemcitabine is in its potential to have a significant and substantial effect on health-related benefits. It understood that nab‑paclitaxel is a novel formulation of paclitaxel and there is a high level of unmet need in terms of clinically effective treatment options for metastatic pancreatic cancer. The committee concluded that all health-related benefits had been adequately captured by the QALYs in the model.\n\n# Conclusion\n\n## Nab-paclitaxel is recommended when other combination chemotherapies are unsuitable\n\nThe committee recognised that, although gemcitabine and combination chemotherapies were appropriate comparators, clinicians could identify patients for whom combination chemotherapies were unsuitable (and who would otherwise have gemcitabine) but for whom nab‑paclitaxel plus gemcitabine could be considered. It is this population who would have treatment with nab‑paclitaxel plus gemcitabine in clinical practice. The committee noted that nab‑paclitaxel plus gemcitabine was more effective than gemcitabine monotherapy. Taking into account the patient access scheme, the most plausible ICER was between £41,000 and £46,000 per QALY gained. The committee considered that the end-of-life criteria were met, because the survival gain of 2.4\xa0months was particularly important relative to the average survival of people with this condition. Therefore, nab‑paclitaxel plus gemcitabine could be considered a cost-effective use of NHS resources. Compared with combination chemotherapies (FOLFIRINOX and gemcitabine plus capecitabine), nab‑paclitaxel plus gemcitabine did not provide a survival benefit, and could not be considered cost effective. The committee therefore concluded that nab‑paclitaxel plus gemcitabine was recommended for people with adenocarcinoma of the pancreas for whom other combination chemotherapies were unsuitable and who would otherwise have gemcitabine monotherapy."}
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https://www.nice.org.uk/guidance/ta476
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Evidence-based recommendations on paclitaxel as albumin-bound nanoparticles (nab-paclitaxel; Abraxane) for untreated metastatic pancreatic cancer in adults.
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72a3a887ae26a580a738d5fce7a4457f1adca9d0
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nice
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Psoriasis: assessment and management
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Psoriasis: assessment and management
This guideline covers assessing and managing psoriasis in adults, young people and children. It aims to improve long-term disease control and quality of life for people with psoriasis.
# Introduction
Psoriasis is an inflammatory skin disease that typically follows a relapsing and remitting course. The prevalence of psoriasis is estimated to be around 1.3% to 2.2% in the UK. Psoriasis can occur at any age, although is uncommon in children (0.71%) and most cases occur before 35 years. Psoriasis is associated with joint disease in a significant proportion of patients (reported in 1 study at 13.8%).
Plaque psoriasis is characterised by well-delineated red, scaly plaques that vary in extent from a few patches to generalised involvement. It is by far the most common form of the condition (about 90% of people with psoriasis). Other types of psoriasis include guttate psoriasis and pustular (localised or generalised) forms. Distinctive nail changes occur in around 50% of all those affected and are more common in people with psoriatic arthritis.
Healthcare professionals and patients using the term psoriasis are usually referring to plaque psoriasis, and unless stipulated otherwise, 'psoriasis' is used in this way in the guideline. The phrase 'difficult-to-treat sites' encompasses the face, flexures, genitalia, scalp, palms and soles and are so-called because psoriasis at these sites may have especially high impact, may result in functional impairment, requires particular care when prescribing topical therapy and can be resistant to treatment.
Psoriasis for many people results in profound functional, psychological, and social morbidity, with consequent reduced levels of employment and income. Factors that contribute to this include symptoms related to the skin (for example, chronic itch, bleeding, scaling and nail involvement), problems related to treatments, psoriatic arthritis, and the effect of living with a highly visible, stigmatising skin disease. Even people with minimal involvement state that psoriasis has a major effect on their life. Several studies have also reported that people with psoriasis, particularly those with severe disease, may be at increased risk of cardiovascular disease, lymphoma and non-melanoma skin cancer.
A wide variety of treatment options are available. Some are expensive and some are accessed only in specialist care; all require monitoring. The treatment pathway in this guideline begins with active topical therapies. The guideline development group (GDG) acknowledged that the use of emollients in psoriasis was already widespread and hence the evidence review was limited to active topical therapies for psoriasis. See the BNF and BNF for children for guidance on use of emollients.
In this guideline, first-line therapy describes traditional topical therapies (such as corticosteroids, vitamin D and vitamin D analogues, dithranol and tar preparations). Second-line therapy includes the phototherapies (broad- or narrowband ultraviolet B light and psoralen plus UVA light ) and systemic non-biological agents such as ciclosporin, methotrexate and acitretin. Third-line therapy refers to systemic biological therapies such as the tumour necrosis factor antagonists adalimumab, etanercept and infliximab, and the monoclonal antibody ustekinumab that targets interleukin‑12 (IL‑12) and IL-23. NICE has published technology appraisals on the use of biological drugs, and this guideline incorporates recommendations from these appraisals where relevant (listed in alphabetical order). Biologic treatment is complicated by a poor response in a minority of people, and this guideline reviewed the literature for the use of a second biological drug.
For most people, psoriasis is managed in primary care, with specialist referral being needed at some point for up to 60% of people. Supra-specialist (level 4) tertiary care is required in the very small minority with especially complex, treatment resistant and/or rare manifestations of psoriasis. Level 4 care is defined as usually taking place entirely within an acute hospital and is carried out by consultant dermatologists and a range of other healthcare professionals with specialist skills in managing complex and/or rare skin disorders – see Quality Standards for Dermatology: providing the right care for people with skin conditions.
A recent UK audit in the adult population demonstrated wide variations in practice, and in particular, access to specialist treatments (including biological therapy), appropriate drug monitoring, specialist nurse support and psychological services (Eedy et al. 2009).
This guideline covers people of all ages and aims to provide clear recommendations on the management of all types of psoriasis. The term 'people' is used to encompass all ages. 'Children' refers to those up to 12 years, who become 'young people' thereafter, before merging with the adult population by 18 years of age. The GDG have focused on areas most likely to improve the management and delivery of care for most people affected, where practice is very varied and/or where clear consensus or guidelines on treatments are lacking. It is hoped that this guideline will facilitate the delivery of high-quality healthcare and improved outcomes for people with psoriasis.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Principles of care
Offer people with any type of psoriasis (and their families or carers), support and information tailored to suit their individual needs and circumstances, in a range of different formats so they can confidently understand:
their diagnosis and treatment options
relevant lifestyle risk factors
when and how to treat their condition
how to use prescribed treatments safely and effectively (for example, how to apply topical treatments, how to minimise the risk of side effects through monitoring for safety of medicines)
when and how to seek further general or specialist review
strategies to deal with the impact on their physical, psychological and social wellbeing.Also see the NICE guidelines on behaviour change: individual approaches and behaviour change: general approaches.
When offering treatments to a person with any type of psoriasis:
ensure the treatment strategy is developed to meet the person's health goals so that the impact of their condition is minimised and use relevant assessment tools to ensure these goals are met
take into account the age and individual circumstances of the person, disease phenotype, severity and impact, coexisting psoriatic arthritis, comorbidities and previous treatment history
discuss the risks and benefits of treatment options with the person (and their families or carers where appropriate); where possible, use absolute risk and natural frequency (also see the appendix for details of the risk-benefit profiles of interventions recommended in this guideline)
discuss the importance of adherence to treatment for optimising outcomes.For more information, see the NICE guidelines on medicines adherence and medicines optimisation.
Assess whether support and information need updating or revising at every review or interaction with the person, in particular:
during transition from children's services to adult services
when new interventions become available
when the person's disease severity or circumstances (for example, in terms of comorbidities or lifestyle) change.See also the NICE guideline on transition from children's to adults' services for young people using health or social care services.
Provide a single point of contact to help people with all types of psoriasis (and their families or carers where appropriate) access appropriate information and advice about their condition and the services available at each stage of the care pathway.
NICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services.
# Assessment and referral
Severe or atypical psoriasis is an HIV indicator condition as described in HIV in Europe's HIV indicator conditions. Also see recommendations 1.1.5 and 1.1.8 in the NICE guideline on HIV testing.
## Assessment tools for disease severity and impact and when to refer for specialist care
For people with any type of psoriasis assess:
disease severity
the impact of disease on physical, psychological and social wellbeing
whether they have psoriatic arthritis
the presence of comorbidities.
Assess the severity and impact of any type of psoriasis:
at first presentation
before referral for specialist advice and at each referral point in the treatment pathway
to evaluate the efficacy of interventions.
When assessing the disease severity in any healthcare setting, record:
the results of a static physician's global assessment (classified as clear, nearly clear, mild, moderate, severe or very severe)
the patient's assessment of current disease severity, for example, using the static patient's global assessment (classified as clear, nearly clear, mild, moderate, severe or very severe)
the body surface area affected
any involvement of nails, high-impact and difficult-to-treat sites (for example, the face, scalp, palms, soles, flexures and genitals)
any systemic upset such as fever and malaise, which are common in unstable forms of psoriasis such as erythroderma or generalised pustular psoriasis.
In specialist settings, use a validated tool to assess severity of psoriasis, for example, the Psoriasis Area and Severity Index (PASI; in addition to the assessments indicated in recommendation 1.2.1.3).
Be aware that:
PASI and body surface area are not validated for use in children and young people
erythema may be underestimated in people with darker skin types, such as skin types 5 and 6 on the Fitzpatrick scale.
Use the Nail Psoriasis Severity Index to assess nail disease in specialist settings:
if there is a major functional or cosmetic impact or
before and after treatment is initiated specifically for nail disease.
Assess the impact of any type of psoriasis on physical, psychological and social wellbeing by asking:
what aspects of their daily living are affected by the person's psoriasis
how the person is coping with their skin condition and any treatments they are using
if they need further advice or support
if their psoriasis has an impact on their mood
if their psoriasis causes them distress (be aware the patient may have levels of distress and not be clinically depressed)
if their condition has any impact on their family or carers. Ask children and young people age-appropriate questions.
In specialist settings, and if practical in non-specialist settings, use a validated tool to assess the impact of any type of psoriasis on physical, psychological and social wellbeing, for example, the:
Dermatology Life Quality Index (DLQI; see also recommendation 1.5.3.3) for adults or
Children's Dermatology Life Quality Index (CDLQI) for children and young people.
When using an assessment tool for a person with any type of psoriasis:
take account of their age, any disabilities (such as physical, visual or cognitive impairment), and any language or other communication difficulties, and provide help and support if needed (see Dermatology Life Quality Index)
ensure that the chosen assessment tool continues to be a sufficiently accurate measure.
Following assessment in a non-specialist setting, refer people for dermatology specialist advice if:
there is diagnostic uncertainty or
any type of psoriasis is severe or extensive, for example, more than 10% of the body surface area is affected or
any type of psoriasis cannot be controlled with topical therapy or
acute guttate psoriasis requires phototherapy (see recommendation 1.4.1.1) or
nail disease has a major functional or cosmetic impact or
any type of psoriasis is having a major impact on a person's physical, psychological or social wellbeing.
People with generalised pustular psoriasis or erythroderma should be referred immediately for same-day specialist assessment and treatment.
Refer children and young people with any type of psoriasis to a specialist at presentation.
## Assessment and referral for psoriatic arthritis
Offer annual assessment for psoriatic arthritis to people with any type of psoriasis. Assessment is especially important within the first 10 years of onset of psoriasis.
Use a validated tool to assess adults for psoriatic arthritis in primary care and specialist settings, for example, the Psoriasis Epidemiological Screening Tool (PEST). Be aware that the PEST does not detect axial arthritis or inflammatory back pain.
As soon as psoriatic arthritis is suspected, refer the person to a rheumatologist for assessment and advice about planning their care. Also see the NICE guideline on spondyloarthritis in over 16s.
## Identification of comorbidities
Offer adults with severe psoriasis of any type (defined as either needing treatment with phototherapy or systemic agents, or needing hospital admission in the studies underpinning this recommendation), a cardiovascular risk assessment at presentation using a validated risk estimation tool. Offer further assessment of cardiovascular risk every 5 years, or more frequently if indicated following assessment. For further information, see the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.
Discuss risk factors for cardiovascular comorbidities with people who have any type of psoriasis (and their families or carers where appropriate). Where appropriate offer preventative advice, healthy lifestyle information and support for behavioural change tailored to meet the needs of the individual in line with the following NICE guidance:
Cardiovascular disease: risk assessment and reduction, including lipid modification
Obesity prevention
Type 2 diabetes prevention: population and community-level interventions
Cardiovascular disease prevention
Alcohol-use disorders: prevention
Stop smoking interventions and services
Physical activity: brief advice for adults in primary care
Physical activity in the workplace
Physical activity for children and young people.
For people with multiple comorbidities and/or multimorbidities and any type of psoriasis needing second- or third-line therapy, ensure multidisciplinary working and communication between specialties and, if needed, interdisciplinary team working (for example, when both skin and joints are significantly affected).
Be aware that psoriasis of any type, especially if severe (identified by hospitalisations for psoriasis or psoriatic arthritis) is a risk factor for venous thromboembolism in adults, and:
explain this risk to adults with any type of psoriasis
-ffer advice on how to minimise the risk (for example, during hospital admission, surgery, or periods of immobility)
manage the risk in line with the NICE guideline on venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.
Assess whether people with any type of psoriasis are depressed when assessing disease severity and impact, and when escalating therapy. If appropriate offer information, advice and support in line with the NICE guidelines on depression in adults with a chronic physical health problem and depression in children and young people.
# Topical therapy
The treatment pathway in this guideline begins with active topical therapies. The guideline development group acknowledged that the use of emollients in psoriasis was already widespread and hence the evidence review was limited to active topical therapies for psoriasis. Refer to the BNF and BNF for children for guidance on use of emollients.
## General recommendations
Offer people with psoriasis topical therapy as first-line treatment.
Offer second- or third-line treatment options (phototherapy or systemic therapy) at the same time when topical therapy alone is unlikely to adequately control psoriasis, such as:
extensive disease (for example, more than 10% of body surface area affected) or
at least 'moderate' on the static Physician's Global Assessment or
where topical therapy is ineffective, such as nail disease. See also recommendations 1.2.1.9; 1.4.1.1; 1.5.2.1; 1.5.3.4; 1.5.3.6; 1.5.3.8 and 1.5.3.10.
Offer practical support and advice about the use and application of topical treatments. Advice should be provided by healthcare professionals who are trained and competent in the use of topical therapies. Support people to adhere to treatment in line with the NICE guideline on medicines adherence. Also see the NICE guideline on medicines optimisation.
When offering topical agents:
take into account patient preference, cosmetic acceptability, practical aspects of application and the site(s) and extent of psoriasis to be treated
discuss the variety of formulations available and, depending on the person's preference, use:
cream, lotion or gel for widespread psoriasis
lotion, solution or gel for the scalp or hair-bearing areas
-intment to treat areas with thick adherent scale
be aware that topical treatment alone may not provide satisfactory disease control, especially in people with psoriasis that is extensive (for example, more than 10% of body surface area affected) or at least 'moderate' on the static Physician's Global Assessment.
If a person of any age with psoriasis requiring topical therapy has a physical disability, or cognitive or visual impairment offer advice and practical support that take into account the person's individual needs.
Arrange a review appointment 4 weeks after starting a new topical treatment in adults, and 2 weeks after starting a new topical treatment in children, to:
evaluate tolerability, toxicity, and initial response to treatment (including measures of severity and impact described in recommendations 1.2.1.3, 1.2.1.6 and 1.2.1.7)
reinforce the importance of adherence when appropriate
reinforce the importance of a 4 week break between courses of potent/very potent corticosteroids (see recommendation 1.3.1.10). If there is little or no improvement at this review, discuss the next treatment option with the person.
Discuss with people whose psoriasis is responding to topical treatment (and their families or carers where appropriate):
the importance of continuing treatment until a satisfactory outcome is achieved (for example, clear or nearly clear) or up to the recommended maximum treatment period for corticosteroids (see the sections on topical treatment of psoriasis affecting the trunk and limbs, scalp and face, flexures and genitals)
that relapse occurs in most people after treatment is stopped
that after the initial treatment period topical treatments can be used when needed to maintain satisfactory disease control.
Offer people with psoriasis a supply of their topical treatment to keep at home for the self-management of their condition.
In people whose psoriasis has not responded satisfactorily to a topical treatment strategy, before changing to an alternative treatment:
discuss with the person whether they have any difficulties with application, cosmetic acceptability or tolerability and where relevant offer an alternative formulation
consider other possible reasons for non-adherence in line with the NICE guideline on medicines adherence.
Also see the NICE guideline on medicines optimisation.
Also see recommendations 1.3.4.2 and 1.3.4.4 for details on safe use of steroids at facial, flexural and genital sites.
Be aware that continuous use of potent or very potent corticosteroids may cause:
irreversible skin atrophy and striae
psoriasis to become unstable
systemic side effects when applied continuously to extensive psoriasis (for example, more than 10% of body surface area affected). Explain the risks of these side effects to people undergoing treatment (and their families or carers where appropriate) and discuss how to avoid them.
Aim for a break of 4 weeks between courses of treatment with potent or very potent corticosteroids. Consider topical treatments that are not steroid based (such as vitamin D or vitamin D analogues or coal tar) as needed to maintain psoriasis disease control during this period.
When offering a corticosteroid for topical treatment select the potency and formulation based on the person's need.
Do not use very potent corticosteroids continuously at any site for longer than 4 weeks.
Do not use potent corticosteroids continuously at any site for longer than 8 weeks.
Do not use very potent corticosteroids in children and young people.
Offer a review at least annually to adults with psoriasis who are using intermittent or short-term courses of a potent or very potent corticosteroid (either as monotherapy or in combined preparations) to assess for the presence of steroid atrophy and other adverse effects. Also see recommendations 1.3.1.12 and 1.3.1.13 for details on safe duration of steroid use.
Offer a review at least annually to children and young people with psoriasis who are using corticosteroids of any potency (either as monotherapy or in combined preparations) to assess for the presence of steroid atrophy and other adverse effects.
## Topical treatment of psoriasis affecting the trunk and limbs
Offer a potent corticosteroid applied once daily plus vitamin D or a vitamin D analogue applied once daily (applied separately, 1 in the morning and the other in the evening) for up to 4 weeks as initial treatment for adults with trunk or limb psoriasis.
If once-daily application of a potent corticosteroid plus once-daily application of vitamin D or a vitamin D analogue does not result in clearance, near clearance or satisfactory control of trunk or limb psoriasis in adults after a maximum of 8 weeks, offer vitamin D or a vitamin D analogue alone applied twice daily. Also see recommendation 1.3.1.8 for additional considerations before changing to the next treatment option.
If twice-daily application of vitamin D or a vitamin D analogue does not result in clearance, near clearance or satisfactory control of trunk or limb psoriasis in adults after 8 to 12 weeks, offer either:
a potent corticosteroid applied twice daily for up to 4 weeks or
a coal tar preparation applied once or twice daily.Also see recommendation 1.3.1.8 for additional considerations before changing to the next treatment option.
If a twice-daily potent corticosteroid or coal tar preparation cannot be used or a once-daily preparation would improve adherence in adults offer a combined product containing calcipotriol monohydrate and betamethasone dipropionate applied once daily for up to 4 weeks.
Offer treatment with very potent corticosteroids in adults with trunk or limb psoriasis only:
in specialist settings under careful supervision
when other topical treatment strategies have failed
for a maximum period of 4 weeks.
Consider short-contact dithranol for treatment-resistant psoriasis of the trunk or limbs and either:
give educational support for self-use or
ensure treatment is given in a specialist setting.
For children and young people with trunk or limb psoriasis consider either:
calcipotriol applied once daily (only for those over 6 years of age) or
a potent corticosteroid applied once daily (only for those over 1 year of age).In August 2017, there were different topical calcipotriol preparations available in the UK, which vary in their licensing status for use in children and young people under 18. Additionally, potent topical corticosteroid preparations available in the UK vary in the age from which they are licensed for use in children. Please refer to the BNF for children for information on appropriate dosing and duration of treatment. Refer to the summary of product characteristics for specific information on individual topical calcipotriol and corticosteroid preparations. See also NICE's information on prescribing medicines.
## Topical treatment of psoriasis affecting the scalp
In children and young people, the specified duration of therapy in recommendations 1.3.3.1, 1.3.3.3, 1.3.3.4 and 1.3.3.5 may not be appropriate. Please refer to the BNF for children for information on appropriate dosing and duration of treatment.
In August 2017, there were several potent topical corticosteroid preparations available in the UK, and the age from which they are licensed for use in children varies. Refer to the summary of product characteristics for information on individual potent topical corticosteroid preparations. See also NICE's information on prescribing medicines.
Offer a potent corticosteroid applied once daily for up to 4 weeks as initial treatment for people with scalp psoriasis.
Show people with scalp psoriasis (and their families or carers where appropriate) how to safely apply corticosteroid topical treatment.
If treatment with a potent corticosteroid does not result in clearance, near clearance or satisfactory control of scalp psoriasis after 4 weeks consider:
a different formulation of the potent corticosteroid (for example, a shampoo or mousse) and/or
topical agents to remove adherent scale (for example, agents containing salicylic acid, emollients and oils) before application of the potent corticosteroid.
If the response to treatment with a potent corticosteroid for scalp psoriasis remains unsatisfactory after a further 4 weeks of treatment (also see recommendation 1.3.1.8 for additional considerations before changing to the next treatment option), offer:
a combined product containing calcipotriol monohydrate and betamethasone dipropionate applied once daily for up to 4 weeks or
vitamin D or a vitamin D analogue applied once daily (only in those who cannot use steroids and with mild to moderate scalp psoriasis).In October 2012, the combined product containing calcipotriol monohydrate and betamethasone dipropionate did not have a UK marketing authorisation for this indication in children and young people.In August 2017, topical calcitriol and tacalcitol preparations available in the UK were not licensed for use in children. Topical calcipotriol preparations available in the UK vary in their licensing status for use in children and young people under 18. Refer to the summary of product characteristics for specific information on individual topical calcipotriol preparations. See NICE's information on prescribing medicines.
If continuous treatment with either a combined product containing calcipotriol monohydrate and betamethasone dipropionate applied once daily or vitamin D or a vitamin D analogue applied once daily for up to 8 weeks does not result in clearance, near clearance or satisfactory control of scalp psoriasis offer:
a very potent corticosteroid applied up to twice daily for 2 weeks for adults only or
coal tar applied once or twice daily or
referral to a specialist for additional support with topical applications and/or advice on other treatment options.In October 2012, the combined product containing calcipotriol monohydrate and betamethasone dipropionate did not have a UK marketing authorisation for this indication in children and young people. See NICE's information on prescribing medicines.
Consider topical vitamin D or a vitamin D analogue alone for the treatment of scalp psoriasis only in people who:
are intolerant of or cannot use topical corticosteroids at this site or
have mild to moderate scalp psoriasis.Refer to the BNF for children for information on appropriate dosing and duration of treatment.In August 2017, topical calcitriol and tacalcitol preparations available in the UK were not licensed for use in children. Topical calcipotriol preparations available in the UK vary in their licensing status for use in children and young people under 18. Refer to the summary of product characteristics for specific information on individual topical calcipotriol preparations. See NICE's information on prescribing medicines.
Do not offer coal tar-based shampoos alone for the treatment of severe scalp psoriasis.
## Topical treatment of psoriasis affecting the face, flexures and genitals
Offer a short-term mild or moderate potency corticosteroid applied once or twice daily (for a maximum of 2 weeks) to people with psoriasis of the face, flexures or genitals.In October 2012, moderate potency corticosteroids did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.In children and young people, the specified duration of therapy may not be appropriate. Please refer to the BNF for children for information on appropriate dosing and duration of treatment.
Be aware that the face, flexures and genitals are particularly vulnerable to steroid atrophy and that corticosteroids should only be used for short-term treatment of psoriasis (1 to 2 weeks per month). Explain the risks to people undergoing this treatment (and their families or carers where appropriate) and how to minimise them.
For adults with psoriasis of the face, flexures or genitals if the response to short-term moderate potency corticosteroids is unsatisfactory, or they require continuous treatment to maintain control and there is serious risk of local corticosteroid-induced side effects, offer a calcineurin inhibitor applied twice daily for up to 4 weeks. Calcineurin inhibitors should be initiated by healthcare professionals with expertise in treating psoriasis.In October 2012, topical calcineurin inhibitors did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.
Do not use potent or very potent corticosteroids on the face, flexures or genitals.
When prescribing topical agents at facial, flexural and genital sites take into account that they may cause irritation and inform people undergoing treatment (and their families and carers where appropriate) of these risks and how to minimise them. See also recommendation 1.3.4.2.
# Phototherapy (broad- or narrowband UVB light and (PUVA)
Offer narrowband ultraviolet B (UVB) phototherapy to people with plaque or guttate-pattern psoriasis that cannot be controlled with topical treatments alone. Treatment with narrowband UVB phototherapy can be given 3 or 2 times a week depending on patient preference. Tell people receiving narrowband UVB that a response may be achieved more quickly with treatment 3 times a week.
Offer alternative second- or third-line treatment when:
narrowband UVB phototherapy results in an unsatisfactory response or is poorly tolerated or
there is a rapid relapse following completion of treatment (rapid relapse is defined as greater than 50% of baseline disease severity within 3 months) or
accessing treatment is difficult for logistical reasons (for example, travel, distance, time off work or immobility) or
the person is at especially high risk of skin cancer.
Consider psoralen (oral or topical) with local ultraviolet A (PUVA) irradiation to treat palmoplantar pustulosis.In October 2012, psoralen did not have a UK marketing authorisation for this or any indication. See NICE's information on prescribing medicines.
When considering PUVA for psoriasis (plaque type or localised palmoplantar pustulosis) discuss with the person:
-ther treatment options
that any exposure is associated with an increased risk of skin cancer (squamous cell carcinoma)
that subsequent use of ciclosporin may increase the risk of skin cancer, particularly if they have already received more than 150 PUVA treatments
that risk of skin cancer is related to the number of PUVA treatments.
Do not routinely offer co-therapy with acitretin when administering PUVA. See the MHRA Drug Safety Update on oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women (June 2019). Also see the summary of product characteristics for further information on this issue.
Consider topical adjunctive therapy in people receiving phototherapy with broadband or narrowband UVB who:
have plaques at sites that are resistant or show an inadequate response (for example, the lower leg) to phototherapy alone, or at difficult-to-treat or high-need, covered sites (for example, flexures and the scalp), and/or
do not wish to take systemic drugs or in whom systemic drugs are contraindicated.
Do not routinely use phototherapy (narrowband UVB, broadband UVB or PUVA) as maintenance therapy.
Ensure that all phototherapy equipment is safety checked and maintained in line with local and national policy. Also see the British Association of Dermatologists service guidance and standards for phototherapy and guidelines on the measurement of ultraviolet radiation levels in ultraviolet phototherapy.
Healthcare professionals who are giving phototherapy should be trained and competent in its use and should ensure an appropriate clinical governance framework is in place to promote adherence to the indications for and contraindications to treatment, dosimetry and national policy on safety standards for phototherapy. Also see the British Association of Dermatologists service guidance and standards for phototherapy and guidelines on the measurement of ultraviolet radiation levels in ultraviolet phototherapy.
## Risk of skin cancer and how to minimise risk
Do not use PUVA in people with psoriasis of any type and a genetic predisposition to skin cancer for example, xeroderma pigmentosum or familial melanoma.
Do not use PUVA when other appropriate treatments are available in:
people with a personal history of skin cancer or
people who have already received 150 PUVA treatments or
children.
Use PUVA with caution or consider other treatment options in:
people at risk of skin cancer (melanoma and non-melanoma type) – see NICE cancer service guidance on improving outcomes for people with skin tumours including melanoma
people with lighter skin types, such as skin types 1 or 2 on the Fitzpatrick scale
people who are likely to require ciclosporin or long-term methotrexate
young people.
Offer lifetime skin cancer surveillance to people treated with PUVA who have:
had more than 150 PUVA treatments or
developed skin cancer.
Ensure that a permanent record of the person's cumulative number of UV treatments is kept (for example, in a national record).
# Systemic therapy
## General recommendations
Responsibility for use of systemic therapy should be in specialist settings only. Certain aspects of supervision and monitoring may be delegated to other healthcare professionals and completed in non-specialist settings, in which case, such arrangements should be formalised.
When offering systemic therapy, tailor the choice of agent and dosing schedule to the needs of the individual and include consideration of:
the person's age
disease phenotype, pattern of activity and previous treatment history
disease severity and impact
the presence of psoriatic arthritis (in consultation with a rheumatologist)
conception plans
comorbidities
the person's views.
Be aware of the benefits of, contraindications to and adverse effects associated with systemic treatments. Explain the risks and benefits to people undergoing this treatment (and their families or carers where appropriate), using absolute risks and natural frequencies when possible. Support and advice should be provided by healthcare professionals who are trained and competent in the use of systemic therapies.
When reviewing response to systemic therapy, take into account:
disease severity compared with baseline (for example, PASI baseline to endpoint score)
control of psoriatic arthritis disease activity (in consultation with a rheumatologist if necessary)
the impact of the disease on the person's physical, psychological and social wellbeing
the benefits versus the risks of continued treatment
the views of the person undergoing treatment (and their family or carers where appropriate).
Monitor people using systemic treatment for all types of psoriasis in accordance with national and local drug guidelines and policy. Take appropriate action in the event of laboratory abnormalities or adverse events.
Offer adjunctive topical therapy to people with psoriasis using systemic therapy to optimise treatment outcomes.
Offer people with psoriasis who are starting treatment with a systemic non-biological or biological drug the opportunity to participate in long-term safety registries (for example, the British Association of Dermatologists Biologic Interventions Register).
## Systemic non-biological therapy
Offer systemic non-biological therapy to people with any type of psoriasis if:
it cannot be controlled with topical therapy and
it has a significant impact on physical, psychological or social wellbeing and
-r more of the following apply:
psoriasis is extensive (for example, more than 10% of body surface area affected or a PASI score of more than 10) or
psoriasis is localised and associated with significant functional impairment and/or high levels of distress (for example, severe nail disease or involvement at high-impact sites) or
phototherapy has been ineffective, cannot be used or has resulted in rapid relapse (rapid relapse is defined as greater than 50% of baseline disease severity within 3 months).
Offer methotrexate as the first choice of systemic agent for people with psoriasis who fulfil the criteria for systemic therapy (see previous recommendation 1.5.2.1) except in the circumstances described in recommendations 1.5.2.4 and 1.5.2.12.In October 2012, methotrexate did not have a UK marketing authorisation for this indication in children and young people. See NICE's information on prescribing medicines.
In people with both active psoriatic arthritis and any type of psoriasis that fulfils the criteria for systemic therapy (see recommendation 1.5.2.1) consider the choice of systemic agent in consultation with a rheumatologist.
Offer ciclosporin as the first choice of systemic agent for people who fulfil the criteria for systemic therapy (see recommendation 1.5.2.1) and who:
need rapid or short-term disease control (for example, a psoriasis flare) or
have palmoplantar pustulosis or
are considering conception (both men and women) and systemic therapy cannot be avoided.In October 2012, ciclosporin did not have a UK marketing authorisation for this indication in children and young people under 16 years of age. See NICE's information on prescribing medicines.
Consider changing from methotrexate to ciclosporin (or vice versa) when response to the first-choice systemic treatment is inadequate.
Consider acitretin for adults, and in exceptional cases only for children and young people, in the following circumstances:
if methotrexate and ciclosporin are not appropriate or have failed or
for people with pustular forms of psoriasis.See the MHRA Drug Safety Update on oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women (June 2019). Also see the summary of product characteristics for further information on this issue.
See also NICE's technology appraisal guidance on apremilast for treating moderate to severe plaque psoriasis and apremilast for treating active psoriatic arthritis.
Use incremental dosing of methotrexate (for example, starting with an initial dose of 5 mg to 10 mg once a week) and gradually increase up to an effective dose and a maximum of 25 mg a week. Assess the treatment response after 3 months at the target dose of methotrexate and stop treatment if the response is inadequate (for example, a decrease of less than 75% in PASI score or a decrease of less than 50% in PASI score and 5 points in DLQI score).
Use the lowest possible therapeutic dose of methotrexate to maintain remission.
Use 2.5 to 3 mg/kg a day of ciclosporin. Escalate to 5 mg/kg a day after 4 weeks only when there is no response to the lower dose or when rapid disease control is necessary (for example, in severe unstable disease). Assess the treatment response after 3 months at the optimum dose of ciclosporin and stop treatment if the response is inadequate (for example, less than a 75% decrease in PASI score, or less than a 50% decrease in PASI score and less than 5 points in DLQI score).In October 2012, ciclosporin did not have a UK marketing authorisation for this indication in children and young people under 16 years of age. See NICE's information on prescribing medicines.
Use the lowest possible therapeutic dose of ciclosporin to maintain remission for up to 1 year. Consider other treatment options when disease relapses rapidly on stopping ciclosporin therapy (rapid relapse is defined as greater than 50% of baseline disease severity within 3 months of stopping treatment). Do not use ciclosporin continuously for more than 1 year unless disease is severe or unstable and other treatment options, including systemic biological therapy, cannot be used.
Use incremental dosing of acitretin to minimise mucocutaneous side effects and achieve a target dose of 25 mg daily in adults. Consider dose escalation to a maximum of 50 mg daily when no other treatment options are available. Assess the treatment response after 4 months at the optimum dose of acitretin and stop treatment if the response is inadequate, for example:
in plaque-type psoriasis, less than a 75% decrease in PASI score or less than a 50% decrease in PASI score and less than 5 points in DLQI score
in pustular forms of psoriasis, not achieving clear or nearly clear on the static Physician's Global Assessment.See the MHRA Drug Safety Update on oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women (June 2019). Also see the summary of product characteristics for further information on this issue.
When considering the risks and benefits of treating any type of psoriasis with methotrexate, be aware that methotrexate can cause a clinically significant rise in transaminases and that long-term therapy may be associated with liver fibrosis (see recommendations 1.5.2.13 to 1.5.2.16).
Before and during methotrexate treatment, offer the person with any type of psoriasis an evaluation for potential risk of hepatotoxicity. Use standard liver function tests and serial serum procollagen III levels to monitor for abnormalities during treatment with methotrexate, taking into account pre-existing risk factors (for example, obesity, diabetes and alcohol use), baseline results and trends over time.
When using serum procollagen III levels to exclude liver fibrosis or cirrhosis, be aware that the:
test cannot be used in children and young people
results may be unreliable in people with psoriatic arthritis
estimated positive predictive value is 23% to 95% and the estimated negative predictive value is 89% to 100%.
Provide advice on modifiable risk factors for liver disease prior to and during therapy, including alcohol intake and weight reduction if appropriate in line with the NICE guidelines on alcohol-use disorders: prevention and obesity prevention. For further advice on how to support attitude and behavioural change, see the NICE guideline on behaviour change.
Seek timely specialist advice and consider referral to a clinician with expertise in liver disease if the results of liver tests are abnormal.
## Systemic biological therapy
The guideline development group did not review evidence for any aspect of the use of a first biological agent because guidance on this is already available in existing NICE technology appraisal guidance on etanercept and efalizumab, infliximab, adalimumab, ustekinumab, secukinumab and ixekizumab.
Biological agents for psoriasis should be initiated and supervised only by specialist physicians experienced in the diagnosis and treatment of psoriasis.
If a person has both psoriasis and psoriatic arthritis, take into account both conditions before initiating or making changes to biological therapy and manage their treatment in consultation with a rheumatologist (see also the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, ustekinumab for treating active psoriatic arthritis, certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs and golimumab for the treatment of psoriatic arthritis, and the NICE guideline on spondyloarthritis in over 16s).Also see the MHRA Drug Safety Updates on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014) and ustekinumab (Stelara): risk of exfoliative dermatitis (January 2015).
When using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.
For guidance on treating psoriasis with adalimumab, see NICE's technology appraisal on adalimumab for the treatment of adults with psoriasis. Also see the MHRA Drug Safety Update on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014).
For guidance on treating psoriasis with etanercept, see NICE's technology appraisal on etanercept and efalizumab for the treatment of adults with psoriasis. Also see the MHRA Drug Safety Update on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014).
For guidance on treating psoriasis with infliximab, see NICE's technology appraisal on infliximab for the treatment of adults with psoriasis. Also see the MHRA Drug Safety Update on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014).
For guidance on treating psoriasis with ixekizumab, see NICE's technology appraisal on ixekizumab for treating moderate to severe plaque psoriasis.
For guidance on treating psoriasis with secukinumab, see NICE's technology appraisal on secukinumab for treating moderate to severe plaque psoriasis.
For guidance on treating psoriasis with ustekinumab, see NICE's technology appraisal guidance on ustekinumab for the treatment of adults with moderate to severe psoriasis. Also see the MHRA Drug Safety Update on ustekinumab (Stelara): risk of exfoliative dermatitis (January 2015).
For guidance on treating psoriasis with adalimumab, etanercept and ustekinumab, see NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people. Also see the MHRA Drug Safety Updates on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014) and ustekinumab (Stelara): risk of exfoliative dermatitis (January 2015).
Consider changing to an alternative biological drug in adults if:
the psoriasis does not respond adequately to a first biological drug as defined in NICE technology appraisal guidance on etanercept and efalizumab, infliximab, adalimumab, ustekinumab, secukinumab and ixekizumab (at 10 weeks after starting treatment for infliximab, 12 weeks for etanercept, ixekizumab and secukinumab, and 16 weeks for adalimumab and ustekinumab; primary failure) or
the psoriasis initially responds adequately but subsequently loses this response (secondary failure) or
the first biological drug cannot be tolerated or becomes contraindicated.
For adults in whom there is an inadequate response to a second biological drug, seek supra-specialist advice from a clinician with expertise in biological therapy.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Fitzpatrick scale
The scale has 6 main skin types based on the colour of the skin and its reaction to sun exposure:
type 1: always burns, never tans
type 2: usually burns, tans minimally
type 3: sometimes burns mildly, tans uniformly
type 4: burns minimally, tans easily
type 5: very rarely burns, tans very easily
type 6: never burns, tans very easily.# Recommendations for research
The guideline development group has made the following recommendations for research.
# Assessment of disease severity and impact
In children, young people and adults with psoriasis, can tools be developed and/or existing ones further refined and validated to:
assess disease severity and impact in both non-specialist and specialist healthcare settings, to facilitate assessment, appropriate referral, treatment planning and measurement of outcomes
measure burden and cumulative effect of disease activity, severity and impact for people with both psoriasis and psoriatic arthritis?
## Why this is important
Assessment of disease severity and impact is fundamental to delivering high-quality health care and measuring outcomes. The evidence review indicates that the existing tools have important limitations, and have not been validated in relevant healthcare settings or in children or young people. Future research should ensure that tools are developed that capture information on site of involvement as well as extent and the impact of previous treatments. Tools should capture all aspects of impact on life including physical, psychological and social wellbeing and factors that may influence this impact, such as distress and beliefs about psoriasis. Tools that can be used by patients (as well as healthcare professionals) to assess disease severity and that encompass new technologies should be evaluated to facilitate, when appropriate, modern healthcare delivery models (for example, remote monitoring of disease activity).
In addition, understanding the true burden and effect of disease activity, severity and impact for both psoriasis and psoriatic arthritis has not previously been comprehensively studied. Capturing this information and distilling out significant factors for focused investigation will lead to better understanding of the needs of this particular group of people and the impact of treatments that benefit both disease compartments (skin and joints).
# Methotrexate and risk of hepatotoxicity
What is the impact of methotrexate compared with other approaches to care (for example, other systemic non-biological or biological treatments) on risk of significant liver disease in people with psoriasis and do risk factors such as obesity, alcohol use or diabetes alter this risk?
## Why this is important
The evidence review indicates that people with psoriasis may be at risk of liver disease, and there is great uncertainty about the contributing role of methotrexate. Clinician and patient concerns about this side effect are a common cause of treatment discontinuation. However, existing studies are poorly controlled for important confounders and many are very old. Methotrexate is a low-cost intervention that is effective in an important proportion of patients. Research in this area will properly delineate the size of risk and how to minimise it. Future research should be adequately powered to detect clinically relevant liver disease, use relevant tools to do so, and properly control for relevant confounders.
# Rapid escalation to systemic treatments
In people with psoriasis, does early intervention with systemic treatments improve the long-term prognosis of psoriasis severity, comorbidities (including psoriatic arthritis), or treatment-related adverse effects, and are there any clinical (for example, demographic or phenotypic) or laboratory (for example, genetic or immune) biomarkers that can be used to identify those most likely to benefit from this treatment approach?
## Why this is important
At present the treatment pathway for people with psoriasis follows clinical need as no studies have been conducted to evaluate whether early intervention with systemic treatments alters prognosis. Consequently, patients with more severe disease sequence through all therapies in the treatment pathway, with a proportion requiring high-cost biological interventions to maintain disease control. The evidence indicates that there are very few treatment options for people with chronic disease, all of them are associated with side effects, many are co-dependent (for example, escalated risk of skin cancer in people treated with the phototherapy and ciclosporin sequence), and loss of response to biological therapies is a significant clinical issue. If early intervention with systemic treatments was shown to alter the prognosis, particularly if there were markers that could stratify those likely to benefit, this would be of major importance to patients, and likely to deliver much more cost-effective treatment strategies.
# Self-management
Do structured psoriasis-focused self-management programmes improve patient confidence, wellbeing and disease control compared with standard care?
## Why this is important
Virtually all patients self-manage their condition to a greater or lesser extent, and this involves complex topical applications as well as systemic therapies to be used over many years in response to fluctuating disease severity. The evidence indicates that in contrast to many chronic disorders, there are no validated programmes to help patients achieve effective self-management. Establishing a focused programme that effectively improves outcomes for patients would be of clinical benefit and likely deliver healthcare savings.
# Topical therapy
In people of all ages with psoriasis:
. How should topical therapies be used to maintain disease control i) safely; ii) effectively and iii) what are the health economic implications?
. What are the risks of 'real life' long-term corticosteroid use, are there particular people at risk and what strategies can be used to modify or avoid risks?
## Why this is important
Currently, topical therapies, in some form or another, are prescribed to virtually everyone with psoriasis, often as first line psoriasis treatment and they are also frequently used adjunctively with other interventions. There is a wide array of potential topical agents available and further research specifically targeting therapeutic strategies together with sequencing of topical agents for maintaining disease control in the long term continues to deserve focused attention. In addition, exploration of the risks associated with long-term corticosteroid use and strategies aimed at modifying risk would be a critical element of this research to fill the current gap in the literature.# Appendix: Information to facilitate discussion of risks and benefits of treatments for people with psoriasis
Data is provided for the proportions of people achieving remission, withdrawing due to adverse events and experiencing specific adverse events (as prioritised by the guideline development group ) for interventions that have been recommended in this guideline. Data are based on pooled estimates where possible and from trials with populations and dosing appropriate to the intervention. For full details of the duration of treatment and dosing schedules please refer to the main text of the guideline.
Text is labelled with an asterisk when the GDG had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.
For a landscape version of the following table, please refer to the full guideline.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once daily: 220/1000
Twice daily: 487/1000
Placebo:
Once daily: 76/1000
Twice daily: 122/1000
Intervention:
Once or twice daily: 23/1000
Placebo:
Once or twice daily: 29/1000
Intervention:
Skin atrophy
Twice daily: 1.9/1000
Placebo:
Skin atrophy
Twice daily: 3.2/1000
Children with chronic plaque psoriasis of trunk and limbs
Note: the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size
Intervention:
Twice daily: 605/1000
Placebo:
Twice daily: 441/1000
Intervention: Not available
Placebo: Not available
Intervention: Not available
Placebo: Not available
Scalp psoriasis
Intervention:
Once daily: 387/1000
Placebo:
Once daily: 219/1000
Intervention:
Once daily: 81/1000
Placebo:
Once daily: 52/1000
Intervention: Not available
Placebo: Not available
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once or twice daily: 394/1000
Placebo:
Once or twice daily: 77/1000
Intervention:
Once daily: 10/1000
Twice daily: 25/1000
Placebo:
Once daily: 79/1000
Twice daily: 0/1000
Intervention:
Skin atrophy
Once or twice daily: 5.5/1000
Placebo:
Skin atrophy
Once or twice daily: 0/1000
Scalp psoriasis
Intervention:
Once or twice daily: 632/1000
Placebo:
Once or twice daily: 223/1000
Intervention:
Once or twice daily: 9.5/1000
Placebo:
Once or twice daily: 41/1000
Intervention: Not available
Placebo: Not available
Note: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
No placebo
Active comparator, calcipotriol:
Twice daily: 469/1000
Intervention:
Active comparator, calcipotriol:
Twice daily: 26/1000
Intervention: Not available
Active comparator: Not available
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once daily: 494/1000
No placebo
Active comparator:
vitamin D once daily: 193/1000
Intervention:
Once daily: 7.5/1000
Active comparator:
Vitamin D once or twice daily: 27/1000
Intervention:
Skin atrophy
Once daily: 4.2/1000
Active comparator:
Skin atrophy
Vitamin D twice daily: 1.8/1000
Scalp psoriasis
Note: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Intervention:
Once daily: 800/1000
Placebo:
Once daily: 500/1000
Intervention:
Once daily: 17/1000
Placebo:
Once daily: 0/1000
Note: the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size
Intervention: Not available
Placebo: Not available
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once or twice daily: 625/1000
Placebo:
Once or twice daily: 13/1000
Intervention:
Once or twice daily: 4.6/1000
Placebo:
Once or twice daily: 6.0/1000
Intervention:
Skin atrophy
Once or twice daily: 23/1000
Placebo:
Skin atrophy
Once or twice daily: 0/1000
Scalp psoriasis
Intervention:
Once or twice daily: 646/1000
Placebo:
Once or twice daily: 80/1000
Intervention:
Once or twice daily: 0/1000
Placebo:
Once or twice daily: 5.9/1000
Intervention:
Skin atrophy
Once or twice daily: 0/1000
Placebo:
Skin atrophy
Once or twice daily: 11/1000
Note: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once daily: 58/1000
Placebo:
Once daily: 20/1000
Intervention:
Once daily: 107/1000
Placebo:
Once daily: 44/1000
Intervention:
Skin atrophy
Once daily: 0/1000
Placebo:
Skin atrophy
Once daily: 0/1000
Note: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once daily: 430/1000
No placebo
Active comparator, calcipotriol:
Twice daily: 588/1000
Intervention:
Once daily: 82/1000
Active comparator, calcipotriol:
Twice daily: 39/1000
Intervention: Not available
Active comparator: Not available
Note: two-third of studies reported home-use of dithranol and in one-third of studies, the setting was unclear.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Chronic plaque psoriasis of trunk and limbs
Intervention:
Once or twice daily: 111/1000 to 519/1000 depending on formulation and follow-up
No placebo
Active comparator, calcipotriol:
Twice daily: 214/1000 to 723/1000 depending on follow-up
Intervention:
Once or twice daily: 0 to 56/1000 depending on formulation and follow-up
Active comparator, calcipotriol:
Twice daily: 0 to 40/1000 depending on follow-up
Intervention: Not available
Active comparator: Not available
Note: the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Psoriasis of the face and flexures
Intervention:
Twice daily: 652/1000
Placebo:
Twice daily: 309/1000
Intervention:
Twice daily: 0/1000
Placebo:
Twice daily: 25/1000
Intervention: Not available
Placebo: Not available
) The guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.
) No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Psoriasis of the flexures
Intervention:
Twice daily: 714/1000
Placebo:
Twice daily: 207/1000
Intervention:
Twice daily: 0/1000
Placebo:
Twice daily: 0/1000
Intervention:
Skin atrophy
Twice daily: 0/1000
Placebo:
Skin atrophy
Twice daily: 0/1000
) The guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.
) No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Intervention and population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
NBUVB versus PUVA
Plaque psoriasis
Intervention:
Twice weekly: 647/1000
No placebo
Active comparator, oral PUVA:
Twice weekly: 915/1000
Intervention:
Twice weekly: 38/1000
No placebo
Active comparator, oral PUVA:
Twice weekly: 47/1000
Intervention: Not available
Active comparator: Not available
PUVA (oral)
Palmoplantar pustulosis
Note: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Intervention:
to 4 times weekly: 941/1000
Placebo, no treatment:
Intervention:
to 4 times weekly: 29/1000
Placebo, no treatment:
Intervention:
Burn
to 4 times weekly: 147/1000
Placebo, no treatment:
PUVA (cream)
Palmoplantar pustulosis
Intervention:
times weekly: 952/1000
No placebo
Active comparator,
NBUVB:
times weekly: 429/1000
Intervention:
times weekly: 45/1000
No placebo
Active comparator,
NBUVB:
times weekly: 0/1000
Intervention: Not available
Active comparator: Not available
NBUVB plus vitamin D or analogues
Plaque psoriasis
Intervention:
times weekly UV + twice daily topical: 900/1000
No placebo
Active comparator,
NBUVB alone:
times weekly: 611/1000
Intervention:
times weekly UV + twice daily topical: 50/1000
No placebo
Active comparator, NBUVB alone:
times weekly: 28/1000
Intervention:
Burn
times weekly UV + twice daily topical: 200/1000
No placebo
Active comparator, NBUVB alone:
Burn
times weekly: 111/1000
BBUVB plus vitamin D or analogues
Plaque psoriasis
Intervention:
Up to 3 times weekly UV + twice daily topical: 449/1000 8 weeks
No placebo
Active comparator, BBUVB alone:
up to 3 times weekly: 208/1000
Intervention:
Up to 3 times weekly UV + twice daily topical: 41/1000
No placebo
Active comparator, BBUVB alone:
up to 3 times weekly: 19/1000
Intervention: Not available
Active comparator: Not available
Liquor carbonic distillate (equivalent 2.3% coal tar) plus NBUVB
Plaque psoriasis
Intervention:
Clear (3 times weekly UV + twice daily topical): 583/1000
No placebo
Active comparator, NBUVB alone:
times weekly: 500/1000
Intervention:
times weekly UV + twice daily topical: 0/1000
No placebo
Active comparator, NBUVB alone:
times weekly: 0/1000
Intervention:
Burn
times weekly UV + twice daily topical: 167/1000
No placebo
Active comparator, NBUVB alone:
Burn
times weekly: 167/1000
Dithranol plus BBUVB
Psoriasis
Intervention:
times weekly UV + twice daily topical: 625/1000
No placebo
Active comparator, BBUVB alone:
times weekly: 458/1000
Intervention: Not available
Active comparator: Not available
Intervention: Not available
Active comparator: Not available
Abbreviations: BBUVB, broadband UVB; NBUVB, narrowband UVB; PUVA, psoralen plus UVA; UVA, ultraviolet A; UVB, ultraviolet B.
Note: for all the interventions except NBUVB versus PUVA, the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.
Intervention and population (psoriasis phenotype)
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity
Numbers experiencing serious or named adverse events
Methotrexate; incremental dosing (plus folic acid)
Chronic plaque psoriasis
Intervention:
Placebo:
Intervention:
Placebo:
Intervention:
Elevated liver enzymes (>1.5 to 2.5 ULN): 91/1000*
Placebo:
Elevated liver enzymes (>1.5 to 2.5 ULN): 75/1000*
Ciclosporin
Chronic plaque psoriasis
Intervention:
to 3 mg: 232/1000
mg: 600/1000
Placebo:
Intervention:
Placebo:
Intervention:
Hypertension:
Decrease in GFR >15%:
mg/kg: 333/1000
mg/kg: 500/1000*
Placebo:
Hypertension:
Decrease in GFR >15%:
Ciclosporin
Palmoplantar pustulosis
Intervention:
Placebo:
Intervention: Not available
Placebo: Not available
Intervention:
Hypertension:
Placebo:
Hypertension
Acitretin – 25 mg
Plaque, pustular and erythrodermic psoriasis*
Intervention:
Placebo:
Intervention:
Placebo:
Intervention:
Cheilitis:
Hair loss:
Elevated liver enzymes (>ULN):
Elevated cholesterol (>ULN):
Placebo:
Cheilitis:
Hair loss:
Elevated liver enzymes (>ULN):
Elevated cholesterol (>ULN):
Abbreviations: GFR, glomerular filtration rate; ULN, upper limit of normal.
Note: The guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.
Intervention and population (psoriasis phenotype)
Prior biologics received
Numbers achieving remissions (clear, nearly clear, or PASI75)
Numbers experiencing withdrawal due to drug toxicity or serious adverse events
Infliximab
Adults with severe plaque psoriasis and prior biologic exposure
Unclear
Intervention:
Placebo:
Intervention: Not available
Placebo: Not available
Etanercept
Adults with severe plaque psoriasis and prior biologic exposure*
Included etanercept, infliximab, and adalimumab (proportions unclear)*
Intervention:
Placebo: Not available*
Active comparator, ustekinumab:
Intervention: Not available*
Placebo: Not available*
Active comparator: Not available*
Ustekinumab
Adults with severe plaque psoriasis and prior biologic exposure
Included etanercept, infliximab, and adalimumab (proportions unclear)
Intervention:
Placebo:
Intervention: Not available
Placebo: Not available
Adalimumab
Adults with severe plaque psoriasis*
Etanercept (32.1%), alefacept (23.1%), ustekinumab (23.1%), efalizumab (21.8%), infliximab (20.5%) and other (17.9%)*
Intervention:
Placebo: Not available*
Active comparator, no prior biologic:
Intervention: Not available*
Placebo: Not available*
Active comparator: Not available*
Note: For the interventions infliximab and ustekinumab, there were no active comparators. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.
Intervention and outcome(s)
Population – psoriasis phenotype
Number experiencing event
Psoralen plus ultraviolet A (PUVA; oral)
Skin cancer – squamous cell carcinoma (SCC)
Plaque (84%), guttate (12%) and erythrodermic (4%) psoriasis
Relative risk compared with the general population:
PUVA exposure <100; relative risk (RR) <100
PUVA exposure 100 to 159; RR 100 to 159
PUVA exposure 160 to 336; RR 160 to 336
PUVA exposure ≥337; RR ≥337
Absolute increase in risk:
PUVA exposure <100; SCCs 18; 1.7% increase in 10-year risk
PUVA exposure 100 to 159; SCCs 15; 2.7% increase in 10-year risk
PUVA exposure 160 to 336; SCCs 68; 8.8% increase in 10-year risk
PUVA exposure ≥337; SCCs 34; 12.7% increase in 10-year risk
Narrowband UVB (NBUVB)
Skin cancer
Insufficient data available
Insufficient data available
Methotrexate
Liver fibrosis, bone marrow suppression and pneumonitis
No long-term data available
No long-term data available
Ciclosporin
Hypertension, renal impairment, gout and hyperuricaemia
No long-term data available
No long-term data available
Acitretin
Hyperlipidaemia, hepatotoxicity, skeletal adverse events and cheilitis
No long-term data available
No long-term data available
|
{'Introduction': "Psoriasis is an inflammatory skin disease that typically follows a relapsing and remitting course. The prevalence of psoriasis is estimated to be around 1.3% to 2.2% in the UK. Psoriasis can occur at any age, although is uncommon in children (0.71%) and most cases occur before 35\xa0years. Psoriasis is associated with joint disease in a significant proportion of patients (reported in 1\xa0study at 13.8%).\n\nPlaque psoriasis is characterised by well-delineated red, scaly plaques that vary in extent from a few patches to generalised involvement. It is by far the most common form of the condition (about 90% of people with psoriasis). Other types of psoriasis include guttate psoriasis and pustular (localised or generalised) forms. Distinctive nail changes occur in around 50% of all those affected and are more common in people with psoriatic arthritis.\n\nHealthcare professionals and patients using the term psoriasis are usually referring to plaque psoriasis, and unless stipulated otherwise, 'psoriasis' is used in this way in the guideline. The phrase 'difficult-to-treat sites' encompasses the face, flexures, genitalia, scalp, palms and soles and are so-called because psoriasis at these sites may have especially high impact, may result in functional impairment, requires particular care when prescribing topical therapy and can be resistant to treatment.\n\nPsoriasis for many people results in profound functional, psychological, and social morbidity, with consequent reduced levels of employment and income. Factors that contribute to this include symptoms related to the skin (for example, chronic itch, bleeding, scaling and nail involvement), problems related to treatments, psoriatic arthritis, and the effect of living with a highly visible, stigmatising skin disease. Even people with minimal involvement state that psoriasis has a major effect on their life. Several studies have also reported that people with psoriasis, particularly those with severe disease, may be at increased risk of cardiovascular disease, lymphoma and non-melanoma skin cancer.\n\nA wide variety of treatment options are available. Some are expensive and some are accessed only in specialist care; all require monitoring. The treatment pathway in this guideline begins with active topical therapies. The guideline development group (GDG) acknowledged that the use of emollients in psoriasis was already widespread and hence the evidence review was limited to active topical therapies for psoriasis. See the BNF and BNF for children for guidance on use of emollients.\n\nIn this guideline, first-line therapy describes traditional topical therapies (such as corticosteroids, vitamin\xa0D and vitamin\xa0D analogues, dithranol and tar preparations). Second-line therapy includes the phototherapies (broad- or narrowband ultraviolet\xa0B light and psoralen plus UVA light [PUVA]) and systemic non-biological agents such as ciclosporin, methotrexate and acitretin. Third-line therapy refers to systemic biological therapies such as the tumour necrosis factor antagonists adalimumab, etanercept and infliximab, and the monoclonal antibody ustekinumab that targets interleukin‑12 (IL‑12) and IL-23. NICE has published technology appraisals on the use of biological drugs, and this guideline incorporates recommendations from these appraisals where relevant (listed in alphabetical order). Biologic treatment is complicated by a poor response in a minority of people, and this guideline reviewed the literature for the use of a second biological drug.\n\nFor most people, psoriasis is managed in primary care, with specialist referral being needed at some point for up to 60% of people. Supra-specialist (level\xa04) tertiary care is required in the very small minority with especially complex, treatment resistant and/or rare manifestations of psoriasis. Level\xa04 care is defined as usually taking place entirely within an acute hospital and is carried out by consultant dermatologists and a range of other healthcare professionals with specialist skills in managing complex and/or rare skin disorders – see Quality Standards for Dermatology: providing the right care for people with skin conditions.\n\nA recent UK audit in the adult population demonstrated wide variations in practice, and in particular, access to specialist treatments (including biological therapy), appropriate drug monitoring, specialist nurse support and psychological services (Eedy et al. 2009).\n\nThis guideline covers people of all ages and aims to provide clear recommendations on the management of all types of psoriasis. The term 'people' is used to encompass all ages. 'Children' refers to those up to 12\xa0years, who become 'young people' thereafter, before merging with the adult population by 18\xa0years of age. The GDG have focused on areas most likely to improve the management and delivery of care for most people affected, where practice is very varied and/or where clear consensus or guidelines on treatments are lacking. It is hoped that this guideline will facilitate the delivery of high-quality healthcare and improved outcomes for people with psoriasis.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Principles of care\n\nOffer people with any type of psoriasis (and their families or carers), support and information tailored to suit their individual needs and circumstances, in a range of different formats so they can confidently understand:\n\ntheir diagnosis and treatment options\n\nrelevant lifestyle risk factors\n\nwhen and how to treat their condition\n\nhow to use prescribed treatments safely and effectively (for example, how to apply topical treatments, how to minimise the risk of side effects through monitoring for safety of medicines)\n\nwhen and how to seek further general or specialist review\n\nstrategies to deal with the impact on their physical, psychological and social wellbeing.Also see the NICE guidelines on behaviour change: individual approaches and behaviour change: general approaches.\n\nWhen offering treatments to a person with any type of psoriasis:\n\nensure the treatment strategy is developed to meet the person's health goals so that the impact of their condition is minimised and use relevant assessment tools to ensure these goals are met\n\ntake into account the age and individual circumstances of the person, disease phenotype, severity and impact, coexisting psoriatic arthritis, comorbidities and previous treatment history\n\ndiscuss the risks and benefits of treatment options with the person (and their families or carers where appropriate); where possible, use absolute risk and natural frequency (also see the appendix for details of the risk-benefit profiles of interventions recommended in this guideline)\n\ndiscuss the importance of adherence to treatment for optimising outcomes.For more information, see the NICE guidelines on medicines adherence and medicines optimisation.\n\nAssess whether support and information need updating or revising at every review or interaction with the person, in particular:\n\nduring transition from children's services to adult services\n\nwhen new interventions become available\n\nwhen the person's disease severity or circumstances (for example, in terms of comorbidities or lifestyle) change.See also the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nProvide a single point of contact to help people with all types of psoriasis (and their families or carers where appropriate) access appropriate information and advice about their condition and the services available at each stage of the care pathway.\n\nNICE has produced guidance on the components of good patient experience in adult NHS services. All healthcare professionals should follow the recommendations in the NICE guideline on patient experience in adult NHS services.\n\n# Assessment and referral\n\nSevere or atypical psoriasis is an HIV indicator condition as described in HIV in Europe's HIV indicator conditions. Also see recommendations 1.1.5 and 1.1.8 in the NICE guideline on HIV testing.\n\n## Assessment tools for disease severity and impact and when to refer for specialist care\n\nFor people with any type of psoriasis assess:\n\ndisease severity\n\nthe impact of disease on physical, psychological and social wellbeing\n\nwhether they have psoriatic arthritis\n\nthe presence of comorbidities.\n\nAssess the severity and impact of any type of psoriasis:\n\nat first presentation\n\nbefore referral for specialist advice and at each referral point in the treatment pathway\n\nto evaluate the efficacy of interventions.\n\nWhen assessing the disease severity in any healthcare setting, record:\n\nthe results of a static physician's global assessment (classified as clear, nearly clear, mild, moderate, severe or very severe)\n\nthe patient's assessment of current disease severity, for example, using the static patient's global assessment (classified as clear, nearly clear, mild, moderate, severe or very severe)\n\nthe body surface area affected\n\nany involvement of nails, high-impact and difficult-to-treat sites (for example, the face, scalp, palms, soles, flexures and genitals)\n\nany systemic upset such as fever and malaise, which are common in unstable forms of psoriasis such as erythroderma or generalised pustular psoriasis.\n\nIn specialist settings, use a validated tool to assess severity of psoriasis, for example, the Psoriasis Area and Severity Index (PASI; in addition to the assessments indicated in recommendation 1.2.1.3).\n\nBe aware that:\n\nPASI and body surface area are not validated for use in children and young people\n\nerythema may be underestimated in people with darker skin types, such as skin types\xa05 and\xa06 on the Fitzpatrick scale.\n\nUse the Nail Psoriasis Severity Index to assess nail disease in specialist settings:\n\nif there is a major functional or cosmetic impact or\n\nbefore and after treatment is initiated specifically for nail disease.\n\nAssess the impact of any type of psoriasis on physical, psychological and social wellbeing by asking:\n\nwhat aspects of their daily living are affected by the person's psoriasis\n\nhow the person is coping with their skin condition and any treatments they are using\n\nif they need further advice or support\n\nif their psoriasis has an impact on their mood\n\nif their psoriasis causes them distress (be aware the patient may have levels of distress and not be clinically depressed)\n\nif their condition has any impact on their family or carers. Ask children and young people age-appropriate questions.\n\nIn specialist settings, and if practical in non-specialist settings, use a validated tool to assess the impact of any type of psoriasis on physical, psychological and social wellbeing, for example, the:\n\nDermatology Life Quality Index (DLQI; see also recommendation 1.5.3.3) for adults or\n\nChildren's Dermatology Life Quality Index (CDLQI) for children and young people.\n\nWhen using an assessment tool for a person with any type of psoriasis:\n\ntake account of their age, any disabilities (such as physical, visual or cognitive impairment), and any language or other communication difficulties, and provide help and support if needed (see Dermatology Life Quality Index)\n\nensure that the chosen assessment tool continues to be a sufficiently accurate measure.\n\nFollowing assessment in a non-specialist setting, refer people for dermatology specialist advice if:\n\nthere is diagnostic uncertainty or\n\nany type of psoriasis is severe or extensive, for example, more than 10% of the body surface area is affected or\n\nany type of psoriasis cannot be controlled with topical therapy or\n\nacute guttate psoriasis requires phototherapy (see recommendation 1.4.1.1) or\n\nnail disease has a major functional or cosmetic impact or\n\nany type of psoriasis is having a major impact on a person's physical, psychological or social wellbeing.\n\nPeople with generalised pustular psoriasis or erythroderma should be referred immediately for same-day specialist assessment and treatment.\n\nRefer children and young people with any type of psoriasis to a specialist at presentation.\n\n## Assessment and referral for psoriatic arthritis\n\nOffer annual assessment for psoriatic arthritis to people with any type of psoriasis. Assessment is especially important within the first 10\xa0years of onset of psoriasis.\n\nUse a validated tool to assess adults for psoriatic arthritis in primary care and specialist settings, for example, the Psoriasis Epidemiological Screening Tool (PEST). Be aware that the PEST does not detect axial arthritis or inflammatory back pain.\n\nAs soon as psoriatic arthritis is suspected, refer the person to a rheumatologist for assessment and advice about planning their care. Also see the NICE guideline on spondyloarthritis in over\xa016s.\n\n## Identification of comorbidities\n\nOffer adults with severe psoriasis of any type (defined as either needing treatment with phototherapy or systemic agents, or needing hospital admission in the studies underpinning this recommendation), a cardiovascular risk assessment at presentation using a validated risk estimation tool. Offer further assessment of cardiovascular risk every 5\xa0years, or more frequently if indicated following assessment. For further information, see the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.\n\nDiscuss risk factors for cardiovascular comorbidities with people who have any type of psoriasis (and their families or carers where appropriate). Where appropriate offer preventative advice, healthy lifestyle information and support for behavioural change tailored to meet the needs of the individual in line with the following NICE guidance:\n\nCardiovascular disease: risk assessment and reduction, including lipid modification\n\nObesity prevention\n\nType 2 diabetes prevention: population and community-level interventions\n\nCardiovascular disease prevention\n\nAlcohol-use disorders: prevention\n\nStop smoking interventions and services\n\nPhysical activity: brief advice for adults in primary care\n\nPhysical activity in the workplace\n\nPhysical activity for children and young people.\n\nFor people with multiple comorbidities and/or multimorbidities and any type of psoriasis needing second- or third-line therapy, ensure multidisciplinary working and communication between specialties and, if needed, interdisciplinary team working (for example, when both skin and joints are significantly affected).\n\nBe aware that psoriasis of any type, especially if severe (identified by hospitalisations [including outpatient visits] for psoriasis [ICD‑10 L40] or psoriatic arthritis) is a risk factor for venous thromboembolism in adults, and:\n\nexplain this risk to adults with any type of psoriasis\n\noffer advice on how to minimise the risk (for example, during hospital admission, surgery, or periods of immobility)\n\nmanage the risk in line with the NICE guideline on venous thromboembolism in over\xa016s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.\n\nAssess whether people with any type of psoriasis are depressed when assessing disease severity and impact, and when escalating therapy. If appropriate offer information, advice and support in line with the NICE guidelines on depression in adults with a chronic physical health problem and depression in children and young people.\n\n# Topical therapy\n\nThe treatment pathway in this guideline begins with active topical therapies. The guideline development group acknowledged that the use of emollients in psoriasis was already widespread and hence the evidence review was limited to active topical therapies for psoriasis. Refer to the BNF and BNF for children for guidance on use of emollients.\n\n## General recommendations\n\nOffer people with psoriasis topical therapy as first-line treatment.\n\nOffer second- or third-line treatment options (phototherapy or systemic therapy) at the same time when topical therapy alone is unlikely to adequately control psoriasis, such as:\n\nextensive disease (for example, more than 10% of body surface area affected) or\n\nat least 'moderate' on the static Physician's Global Assessment or\n\nwhere topical therapy is ineffective, such as nail disease. See also recommendations 1.2.1.9; 1.4.1.1; 1.5.2.1; 1.5.3.4; 1.5.3.6; 1.5.3.8 and 1.5.3.10.\n\nOffer practical support and advice about the use and application of topical treatments. Advice should be provided by healthcare professionals who are trained and competent in the use of topical therapies. Support people to adhere to treatment in line with the NICE guideline on medicines adherence. Also see the NICE guideline on medicines optimisation.\n\nWhen offering topical agents:\n\ntake into account patient preference, cosmetic acceptability, practical aspects of application and the site(s) and extent of psoriasis to be treated\n\ndiscuss the variety of formulations available and, depending on the person's preference, use:\n\n\n\ncream, lotion or gel for widespread psoriasis\n\nlotion, solution or gel for the scalp or hair-bearing areas\n\nointment to treat areas with thick adherent scale\n\n\n\nbe aware that topical treatment alone may not provide satisfactory disease control, especially in people with psoriasis that is extensive (for example, more than 10% of body surface area affected) or at least 'moderate' on the static Physician's Global Assessment.\n\nIf a person of any age with psoriasis requiring topical therapy has a physical disability, or cognitive or visual impairment offer advice and practical support that take into account the person's individual needs.\n\nArrange a review appointment 4\xa0weeks after starting a new topical treatment in adults, and 2\xa0weeks after starting a new topical treatment in children, to:\n\nevaluate tolerability, toxicity, and initial response to treatment (including measures of severity and impact described in recommendations 1.2.1.3, 1.2.1.6 and 1.2.1.7)\n\nreinforce the importance of adherence when appropriate\n\nreinforce the importance of a 4\xa0week break between courses of potent/very potent corticosteroids (see recommendation 1.3.1.10). If there is little or no improvement at this review, discuss the next treatment option with the person.\n\nDiscuss with people whose psoriasis is responding to topical treatment (and their families or carers where appropriate):\n\nthe importance of continuing treatment until a satisfactory outcome is achieved (for example, clear or nearly clear) or up to the recommended maximum treatment period for corticosteroids (see the sections on topical treatment of psoriasis affecting the trunk and limbs, scalp and face, flexures and genitals)\n\nthat relapse occurs in most people after treatment is stopped\n\nthat after the initial treatment period topical treatments can be used when needed to maintain satisfactory disease control.\n\nOffer people with psoriasis a supply of their topical treatment to keep at home for the self-management of their condition.\n\nIn people whose psoriasis has not responded satisfactorily to a topical treatment strategy, before changing to an alternative treatment:\n\ndiscuss with the person whether they have any difficulties with application, cosmetic acceptability or tolerability and where relevant offer an alternative formulation\n\nconsider other possible reasons for non-adherence in line with the NICE guideline on medicines adherence.\n\nAlso see the NICE guideline on medicines optimisation.\n\nAlso see recommendations 1.3.4.2 and 1.3.4.4 for details on safe use of steroids at facial, flexural and genital sites.\n\nBe aware that continuous use of potent or very potent corticosteroids may cause:\n\nirreversible skin atrophy and striae\n\npsoriasis to become unstable\n\nsystemic side effects when applied continuously to extensive psoriasis (for example, more than 10% of body surface area affected). Explain the risks of these side effects to people undergoing treatment (and their families or carers where appropriate) and discuss how to avoid them.\n\nAim for a break of 4\xa0weeks between courses of treatment with potent or very potent corticosteroids. Consider topical treatments that are not steroid based (such as vitamin\xa0D or vitamin\xa0D analogues or coal tar) as needed to maintain psoriasis disease control during this period.\n\nWhen offering a corticosteroid for topical treatment select the potency and formulation based on the person's need.\n\nDo not use very potent corticosteroids continuously at any site for longer than 4\xa0weeks.\n\nDo not use potent corticosteroids continuously at any site for longer than 8\xa0weeks.\n\nDo not use very potent corticosteroids in children and young people.\n\nOffer a review at least annually to adults with psoriasis who are using intermittent or short-term courses of a potent or very potent corticosteroid (either as monotherapy or in combined preparations) to assess for the presence of steroid atrophy and other adverse effects. Also see recommendations 1.3.1.12 and 1.3.1.13 for details on safe duration of steroid use.\n\nOffer a review at least annually to children and young people with psoriasis who are using corticosteroids of any potency (either as monotherapy or in combined preparations) to assess for the presence of steroid atrophy and other adverse effects.\n\n## Topical treatment of psoriasis affecting the trunk and limbs\n\nOffer a potent corticosteroid applied once daily plus vitamin\xa0D or a vitamin\xa0D analogue applied once daily (applied separately, 1\xa0in the morning and the other in the evening) for up to 4\xa0weeks as initial treatment for adults with trunk or limb psoriasis.\n\nIf once-daily application of a potent corticosteroid plus once-daily application of vitamin\xa0D or a vitamin\xa0D analogue does not result in clearance, near clearance or satisfactory control of trunk or limb psoriasis in adults after a maximum of 8\xa0weeks, offer vitamin\xa0D or a vitamin\xa0D analogue alone applied twice daily. Also see recommendation 1.3.1.8 for additional considerations before changing to the next treatment option.\n\nIf twice-daily application of vitamin\xa0D or a vitamin\xa0D analogue does not result in clearance, near clearance or satisfactory control of trunk or limb psoriasis in adults after 8\xa0to\xa012\xa0weeks, offer either:\n\na potent corticosteroid applied twice daily for up to 4\xa0weeks or\n\na coal tar preparation applied once or twice daily.Also see recommendation 1.3.1.8 for additional considerations before changing to the next treatment option.\n\nIf a twice-daily potent corticosteroid or coal tar preparation cannot be used or a once-daily preparation would improve adherence in adults offer a combined product containing calcipotriol monohydrate and betamethasone dipropionate applied once daily for up to 4\xa0weeks.\n\nOffer treatment with very potent corticosteroids in adults with trunk or limb psoriasis only:\n\nin specialist settings under careful supervision\n\nwhen other topical treatment strategies have failed\n\nfor a maximum period of 4\xa0weeks.\n\nConsider short-contact dithranol for treatment-resistant psoriasis of the trunk or limbs and either:\n\ngive educational support for self-use or\n\nensure treatment is given in a specialist setting.\n\nFor children and young people with trunk or limb psoriasis consider either:\n\ncalcipotriol applied once daily (only for those over 6\xa0years of age) or\n\na potent corticosteroid applied once daily (only for those over 1\xa0year of age).In August 2017, there were different topical calcipotriol preparations available in the UK, which vary in their licensing status for use in children and young people under\xa018. Additionally, potent topical corticosteroid preparations available in the UK vary in the age from which they are licensed for use in children. Please refer to the BNF for children for information on appropriate dosing and duration of treatment. Refer to the summary of product characteristics for specific information on individual topical calcipotriol and corticosteroid preparations. See also NICE's information on prescribing medicines.\n\n## Topical treatment of psoriasis affecting the scalp\n\nIn children and young people, the specified duration of therapy in recommendations 1.3.3.1, 1.3.3.3, 1.3.3.4 and 1.3.3.5 may not be appropriate. Please refer to the BNF for children for information on appropriate dosing and duration of treatment.\n\nIn August 2017, there were several potent topical corticosteroid preparations available in the UK, and the age from which they are licensed for use in children varies. Refer to the summary of product characteristics for information on individual potent topical corticosteroid preparations. See also NICE's information on prescribing medicines.\n\nOffer a potent corticosteroid applied once daily for up to 4\xa0weeks as initial treatment for people with scalp psoriasis.\n\nShow people with scalp psoriasis (and their families or carers where appropriate) how to safely apply corticosteroid topical treatment.\n\nIf treatment with a potent corticosteroid does not result in clearance, near clearance or satisfactory control of scalp psoriasis after 4\xa0weeks consider:\n\na different formulation of the potent corticosteroid (for example, a shampoo or mousse) and/or\n\ntopical agents to remove adherent scale (for example, agents containing salicylic acid, emollients and oils) before application of the potent corticosteroid.\n\nIf the response to treatment with a potent corticosteroid for scalp psoriasis remains unsatisfactory after a further 4\xa0weeks of treatment (also see recommendation 1.3.1.8 for additional considerations before changing to the next treatment option), offer:\n\na combined product containing calcipotriol monohydrate and betamethasone dipropionate applied once daily for up to 4\xa0weeks or\n\nvitamin\xa0D or a vitamin\xa0D analogue applied once daily (only in those who cannot use steroids and with mild to moderate scalp psoriasis).In October 2012, the combined product containing calcipotriol monohydrate and betamethasone dipropionate did not have a UK marketing authorisation for this indication in children and young people.In August 2017, topical calcitriol and tacalcitol preparations available in the UK were not licensed for use in children. Topical calcipotriol preparations available in the UK vary in their licensing status for use in children and young people under 18. Refer to the summary of product characteristics for specific information on individual topical calcipotriol preparations. See NICE's information on prescribing medicines.\n\nIf continuous treatment with either a combined product containing calcipotriol monohydrate and betamethasone dipropionate applied once daily or vitamin\xa0D or a vitamin\xa0D analogue applied once daily for up to 8\xa0weeks does not result in clearance, near clearance or satisfactory control of scalp psoriasis offer:\n\na very potent corticosteroid applied up to twice daily for 2\xa0weeks for adults only or\n\ncoal tar applied once or twice daily or\n\nreferral to a specialist for additional support with topical applications and/or advice on other treatment options.In October 2012, the combined product containing calcipotriol monohydrate and betamethasone dipropionate did not have a UK marketing authorisation for this indication in children and young people. See NICE's information on prescribing medicines.\n\nConsider topical vitamin\xa0D or a vitamin\xa0D analogue alone for the treatment of scalp psoriasis only in people who:\n\nare intolerant of or cannot use topical corticosteroids at this site or\n\nhave mild to moderate scalp psoriasis.Refer to the BNF for children for information on appropriate dosing and duration of treatment.In August 2017, topical calcitriol and tacalcitol preparations available in the UK were not licensed for use in children. Topical calcipotriol preparations available in the UK vary in their licensing status for use in children and young people under\xa018. Refer to the summary of product characteristics for specific information on individual topical calcipotriol preparations. See NICE's information on prescribing medicines.\n\nDo not offer coal tar-based shampoos alone for the treatment of severe scalp psoriasis.\n\n## Topical treatment of psoriasis affecting the face, flexures and genitals\n\nOffer a short-term mild or moderate potency corticosteroid applied once or twice daily (for a maximum of 2\xa0weeks) to people with psoriasis of the face, flexures or genitals.In October 2012, moderate potency corticosteroids did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.In children and young people, the specified duration of therapy may not be appropriate. Please refer to the BNF for children for information on appropriate dosing and duration of treatment.\n\nBe aware that the face, flexures and genitals are particularly vulnerable to steroid atrophy and that corticosteroids should only be used for short-term treatment of psoriasis (1\xa0to 2\xa0weeks per month). Explain the risks to people undergoing this treatment (and their families or carers where appropriate) and how to minimise them.\n\nFor adults with psoriasis of the face, flexures or genitals if the response to short-term moderate potency corticosteroids is unsatisfactory, or they require continuous treatment to maintain control and there is serious risk of local corticosteroid-induced side effects, offer a calcineurin inhibitor applied twice daily for up to 4\xa0weeks. Calcineurin inhibitors should be initiated by healthcare professionals with expertise in treating psoriasis.In October 2012, topical calcineurin inhibitors did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.\n\nDo not use potent or very potent corticosteroids on the face, flexures or genitals.\n\nWhen prescribing topical agents at facial, flexural and genital sites take into account that they may cause irritation and inform people undergoing treatment (and their families and carers where appropriate) of these risks and how to minimise them. See also recommendation 1.3.4.2.\n\n# Phototherapy (broad- or narrowband UVB light and (PUVA)\n\nOffer narrowband ultraviolet\xa0B (UVB) phototherapy to people with plaque or guttate-pattern psoriasis that cannot be controlled with topical treatments alone. Treatment with narrowband UVB phototherapy can be given 3\xa0or 2\xa0times a week depending on patient preference. Tell people receiving narrowband UVB that a response may be achieved more quickly with treatment 3\xa0times a week.\n\nOffer alternative second- or third-line treatment when:\n\nnarrowband UVB phototherapy results in an unsatisfactory response or is poorly tolerated or\n\nthere is a rapid relapse following completion of treatment (rapid relapse is defined as greater than 50% of baseline disease severity within 3\xa0months) or\n\naccessing treatment is difficult for logistical reasons (for example, travel, distance, time off work or immobility) or\n\nthe person is at especially high risk of skin cancer.\n\nConsider psoralen (oral or topical) with local ultraviolet\xa0A (PUVA) irradiation to treat palmoplantar pustulosis.In October 2012, psoralen did not have a UK marketing authorisation for this or any indication. See NICE's information on prescribing medicines.\n\nWhen considering PUVA for psoriasis (plaque type or localised palmoplantar pustulosis) discuss with the person:\n\nother treatment options\n\nthat any exposure is associated with an increased risk of skin cancer (squamous cell carcinoma)\n\nthat subsequent use of ciclosporin may increase the risk of skin cancer, particularly if they have already received more than 150\xa0PUVA treatments\n\nthat risk of skin cancer is related to the number of PUVA treatments.\n\nDo not routinely offer co-therapy with acitretin when administering PUVA. See the MHRA Drug Safety Update on oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women (June 2019). Also see the summary of product characteristics for further information on this issue.\n\nConsider topical adjunctive therapy in people receiving phototherapy with broadband or narrowband UVB who:\n\nhave plaques at sites that are resistant or show an inadequate response (for example, the lower leg) to phototherapy alone, or at difficult-to-treat or high-need, covered sites (for example, flexures and the scalp), and/or\n\ndo not wish to take systemic drugs or in whom systemic drugs are contraindicated.\n\nDo not routinely use phototherapy (narrowband UVB, broadband UVB or PUVA) as maintenance therapy.\n\nEnsure that all phototherapy equipment is safety checked and maintained in line with local and national policy. Also see the British Association of Dermatologists service guidance and standards for phototherapy and guidelines on the measurement of ultraviolet radiation levels in ultraviolet phototherapy.\n\nHealthcare professionals who are giving phototherapy should be trained and competent in its use and should ensure an appropriate clinical governance framework is in place to promote adherence to the indications for and contraindications to treatment, dosimetry and national policy on safety standards for phototherapy. Also see the British Association of Dermatologists service guidance and standards for phototherapy and guidelines on the measurement of ultraviolet radiation levels in ultraviolet phototherapy.\n\n## Risk of skin cancer and how to minimise risk\n\nDo not use PUVA in people with psoriasis of any type and a genetic predisposition to skin cancer for example, xeroderma pigmentosum or familial melanoma.\n\nDo not use PUVA when other appropriate treatments are available in:\n\npeople with a personal history of skin cancer or\n\npeople who have already received 150\xa0PUVA treatments or\n\nchildren.\n\nUse PUVA with caution or consider other treatment options in:\n\npeople at risk of skin cancer (melanoma and non-melanoma type) – see NICE cancer service guidance on improving outcomes for people with skin tumours including melanoma\n\npeople with lighter skin types, such as skin types\xa01 or\xa02 on the Fitzpatrick scale\n\npeople who are likely to require ciclosporin or long-term methotrexate\n\nyoung people.\n\nOffer lifetime skin cancer surveillance to people treated with PUVA who have:\n\nhad more than 150\xa0PUVA treatments or\n\ndeveloped skin cancer.\n\nEnsure that a permanent record of the person's cumulative number of UV treatments is kept (for example, in a national record).\n\n# Systemic therapy\n\n## General recommendations\n\nResponsibility for use of systemic therapy should be in specialist settings only. Certain aspects of supervision and monitoring may be delegated to other healthcare professionals and completed in non-specialist settings, in which case, such arrangements should be formalised.\n\nWhen offering systemic therapy, tailor the choice of agent and dosing schedule to the needs of the individual and include consideration of:\n\nthe person's age\n\ndisease phenotype, pattern of activity and previous treatment history\n\ndisease severity and impact\n\nthe presence of psoriatic arthritis (in consultation with a rheumatologist)\n\nconception plans\n\ncomorbidities\n\nthe person's views.\n\nBe aware of the benefits of, contraindications to and adverse effects associated with systemic treatments. Explain the risks and benefits to people undergoing this treatment (and their families or carers where appropriate), using absolute risks and natural frequencies when possible. Support and advice should be provided by healthcare professionals who are trained and competent in the use of systemic therapies.\n\nWhen reviewing response to systemic therapy, take into account:\n\ndisease severity compared with baseline (for example, PASI baseline to endpoint score)\n\ncontrol of psoriatic arthritis disease activity (in consultation with a rheumatologist if necessary)\n\nthe impact of the disease on the person's physical, psychological and social wellbeing\n\nthe benefits versus the risks of continued treatment\n\nthe views of the person undergoing treatment (and their family or carers where appropriate).\n\nMonitor people using systemic treatment for all types of psoriasis in accordance with national and local drug guidelines and policy. Take appropriate action in the event of laboratory abnormalities or adverse events.\n\nOffer adjunctive topical therapy to people with psoriasis using systemic therapy to optimise treatment outcomes.\n\nOffer people with psoriasis who are starting treatment with a systemic non-biological or biological drug the opportunity to participate in long-term safety registries (for example, the British Association of Dermatologists Biologic Interventions Register).\n\n## Systemic non-biological therapy\n\nOffer systemic non-biological therapy to people with any type of psoriasis if:\n\nit cannot be controlled with topical therapy and\n\nit has a significant impact on physical, psychological or social wellbeing and\n\nor more of the following apply:\n\n\n\npsoriasis is extensive (for example, more than 10% of body surface area affected or a PASI score of more than\xa010) or\n\npsoriasis is localised and associated with significant functional impairment and/or high levels of distress (for example, severe nail disease or involvement at high-impact sites) or\n\nphototherapy has been ineffective, cannot be used or has resulted in rapid relapse (rapid relapse is defined as greater than 50% of baseline disease severity within 3\xa0months).\n\n\n\nOffer methotrexate as the first choice of systemic agent for people with psoriasis who fulfil the criteria for systemic therapy (see previous recommendation 1.5.2.1) except in the circumstances described in recommendations 1.5.2.4 and 1.5.2.12.In October 2012, methotrexate did not have a UK marketing authorisation for this indication in children and young people. See NICE's information on prescribing medicines.\n\nIn people with both active psoriatic arthritis and any type of psoriasis that fulfils the criteria for systemic therapy (see recommendation 1.5.2.1) consider the choice of systemic agent in consultation with a rheumatologist.\n\nOffer ciclosporin as the first choice of systemic agent for people who fulfil the criteria for systemic therapy (see recommendation 1.5.2.1) and who:\n\nneed rapid or short-term disease control (for example, a psoriasis flare) or\n\nhave palmoplantar pustulosis or\n\nare considering conception (both men and women) and systemic therapy cannot be avoided.In October 2012, ciclosporin did not have a UK marketing authorisation for this indication in children and young people under 16\xa0years of age. See NICE's information on prescribing medicines.\n\nConsider changing from methotrexate to ciclosporin (or vice versa) when response to the first-choice systemic treatment is inadequate.\n\nConsider acitretin for adults, and in exceptional cases only for children and young people, in the following circumstances:\n\nif methotrexate and ciclosporin are not appropriate or have failed or\n\nfor people with pustular forms of psoriasis.See the MHRA Drug Safety Update on oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women (June 2019). Also see the summary of product characteristics for further information on this issue.\n\nSee also NICE's technology appraisal guidance on apremilast for treating moderate to severe plaque psoriasis and apremilast for treating active psoriatic arthritis.\n\nUse incremental dosing of methotrexate (for example, starting with an initial dose of 5\xa0mg to 10\xa0mg once a week) and gradually increase up to an effective dose and a maximum of 25\xa0mg a week. Assess the treatment response after 3\xa0months at the target dose of methotrexate and stop treatment if the response is inadequate (for example, a decrease of less than 75% in PASI score or a decrease of less than 50% in PASI score and 5\xa0points in DLQI score).\n\nUse the lowest possible therapeutic dose of methotrexate to maintain remission.\n\nUse 2.5 to 3\xa0mg/kg a day of ciclosporin. Escalate to 5\xa0mg/kg a day after 4\xa0weeks only when there is no response to the lower dose or when rapid disease control is necessary (for example, in severe unstable disease). Assess the treatment response after 3\xa0months at the optimum dose of ciclosporin and stop treatment if the response is inadequate (for example, less than a 75% decrease in PASI score, or less than a 50% decrease in PASI score and less than 5\xa0points in DLQI score).In October 2012, ciclosporin did not have a UK marketing authorisation for this indication in children and young people under 16\xa0years of age. See NICE's information on prescribing medicines.\n\nUse the lowest possible therapeutic dose of ciclosporin to maintain remission for up to 1\xa0year. Consider other treatment options when disease relapses rapidly on stopping ciclosporin therapy (rapid relapse is defined as greater than 50% of baseline disease severity within 3\xa0months of stopping treatment). Do not use ciclosporin continuously for more than 1\xa0year unless disease is severe or unstable and other treatment options, including systemic biological therapy, cannot be used.\n\nUse incremental dosing of acitretin to minimise mucocutaneous side effects and achieve a target dose of 25\xa0mg daily in adults. Consider dose escalation to a maximum of 50\xa0mg daily when no other treatment options are available. Assess the treatment response after 4\xa0months at the optimum dose of acitretin and stop treatment if the response is inadequate, for example:\n\nin plaque-type psoriasis, less than a 75% decrease in PASI score or less than a 50% decrease in PASI score and less than 5\xa0points in DLQI score\n\nin pustular forms of psoriasis, not achieving clear or nearly clear on the static Physician's Global Assessment.See the MHRA Drug Safety Update on oral retinoid medicines: revised and simplified pregnancy prevention educational materials for healthcare professionals and women (June 2019). Also see the summary of product characteristics for further information on this issue.\n\nWhen considering the risks and benefits of treating any type of psoriasis with methotrexate, be aware that methotrexate can cause a clinically significant rise in transaminases and that long-term therapy may be associated with liver fibrosis (see recommendations 1.5.2.13 to 1.5.2.16).\n\nBefore and during methotrexate treatment, offer the person with any type of psoriasis an evaluation for potential risk of hepatotoxicity. Use standard liver function tests and serial serum procollagen III levels to monitor for abnormalities during treatment with methotrexate, taking into account pre-existing risk factors (for example, obesity, diabetes and alcohol use), baseline results and trends over time.\n\nWhen using serum procollagen III levels to exclude liver fibrosis or cirrhosis, be aware that the:\n\ntest cannot be used in children and young people\n\nresults may be unreliable in people with psoriatic arthritis\n\nestimated positive predictive value is 23% to 95% and the estimated negative predictive value is 89% to\xa0100%.\n\nProvide advice on modifiable risk factors for liver disease prior to and during therapy, including alcohol intake and weight reduction if appropriate in line with the NICE guidelines on alcohol-use disorders: prevention and obesity prevention. For further advice on how to support attitude and behavioural change, see the NICE guideline on behaviour change.\n\nSeek timely specialist advice and consider referral to a clinician with expertise in liver disease if the results of liver tests are abnormal.\n\n## Systemic biological therapy\n\nThe guideline development group did not review evidence for any aspect of the use of a first biological agent because guidance on this is already available in existing NICE technology appraisal guidance on etanercept and efalizumab, infliximab, adalimumab, ustekinumab, secukinumab and ixekizumab.\n\nBiological agents for psoriasis should be initiated and supervised only by specialist physicians experienced in the diagnosis and treatment of psoriasis.\n\nIf a person has both psoriasis and psoriatic arthritis, take into account both conditions before initiating or making changes to biological therapy and manage their treatment in consultation with a rheumatologist (see also the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis, ustekinumab for treating active psoriatic arthritis, certolizumab pegol and secukinumab for treating active psoriatic arthritis after inadequate response to DMARDs and golimumab for the treatment of psoriatic arthritis, and the NICE guideline on spondyloarthritis in over\xa016s).Also see the MHRA Drug Safety Updates on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014) and ustekinumab (Stelara): risk of exfoliative dermatitis (January 2015).\n\nWhen using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any adjustments they consider appropriate.\n\nFor guidance on treating psoriasis with adalimumab, see NICE's technology appraisal on adalimumab for the treatment of adults with psoriasis. Also see the MHRA Drug Safety Update on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014).\n\nFor guidance on treating psoriasis with etanercept, see NICE's technology appraisal on etanercept and efalizumab for the treatment of adults with psoriasis. Also see the MHRA Drug Safety Update on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014).\n\nFor guidance on treating psoriasis with infliximab, see NICE's technology appraisal on infliximab for the treatment of adults with psoriasis. Also see the MHRA Drug Safety Update on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014).\n\nFor guidance on treating psoriasis with ixekizumab, see NICE's technology appraisal on ixekizumab for treating moderate to severe plaque psoriasis.\n\nFor guidance on treating psoriasis with secukinumab, see NICE's technology appraisal on secukinumab for treating moderate to severe plaque psoriasis.\n\nFor guidance on treating psoriasis with ustekinumab, see NICE's technology appraisal guidance on ustekinumab for the treatment of adults with moderate to severe psoriasis. Also see the MHRA Drug Safety Update on ustekinumab (Stelara): risk of exfoliative dermatitis (January 2015).\n\nFor guidance on treating psoriasis with adalimumab, etanercept and ustekinumab, see NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people. Also see the MHRA Drug Safety Updates on tumour necrosis factor alpha inhibitors – risk of tuberculosis (April 2014) and ustekinumab (Stelara): risk of exfoliative dermatitis (January 2015).\n\nConsider changing to an alternative biological drug in adults if:\n\nthe psoriasis does not respond adequately to a first biological drug as defined in NICE technology appraisal guidance on etanercept and efalizumab, infliximab, adalimumab, ustekinumab, secukinumab and ixekizumab (at 10\xa0weeks after starting treatment for infliximab, 12\xa0weeks for etanercept, ixekizumab and secukinumab, and 16\xa0weeks for adalimumab and ustekinumab; primary failure) or\n\nthe psoriasis initially responds adequately but subsequently loses this response (secondary failure) or\n\nthe first biological drug cannot be tolerated or becomes contraindicated.\n\nFor adults in whom there is an inadequate response to a second biological drug, seek supra-specialist advice from a clinician with expertise in biological therapy.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Fitzpatrick scale\n\nThe scale has 6\xa0main skin types based on the colour of the skin and its reaction to sun exposure:\n\ntype 1: always burns, never tans\n\ntype 2: usually burns, tans minimally\n\ntype 3: sometimes burns mildly, tans uniformly\n\ntype 4: burns minimally, tans easily\n\ntype 5: very rarely burns, tans very easily\n\ntype 6: never burns, tans very easily.", 'Recommendations for research': "The guideline development group has made the following recommendations for research.\n\n# Assessment of disease severity and impact\n\nIn children, young people and adults with psoriasis, can tools be developed and/or existing ones further refined and validated to:\n\nassess disease severity and impact in both non-specialist and specialist healthcare settings, to facilitate assessment, appropriate referral, treatment planning and measurement of outcomes\n\nmeasure burden and cumulative effect of disease activity, severity and impact for people with both psoriasis and psoriatic arthritis?\n\n## Why this is important\n\nAssessment of disease severity and impact is fundamental to delivering high-quality health care and measuring outcomes. The evidence review indicates that the existing tools have important limitations, and have not been validated in relevant healthcare settings or in children or young people. Future research should ensure that tools are developed that capture information on site of involvement as well as extent and the impact of previous treatments. Tools should capture all aspects of impact on life including physical, psychological and social wellbeing and factors that may influence this impact, such as distress and beliefs about psoriasis. Tools that can be used by patients (as well as healthcare professionals) to assess disease severity and that encompass new technologies should be evaluated to facilitate, when appropriate, modern healthcare delivery models (for example, remote monitoring of disease activity).\n\nIn addition, understanding the true burden and effect of disease activity, severity and impact for both psoriasis and psoriatic arthritis has not previously been comprehensively studied. Capturing this information and distilling out significant factors for focused investigation will lead to better understanding of the needs of this particular group of people and the impact of treatments that benefit both disease compartments (skin and joints).\n\n# Methotrexate and risk of hepatotoxicity\n\nWhat is the impact of methotrexate compared with other approaches to care (for example, other systemic non-biological or biological treatments) on risk of significant liver disease in people with psoriasis and do risk factors such as obesity, alcohol use or diabetes alter this risk?\n\n## Why this is important\n\nThe evidence review indicates that people with psoriasis may be at risk of liver disease, and there is great uncertainty about the contributing role of methotrexate. Clinician and patient concerns about this side effect are a common cause of treatment discontinuation. However, existing studies are poorly controlled for important confounders and many are very old. Methotrexate is a low-cost intervention that is effective in an important proportion of patients. Research in this area will properly delineate the size of risk and how to minimise it. Future research should be adequately powered to detect clinically relevant liver disease, use relevant tools to do so, and properly control for relevant confounders.\n\n# Rapid escalation to systemic treatments\n\nIn people with psoriasis, does early intervention with systemic treatments improve the long-term prognosis of psoriasis severity, comorbidities (including psoriatic arthritis), or treatment-related adverse effects, and are there any clinical (for example, demographic or phenotypic) or laboratory (for example, genetic or immune) biomarkers that can be used to identify those most likely to benefit from this treatment approach?\n\n## Why this is important\n\nAt present the treatment pathway for people with psoriasis follows clinical need as no studies have been conducted to evaluate whether early intervention with systemic treatments alters prognosis. Consequently, patients with more severe disease sequence through all therapies in the treatment pathway, with a proportion requiring high-cost biological interventions to maintain disease control. The evidence indicates that there are very few treatment options for people with chronic disease, all of them are associated with side effects, many are co-dependent (for example, escalated risk of skin cancer in people treated with the phototherapy and ciclosporin sequence), and loss of response to biological therapies is a significant clinical issue. If early intervention with systemic treatments was shown to alter the prognosis, particularly if there were markers that could stratify those likely to benefit, this would be of major importance to patients, and likely to deliver much more cost-effective treatment strategies.\n\n# Self-management\n\nDo structured psoriasis-focused self-management programmes improve patient confidence, wellbeing and disease control compared with standard care?\n\n## Why this is important\n\nVirtually all patients self-manage their condition to a greater or lesser extent, and this involves complex topical applications as well as systemic therapies to be used over many years in response to fluctuating disease severity. The evidence indicates that in contrast to many chronic disorders, there are no validated programmes to help patients achieve effective self-management. Establishing a focused programme that effectively improves outcomes for patients would be of clinical benefit and likely deliver healthcare savings.\n\n# Topical therapy\n\nIn people of all ages with psoriasis:\n\n. How should topical therapies be used to maintain disease control i) safely; ii) effectively and iii) what are the health economic implications?\n\n. What are the risks of 'real life' long-term corticosteroid use, are there particular people at risk and what strategies can be used to modify or avoid risks?\n\n## Why this is important\n\nCurrently, topical therapies, in some form or another, are prescribed to virtually everyone with psoriasis, often as first line psoriasis treatment and they are also frequently used adjunctively with other interventions. There is a wide array of potential topical agents available and further research specifically targeting therapeutic strategies together with sequencing of topical agents for maintaining disease control in the long term continues to deserve focused attention. In addition, exploration of the risks associated with long-term corticosteroid use and strategies aimed at modifying risk would be a critical element of this research to fill the current gap in the literature.", 'Appendix: Information to facilitate discussion of risks and benefits of treatments for people with psoriasis': 'Data is provided for the proportions of people achieving remission, withdrawing due to adverse events and experiencing specific adverse events (as prioritised by the guideline development group [GDG]) for interventions that have been recommended in this guideline. Data are based on pooled estimates where possible and from trials with populations and dosing appropriate to the intervention. For full details of the duration of treatment and dosing schedules please refer to the main text of the guideline.\n\nText is labelled with an asterisk when the GDG had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.\n\nFor a landscape version of the following table, please refer to the full guideline.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\nOnce daily: 220/1000\n\nTwice daily: 487/1000\n\n\n\nPlacebo:\n\nOnce daily: 76/1000\n\nTwice daily: 122/1000\n\nIntervention:\n\nOnce or twice daily: 23/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 29/1000\n\nIntervention:\n\nSkin atrophy\n\nTwice daily: 1.9/1000\n\n\n\nPlacebo:\n\nSkin atrophy\n\nTwice daily: 3.2/1000\n\nChildren with chronic plaque psoriasis of trunk and limbs\n\nNote: the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size\n\nIntervention:\n\nTwice daily: 605/1000\n\n\n\nPlacebo:\n\nTwice daily: 441/1000\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nScalp psoriasis\n\nIntervention:\n\nOnce daily: 387/1000\n\n\n\nPlacebo:\n\nOnce daily: 219/1000\n\nIntervention:\n\nOnce daily: 81/1000\n\n\n\nPlacebo:\n\nOnce daily: 52/1000\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\nOnce or twice daily: 394/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 77/1000\n\nIntervention:\n\nOnce daily: 10/1000\n\nTwice daily: 25/1000\n\n\n\nPlacebo:\n\nOnce daily: 79/1000\n\nTwice daily: 0/1000\n\nIntervention:\n\nSkin atrophy\n\nOnce or twice daily: 5.5/1000\n\n\n\nPlacebo:\n\nSkin atrophy\n\nOnce or twice daily: 0/1000\n\n\n\nScalp psoriasis\n\nIntervention:\n\nOnce or twice daily: 632/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 223/1000\n\nIntervention:\n\nOnce or twice daily: 9.5/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 41/1000\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nNote: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\n/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, calcipotriol:\n\nTwice daily: 469/1000\n\nIntervention:\n\n/1000\n\n\n\nActive comparator, calcipotriol:\n\nTwice daily: 26/1000\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\nOnce daily: 494/1000\n\n\n\nNo placebo\n\n\n\nActive comparator:\n\nvitamin D once daily: 193/1000\n\nIntervention:\n\nOnce daily: 7.5/1000\n\n\n\nActive comparator:\n\nVitamin D once or twice daily: 27/1000\n\nIntervention:\n\nSkin atrophy\n\nOnce daily: 4.2/1000\n\n\n\nActive comparator:\n\nSkin atrophy\n\nVitamin D twice daily: 1.8/1000\n\nScalp psoriasis\n\nNote: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nIntervention:\n\nOnce daily: 800/1000\n\n\n\nPlacebo:\n\nOnce daily: 500/1000\n\nIntervention:\n\nOnce daily: 17/1000\n\n\n\nPlacebo:\n\nOnce daily: 0/1000\n\n\n\nNote: the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\n\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\nOnce or twice daily: 625/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 13/1000\n\nIntervention:\n\nOnce or twice daily: 4.6/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 6.0/1000\n\nIntervention:\n\nSkin atrophy\n\nOnce or twice daily: 23/1000\n\n\n\nPlacebo:\n\nSkin atrophy\n\nOnce or twice daily: 0/1000\n\nScalp psoriasis\n\nIntervention:\n\nOnce or twice daily: 646/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 80/1000\n\nIntervention:\n\nOnce or twice daily: 0/1000\n\n\n\nPlacebo:\n\nOnce or twice daily: 5.9/1000\n\nIntervention:\n\nSkin atrophy\n\nOnce or twice daily: 0/1000\n\n\n\nPlacebo:\n\nSkin atrophy\n\nOnce or twice daily: 11/1000\n\nNote: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\nOnce daily: 58/1000\n\n\n\nPlacebo:\n\nOnce daily: 20/1000\n\nIntervention:\n\nOnce daily: 107/1000\n\n\n\nPlacebo:\n\nOnce daily: 44/1000\n\nIntervention:\n\nSkin atrophy\n\nOnce daily: 0/1000\n\n\n\nPlacebo:\n\nSkin atrophy\n\nOnce daily: 0/1000\n\nNote: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\nIntervention:\n\nOnce daily: 430/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, calcipotriol:\n\nTwice daily: 588/1000\n\nIntervention:\n\nOnce daily: 82/1000\n\n\n\nActive comparator, calcipotriol:\n\nTwice daily: 39/1000\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nNote: two-third of studies reported home-use of dithranol and in one-third of studies, the setting was unclear.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nChronic plaque psoriasis of trunk and limbs\n\n\n\nIntervention:\n\nOnce or twice daily: 111/1000 to 519/1000 depending on formulation and follow-up\n\n\n\nNo placebo\n\n\n\nActive comparator, calcipotriol:\n\nTwice daily: 214/1000 to 723/1000 depending on follow-up\n\nIntervention:\n\nOnce or twice daily: 0 to 56/1000 depending on formulation and follow-up\n\n\n\nActive comparator, calcipotriol:\n\nTwice daily: 0 to 40/1000 depending on follow-up\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nNote: the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nPsoriasis of the face and flexures\n\nIntervention:\n\nTwice daily: 652/1000\n\n\n\nPlacebo:\n\nTwice daily: 309/1000\n\nIntervention:\n\nTwice daily: 0/1000\n\n\n\nPlacebo:\n\nTwice daily: 25/1000\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\n) The guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.\n\n) No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nPopulation (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nPsoriasis of the flexures\n\nIntervention:\n\nTwice daily: 714/1000\n\n\n\nPlacebo:\n\nTwice daily: 207/1000\n\nIntervention:\n\nTwice daily: 0/1000\n\n\n\nPlacebo:\n\nTwice daily: 0/1000\n\nIntervention:\n\nSkin atrophy\n\nTwice daily: 0/1000\n\n\n\nPlacebo:\n\nSkin atrophy\n\nTwice daily: 0/1000\n\n\n\n) The guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.\n\n) No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nIntervention and population (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nNBUVB versus PUVA\n\n\n\nPlaque psoriasis\n\nIntervention:\n\nTwice weekly: 647/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, oral PUVA:\n\nTwice weekly: 915/1000\n\nIntervention:\n\nTwice weekly: 38/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, oral PUVA:\n\nTwice weekly: 47/1000\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nPUVA (oral)\n\n\n\nPalmoplantar pustulosis\n\n\n\nNote: No active comparator. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nIntervention:\n\nto 4 times weekly: 941/1000\n\n\n\nPlacebo, no treatment:\n\n/1000\n\nIntervention:\n\nto 4 times weekly: 29/1000\n\n\n\nPlacebo, no treatment:\n\n/1000\n\n\n\nIntervention:\n\nBurn\n\nto 4 times weekly: 147/1000\n\n\n\nPlacebo, no treatment:\n\n/1000\n\n\n\nPUVA (cream)\n\n\n\nPalmoplantar pustulosis\n\n\n\n\n\nIntervention:\n\ntimes weekly: 952/1000\n\n\n\nNo placebo\n\n\n\nActive comparator,\n\nNBUVB:\n\ntimes weekly: 429/1000\n\n\n\nIntervention:\n\ntimes weekly: 45/1000\n\n\n\nNo placebo\n\n\n\nActive comparator,\n\nNBUVB:\n\ntimes weekly: 0/1000\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nNBUVB plus vitamin D or analogues\n\n\n\nPlaque psoriasis\n\n\n\n\n\nIntervention:\n\ntimes weekly UV + twice daily topical: 900/1000\n\n\n\nNo placebo\n\n\n\nActive comparator,\n\nNBUVB alone:\n\ntimes weekly: 611/1000\n\nIntervention:\n\ntimes weekly UV + twice daily topical: 50/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, NBUVB alone:\n\ntimes weekly: 28/1000\n\nIntervention:\n\nBurn\n\ntimes weekly UV + twice daily topical: 200/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, NBUVB alone:\n\nBurn\n\ntimes weekly: 111/1000\n\nBBUVB plus vitamin D or analogues\n\n\n\nPlaque psoriasis\n\nIntervention:\n\nUp to 3 times weekly UV + twice daily topical: 449/1000 8\xa0weeks\n\n\n\nNo placebo\n\n\n\nActive comparator, BBUVB alone:\n\nup to 3 times weekly: 208/1000\n\nIntervention:\n\nUp to 3 times weekly UV + twice daily topical: 41/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, BBUVB alone:\n\nup to 3 times weekly: 19/1000\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nLiquor carbonic distillate (equivalent 2.3% coal tar) plus NBUVB\n\n\n\nPlaque psoriasis\n\nIntervention:\n\nClear (3 times weekly UV + twice daily topical): 583/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, NBUVB alone:\n\ntimes weekly: 500/1000\n\nIntervention:\n\ntimes weekly UV + twice daily topical: 0/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, NBUVB alone:\n\ntimes weekly: 0/1000\n\nIntervention:\n\nBurn\n\ntimes weekly UV + twice daily topical: 167/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, NBUVB alone:\n\nBurn\n\ntimes weekly: 167/1000\n\nDithranol plus BBUVB\n\n\n\nPsoriasis\n\nIntervention:\n\ntimes weekly UV + twice daily topical: 625/1000\n\n\n\nNo placebo\n\n\n\nActive comparator, BBUVB alone:\n\ntimes weekly: 458/1000\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nIntervention: Not available\n\n\n\nActive comparator: Not available\n\nAbbreviations: BBUVB, broadband UVB; NBUVB, narrowband UVB; PUVA, psoralen plus UVA; UVA, ultraviolet A; UVB, ultraviolet B.\n\nNote: for all the interventions except NBUVB versus PUVA, the guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.\n\nIntervention and population (psoriasis phenotype)\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity\n\nNumbers experiencing serious or named adverse events\n\nMethotrexate; incremental dosing (plus folic acid)\n\n\n\nChronic plaque psoriasis\n\nIntervention:\n\n/1000\n\n\n\nPlacebo:\n\n/1000\n\nIntervention:\n\n/1000*\n\n\n\nPlacebo:\n\n/1000*\n\nIntervention:\n\nElevated liver enzymes (>1.5 to 2.5 ULN): 91/1000*\n\n\n\nPlacebo:\n\nElevated liver enzymes (>1.5 to 2.5 ULN): 75/1000*\n\nCiclosporin\n\n\n\nChronic plaque psoriasis\n\nIntervention:\n\nto 3 mg: 232/1000\n\nmg: 600/1000\n\n\n\nPlacebo:\n\n/1000\n\nIntervention:\n\n/1000*\n\nPlacebo:\n\n/1000*\n\nIntervention:\n\nHypertension:\n\n/1000\n\nDecrease in GFR >15%:\n\nmg/kg: 333/1000\n\nmg/kg: 500/1000*\n\n\n\nPlacebo:\n\nHypertension:\n\n/1000\n\nDecrease in GFR >15%:\n\n/1000*\n\nCiclosporin\n\n\n\nPalmoplantar pustulosis\n\nIntervention:\n\n/1000\n\n\n\nPlacebo:\n\n/1000\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nIntervention:\n\nHypertension:\n\n/1000*\n\n\n\nPlacebo:\n\nHypertension\n\n/1000*\n\nAcitretin – 25 mg\n\n\n\nPlaque, pustular and erythrodermic psoriasis*\n\nIntervention:\n\n/1000*\n\n\n\nPlacebo:\n\n/1000*\n\nIntervention:\n\n/1000*\n\n\n\nPlacebo:\n\n/1000*\n\nIntervention:\n\nCheilitis:\n\n/1000\n\nHair loss:\n\n/1000\n\nElevated liver enzymes (>ULN):\n\n/1000\n\nElevated cholesterol (>ULN):\n\n/1000*\n\n\n\nPlacebo:\n\nCheilitis:\n\n/1000\n\nHair loss:\n\n/1000\n\nElevated liver enzymes (>ULN):\n\n/1000\n\nElevated cholesterol (>ULN):\n\n/1000*\n\nAbbreviations: GFR, glomerular filtration rate; ULN, upper limit of normal.\n\nNote: The guideline development group (GDG) had very low confidence in the absolute estimates, for example, due to confounding and inadequate sample size.\n\nIntervention and population (psoriasis phenotype)\n\nPrior biologics received\n\nNumbers achieving remissions (clear, nearly clear, or PASI75)\n\nNumbers experiencing withdrawal due to drug toxicity or serious adverse events\n\nInfliximab\n\n\n\nAdults with severe plaque psoriasis and prior biologic exposure\n\n\n\n\n\nUnclear\n\nIntervention:\n\n/1000\n\n\n\nPlacebo:\n\n/1000*\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nEtanercept\n\n\n\nAdults with severe plaque psoriasis and prior biologic exposure*\n\nIncluded etanercept, infliximab, and adalimumab (proportions unclear)*\n\nIntervention:\n\n/1000*\n\n\n\nPlacebo: Not available*\n\n\n\nActive comparator, ustekinumab:\n\n/1000*\n\nIntervention: Not available*\n\nPlacebo: Not available*\n\nActive comparator: Not available*\n\nUstekinumab\n\n\n\nAdults with severe plaque psoriasis and prior biologic exposure\n\nIncluded etanercept, infliximab, and adalimumab (proportions unclear)\n\nIntervention:\n\n/1000\n\n\n\nPlacebo:\n\n/1000\n\nIntervention: Not available\n\n\n\nPlacebo: Not available\n\nAdalimumab\n\n\n\nAdults with severe plaque psoriasis*\n\nEtanercept (32.1%), alefacept (23.1%), ustekinumab (23.1%), efalizumab (21.8%), infliximab (20.5%) and other (17.9%)*\n\nIntervention:\n\n/1000*\n\n\n\nPlacebo: Not available*\n\n\n\nActive comparator, no prior biologic:\n\n/1000*\n\nIntervention: Not available*\n\nPlacebo: Not available*\n\nActive comparator: Not available*\n\nNote: For the interventions infliximab and ustekinumab, there were no active comparators. An active comparator will only be included if no placebo comparison is available; the standard intervention will be chosen if multiple active comparators are available.\n\nIntervention and outcome(s)\n\nPopulation – psoriasis phenotype\n\nNumber experiencing event\n\nPsoralen plus ultraviolet A (PUVA; oral)\n\n\n\nSkin cancer – squamous cell carcinoma (SCC)\n\nPlaque (84%), guttate (12%) and erythrodermic (4%) psoriasis\n\nRelative risk compared with the general population:\n\nPUVA exposure <100; relative risk (RR) <100\n\nPUVA exposure 100 to 159; RR 100 to 159\n\nPUVA exposure 160 to 336; RR 160 to 336\n\nPUVA exposure ≥337; RR ≥337\n\n\n\nAbsolute increase in risk:\n\nPUVA exposure <100; SCCs 18; 1.7% increase in 10-year risk\n\nPUVA exposure 100 to 159; SCCs 15; 2.7% increase in 10-year risk\n\nPUVA exposure 160 to 336; SCCs 68; 8.8% increase in 10-year risk\n\nPUVA exposure ≥337; SCCs 34; 12.7% increase in 10-year risk\n\nNarrowband UVB (NBUVB)\n\n\n\nSkin cancer\n\n\n\nInsufficient data available\n\nInsufficient data available\n\nMethotrexate\n\n\n\nLiver fibrosis, bone marrow suppression and pneumonitis\n\nNo long-term data available\n\nNo long-term data available\n\nCiclosporin\n\n\n\nHypertension, renal impairment, gout and hyperuricaemia\n\nNo long-term data available\n\nNo long-term data available\n\nAcitretin\n\n\n\nHyperlipidaemia, hepatotoxicity, skeletal adverse events and cheilitis\n\nNo long-term data available\n\nNo long-term data available'}
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https://www.nice.org.uk/guidance/cg153
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This guideline covers assessing and managing psoriasis in adults, young people and children. It aims to improve long-term disease control and quality of life for people with psoriasis.
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aedb9c48317d3c2b005214e42e83853a38e872e6
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nice
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Cetuximab for treating recurrent or metastatic squamous cell cancer of the head and neck
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Cetuximab for treating recurrent or metastatic squamous cell cancer of the head and neck
Evidence-based recommendations on cetuximab (Erbitux) for treating recurrent or metastatic squamous cell cancer of the head and neck in adults.
# Recommendations
Cetuximab in combination with platinum-based chemotherapy is recommended as an option for treating recurrent or metastatic squamous cell cancer of the head and neck in adults only:
if the cancer started in the oral cavity and
when the company provides the drug in line with the commercial access agreement with NHS England.
These recommendations are not intended to affect treatment with cetuximab that was started within the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Cetuximab (Erbitux; Merck) is a recombinant monoclonal antibody that blocks human epidermal growth factor receptor (EGFR). It inhibits the proliferation of cells that depend on EGFR activation for growth.
Marketing authorisation
Cetuximab has a UK marketing authorisation 'for the treatment of patients with squamous cell cancer of the head and neck… in combination with platinum-based chemotherapy for recurrent and/or metastatic disease'.
Adverse reactions
Very common adverse reactions with cetuximab include skin reactions, which occur in more than 80% of patients, and low blood magnesium levels, mild or moderate infusion-related reactions (such as fever, chills, nausea, vomiting, headache, dizziness or shortness of breath), inflammation of the lining of the digestive tract, and raised liver enzymes, which all occur in 10% or more of patients. Common side effects (occurring in 1% or more and less than 10% of patients) include severe infusion-related reactions (including anaphylactic reactions), dehydration, low blood calcium levels, anorexia, headache, conjunctivitis, fatigue, diarrhoea, nausea and vomiting. Cetuximab in combination with platinum-based chemotherapy may increase the frequency of severe leukopenia or severe neutropenia, and this may lead to a higher rate of infectious complications than platinum-based chemotherapy alone. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Cetuximab is administered intravenously. It is used in combination with platinum-based chemotherapy followed by cetuximab as maintenance therapy until disease progression. The initial loading dose is 400 mg/m2 body surface area (BSA) given at a rate not exceeding 5 mg/minute. Subsequent weekly maintenance doses are 250 mg/m2 BSA each.
Price
The list price of cetuximab is £178.10 for a 5 mg/ml 20‑ml vial and £890.50 for a 5 mg/ml 100‑ml vial (excluding VAT; British national formulary online, accessed February 2017). Assuming that vials are not shared among patients, a person with a BSA of 1.75 m2 would have 7 vials per loading dose and 5 vials per maintenance dose, equating to a cost of £1,246.70 for the loading dose and £890.50 for each maintenance dose.
The pricing arrangement considered during guidance development was one in which the company (Merck) had agreed a patient access scheme with the Department of Health. This scheme would have provided a simple discount to the list price of cetuximab with the discount applied at the point of purchase or invoice. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS. This has now been replaced by a commercial access agreement between the company and NHS England, which incorporates this same simple discount applied at the point of purchase or invoice of all cetuximab but also includes additional and separate commercial arrangements. The financial terms of the agreement are commercial in confidence.# Evidence
The appraisal committee (section 6) considered evidence submitted by Merck and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). Sections 4.2 to 4.11 reflect the committee's consideration of the evidence submitted in the original appraisal. Sections 4.12 to 4.24 reflect the committee's considerations of the evidence submitted for the Cancer Drugs Fund reconsideration. The company focused on the subgroup of patients with oral cavity cancer from the EXTREME trial, and cost-effectiveness analyses using a patient access scheme that provides cetuximab at a reduced cost. After consultation, the company submitted additional 5‑year follow‑up data for this subgroup of patients, and a revised patient access scheme with a further discount. The level of discount is commercial in confidence.
See the committee papers for full details of the Cancer Drugs Fund reconsideration evidence, and the history for full details of the evidence used in NICE's original technology appraisal guidance on cetuximab for the treatment of recurrent and/or metastatic SCCHN.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of cetuximab, having considered evidence on the nature of recurrent or metastatic squamous cell cancer of the head and neck (SCCHN) and the value placed on the benefits of cetuximab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical effectiveness (NICE technology appraisal guidance 172)
The committee reviewed the evidence available on the clinical effectiveness of cetuximab as presented in the company's submission and the evidence review group's (ERG's) report. It noted that there was only 1 relevant randomised controlled trial that compared cetuximab plus platinum-based chemotherapy with chemotherapy alone in patients with recurrent or metastatic SCCHN (the EXTREME trial). The committee noted that few of the patients included in the clinical trial were from the UK although many were from other European countries. It was also aware of the ERG's concern that the patients in the trial appeared younger and fitter, on the basis of a higher Karnofsky performance status (KPS), than patients in UK clinical practice. Therefore, there was some uncertainty about whether the benefits of cetuximab would be seen in patients with this condition in the UK. Additionally, the committee heard from the clinical experts that most patients presenting with recurrent or metastatic SCCHN in the UK were older and had poorer general health than those recruited to the trial. However, patients for whom platinum-based chemotherapy would be considered appropriate were more likely to be of a similar age and performance status to those in the EXTREME trial. Overall, the committee accepted the evidence from the clinical experts that the results of the EXTREME trial would be applicable to the UK population.
The committee discussed the reported results from the clinical trial. It noted that the company had presented results for the total population of the trial and for a number of pre-planned subgroups. It noted the statistically significant improvement in overall survival associated with cetuximab in the total population represented in the trial. The committee was aware that, in the pre-planned subgroup analyses, only tumour location showed a significant interaction with treatment, suggesting greater effectiveness in tumours in the oral cavity. The committee heard from the clinical experts that patients with tumours in the oral cavity have a relatively favourable prognosis compared with the average prognosis for recurrent or metastatic SCCHN. The experts were not aware of any biological reason for cetuximab to be more clinically effective in oral cavity tumours. The committee accepted that the trial showed the efficacy of cetuximab plus platinum-based chemotherapy in patients with recurrent or metastatic SCCHN, but it was not persuaded that the evidence supported using the subgroup estimate for clinical effectiveness in the economic model.
The committee reviewed the additional cost-effectiveness analyses submitted by the company for additional subgroups based on age (younger than 65 years) and KPS (KPS of 90 or more and KPS of 80 or more). It was aware that the pre-planned subgroup analyses in the clinical study presented results for patients with a KPS of 80 or more (rather than 90 or more) and for patients who were younger than 65 years, but subgroups combining age and KPS were not included. The committee noted the concerns raised by the ERG about the validity of the modelled overall survival gains for the additional subgroup and whether the number of patients included was sufficient to provide robust evidence of efficacy. It was therefore not persuaded that the evidence provided by the company supported the predicted life years gained for the combined age and KPS subgroup. On this basis, the committee concluded that the estimates of cost effectiveness for the subgroup of patients who were younger than 65 years with a KPS of 90 or more could not be considered reliable.
The committee discussed the adverse effects of cetuximab treatment. It noted that the incidence of severe adverse events in the cetuximab plus platinum-based chemotherapy group and the platinum-based chemotherapy only group were generally similar with the exception of acne and acneiform dermatitis, which were reported only for the cetuximab plus platinum-based chemotherapy group. The clinical experts and a patient expert advised the committee that the adverse events reported for the trial were consistent with those seen in clinical practice when cetuximab had been used for locally advanced SCCHN and colorectal cancer.
# Cost effectiveness (NICE technology appraisal guidance 172)
The committee discussed the cost effectiveness of cetuximab plus platinum-based chemotherapy compared with platinum-based chemotherapy alone. It was aware that the incremental cost-effectiveness ratios (ICERs) presented by the company for the base-case and pre-planned subgroup analyses were substantially higher than those normally considered to be an acceptable use of NHS resources. In addition, the committee noted the concerns raised by the ERG about extrapolation of the trial results to estimate survival in the economic model, and the uncertainty about the number of patients available for analysis in each of the pre-planned subgroups. The committee noted the exploratory analyses done by the ERG using alternative assumptions and parameters in the economic model. The committee concluded that there remained considerable uncertainty around the results of the company's analyses, and that it was plausible that the true cost-effectiveness estimate for cetuximab plus platinum-based chemotherapy would be even higher than that presented by the company.
# End-of-life considerations (NICE technology appraisal guidance 172)
The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy, and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
No alternative treatment with comparable benefits is available through the NHS.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.
The committee discussed whether cetuximab, in combination with platinum-based chemotherapy for the treatment of recurrent or metastatic SCCHN, fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It considered the criteria only in relation to the estimate of overall survival for the cohort population because it did not consider the subgroup data to be robust (see sections 4.3 and 4.4). The committee noted from the EXTREME trial that life expectancy for patients treated with chemotherapy alone was unlikely to be more than 24 months and could be as low as 7 months. It observed that the trial data suggested that cetuximab plus platinum-based chemotherapy extended median survival by 2.7 months compared with platinum-based chemotherapy alone. The committee was concerned about the uncertainty associated with this estimate because of the wide confidence interval. It was also aware that the predicted life years gained from the economic modelling for this group was 0.187, reflecting a gain in overall survival of approximately 2.2 months. The committee therefore did not consider that this estimate of gain in overall survival was in keeping with the criteria relating to extension of life or that the addition of cetuximab represented a marked change from current treatment for SCCHN.
The committee also understood that an estimated 3,000 people in England and Wales are diagnosed with recurrent or metastatic SCCHN every year. However, based on the evidence from clinical experts, cetuximab plus platinum-based chemotherapy would be appropriate for only a small proportion of these patients (that is, those whose disease was unsuitable for local treatment and who were well enough to have platinum-based chemotherapy). However, the committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that cetuximab was licensed for a number of other indications involving much larger patient groups.
In summary, the committee was not persuaded that the use of cetuximab plus platinum-based chemotherapy fulfilled all the criteria to be considered as a life-extending, end-of-life treatment. It came to this conclusion taking into account the importance of supporting the development of innovative treatments licensed for small groups of patients who have an incurable illness.
The committee concluded that cetuximab, given in combination with platinum-based chemotherapy for the treatment of recurrent or metastatic SCCHN, could not be recommended as a cost-effective use of NHS resources. The committee noted that some people may be currently having cetuximab in combination with platinum-based chemotherapy for this indication, and recommended that these people should have the option to continue treatment until they and their clinician consider it appropriate to stop.
# Cancer Drugs Fund reconsideration
This appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck. At its first reconsideration meeting, the committee considered the company's submission that:
included only the oral cavity cancer subgroup
included a patient access scheme that would have provided a simple discount to the list price of cetuximab (this scheme was subsequently replaced by a commercial access agreement between the company and NHS England )
addressed some of the committee's preferred assumptions (see section 4.6).The committee also considered the ERG's critique of the company's reconsideration submission and the ERG's exploratory analyses.
At its second reconsideration meeting, the committee considered the company's responses to the appraisal consultation document, specifically:
additional 5‑year survival data for the oral cavity cancer subgroup from the EXTREME trial
a new economic analysis based on the updated trial data
a revised patient access scheme providing a further discount to that considered at the first meeting.The committee also considered the ERG's critique of the company's responses to the appraisal consultation document and the ERG's exploratory analyses.
## Cetuximab in the clinical management of head and neck cancer
The committee heard from the clinical experts that the EXTREME trial population represented patients who would be offered cetuximab plus platinum-based chemotherapy in the UK. The clinical experts also noted that the comparator used in the trial is the standard of care in the UK, although the clinical effectiveness of cisplatin plus fluorouracil was not studied in clinical trials before being introduced into clinical practice. The clinical experts stated that cetuximab is used according to the protocol described in the EXTREME trial in their clinics, and that they have seen similar outcomes to the trial. However, they noted that they were aware of other clinicians using different dosing protocols in the UK. At the second meeting, the Cancer Drugs Fund clinical lead provided anecdotal evidence that cetuximab is always given weekly with chemotherapy, but that it may be given every 1 or 2 weeks during the maintenance phase. If it is given every 2 weeks, the dose is doubled so that the overall cumulative dose remains the same. This regimen is not consistent with that set out in the summary of product characteristics for cetuximab. The committee heard from the company that there are no data available on the clinical effectiveness of this regimen in people with SCCHN, but that it is safe in people with colorectal cancer. The committee concluded that cetuximab should be appraised according to the regimen set out in the summary of product characteristics but it supported the potential advantages in studying different dosing regimens.
## Subgroup analysis
The committee noted that the company had based its submission on a subgroup of patients with oral cavity cancer. It also noted that, in its earlier deliberations, it had not been persuaded that the estimate from the subgroup was sufficiently reliable for use in the economic model. The company argued that, in the EXTREME trial, these patients had a poorer prognosis and gained greater benefit from cetuximab than the overall population of the trial. It noted that at the 2‑year cut‑off in the trial, cetuximab increased median overall survival by 6.6 months in patients with tumours of the oral cavity compared with an increase of 2.7 months in the whole population of the trial. The results for median progression-free survival were also better in the oral cavity cancer subgroup than in the whole trial population (3.3 months compared with 2.3 months). However, the committee noted that the subgroup was small (n=88) compared with the whole trial population (n=442), adding to the uncertainty inherent when considering estimates of effectiveness based on subgroup data. The clinical experts at the meeting confirmed that, in the EXTREME trial, patients with tumours in the oral cavity had a poorer prognosis than people with tumours in other locations. They also confirmed that, before the EXTREME trial, no other treatments had been shown to be of benefit in clinical trials in this patient group. This suggested an unmet need in this patient group, who were often older and had comorbidities. However, the experts were not aware of a biological mechanism that could explain why cetuximab would differ in its relative effects between different tumour types. The committee also discussed the additional published evidence on epidermal growth factor receptor (EGFR) overexpression in SCCHN that the company had provided after consultation. The committee concluded that it was possible that cetuximab might have greater benefits in oral cavity tumours but that the evidence in support of this was limited.
## Progression-free and overall survival from the EXTREME trial
The committee noted that the company's new model, submitted after consultation, used 5‑year survival data from the oral cavity cancer subgroup of the EXTREME trial directly to estimate progression-free survival and overall survival in both trial arms (that is, it did not use any survival curve fitting). The committee noted that the difference in mean overall survival seen with cetuximab after 5 years of follow‑up was similar to the difference in median overall survival seen after 2 years. It also noted that the difference in mean progression-free survival after 5 years was increased compared with the median progression-free survival after 2 years. The ERG noted that only 1 patient in the cetuximab plus chemotherapy arm of EXTREME remained event free at 5‑year follow‑up. The ERG argued that this patient alone contributed substantially to the mean progression-free and overall survival benefit, and that this could influence the results in favour of cetuximab plus chemotherapy. The ERG had attempted to adjust the survival analyses to take into account the 'long tail' associated with patients who remained event free. Taking this adjustment into account, the ERG estimated slightly shorter progression-free and overall survival values. The company disputed this approach, arguing that this patient also contributed to cumulative costs as well as quality-adjusted life-year gains. The committee noted that although patients whose disease responds extremely well to treatment are not uncommon in clinical trials, the extraordinary response seen in this single patient added to the uncertainty in the estimates resulting from the oral cavity cancer subgroup.
The ERG noted that the company had not supplied detailed clinical trial data in its response to consultation to allow for an analysis of survival after disease progression in the new model. However, the ERG was able to estimate the mean post-progression survival gain attributable to cetuximab plus chemotherapy from the difference between the mean overall survival and mean progression-free survival. This indicated that more than a third of the overall survival benefit may come after disease progression. The ERG believed that this is uncommon in trials of advanced cancer treatments with chemotherapy, in which the disease more often reverts to following the typical progressive disease trajectory, independent of the choice of previous treatment. The committee noted that at its first reconsideration meeting, the clinical experts had considered some survival gain after disease progression to be plausible because of the potential immune effects of cetuximab and a lower disease burden because of tumour response. However, the committee concluded that even if this were the case, the extent of survival gain after disease progression was uncertain.
## Choice of utility values
The committee noted that after consultation, the company had estimated utilities based on quality-of-life data from the oral cavity cancer subgroup of the EXTREME trial, rather than the full trial population. It had, however, noted in the first committee meeting that the questionnaire used did not include a measure of adverse events. The data were converted to utilities using an algorithm. The company used the same utility estimates for both treatment arms in the post-progression health state, but different utility estimates for both treatment arms in the pre-progression health state. The ERG considered that the data from the EXTREME trial did not allow for reliable utility estimates for the 2 treatment arms. It stated that there was no justification for not using a common utility estimate for the pre-progression health state. The committee heard from the company that its quality-of-life questionnaire, on which its utility estimates were based, was not mandatory and was most likely to have omitted the most sick patients. When the ERG used a common utility value for both treatment arms, the ICER increased. The committee noted that, contrary to the implications of the company's utility values, adverse events were more frequent for patients having cetuximab than for those having standard therapy in the oral cavity subgroup. The committee concluded that the pre-progression utility value used by the company may have resulted in an ICER for cetuximab that was too low, and that it preferred the approach taken by the ERG.
## Drug acquisition costs
The ERG identified an error in the method used to calculate drug costs in the company's new model, submitted after consultation. Correcting this error resulted in an increase in the number of vials used per patient session and a corresponding increase in the ICER. The company did not provide details of the body surface area (BSA) measurements from the oral cavity cancer subgroup in its response to consultation. It had previously considered that the mean BSA in EXTREME was lower than that of people with head and neck cancer in the UK. The ERG re‑estimated the drug doses based on the mean value and the distribution seen in BSA in a UK audit of people with head and neck cancer. It also applied an adjustment for gender ratio based on the EXTREME trial. Cetuximab is available in 100‑mg vials; these adjustments suggested that 7 to 8 vials are needed for initial dosing, and 4 to 5 vials are needed for each subsequent dose. Adjusting for vial wastage also increased the drug costs by an estimated 11%. These adjustments resulted in a higher ICER for cetuximab than that in the company's base case. The committee concluded that the ERG's corrected calculation, including its adjustments, provided a better estimate of the costs of treatment for patients in the NHS.
## Treatment administration costs
The committee noted the company has collected evidence in the UK that suggests cetuximab may be given less often in the maintenance phase than the standard weekly dosing regimen used in the EXTREME trial. However, the committee and ERG agreed that it is not clear how this is managed in terms of the total dose administered per cycle, the extent of this dosing in practise and how different regimens affect treatment outcomes. The ERG considered that it was not appropriate to model the patient survival outcomes reported in the EXTREME trial while also reducing treatment administration costs; this fails to consider how variations in treatment intensity and dose timing may affect treatment effectiveness. The committee noted that EXTREME is the only source of evidence relevant to the small subgroup being considered, and that the trial used weekly dosing. It agreed with the ERG that there was too much uncertainty attached to this deviation in dosing regimen to warrant its inclusion in the cost-effectiveness analysis, and that only the standard weekly dosing regimen should be included in the analysis.
## Discounting
The committee noted that the company had not applied standard discounting to the new base case; the company explained that it did not consider this to be a major limitation, given the short time horizon of the model (5 years). The committee concluded that discounting should be applied to the revised base case, noting that this would have only a small effect on the ICER.
## End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that, at 5‑year follow‑up in EXTREME, the mean life expectancy of people with oral cavity cancer was less than 24 months. It also noted that the difference in mean survival was similar to the difference in median survival seen after 2 years (that is, 6.6 months). The committee was aware of the uncertainty surrounding the magnitude of the survival benefit because of the limited number of people included in the oral cavity cancer subgroup. Nonetheless, despite this uncertainty, the committee agreed that it was plausible that the survival benefit in the subgroup was larger than that in the whole population. It therefore concluded that all of the end-of-life criteria were met for people with oral cavity cancer treated with cetuximab.
## Conclusions
The committee discussed the most plausible ICER for cetuximab plus platinum-based chemotherapy compared with platinum-based chemotherapy alone. To protect the level of discount, the ICERs including the patient access scheme were considered commercial in confidence and cannot be presented here. The committee went on to discuss the range of cost-effectiveness estimates. It highlighted that:
There remained some uncertainty about the clinical-effectiveness evidence for cetuximab in oral cavity cancer, particularly because of the small subgroup size in the EXTREME trial (see section 4.15).
The committee preferred common utility values, as used by the ERG (see section 4.18).
It would have preferred drug costs to be estimated using the BSA values from the UK audit study, with adjustment for the gender ratio (see section 4.19).The committee assumed that the oral cavity subgroup data were accurate, and that cetuximab was indeed more effective in this subgroup. On this basis, it agreed that the most plausible ICER would need to be based on correct estimates of drug costs and with common utilities for pre-progression health states in both arms of the model. The committee took into account the clinical- and cost-effectiveness evidence for cetuximab in patients with oral cavity cancer, including the discount in the revised patient access scheme. Using this, it concluded that the most plausible ICER for cetuximab plus platinum-based chemotherapy compared with platinum-based therapy alone was above the range that would normally be considered cost effective if the end-of-life criteria apply. In addition, the uncertainties around this estimate, principally arising from the reliability of the estimation of clinical effectiveness in the subgroup, were too great to allow it to recommended cetuximab for routine use.
Subsequent to the committee meeting, a commercial access agreement was negotiated with NHS England. This arrangement was sufficient to reduce the ICER so that cetuximab could be recommended as a cost-effective use of NHS resources for the treatment of cancer starting in the oral cavity.
# Summary of appraisal committee's key conclusions
TA473
Appraisal title: Cetuximab for treating recurrent or metastatic squamous cell cancer of the head and neck
Section
Key conclusion: Cancer Drugs Fund reconsideration
Cetuximab in combination with platinum-based chemotherapy is recommended as an option for treating recurrent or metastatic squamous cell cancer of the head and neck in adults only:
if the cancer started in the oral cavity and
when the company provides the drug at the prices agreed with NHS England in the commercial access agreement.
The committee discussed the most plausible incremental cost-effectiveness ratio (ICER) for cetuximab plus platinum-based chemotherapy compared with platinum-based chemotherapy alone. To protect the level of discount, the ICERs including the patient access scheme were considered commercial in confidence and cannot be presented here. Based on the clinical- and cost-effectiveness analyses, including the discount in the revised patient access scheme, the committee considered that the most plausible ICER for cetuximab plus platinum-based chemotherapy compared with platinum-based therapy alone was above the range that would normally be considered cost effective if the end-of-life criteria apply and so could not recommend it for routine use. A subsequently negotiated commercial access agreement reduced this ICER to the extent that cetuximab could be recommended as a cost-effective use of NHS resources for the treatment of cancer starting in the oral cavity.
|
{'Recommendations': 'Cetuximab in combination with platinum-based chemotherapy is recommended as an option for treating recurrent or metastatic squamous cell cancer of the head and neck in adults only:\n\nif the cancer started in the oral cavity and\n\nwhen the company provides the drug in line with the commercial access agreement with NHS England.\n\nThese recommendations are not intended to affect treatment with cetuximab that was started within the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nCetuximab (Erbitux; Merck) is a recombinant monoclonal antibody that blocks human epidermal growth factor receptor (EGFR). It inhibits the proliferation of cells that depend on EGFR activation for growth.\n\nMarketing authorisation\n\nCetuximab has a UK marketing authorisation 'for the treatment of patients with squamous cell cancer of the head and neck… in combination with platinum-based chemotherapy for recurrent and/or metastatic disease'.\n\nAdverse reactions\n\nVery common adverse reactions with cetuximab include skin reactions, which occur in more than 80% of patients, and low blood magnesium levels, mild or moderate infusion-related reactions (such as fever, chills, nausea, vomiting, headache, dizziness or shortness of breath), inflammation of the lining of the digestive tract, and raised liver enzymes, which all occur in 10% or more of patients. Common side effects (occurring in 1% or more and less than 10% of patients) include severe infusion-related reactions (including anaphylactic reactions), dehydration, low blood calcium levels, anorexia, headache, conjunctivitis, fatigue, diarrhoea, nausea and vomiting. Cetuximab in combination with platinum-based chemotherapy may increase the frequency of severe leukopenia or severe neutropenia, and this may lead to a higher rate of infectious complications than platinum-based chemotherapy alone. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nCetuximab is administered intravenously. It is used in combination with platinum-based chemotherapy followed by cetuximab as maintenance therapy until disease progression. The initial loading dose is 400\xa0mg/m2 body surface area (BSA) given at a rate not exceeding 5\xa0mg/minute. Subsequent weekly maintenance doses are 250\xa0mg/m2 BSA each.\n\nPrice\n\nThe list price of cetuximab is £178.10 for a 5\xa0mg/ml 20‑ml vial and £890.50 for a 5\xa0mg/ml 100‑ml vial (excluding VAT; British national formulary [BNF] online, accessed February 2017). Assuming that vials are not shared among patients, a person with a BSA of 1.75\xa0m2 would have 7\xa0vials per loading dose and 5\xa0vials per maintenance dose, equating to a cost of £1,246.70 for the loading dose and £890.50 for each maintenance dose.\n\nThe pricing arrangement considered during guidance development was one in which the company (Merck) had agreed a patient access scheme with the Department of Health. This scheme would have provided a simple discount to the list price of cetuximab with the discount applied at the point of purchase or invoice. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS. This has now been replaced by a commercial access agreement between the company and NHS England, which incorporates this same simple discount applied at the point of purchase or invoice of all cetuximab but also includes additional and separate commercial arrangements. The financial terms of the agreement are commercial in confidence.", 'Evidence': "The appraisal committee (section\xa06) considered evidence submitted by Merck and a review of this submission by the evidence review group. This appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). Sections\xa04.2 to\xa04.11 reflect the committee's consideration of the evidence submitted in the original appraisal. Sections\xa04.12 to\xa04.24 reflect the committee's considerations of the evidence submitted for the Cancer Drugs Fund reconsideration. The company focused on the subgroup of patients with oral cavity cancer from the EXTREME trial, and cost-effectiveness analyses using a patient access scheme that provides cetuximab at a reduced cost. After consultation, the company submitted additional 5‑year follow‑up data for this subgroup of patients, and a revised patient access scheme with a further discount. The level of discount is commercial in confidence.\n\nSee the committee papers for full details of the Cancer Drugs Fund reconsideration evidence, and the history for full details of the evidence used in NICE's original technology appraisal guidance on cetuximab for the treatment of recurrent and/or metastatic SCCHN.", 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of cetuximab, having considered evidence on the nature of recurrent or metastatic squamous cell cancer of the head and neck (SCCHN) and the value placed on the benefits of cetuximab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness (NICE technology appraisal guidance\xa0172)\n\nThe committee reviewed the evidence available on the clinical effectiveness of cetuximab as presented in the company's submission and the evidence review group's (ERG's) report. It noted that there was only 1\xa0relevant randomised controlled trial that compared cetuximab plus platinum-based chemotherapy with chemotherapy alone in patients with recurrent or metastatic SCCHN (the EXTREME trial). The committee noted that few of the patients included in the clinical trial were from the UK although many were from other European countries. It was also aware of the ERG's concern that the patients in the trial appeared younger and fitter, on the basis of a higher Karnofsky performance status (KPS), than patients in UK clinical practice. Therefore, there was some uncertainty about whether the benefits of cetuximab would be seen in patients with this condition in the UK. Additionally, the committee heard from the clinical experts that most patients presenting with recurrent or metastatic SCCHN in the UK were older and had poorer general health than those recruited to the trial. However, patients for whom platinum-based chemotherapy would be considered appropriate were more likely to be of a similar age and performance status to those in the EXTREME trial. Overall, the committee accepted the evidence from the clinical experts that the results of the EXTREME trial would be applicable to the UK population.\n\nThe committee discussed the reported results from the clinical trial. It noted that the company had presented results for the total population of the trial and for a number of pre-planned subgroups. It noted the statistically significant improvement in overall survival associated with cetuximab in the total population represented in the trial. The committee was aware that, in the pre-planned subgroup analyses, only tumour location showed a significant interaction with treatment, suggesting greater effectiveness in tumours in the oral cavity. The committee heard from the clinical experts that patients with tumours in the oral cavity have a relatively favourable prognosis compared with the average prognosis for recurrent or metastatic SCCHN. The experts were not aware of any biological reason for cetuximab to be more clinically effective in oral cavity tumours. The committee accepted that the trial showed the efficacy of cetuximab plus platinum-based chemotherapy in patients with recurrent or metastatic SCCHN, but it was not persuaded that the evidence supported using the subgroup estimate for clinical effectiveness in the economic model.\n\nThe committee reviewed the additional cost-effectiveness analyses submitted by the company for additional subgroups based on age (younger than 65\xa0years) and KPS (KPS of 90\xa0or more and KPS of 80\xa0or more). It was aware that the pre-planned subgroup analyses in the clinical study presented results for patients with a KPS of 80\xa0or more (rather than 90\xa0or more) and for patients who were younger than 65\xa0years, but subgroups combining age and KPS were not included. The committee noted the concerns raised by the ERG about the validity of the modelled overall survival gains for the additional subgroup and whether the number of patients included was sufficient to provide robust evidence of efficacy. It was therefore not persuaded that the evidence provided by the company supported the predicted life years gained for the combined age and KPS subgroup. On this basis, the committee concluded that the estimates of cost effectiveness for the subgroup of patients who were younger than 65\xa0years with a KPS of 90\xa0or more could not be considered reliable.\n\nThe committee discussed the adverse effects of cetuximab treatment. It noted that the incidence of severe adverse events in the cetuximab plus platinum-based chemotherapy group and the platinum-based chemotherapy only group were generally similar with the exception of acne and acneiform dermatitis, which were reported only for the cetuximab plus platinum-based chemotherapy group. The clinical experts and a patient expert advised the committee that the adverse events reported for the trial were consistent with those seen in clinical practice when cetuximab had been used for locally advanced SCCHN and colorectal cancer.\n\n# Cost effectiveness (NICE technology appraisal guidance\xa0172)\n\nThe committee discussed the cost effectiveness of cetuximab plus platinum-based chemotherapy compared with platinum-based chemotherapy alone. It was aware that the incremental cost-effectiveness ratios (ICERs) presented by the company for the base-case and pre-planned subgroup analyses were substantially higher than those normally considered to be an acceptable use of NHS resources. In addition, the committee noted the concerns raised by the ERG about extrapolation of the trial results to estimate survival in the economic model, and the uncertainty about the number of patients available for analysis in each of the pre-planned subgroups. The committee noted the exploratory analyses done by the ERG using alternative assumptions and parameters in the economic model. The committee concluded that there remained considerable uncertainty around the results of the company's analyses, and that it was plausible that the true cost-effectiveness estimate for cetuximab plus platinum-based chemotherapy would be even higher than that presented by the company.\n\n# End-of-life considerations (NICE technology appraisal guidance\xa0172)\n\nThe committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy, and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nNo alternative treatment with comparable benefits is available through the NHS.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe committee discussed whether cetuximab, in combination with platinum-based chemotherapy for the treatment of recurrent or metastatic SCCHN, fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It considered the criteria only in relation to the estimate of overall survival for the cohort population because it did not consider the subgroup data to be robust (see sections\xa04.3 and\xa04.4). The committee noted from the EXTREME trial that life expectancy for patients treated with chemotherapy alone was unlikely to be more than 24\xa0months and could be as low as 7\xa0months. It observed that the trial data suggested that cetuximab plus platinum-based chemotherapy extended median survival by 2.7\xa0months compared with platinum-based chemotherapy alone. The committee was concerned about the uncertainty associated with this estimate because of the wide confidence interval. It was also aware that the predicted life years gained from the economic modelling for this group was\xa00.187, reflecting a gain in overall survival of approximately 2.2\xa0months. The committee therefore did not consider that this estimate of gain in overall survival was in keeping with the criteria relating to extension of life or that the addition of cetuximab represented a marked change from current treatment for SCCHN.\n\nThe committee also understood that an estimated 3,000\xa0people in England and Wales are diagnosed with recurrent or metastatic SCCHN every year. However, based on the evidence from clinical experts, cetuximab plus platinum-based chemotherapy would be appropriate for only a small proportion of these patients (that is, those whose disease was unsuitable for local treatment and who were well enough to have platinum-based chemotherapy). However, the committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that cetuximab was licensed for a number of other indications involving much larger patient groups.\n\nIn summary, the committee was not persuaded that the use of cetuximab plus platinum-based chemotherapy fulfilled all the criteria to be considered as a life-extending, end-of-life treatment. It came to this conclusion taking into account the importance of supporting the development of innovative treatments licensed for small groups of patients who have an incurable illness.\n\nThe committee concluded that cetuximab, given in combination with platinum-based chemotherapy for the treatment of recurrent or metastatic SCCHN, could not be recommended as a cost-effective use of NHS resources. The committee noted that some people may be currently having cetuximab in combination with platinum-based chemotherapy for this indication, and recommended that these people should have the option to continue treatment until they and their clinician consider it appropriate to stop.\n\n# Cancer Drugs Fund reconsideration\n\nThis appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on cetuximab for the treatment of recurrent and/or metastatic squamous cell cancer of the head and neck. At its first reconsideration meeting, the committee considered the company's submission that:\n\nincluded only the oral cavity cancer subgroup\n\nincluded a patient access scheme that would have provided a simple discount to the list price of cetuximab (this scheme was subsequently replaced by a commercial access agreement between the company and NHS England [see 'price' in section\xa02 for more details])\n\naddressed some of the committee's preferred assumptions (see section\xa04.6).The committee also considered the ERG's critique of the company's reconsideration submission and the ERG's exploratory analyses.\n\nAt its second reconsideration meeting, the committee considered the company's responses to the appraisal consultation document, specifically:\n\nadditional 5‑year survival data for the oral cavity cancer subgroup from the EXTREME trial\n\na new economic analysis based on the updated trial data\n\na revised patient access scheme providing a further discount to that considered at the first meeting.The committee also considered the ERG's critique of the company's responses to the appraisal consultation document and the ERG's exploratory analyses.\n\n## Cetuximab in the clinical management of head and neck cancer\n\nThe committee heard from the clinical experts that the EXTREME trial population represented patients who would be offered cetuximab plus platinum-based chemotherapy in the UK. The clinical experts also noted that the comparator used in the trial is the standard of care in the UK, although the clinical effectiveness of cisplatin plus fluorouracil was not studied in clinical trials before being introduced into clinical practice. The clinical experts stated that cetuximab is used according to the protocol described in the EXTREME trial in their clinics, and that they have seen similar outcomes to the trial. However, they noted that they were aware of other clinicians using different dosing protocols in the UK. At the second meeting, the Cancer Drugs Fund clinical lead provided anecdotal evidence that cetuximab is always given weekly with chemotherapy, but that it may be given every 1\xa0or 2\xa0weeks during the maintenance phase. If it is given every 2\xa0weeks, the dose is doubled so that the overall cumulative dose remains the same. This regimen is not consistent with that set out in the summary of product characteristics for cetuximab. The committee heard from the company that there are no data available on the clinical effectiveness of this regimen in people with SCCHN, but that it is safe in people with colorectal cancer. The committee concluded that cetuximab should be appraised according to the regimen set out in the summary of product characteristics but it supported the potential advantages in studying different dosing regimens.\n\n## Subgroup analysis\n\nThe committee noted that the company had based its submission on a subgroup of patients with oral cavity cancer. It also noted that, in its earlier deliberations, it had not been persuaded that the estimate from the subgroup was sufficiently reliable for use in the economic model. The company argued that, in the EXTREME trial, these patients had a poorer prognosis and gained greater benefit from cetuximab than the overall population of the trial. It noted that at the 2‑year cut‑off in the trial, cetuximab increased median overall survival by 6.6\xa0months in patients with tumours of the oral cavity compared with an increase of 2.7\xa0months in the whole population of the trial. The results for median progression-free survival were also better in the oral cavity cancer subgroup than in the whole trial population (3.3\xa0months compared with 2.3\xa0months). However, the committee noted that the subgroup was small (n=88) compared with the whole trial population (n=442), adding to the uncertainty inherent when considering estimates of effectiveness based on subgroup data. The clinical experts at the meeting confirmed that, in the EXTREME trial, patients with tumours in the oral cavity had a poorer prognosis than people with tumours in other locations. They also confirmed that, before the EXTREME trial, no other treatments had been shown to be of benefit in clinical trials in this patient group. This suggested an unmet need in this patient group, who were often older and had comorbidities. However, the experts were not aware of a biological mechanism that could explain why cetuximab would differ in its relative effects between different tumour types. The committee also discussed the additional published evidence on epidermal growth factor receptor (EGFR) overexpression in SCCHN that the company had provided after consultation. The committee concluded that it was possible that cetuximab might have greater benefits in oral cavity tumours but that the evidence in support of this was limited.\n\n## Progression-free and overall survival from the EXTREME trial\n\nThe committee noted that the company's new model, submitted after consultation, used 5‑year survival data from the oral cavity cancer subgroup of the EXTREME trial directly to estimate progression-free survival and overall survival in both trial arms (that is, it did not use any survival curve fitting). The committee noted that the difference in mean overall survival seen with cetuximab after 5\xa0years of follow‑up was similar to the difference in median overall survival seen after 2\xa0years. It also noted that the difference in mean progression-free survival after 5\xa0years was increased compared with the median progression-free survival after 2\xa0years. The ERG noted that only 1\xa0patient in the cetuximab plus chemotherapy arm of EXTREME remained event free at 5‑year follow‑up. The ERG argued that this patient alone contributed substantially to the mean progression-free and overall survival benefit, and that this could influence the results in favour of cetuximab plus chemotherapy. The ERG had attempted to adjust the survival analyses to take into account the 'long tail' associated with patients who remained event free. Taking this adjustment into account, the ERG estimated slightly shorter progression-free and overall survival values. The company disputed this approach, arguing that this patient also contributed to cumulative costs as well as quality-adjusted life-year gains. The committee noted that although patients whose disease responds extremely well to treatment are not uncommon in clinical trials, the extraordinary response seen in this single patient added to the uncertainty in the estimates resulting from the oral cavity cancer subgroup.\n\nThe ERG noted that the company had not supplied detailed clinical trial data in its response to consultation to allow for an analysis of survival after disease progression in the new model. However, the ERG was able to estimate the mean post-progression survival gain attributable to cetuximab plus chemotherapy from the difference between the mean overall survival and mean progression-free survival. This indicated that more than a third of the overall survival benefit may come after disease progression. The ERG believed that this is uncommon in trials of advanced cancer treatments with chemotherapy, in which the disease more often reverts to following the typical progressive disease trajectory, independent of the choice of previous treatment. The committee noted that at its first reconsideration meeting, the clinical experts had considered some survival gain after disease progression to be plausible because of the potential immune effects of cetuximab and a lower disease burden because of tumour response. However, the committee concluded that even if this were the case, the extent of survival gain after disease progression was uncertain.\n\n## Choice of utility values\n\nThe committee noted that after consultation, the company had estimated utilities based on quality-of-life data from the oral cavity cancer subgroup of the EXTREME trial, rather than the full trial population. It had, however, noted in the first committee meeting that the questionnaire used did not include a measure of adverse events. The data were converted to utilities using an algorithm. The company used the same utility estimates for both treatment arms in the post-progression health state, but different utility estimates for both treatment arms in the pre-progression health state. The ERG considered that the data from the EXTREME trial did not allow for reliable utility estimates for the 2\xa0treatment arms. It stated that there was no justification for not using a common utility estimate for the pre-progression health state. The committee heard from the company that its quality-of-life questionnaire, on which its utility estimates were based, was not mandatory and was most likely to have omitted the most sick patients. When the ERG used a common utility value for both treatment arms, the ICER increased. The committee noted that, contrary to the implications of the company's utility values, adverse events were more frequent for patients having cetuximab than for those having standard therapy in the oral cavity subgroup. The committee concluded that the pre-progression utility value used by the company may have resulted in an ICER for cetuximab that was too low, and that it preferred the approach taken by the ERG.\n\n## Drug acquisition costs\n\nThe ERG identified an error in the method used to calculate drug costs in the company's new model, submitted after consultation. Correcting this error resulted in an increase in the number of vials used per patient session and a corresponding increase in the ICER. The company did not provide details of the body surface area (BSA) measurements from the oral cavity cancer subgroup in its response to consultation. It had previously considered that the mean BSA in EXTREME was lower than that of people with head and neck cancer in the UK. The ERG re‑estimated the drug doses based on the mean value and the distribution seen in BSA in a UK audit of people with head and neck cancer. It also applied an adjustment for gender ratio based on the EXTREME trial. Cetuximab is available in 100‑mg vials; these adjustments suggested that 7\xa0to 8\xa0vials are needed for initial dosing, and 4\xa0to 5\xa0vials are needed for each subsequent dose. Adjusting for vial wastage also increased the drug costs by an estimated\xa011%. These adjustments resulted in a higher ICER for cetuximab than that in the company's base case. The committee concluded that the ERG's corrected calculation, including its adjustments, provided a better estimate of the costs of treatment for patients in the NHS.\n\n## Treatment administration costs\n\nThe committee noted the company has collected evidence in the UK that suggests cetuximab may be given less often in the maintenance phase than the standard weekly dosing regimen used in the EXTREME trial. However, the committee and ERG agreed that it is not clear how this is managed in terms of the total dose administered per cycle, the extent of this dosing in practise and how different regimens affect treatment outcomes. The ERG considered that it was not appropriate to model the patient survival outcomes reported in the EXTREME trial while also reducing treatment administration costs; this fails to consider how variations in treatment intensity and dose timing may affect treatment effectiveness. The committee noted that EXTREME is the only source of evidence relevant to the small subgroup being considered, and that the trial used weekly dosing. It agreed with the ERG that there was too much uncertainty attached to this deviation in dosing regimen to warrant its inclusion in the cost-effectiveness analysis, and that only the standard weekly dosing regimen should be included in the analysis.\n\n## Discounting\n\nThe committee noted that the company had not applied standard discounting to the new base case; the company explained that it did not consider this to be a major limitation, given the short time horizon of the model (5\xa0years). The committee concluded that discounting should be applied to the revised base case, noting that this would have only a small effect on the ICER.\n\n## End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that, at 5‑year follow‑up in EXTREME, the mean life expectancy of people with oral cavity cancer was less than 24\xa0months. It also noted that the difference in mean survival was similar to the difference in median survival seen after 2\xa0years (that is, 6.6\xa0months). The committee was aware of the uncertainty surrounding the magnitude of the survival benefit because of the limited number of people included in the oral cavity cancer subgroup. Nonetheless, despite this uncertainty, the committee agreed that it was plausible that the survival benefit in the subgroup was larger than that in the whole population. It therefore concluded that all of the end-of-life criteria were met for people with oral cavity cancer treated with cetuximab.\n\n## Conclusions\n\nThe committee discussed the most plausible ICER for cetuximab plus platinum-based chemotherapy compared with platinum-based chemotherapy alone. To protect the level of discount, the ICERs including the patient access scheme were considered commercial in confidence and cannot be presented here. The committee went on to discuss the range of cost-effectiveness estimates. It highlighted that:\n\nThere remained some uncertainty about the clinical-effectiveness evidence for cetuximab in oral cavity cancer, particularly because of the small subgroup size in the EXTREME trial (see section\xa04.15).\n\nThe committee preferred common utility values, as used by the ERG (see section\xa04.18).\n\nIt would have preferred drug costs to be estimated using the BSA values from the UK audit study, with adjustment for the gender ratio (see section\xa04.19).The committee assumed that the oral cavity subgroup data were accurate, and that cetuximab was indeed more effective in this subgroup. On this basis, it agreed that the most plausible ICER would need to be based on correct estimates of drug costs and with common utilities for pre-progression health states in both arms of the model. The committee took into account the clinical- and cost-effectiveness evidence for cetuximab in patients with oral cavity cancer, including the discount in the revised patient access scheme. Using this, it concluded that the most plausible ICER for cetuximab plus platinum-based chemotherapy compared with platinum-based therapy alone was above the range that would normally be considered cost effective if the end-of-life criteria apply. In addition, the uncertainties around this estimate, principally arising from the reliability of the estimation of clinical effectiveness in the subgroup, were too great to allow it to recommended cetuximab for routine use.\n\nSubsequent to the committee meeting, a commercial access agreement was negotiated with NHS England. This arrangement was sufficient to reduce the ICER so that cetuximab could be recommended as a cost-effective use of NHS resources for the treatment of cancer starting in the oral cavity.\n\n# Summary of appraisal committee's key conclusions\n\nTA473\n\nAppraisal title: Cetuximab for treating recurrent or metastatic squamous cell cancer of the head and neck\n\nSection\n\nKey conclusion: Cancer Drugs Fund reconsideration\n\nCetuximab in combination with platinum-based chemotherapy is recommended as an option for treating recurrent or metastatic squamous cell cancer of the head and neck in adults only:\n\nif the cancer started in the oral cavity and\n\nwhen the company provides the drug at the prices agreed with NHS England in the commercial access agreement.\n\n\n\nThe committee discussed the most plausible incremental cost-effectiveness ratio (ICER) for cetuximab plus platinum-based chemotherapy compared with platinum-based chemotherapy alone. To protect the level of discount, the ICERs including the patient access scheme were considered commercial in confidence and cannot be presented here. Based on the clinical- and cost-effectiveness analyses, including the discount in the revised patient access scheme, the committee considered that the most plausible ICER for cetuximab plus platinum-based chemotherapy compared with platinum-based therapy alone was above the range that would normally be considered cost effective if the end-of-life criteria apply and so could not recommend it for routine use. A subsequently negotiated commercial access agreement reduced this ICER to the extent that cetuximab could be recommended as a cost-effective use of NHS resources for the treatment of cancer starting in the oral cavity.\n\n, 4.24"}
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https://www.nice.org.uk/guidance/ta473
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Evidence-based recommendations on cetuximab (Erbitux) for treating recurrent or metastatic squamous cell cancer of the head and neck in adults.
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c3048e5af3fff5f0a68cdd82307bf76407960932
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Vitamin D: supplement use in specific population groups
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Vitamin D: supplement use in specific population groups
This guideline covers vitamin D supplement use. It aims to prevent vitamin D deficiency among specific population groups including infants and children aged under 4, pregnant and breastfeeding women, particularly teenagers and young women, people over 65, people who have low or no exposure to the sun and people with dark skin.
# What is this guideline about?
# Introduction
This guideline aims to increase supplement use to prevent vitamin D deficiency among specific population groups, as identified in 2012 by the UK Health Departments (Vitamin D – advice on supplements for at risk groups – letter from UK Chief Medical Officers Department of Health), and in 2016 by the Scientific Advisory Committee on Nutrition's vitamin D and health report).
Vitamin D is essential for skeletal growth and bone health. Severe deficiency can result in rickets (among children) and osteomalacia (among children and adults).
Dietary sources of vitamin D are limited. The main natural source is from the action of sunlight on skin. However, from October to the beginning of April in the UK there is no ambient ultraviolet sunlight of the appropriate wavelength for skin synthesis of vitamin D. National surveys suggest that around a fifth of adults and 8 to 24% of children (depending on age and gender) may have low vitamin D status. (See context for more details.)
The risks and benefits of sunlight exposure (including exposure to prevent vitamin D deficiency) are covered in a separate guideline (see related NICE guidance).
# Definition of supplement
For the purpose of this guideline, a supplement refers to supplements of vitamin D, either alone or contained in multi-vitamin products (including Healthy Start supplements). It includes licensed products available only on prescription or through pharmacies and (unlicensed) food supplements available from a range of pharmacies and retail outlets.
# SACN review
The Scientific Advisory Committee on Nutrition (SACN) reviewed the dietary reference values for vitamin D intake in the UK population in 2016. They recommend that vitamin D supplements are made available for the entire population (4 years old or more) throughout the year. The recommendations should be read in conjunction with the SACN vitamin D and health report 2016.
# Clinical judgement
Clinical judgement will be needed to determine whether NICE's recommendations in this guideline are suitable for people with conditions that increase the risk of vitamin D deficiency.
# Who is this guideline for?
The guideline is for: commissioners, managers and other professionals with public health as part of their remit, working within the NHS, local authorities and the wider public, private, voluntary and community sectors. It is also aimed at manufacturers and providers of vitamin D supplements. (For further details, see who should take action?) In addition, it may be of interest to members of the public.
See about this guideline for details of how the guideline was developed and its current status.# Recommendations
This guideline replaces recommendation 3 in the NICE guideline on maternal and child nutrition.
# Recommendation 1 Increase access to vitamin D supplements
The Department of Health should:
Work with manufacturers to ensure vitamin D supplements providing the reference nutrient intake (RNI) as recommended by the Scientific Advisory Committee on Nutrition, are widely available for the following specific population groups:
infants and children aged under 4
pregnant and breastfeeding women, particularly teenagers and young women
people over 65
people who have low or no exposure to the sun, for example, those who cover their skin for cultural reasons, who are housebound or confined indoors for long periods
people with dark skin, for example, people of African, African-Caribbean or South Asian family origin.Suitable supplements should also be available for people with particular dietary needs (for example, people who avoid nuts, are vegan or have a halal or kosher diet). Supplements should undergo quality control checks to ensure they contain the correct dose of vitamin D.
Work with manufacturers to ensure licensed products containing the recommended reference nutrient intake for specific population groups are available on prescription and are listed in the British National Formulary.
Amend existing legislation to allow Healthy Start vitamins to be more widely distributed and sold. This includes encouraging manufacturers to sell them direct to pharmacies.
Encourage manufacturers of multivitamin food supplements to include the recommended reference nutrient intake for vitamin D in their preparations.
# Recommendation 2 Clarify existing guidance
Public Health England and the Department of Health should:
Consider whether there are any risks to infants from taking a supplement containing the RNI when they are consuming more than 500 ml of infant formula per day. Be aware that the complexity of existing advice (based on feeding type and maternal supplementation) may hinder uptake.
Make it clear which type of supplement most people would benefit from. Be aware that people may be more likely to take a vitamin D-only supplement than one that is combined with calcium. Supplements containing vitamin D and calcium may be harder to swallow and cause side effects such as constipation.
# Recommendation 3 Develop national activities to increase awareness about vitamin D
Public Health England should:
Lead development of national action to raise the population's awareness of the importance of vitamin D. This should start as soon as existing recommendations on vitamin D have been clarified and made consistent (see recommendation 2). Awareness-raising activities should:
Emphasise the importance of vitamin D for good health.
Emphasise the limitations of other UK sources of vitamin D (it is only contained in a few foods and sunlight is only effective from the beginning of April to October).
Emphasise the importance of a daily supplement providing the reference nutrient intake.
Explain existing advice as clearly as possible, particularly if it may be misinterpreted. This includes making clear: what a term such as 'low sun exposure' means; who is covered by 'dark skin'; which women and children are at risk (note that children aged 4 to 5 years are not usually eligible for Healthy Start supplements).
Let people know where they can get vitamin D supplements free or as cheaply as possible.
Develop resources that are accessible and easy to adapt for local use by a range of agencies, to ensure a consistent message and to minimise duplication of effort.
# Recommendation 4 Ensure a consistent multiagency approach
Directors of public health should:
Ensure a consistent, multiagency approach is adopted to improve the vitamin D status of the local population. This should include commissioners and senior managers in local authorities and the NHS, council leaders, elected members, public health teams and voluntary and community organisations. They should:
address local needs, as identified by the joint strategic needs assessment and other local data
target specific population groups
target health, social care and other practitioners in contact with specific population groups
work with relevant community and voluntary groups
ensure mechanisms are in place to increase the availability and uptake of supplements
ensure mechanisms are in place to increase awareness of vitamin D
ensure action is culturally appropriate (for example, involve community organisations and develop messages that resonate with the community or take account of any cultural barriers to taking supplements).
# Recommendation 5 Increase local availability of vitamin D supplements for specific population groups
Local authorities should ensure vitamin D supplements containing the recommended reference nutrient intake are widely available by:
Establishing arrangements with a range of settings to promote and distribute them. This could include local pharmacies, children's centres, midwifery and health visiting services and GP reception areas.
Considering providing free supplements for specific population groups.
Encouraging pharmacies and other outlets selling food supplements (such as supermarkets) to stock the lowest cost vitamin D supplements and promote them to specific population groups.
Ensure improvements in the availability of vitamin D supplements are supported by local awareness-raising activities (see recommendations 9 and 10).
# Recommendation 6 Improve access to Healthy Start supplements
Local authorities should:
Review current accessibility, availability and uptake of Healthy Start supplements.
Consider how accessibility, availability and uptake could be improved. For example:
Encourage a range of outlets where pregnant and breastfeeding women and families and carers of under-4s may go to stock and promote Healthy Start supplements. This includes high street and supermarket pharmacies, children's centres, schools and clinics with a range of opening times. Many of them should also be accessible by public transport.
Consider offering free Healthy Start supplements to all pregnant and breastfeeding women and children aged under 4 years.
Encourage pharmacies to sell the Healthy Start supplement to:
pregnant and breastfeeding women and children under 4 years
children aged over 3 who are in 1 of the other specific population groups
women planning a pregnancy and women of child bearing age (see recommendation 1).
Set up a central point for ordering, storing and distributing Healthy Start supplements across the local authority area. Individual distribution sites should be encouraged to order supplements from the central distribution point, rather than managing their own stock.
Consider using an electronic card system to distribute supplements and use the data collected to improve the supply chain and for system monitoring.
# Recommendation 7 Only test vitamin D status if someone has symptoms of deficiency or is at very high risk
Health professionals should not routinely test people's vitamin D status unless:
they have symptoms of deficiency
they are considered to be at particularly high risk of deficiency (for example, they have very low exposure to sunlight)
there is a clinical reason to do so (for example, they have osteomalacia or have had a fall).
# Recommendation 8 Ensure health professionals recommend vitamin D supplements
Local authorities, primary care, and clinical commissioning groups should:
Ensure computerised prompts on vitamin D are integrated into health and social care systems.
Ensure health professionals recommend and record vitamin D supplement use among specific population groups (and other family members, as appropriate) whenever possible. This could take place during registration appointments with new patients in general practice, flu, other vaccine and screening appointments. It could also take place during routine appointments and health checks including, for example:
NHS Health Check
diabetes check-ups
falls appointments and check-ups
health assessments for looked-after children
the first contact with someone who is pregnant
antenatal and postnatal appointments
medicine use and prescription reviews
health visitor appointments
developmental checks for infants and children.
Developers of standardised electronic and handheld maternity notes and developers of personal child health records (the 'red book') should:
add specific questions about the use of vitamin D supplements.
# Recommendation 9 Raise awareness among health, social care and other relevant practitioners of the importance of vitamin D
Health Education England, Public Health England, clinical commissioning groups, health and wellbeing boards and local authorities should:
Ensure health and social care practitioners receive information on the following as part of their registration and post-registration training and continuing professional development:
the importance of vitamin D for good health
sources of vitamin D in the UK (from safe sun exposure, supplements and limited dietary sources)
groups at risk of low vitamin D status
supplement recommendations for different groups (this should address any confusion about, for example, age groups or the type of supplement to recommend)
how to encourage people to start and continue taking supplements (see medicines adherence NICE guideline CG76).
Ensure health, social care and other relevant practitioners in contact with specific population groups are made aware of the following:
local policies and procedures in relation to vitamin D
local sources of vitamin D supplements (including Healthy Start)
eligibility for Healthy Start vitamin supplements.
# Recommendation 10 Raise awareness of the importance of vitamin D supplements among the local population
Local public health teams, health and social care practitioners and voluntary and community groups working with specific population groups (see who should take action?) should:
Increase people's awareness of:
the importance of vitamin D for good health
sources of vitamin D in the UK (from safe sun exposure, supplements and limited dietary sources)
specific population groups and the importance of a daily vitamin D supplement for some of those groups
local sources of vitamin D supplements (including Healthy Start)
eligibility for Healthy Start vitamin supplements
sources of further information.
Adapt any national resources for local use to minimise the risk of inconsistent advice (see recommendation 3).
Ensure awareness-raising activities meet the needs of all specific population groups. This includes:
addressing any misconceptions specific groups may have about their risk
working with local practitioners, role models and peers to tailor national messages for local communities to ensure information about vitamin D is culturally appropriate.
Share vitamin D messages and information with specific population groups using:
local newspapers, social media and local radio channels targeted at these groups
local shops and businesses
community workers, groups and events
social establishments
nurseries and educational institutions
workplaces
places of worship
local health care establishments, for example, community health facilities, hospitals and urgent care centres.
# Recommendation 11 Monitor and evaluate the provision and uptake of vitamin D supplements
The Department of Health, Public Health England and local authority commissioners should:
Monitor national and local awareness of, access to, and uptake of, vitamin D supplements among specific population groups (including those covered by Healthy Start).
Use a range of sources to assess local uptake, for example, orders for supplements and information collected in personal child health records, maternal antenatal notes and computerised prompts (see recommendation 8).
Use monitoring data to improve activities related to the awareness of, access to and uptake of vitamin D supplements.# Who should take action?
# Introduction
The guideline is for: commissioners, managers and other professionals with public health as part of their remit working within the NHS, local authorities and the wider public, private, voluntary and community sectors. It is also aimed at the suppliers and providers of vitamin D supplements.
In addition, it may be of interest to people at risk of vitamin D deficiency, their families and carers and other members of the public.
Who should take action?
Recommendation
Clinical commissioning groups
Commissioners and senior managers in local authorities and the NHS
Council leaders and elected members
Department of Health
Developers of standardised medical notes
Directors of public health
Health and social care practitioners
Health and wellbeing boards
Health Education England
Primary care practitioners
Public health teams
Public Heath England
Supplement manufacturers
Voluntary and community organisations
# Who should take action in detail
## Recommendation 1
Department of Health; supplement manufacturers
## Recommendation 2
Public Health England, the Department of Health
## Recommendation 3
Public Heath England
## Recommendation 4
Council leaders; elected members; directors of public health; public health teams; commissioners and senior managers in local authorities and NHS trusts; and voluntary and community organisations
## Recommendation 5
Local authorities
## Recommendation 6
Local authorities
## Recommendation 7
Health professionals
## Recommendation 8
Developers of standardised medical notes; developers of personal child health records; health professionals; local authorities; primary care; clinical commissioning groups
## Recommendation 9
Public Health England; Health Education England; clinical commissioning groups; health and wellbeing boards; local authorities
## Recommendation 10
Local public health teams; voluntary and community groups; health, social care and other practitioners working with specific population groups. This includes: dietitians, district nurses, GPs, health visitors, midwives, nursing assistants, pharmacists, physiotherapists, practice nurses, registered nutritionists and social workers. It also includes people working in nursing or care homes, nurseries, schools, children's centres, and secure settings such as prisons
## Recommendation 11
Department of Health; Public Health England; local authority commissioners# Context
# Background
Vitamin D is essential for skeletal growth and bone health. Dietary sources in the UK are very limited and oily fish is the only significant source. Small amounts are provided by egg yolk, red meat and fortified foods, such as formula milks for infants and toddlers, some breakfast cereals and fat spreads (margarine). The major natural source is from skin synthesis following exposure to sunlight.
From October to the beginning of April in the UK there is no ambient ultraviolet sunlight of the appropriate wavelength for skin synthesis of vitamin D. During this time, the population relies on both body stores from sun exposure in the summer and dietary sources to maintain vitamin D status (Scientific Advisory Committee on Nutrition's update on vitamin D 2007).
The National Diet and Nutrition Survey: results from Years 1 to 4 (combined) of the rolling programme for 2008 and 2009 to 2011 and 2012 (Public Health England and Food Standards Agency) shows that vitamin D status is highest among all age groups in the summer months and lowest in the winter. For example, only 8% of adults aged 19–64 had a low vitamin D status in July to September, compared with 39% in January to March. Similarly, around 2% of children aged 4 to 10 years had a low vitamin D status in July to September, compared to 32% in January to March.
Severe vitamin D deficiency can result in rickets among children: there has been concern that rickets may be re-emerging among children in the UK (Pearce and Cheetham 2010). It can also result in osteomalacia (soft bones, among children and adults) and hypocalaemia (low levels of calcium in the blood) in children. In addition, low vitamin D status has been associated with some diseases and other long-term conditions such as osteoporosis, diabetes and some cancers, although the evidence is inconclusive (Update on vitamin D).
# People at risk
The National Diet and Nutrition Survey suggests that almost a fifth of UK adults have a low vitamin D status. This means they have less than 25 nmol/litre of the main circulating form of vitamin D in their body – 25 hydroxyvitamin D (25D) ('National Diet and Nutrition Survey: results from Years 1 to 4 (combined) of the rolling programme for 2008 and 2009 to 2011 and 2012').
A newborn baby's vitamin D status is largely determined by the mother's level of vitamin D during pregnancy.
Breast milk is not a significant source of vitamin D. Formula milks for infants have to be fortified with vitamin D (this is voluntary for formula milks for toddlers).
Infants who are exclusively breastfed, or have less than 500 ml a day of infant formula, may not get enough vitamin D to meet their needs. (See NICE guidance on antenatal care and maternal and child nutrition.) Infants from Asian families are at particular risk. The Asian Feeding Survey (Infant feeding in Asian families, 1994–1996 Office for National Statistics) found that up to a third of Indian, Bangladeshi or Pakistani children had low vitamin D status at age 2.
People with dark skin are at increased risk of deficiency as their skin is less efficient at synthesising vitamin D. In other words, they need to expose their skin to sunlight for longer to make the same amount of vitamin D as people with paler skin. People of African, African-Caribbean and South Asian family origin, and those who remain covered when outside, are at particular risk. Almost 75% of Asian adults may have low vitamin D status in the winter. (For more details see the expert paper Vitamin D intakes and status.)
Older people are also at increased risk, particularly if they are frail, because they may spend more time indoors and have limited sun exposure.
People who are housebound and others who have limited exposure to the sun all year round (for example, those in prison) are also at increased risk (the SACN update on vitamin D). For example, the National Diet and Nutrition survey suggests that between 10 and 20% of older adults have low vitamin D status. This can increase up to 38% among people living in institutions.
There is substantial variation in vitamin D status across England, with people living in more southerly regions tending to have a better vitamin D status. London is the exception.
The Health Survey for England (NHS Information Centre for Health and Social Care 2010) found that 35% of adults in London had low status compared to the national average of 24%. (For more details see the expert paper 'Vitamin D intakes and status'). This may reflect the higher number of people from the minority ethnic groups at risk of vitamin D deficiency living in London, compared to other parts of England.
# UK recommendations on vitamin D supplements
All UK health departments (for example, see the 2012 Chief Medical Officers' report Vitamin D – advice on supplements for at risk groups) and NICE (see our pathways on antenatal care and maternal and child nutrition) have issued evidence-based guidance on vitamin D supplements for various population groups. They have also provided guidance on how to distribute free Healthy Start supplements (that contain vitamin D) to eligible families.
The 4 UK chief medical officers have also flagged that health professionals could make 'a significant difference' if they ensure those at risk of vitamin D deficiency understand how important the vitamin is and how to get a daily supplement. They say that all at‑risk groups should be made aware of how they can obtain the vitamins locally ('Vitamin D – advice on supplements for at risk groups').
The Chief Medical Officers also stress the need to ensure people who may be eligible for the Healthy Start scheme know how they can apply. Note: this scheme provides vouchers that can be used to buy infant formula, cow's milk and plain fresh or frozen fruit and vegetables. People also receive coupons that can be exchanged for vitamin supplements that include the recommended amounts of vitamin D.
Evidence suggests implementation of these recommendations has been limited ('Vitamin D – advice on supplements for at risk groups'). For example, a report commissioned by the Department of Health's Policy Research Programme (Healthy start: understanding the use of vouchers and vitamins) found that parents find it difficult to access Healthy Start vitamins, health professionals do not promote the scheme and eligible families are often unaware of it. It also found that the distribution system is complex, confused and weak, and mothers are not motivated to take the vitamins or to give them to their children.
The cost effectiveness of implementing interventions to prevent vitamin D deficiency also remains unclear. Testing for vitamin D insufficiency has been reported to have increased 2- to 6-fold in recent years and, at approximately £20 a test, is likely to be a considerable cost for the NHS (Sattar et al. 2012). Primary care spending on treatments for vitamin D deficiency rose from £28 million in 2004 to £76 million in 2011 (Treating vitamin D deficiency GP, 13 February 2012; Prescription cost analysis England 2011 Health and Social Care Information Centre). In 2006, it cost an estimated £2500 to treat each child identified with symptomatic vitamin D deficiency (Zipitis et al. 2006).
# How to get vitamin D supplements
Supplements containing vitamin D are available on prescription or for sale from pharmacies or shops. However, there is wide variation in the content and price and some supplements may not be suitable for particular at‑risk groups. (For example many multivitamins contain vitamin A, which pregnant women should avoid during pregnancy.)
Healthy Start vitamins tend to be available from health clinics, children's centres, Sure Start centres, outreach programmes or GP surgeries, although there have been national and local supply problems. Manufacturers have not made them directly available to pharmacies.
In 2013, the Chief Medical Officer for England recommended a review of the cost effectiveness of extending the provision of free Healthy Start vitamins to every child. This was due to concerns that 'providing free vitamins to targeted groups has not led to high enough levels of uptake' (CMO's annual report 2012: our children deserve better Department of Health).
Up to April 2013, people not eligible for Healthy Start were able to buy the supplements at a much lower cost than commercial preparations. However, this option was encouraged in only a limited number of areas (Help pregnant women, new mothers and children get their free healthy start vitamins Department of Health). Since April 2013, following a change in health and social care legislation, these supplements can no longer be sold.# Considerations
The Public Health Advisory Committee (PHAC) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain recommendations. (See recommendations.)
# Background
The PHAC considered only the implementation of existing recommendations on vitamin D to prevent deficiency. The evidence base on which existing recommendations were made – and the contribution of dietary intake (including fortified foods) and sunlight exposure to vitamin D status – was outside its remit. Whether older adults should take vitamin D alone, or with calcium, was also outside its remit. Members were aware that the Scientific Advisory Committee on Nutrition (SACN) was considering many of these issues. Wherever possible, the guidance is consistent with SACN's advice and ongoing work in this area. NICE is also developing an associated guideline on the benefits and risks of sunlight exposure. It is hoped that these 3 pieces of work will provide the basis for clear, consistent advice to reduce the risk of low vitamin D status among all specific population groups.
A number of fundamental issues hinder the uptake of existing guidance among specific population groups. For example, many health professionals and the public may be unaware that the skin cannot synthesise vitamin D from sunlight during winter months in the UK. They may also be unaware that a balanced diet alone will not provide sufficient vitamin D. In addition, they do not know enough about the importance of vitamin D supplements for specific population groups. The availability of suitable low cost supplements may also be limited – and health professionals and the public may not know where they can get them locally. The PHAC decided that there will only be significant increases in uptake if all these issues are addressed. Members also discussed and made recommendations on other actions to prevent any further confusion about the existing guidance. This includes having a viable distribution policy to reach specific population groups before carrying out further awareness-raising activities.
# Communications
Advice on the use of vitamin D supplements to maintain good bone health has been available since 1991. (Dietary reference values for food energy and nutrients for the United Kingdom. Report of the panel on dietary reference values of the Committee on Medical Aspects of Food Policy Department of Health.) This includes existing recommendations on vitamin D from SACN, the 4 UK chief medical officers and NICE. However, awareness and implementation of the advice has been poor. The PHAC noted that, although existing recommendations are broadly consistent, the complexity of the advice and poor communications may have been the cause of confusion among both health professionals and the public. Members also noted the lack of clarity about who is 'at risk'. For example, health professionals and the public alike may question what constitutes 'a low exposure' to sunlight or 'dark' skin. Similarly, the disparity between those who are eligible for the Healthy Start scheme and the recommendations on vitamin D supplements for women and children appear to be another source of confusion.
# Availability of vitamin D supplements
The PHAC discussed the importance of increasing the availability of vitamin D supplements for all specific population groups. Members were unable to recommend free supplements for these groups, due to a lack of evidence on the effect that differential costs have on uptake. They did recognise that free provision had contributed to increased uptake in some areas. Members also noted the strong economic case for offering free or low cost supplements to specific population groups to prevent deficiency, when compared to the cost of widespread testing for vitamin D deficiency. They felt it was important to determine the effectiveness and cost effectiveness of providing free supplements to specific population groups and made a recommendation for research on this. Allied to this, the PHAC discussed the potential for confusion among the public if free or low cost supplements were available in some areas but not others. Members agreed that this issue cannot be ignored by areas considering such a policy.
Until recently, low cost vitamin D-only supplements containing 100% of the reference nutrient intake were not widely available for sale. The PHAC noted that many vitamin D supplements also contain calcium (which may be poorly tolerated) and that some people may be deterred by the cost of supplements. Members agreed that there is unlikely to be a significant increase in the number of people in specific populations taking a vitamin supplement unless a free or low cost vitamin D-only supplement is widely available. This may be particularly true for lower income groups. The PHAC also noted that there is little point in awareness-raising activities to promote vitamin D supplements if affordable supplements are not widely available.
# Evidence
The evidence reviews identified very little data on how existing guidance on vitamin D supplements has been implemented. The evidence available tends to be relatively poor and usually focuses on groups targeted by the Healthy Start initiative. No evidence was identified for interventions aimed at increasing the uptake of vitamin D supplements among: people aged 65 or older, people who have low or no exposure to the sun, or people who have dark skin. In addition, only very limited information was available on the views of those taking supplements or in specific population groups. The effectiveness of specific interventions was also difficult to determine. For example, it was difficult to quantify the relative impact of: training for health professionals; making vitamin D or Healthy Start supplements more widely available (including the impact of cost); and activities to increase awareness of the importance of taking them among specific population groups.
The evidence on the implementation of existing vitamin D guidance was very limited. As a result, following discussion with PHAC, NICE commissioned an additional review of reviews on effective implementation of a range of public health and clinical guidelines. Several key themes emerged. For example, the PHAC noted that implementation of any health intervention is likely to be more effective if health professionals are made aware of the issue and are prompted to raise it. Other 'effectiveness' factors include consistent guidance and advice and simple, inexpensive interventions.
The PHAC noted the importance of ongoing monitoring and evaluation of the availability and uptake of vitamin D supplements among specific population groups, at a national and local level. Members were also aware that data collection may involve using limited resources. Nevertheless, monitoring and evaluation appears to have been insufficient and inconsistent to date and there has been little opportunity to learn from good practice.
# Healthy Start
The limited evidence available points to extremely low uptake of Healthy Start supplements among eligible pregnant and breastfeeding women and children younger than 4 years. One study of 13 primary care trusts across all regions of England reported uptake to be below 10% (Jessiman et al. 2013). Another reported it to be less than 3% (Moonan et al. 2012). Variation between areas suggests that action can be taken to improve uptake. (For example, members discussed increasing the number of outlets providing the supplement and providing training for health professionals.)
The PHAC was aware that uptake of Healthy Start vouchers for infant formula, cow's milk and fruit and vegetables was good (at around 77% of those eligible) (Jessiman et al. 2013). Members noted that this could be because the voucher can be used at a variety of outlets as part of everyday shopping.
The PHAC discussed the need to give people eligible for Healthy Start support a clear explanation of the different benefits gained by taking Healthy Start supplements and consuming the milk, fruit and vegetables provided. Members were concerned that users of the scheme may be unaware of the importance of taking the supplement.
The PHAC was aware that numerous aspects of the system for distributing Healthy Start vitamins may hinder implementation. For example a report commissioned by the Department of Health's Policy Research Programme Healthy start: understanding the use of vouchers and vitamins identified that senior public health practitioners may spend considerable time administering the scheme. In addition, the order and reimbursement processes are slow and complex, and there are ongoing concerns about shelf-life and storage. The study's authors also reported that the voucher format and the process for getting supplements are confusing for the public.
The PHAC discussed the fact that universal free provision of Healthy Start vitamins can improve uptake, but that without wider action the impact may be limited. One study suggests uptake may almost treble with universal free provision, but only to around 4% for children's drops and 7.7% for women's tablets. Another study showed a year-on-year increase in uptake to 23% for women's tablets and 20% for children's drops when universal free supplementation was supported by action to increase awareness (McGee and Shaw 2013). No studies were identified that compared universal free provision of vitamin D supplements with universal provision of supplements that have to be paid for (albeit at a low cost). This prevented the committee from commenting on the relative benefits of these approaches and members felt that this is an important area for future research.
The PHAC was concerned that most mothers and children at risk of vitamin D deficiency are not eligible for the Healthy Start scheme. The lack of a similar alternative, or the cost of commercial supplements, may deter them from taking a supplement (particularly those from lower income groups). Some areas had made local arrangements to sell Healthy Start vitamins. But health and social care legislation, introduced in April 2013, means this is no longer possible. Furthermore, the Department of Health's existing arrangements with manufacturers mean it is not possible to get Healthy Start supplements from many places where people might expect to find them. (For example, they are not available in high street or supermarket pharmacies.)
# Training
The PHAC agreed that health, social care and other practitioners in contact with specific population groups need training to provide robust, consistent advice – and that this is essential if vitamin D supplementation is to increase. But members also recognised that this would have limited impact if the availability of supplements and inconsistencies in current guidelines are not resolved.
# Cost effectiveness
The main question asked in the economic model was: 'What is the most cost‑effective way of providing vitamin D supplements to specific population groups?'. Because of the focus of the guideline, 'What is the cost effectiveness of vitamin D supplementation among specific population groups?' was a subsidiary question for pregnant and breastfeeding women, and for children under 5 years. Modelling was based on 4 specific population groups: pregnant women and breastfeeding women, children aged under 5 years, people aged 65 or over and people whose skin is darker. There were not enough data to model this question for 'people whose skin is not sufficiently exposed to the sun'. (We do not know how many people in the population this affects, nor the extent of the deficiency among this group.) The cost of giving everyone in each group a daily supplement was compared with the cost of testing everyone and giving vitamin D supplements only to those with an identified deficiency. The model included estimated costs of intervention administration and delivery, based on an intervention in Birmingham (McGee and Shaw 2013).
The economic model found that it is cost saving to give everyone in each group a daily vitamin D supplement, rather than testing them all and supplementing only those who are deficient. It was assumed that the cost of a test is fixed at £16.50.
A potential limitation of the modelling analysis is that it assumes everyone is given a prophylactic supplement without being tested. This may mean that less emphasis is given to finding people who are severely deficient and who may need a higher dose of vitamin D. However, people showing the symptoms of severe deficiency may well be tested. Aspects of this situation are explored in a sensitivity analysis in the cost effectiveness report. The model did not consider any risks associated with taking a supplement containing the reference nutrient intake for vitamin D. The PHAC agreed that there is a negligible risk associated with taking the prophylactic dose.
The subsidiary analysis looked at increasing the uptake of vitamin D supplements among pregnant and breastfeeding women and children aged 5 years and younger. The estimated cost of supplementation for each additional woman who is pregnant or breastfeeding was £10.15. This resulted in an estimated cost per deficiency averted of £2859. For children aged 5 or younger, the estimated cost of supplementation per additional child was £4.62. This resulted in an estimated cost per deficiency averted of £1229.
A limitation of the subsidiary analysis (see 4.19) is that people with a vitamin D deficiency are defined in the model in terms of the symptoms of deficiency, rather than by their vitamin D status. So if someone had a low vitamin D status but did not show any symptoms of deficiency, the model assumed they would not benefit from a supplement. Because people with symptoms of deficiency are likely to be a relatively small subset of those defined as having a low vitamin D status, the model almost certainly overstates the cost of averting a 'deficiency'.# Recommendations for research
The Public Health Advisory Committee (PHAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.
All the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.
Outcomes for all the questions below may include vitamin D status, user adherence or any unintentional consequences. The recommendations apply to all specific population groups, but there is a particular need for research in people over 65, people with dark skin and people living in institutions.
How effective and cost effective are interventions to increase vitamin D access, uptake, adherence or status among identified specific population groups? Does effectiveness vary by age, gender, ethnicity, socioeconomic or other specific population characteristics (such as depression or a disability)? The following could be considered:
availability and uptake of supplements (including the impact of the cost of supplements)
type of supplements provided and how that impacts on adherence
knowledge and attitudes (of both the public and health and social care practitioners).
How cost effective are preventive approaches to vitamin D deficiency among all specific population groups, compared with the cost of testing and treatment? This should include a comparison of universal provision of free supplements with the provision of low or standard cost supplements for different specific population groups. (If there is any new legislation allowing for the sale of Healthy Start supplements, this would provide an opportunity to test this question.)
How can a multiagency approach to improving awareness, availability and uptake of vitamin D supplements best be established, improved and sustained? For example, what are the key components, who are the key partners and how does the local context affect effectiveness? The latter may include local population characteristics (such as age, ethnicity or levels of deprivation), setting and the approach to commissioning. Research should be conceived, developed and implemented as a collaboration between academics and local practitioners or the local community.
What type of training and awareness-raising can improve how health and social care practitioners:
promote vitamin D supplements among specific population groups
improve the local population's awareness of, and attitudes towards, vitamin D supplements
uptake of vitamin D supplements?
What is the best way of monitoring the local system for distributing vitamin D supplements? Assessments of methods that enable robust data collection – such as computerised data capture systems – would be particularly useful. (The aim would be to use that data to improve the service.)
More detail identified during development of this guideline is provided in gaps in the evidence.# Related NICE guidance
Physical health of people in prison NICE guideline 57 (2016)
Sunlight exposure: risks and benefits NICE guideline 34 (2016)
Falls: assessment and prevention of falls in older people NICE guideline CG161 (2013).
Behaviour change – individual approaches NICE guideline PH49 (2014).
Skin cancer prevention: information, resources and environmental changes NICE guideline PH32 (2010).
Weight management before, during and after pregnancy NICE guideline PH27 (2010).
Maternal and child nutrition NICE guideline PH11 (2008).
Antenatal care NICE guideline CG62 (2008).
Postnatal care NICE guideline CG37 (2006).# Glossary
# At-risk groups
Although the entire UK population is at risk of having a low vitamin D status, these population groups are at higher risk:
People who have low or no exposure to the sun. For example, those who cover their skin for cultural reasons, who are housebound or confided indoors for long periods.
People who have dark skin, for example, people of African, African-Caribbean and South Asian origin.
# Culturally appropriate
Culturally appropriate interventions take account of the community's cultural or religious beliefs and language and literacy skills by:
Using community resources to improve awareness of, and increase access to, interventions. For example, they involve community organisations and leaders early in the development stage, use media, plan events or make use of community-specific festivals.
Understanding the target community and the messages that resonate with them.
Identifying and addressing barriers to access and participation, for example, keeping costs low to ensure affordability and taking account of working patterns and education levels.
Developing communication strategies that are sensitive to language use and information needs. For example, involve staff who can speak the languages used by the community, and provide information in different languages and for varying levels of literacy (for example, using colour-coded visual aids and spoken rather than written information).
Taking account of cultural or religious values, for example, in relation to body image, separate physical activity sessions for men and women, beliefs and practices about hospitality and food, or dates, days, settings, or timings considered unsuitable for community events or interventions.
Providing opportunities to discuss how interventions would work in the context of people's lives.
Considering how closely aligned people are to their ethnic group or religion and whether they are exposed to influences from both the mainstream and their community in relation to diet and physical activity.
# Dietary reference values
Dietary reference values is a collective term for reference nutrient intake, estimated average requirement and lower reference nutrient intakes. Dietary reference values reflect the amount of energy and nutrients needed by healthy people according to their age and gender. For certain nutrients, set increments reflect the increased demands associated with pregnancy and lactation.
# Existing recommendations on vitamin D
The UK Health Departments, the Scientific Advisory Committee on Nutrition and NICE have all issued evidence-based guidance on vitamin D supplements for various specific population groups. (See the NICE guideline on antenatal care and maternal and child nutrition.) They have also provided advice on how to distribute free Healthy Start supplements (containing vitamin D) to eligible families.
# Halal
Halal refers to foods or non-food items such as cosmetics or pharmaceuticals permitted by and prepared according to Islamic law.
# Healthy Start
Healthy Start is a UK-wide government scheme that provides a 'nutritional safety net' for pregnant women and families on benefits and tax credits. Women who are at least 10 weeks pregnant and families with children younger than 4 years qualify if the family receives the relevant benefits:
pregnant women get 1 Healthy Start voucher a week worth £3.10
babies younger than 1 year get 2 vouchers a week worth £6.20
children over 1 and under 4 years of age get 1 voucher a week worth £3.10.
Vouchers are posted every 4 weeks. They can be spent on plain cow's milk, plain fresh or frozen fruit and vegetables, or infant formula milk at retail outlets registered to accept them. These include supermarkets, grocery stores, chemists and milk rounds.
Every 8 weeks, beneficiaries get vitamin coupons to swap for Healthy Start vitamins. It is the responsibility of NHS England until October 2015 – and from then on, local areas – to provide or arrange the provision of Healthy Start vitamins. The vitamin tablets for mothers contain folic acid and vitamins C and D. Healthy start vitamin drops for children contain vitamins A, C and D.
# Kosher
Kosher refers to food (or premises where food is sold, cooked or eaten), cosmetics and pharmaceuticals that comply with Jewish law.
# Low vitamin D status
Low vitamin D status (sometimes called vitamin D deficiency) is defined by the Department of Health as a plasma concentration of 25 hydroxyvitamin D (the main circulating form of the vitamin) of below 25 nmol/litre (equal to 10 ng/ml).
# Reference nutrient intake
Reference nutrient intake is the amount of a nutrient needed to meet the needs of 97.5% of individuals in a group. Reference nutrient intake for a given nutrient may vary by gender, age and physiological status (for example during pregnancy and lactation). The reference nutrient intake is not a minimum target that all people need to achieve, but the risk of deficiency is minimised if the average population intake exceeds it.
The current reference nutrient intakes (µg/day) for vitamin D are:
micrograms of vitamin D per day, throughout the year, for everyone in the general population aged 4 years and older
micrograms of vitamin D per day for pregnant and lactating women and population groups at increased risk of vitamin D deficiency.
# Safe intake
Safe intakes are different to RNIs. A safe intake is used where there is insufficient evidence to set a RNI. The safe intake is the amount judged to be enough for almost everyone, but below a level that could have undesirable effects.
a 'safe intake' of 8.5 to 10 micrograms per day for all infants from birth to 1 year of age
a 'safe intake' of 10 micrograms per day for children aged 1 to 4 years.
All population groups are currently advised to take a supplement that meets 100% of the reference nutrient intake for their age group (as above). The reference nutrient intake for population groups is 10 micrograms/day (1 microgram=40 international units, so 10 micrograms=400 IU).
# Specific population groups
Although the entire population of the UK are at risk of having a low vitamin D status, evidence was only considered in regard to increasing the supplement use for these specific population groups:
All pregnant and breastfeeding women, particularly teenagers and young women.
Infants and children under 4 years (breast fed, non-breast fed and mixed fed).
People over 65.
People who have low or no exposure to the sun. For example, those who cover their skin for cultural reasons, who are housebound or confined indoors for long periods.
People who have dark skin, for example, people of African, African–Caribbean and South Asian origin.
All population groups are currently advised to take a supplement that meets 100% of the reference nutrient intake for their age group. The reference nutrient intake levels are noted above.
All infants and young children aged 6 months to 3 years are advised to take a daily supplement containing vitamin D in the form of vitamin drops. But infants who are fed infant formula will not need them until they have less than 500 ml of infant formula a day, because these products are fortified with vitamin D. Breastfed infants may need drops containing vitamin D from 1 month of age if their mother has not taken vitamin D supplements throughout pregnancy. ('Vitamin D – advice for supplements for at risk groups – letter from the UK Chief Medical Officers' Department of Health).
# Vegan
People who follow a vegan diet consume only plant products. They avoid all food, drink and non-food items, such as pharmaceuticals that contain any animal products.
# Vitamin D
Vitamin D is a fat soluble pro-hormone. It is obtained through the action of sunlight on skin and from dietary sources. The action of sunlight (ultraviolet radiation of wavelength 290–310 nm) on skin converts 7‑dehydrocholesterol to previtamin D3, which is then metabolised to vitamin D3.
Dietary vitamin D exists as either ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3).
The liver 25-hydroxylase enzymes convert vitamin D2 and D3 (from diet or from the action of sunlight on skin) to the main circulating form of the vitamin, 25 hydroxyvitamin D – also known as 25(OH)D. This is then converted by the kidney and other tissues to the active form of the vitamin 1,25-dihydroxyvitamin D.# References
Jessiman T, Cameron A, Wiggins M et al. (2013) A qualitative study of uptake of free vitamins in England. Archives of Disease in Childhood 98: 587–91
McGee E, Shaw N (2013) Vitamin D supplementation: Putting recommendations into practice. Journal of Health Visiting 1 (3): 138–43
Moonan M, Hanratty B, Whitehead M (2012) Which is more effective, a universal or targeted approach, to implementing the National Healthy Start Programme? A mixed methods study. Journal of Epidemiology and Community Health 66: A44–5
Pearce SHS, Cheetham TD (2010) Diagnosis and management of vitamin D deficiency. BMJ 340: b5664
Sattar N, Welsh P, Panarelli M et al. (2012) Increasing requests for vitamin D measurement: costly, confusing, and without credibility The Lancet 379 (9811): 95–6
Zipitis CS, Markides GA, Swann IL (2006) Vitamin D deficiency: prevention or treatment? Archives of Disease in Childhood 91: 1011–4# Summary of the methods used to develop this guideline
# Introduction
The review and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.
The minutes of the Public Health Advisory Committee (PHAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.
# Guideline development
The stages involved in developing public health guidelines are outlined in the box below.
. Draft scope released for consultation
. Stakeholder meeting about the draft scope
. Stakeholder comments used to revise the scope
. Final scope and responses to comments published on website
. Effectiveness reviews and economic modelling undertaken and submitted to PHAC
. PHAC produces draft recommendations
. Draft guideline (and evidence) released for consultation
. PHAC amends recommendations
. Final guideline published on website
. Responses to comments published on website
# Key questions
The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PHAC to help develop the recommendations. The overarching questions were:
. How effective and cost effective are interventions to increase awareness and implementation of existing guidance on vitamin D among health professionals or others working with specific population groups? What are the implications for professional training and practice?
. How effective and cost effective are interventions to increase awareness and uptake of existing guidance on vitamin D among specific population groups (with special consideration given to those eligible for the Healthy Start scheme)?
. What helps or hinders the implementation of existing guidance on vitamin D by commissioners, providers, practitioners, those working with specific population groups and people in specific population groups?
. What local provision is made to ensure vitamin D supplements are available for different specific population groups (including Healthy Start, prescriptions and over-the-counter sales)?
These questions were made more specific for the effectiveness review 'Vitamin D: a systematic review of effectiveness and cost-effectiveness of activities to increase awareness, uptake and provision of vitamin D supplements in specific population groups'.
# Reviewing the evidence
## Effectiveness review
One effectiveness review was conducted.
Several databases were searched in June 2013 for evidence of any type published from 2000 onwards. See review 1: Vitamin D: a systematic review of effectiveness and cost-effectiveness of activities to increase awareness, uptake and provision of vitamin D supplements in at-risk groups for details.
Evidence was also identified through:
citation searches of papers identified for inclusion
a search for additional studies by authors of papers identified for inclusion
a search of identified webpages
a call for evidence issued by NICE in March 2013.
Studies were included in the effectiveness review if they:
were undertaken in the UK
addressed at least 1 of the key questions.
Studies were excluded if they focused on:
the management of vitamin D deficiency or conditions that may increase the risk
fortification of food and drinks with vitamin D
vitamin D for different population groups.
See review 1 for details.
## Review of systematic review
One review of systematic reviews was conducted.
Review 2 Review of systematic reviews exploring guideline uptake/implementation
Several systematic review databases were searched in November 2013 for systematic reviews published from 2004 onwards.
Studies were included if they were systematic reviews and addressed at least 1 of the key questions. Studies were excluded if they were not systematic reviews. See review 2.
## Quality appraisal
Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. A checklist developed by Cardiff University was used for the cross-sectional studies and survey reports. Systematic reviews were assessed using the AMSTAR checklist. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution.
++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.
- Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.
− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.
## Summarising the evidence and making evidence statements
The review data were summarised in evidence tables (see review 1 and review 2).
The findings from the review were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractor (see Supporting evidence). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.
# Cost effectiveness
There was a review of economic evaluations and an economic modelling exercise.
## Review of economic evaluations
This was conducted as part of the effectiveness reviews (see above).
## Economic modelling
An economic model was constructed, incorporating data from the reviews of effectiveness and cost effectiveness. The results are reported in: An economic evaluation of interventions to improve the uptake of vitamin D supplements in England.
# How the PHAC formulated the recommendations
At its meetings in September and October 2013, the Public Health Advisory Committee (PHAC) considered the evidence, expert testimony and cost effectiveness to determine:
whether there was sufficient evidence (in terms of strength and applicability) to form a judgement
where relevant, whether (on balance) the evidence demonstrates that the intervention or programme or activity can be effective or is inconclusive
where relevant, the typical size of effect
whether the evidence is applicable to the target groups and context covered by the guideline.
The PHAC developed recommendations through informal consensus, based on the following criteria:
Strength (type, quality, quantity and consistency) of the evidence.
The applicability of the evidence to the populations/settings referred to in the scope.
Effect size and potential impact on the target population's health.
Impact on inequalities in health between different groups of the population.
Equality and diversity legislation.
Ethical issues and social value judgements.
Cost effectiveness (for the NHS and other public sector organisations).
Balance of harms and benefits.
Ease of implementation and any anticipated changes in practice.
Where possible, recommendations were linked to an evidence statement (see The evidence for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# The evidence
# Introduction
The evidence statements from 1 review are provided by external contractors (see Supporting evidence).
This section lists how the evidence statements and expert papers link to the recommendations and sets out a brief summary of findings from the economic analysis.
# How the evidence links to the recommendations
The evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from.
Evidence statement number 1.1 indicates that the linked statement is numbered 1 in review 1.
EM indicates that the economic modelling report is linked to a recommendation.
Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).
Recommendation 1: evidence statements 1.11, 1.14, 1.15, 1.16
Recommendation 2: evidence statements 1.10, 2.12; IDE
Recommendation 3: evidence statements 1.1, 1.10, 1.11; 2.12; IDE
Recommendation 4: evidence statements 1.1, 1.3, 1.10, 1.11, 1.14, 1.15, 2.10, 2.13
Recommendation 5: evidence statements 1.1, 1.3, 1.5, 1.7, 1.9, 1.11, 1.14, 1.15, 1.16, 2.10; EM
Recommendation 6: evidence statements 1.1, 1.3, 1.5, 1.7, 1.8, 1.9, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 2.2; EM
Recommendation 7: evidence statements 1.7; EM; IDE
Recommendation 8: evidence statements 1.10, 1.11, 2.2, 2.9
Recommendation 9: evidence statements 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.10, 1.11, 2.3, 2.4, 2.5, 2.13
Recommendation 10: evidence statements 1.10, 1.11, 1.12, 2.14
Recommendation 11: evidence statement 2.6; IDE
# Economic modelling
The economic model addressed the question: 'What is the most cost-effective way of providing vitamin D to specific population groups (pregnant women, children under 5 years, people aged 65 or over and people whose skin is darker)?' There were not enough data to model this question for 'people whose skin is not sufficiently exposed to the sun'.
There were 2 sets of analysis. The first compared the cost of providing each group with a daily supplement (without testing for deficiency) with the cost of testing everyone and giving those with a deficiency a supplement.
The second analysis looked at increasing uptake of supplements among pregnant and breastfeeding women, and among children up to the age of 5.
See An economic evaluation of interventions to improve the uptake of vitamin D supplements in England.# Gaps in the evidence
The Public Health Advisory Committee (PHAC) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence, expert and stakeholder comment. These gaps are set out below.
. There is a lack of good quality interventions aiming to increase Vitamin D supplement use among specific population groups in England.
. There is a lack of good quality evidence on the relative impact of the following on the uptake of vitamin D supplements among specific population groups: awareness-raising activities, health professional training and supplement provision.
. There is a lack of good quality evidence on whether making a free or low cost vitamin D‑only supplement available affects uptake among specific population groups.
. There is a lack of evidence on whether the following affect the effectiveness of interventions to increase vitamin D supplement use among specific population groups: sexual orientation, disability, religion, place of residence, occupation, education, socioeconomic position or a sense of community (or 'social capital').
. There is a lack of evidence on what strategies may encourage people to take a vitamin D supplement on a regular basis.
. There is a lack of evidence on whether health professional training leads to more effective interventions to improve uptake of vitamin D supplements among specific population groups.
(Source: review 1 and review 2)
The Committee made 5 recommendations for research into areas that it believes will be a priority for developing future guidelines. These are listed in recommendations for research.# About this guideline
# What does this guideline cover?
The Department of Health asked the National Institute for Health and Care Excellence (NICE) to produce a guideline on how to increase supplement use to prevent vitamin D deficiency among specific population groups. The guideline focuses on supplement use (see the scope).
This guideline is a partial update of maternal and child nutrition, NICE guideline PH11 (2008). The recommendations will replace recommendation 3 in 'Maternal and child nutrition'.
This guideline does not provide detail on the benefits and risks of sunlight exposure or management of vitamin D deficiency. (See related NICE guidance for other recommendations that may be relevant to the prevention or management of vitamin D deficiency.)
This guideline does not examine the cost effectiveness of extending the Healthy Start vitamin programme from the current targeted offering to a universal offering. NICE is working on a separate report on this issue. This will be forwarded to the Chief Medical Officer in 2015.
The absence of any recommendations on interventions that fall within the scope of this guideline is a result of lack of evidence. It should not be taken as a judgement on whether they are cost effective.
# Other guidance and policies
The guideline should be implemented alongside other guidance and regulations including:
Scientific Advisory Committee on Nutrition report on vitamin D (expected 2015).
# How was this guideline developed?
The recommendations are based on the best available evidence. They were developed by the Public Health Advisory Committee (PHAC).
Members of the PHAC are listed in membership of the Public Health Advisory Committee and the NICE project team.
For information on how NICE public health guidelines are developed, see the NICE public health guidance process and methods guides.
# What evidence is the guideline based on?
The evidence that the PHAC considered included:
Evidence reviews:
Review 1 'Vitamin D: a systematic review of effectiveness and cost-effectiveness of activities to increase awareness, uptake and provision of vitamin D supplements in at‑risk groups', was carried out by York Health Economics Consortium. The principal authors were: Anne Morgan, Danielle Varley, Mick Arber, Maria Cikalo, Victoria Burley, Anita Fitzgerald and Julie Glanville.
Review 2 'Review of systematic reviews exploring guideline uptake/ implementation' was carried out by York Health Economics Consortium. The principal authors were: Anita Fitzgerald, Anne Lethaby, Maria Cikalo, Julie Glanville and Hannah Wood.
Economic modelling 'An economic evaluation of interventions to improve the uptake of vitamin D supplements in England' was carried out by York Health Economics Consortium. The principal authors were: Alexandra Filby, Lily Lewis and Matthew Taylor.
Expert paper: 'Vitamin D intakes and status' by Gillian Swan, Public Health England.
Note: the views expressed in the expert papers above are the views of the authors and not those of NICE.
In some cases the evidence was insufficient and the PHAC has made recommendations for future research. For the research recommendations and gaps in research, see Recommendations for research and Gaps in the evidence.
# Status of this guideline
The draft guideline, including the recommendations, was released for consultation in May and June 2014. At its meeting in September 2014, the PHAC amended the guideline in light of comments from stakeholders and experts and the fieldwork. The guideline was signed off by the NICE Guidance Executive in November 2014.
The guideline complements the NICE guideline on sunlight exposure and replaces recommendation 3 in the NICE guideline on maternal and child nutrition. (For further details, see Related NICE guidance).
The recommendations should be read in conjunction with existing NICE guidance unless explicitly stated otherwise. They should be implemented in light of duties set out in the Equality Act 2010.
The guideline is available on NICE's website. The recommendations are also available in the NICE Pathway on vitamin D: supplement use for specific population groups, for professionals whose remit includes public health and for interested members of the public.
NICE produces guidance, standards and information on commissioning and providing high‑quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government and the Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.
# Implementation
NICE guidance can help:
Commissioners and providers of NHS services to meet the requirements of the NHS outcomes framework 2013–14. This includes helping them to deliver against domain 1: preventing people from dying prematurely.
Local health and wellbeing boards to meet the requirements of the Health and Social Care Act (2012) and the Public health outcomes framework for England 2013–16.
Local authorities, NHS services and local organisations determine how to improve health outcomes and reduce health inequalities during the joint strategic needs assessment process.
NICE has developed tools to help organisations put this guideline into practice. Details will be available on our website after the guideline has been issued.
ISBN: 978-1-4731-0853-0
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{'What is this guideline about?': "# Introduction\n\nThis guideline aims to increase supplement use to prevent vitamin D deficiency among specific population groups, as identified in 2012 by the UK Health Departments (Vitamin D – advice on supplements for at risk groups – letter from UK Chief Medical Officers Department of Health), and in 2016 by the Scientific Advisory Committee on Nutrition's vitamin D and health report).\n\nVitamin\xa0D is essential for skeletal growth and bone health. Severe deficiency can result in rickets (among children) and osteomalacia (among children and adults).\n\nDietary sources of vitamin\xa0D are limited. The main natural source is from the action of sunlight on skin. However, from October to the beginning of April in the UK there is no ambient ultraviolet sunlight of the appropriate wavelength for skin synthesis of vitamin\xa0D. National surveys suggest that around a fifth of adults and 8 to 24% of children (depending on age and gender) may have low vitamin D status. (See context for more details.)\n\nThe risks and benefits of sunlight exposure (including exposure to prevent vitamin\xa0D deficiency) are covered in a separate guideline (see related NICE guidance).\n\n# Definition of supplement\n\nFor the purpose of this guideline, a supplement refers to supplements of vitamin D, either alone or contained in multi-vitamin products (including Healthy Start supplements). It includes licensed products available only on prescription or through pharmacies and (unlicensed) food supplements available from a range of pharmacies and retail outlets.\n\n# SACN review\n\nThe Scientific Advisory Committee on Nutrition (SACN) reviewed the dietary reference values for vitamin D intake in the UK population in 2016. They recommend that vitamin D supplements are made available for the entire population (4 years old or more) throughout the year. The recommendations should be read in conjunction with the SACN vitamin D and health report 2016.\n\n# Clinical judgement\n\nClinical judgement will be needed to determine whether NICE's recommendations in this guideline are suitable for people with conditions that increase the risk of vitamin D deficiency.\n\n# Who is this guideline for?\n\nThe guideline is for: commissioners, managers and other professionals with public health as part of their remit, working within the NHS, local authorities and the wider public, private, voluntary and community sectors. It is also aimed at manufacturers and providers of vitamin\xa0D supplements. (For further details, see who should take action?) In addition, it may be of interest to members of the public.\n\nSee about this guideline for details of how the guideline was developed and its current status.", 'Recommendations ': "This guideline replaces recommendation 3 in the NICE guideline on maternal and child nutrition.\n\n# Recommendation 1 Increase access to vitamin\xa0D supplements\n\nThe Department of Health should:\n\nWork with manufacturers to ensure vitamin\xa0D supplements providing the reference nutrient intake (RNI) as recommended by the Scientific Advisory Committee on Nutrition, are widely available for the following specific population groups:\n\n\n\ninfants and children aged under\xa04\n\npregnant and breastfeeding women, particularly teenagers and young women\n\npeople over 65\n\npeople who have low or no exposure to the sun, for example, those who cover their skin for cultural reasons, who are housebound or confined indoors for long periods\n\npeople with dark skin, for example, people of African, African-Caribbean or South Asian family origin.Suitable supplements should also be available for people with particular dietary needs (for example, people who avoid nuts, are vegan or have a halal or kosher diet). Supplements should undergo quality control checks to ensure they contain the correct dose of vitamin D.\n\n\n\nWork with manufacturers to ensure licensed products containing the recommended reference nutrient intake for specific population groups are available on prescription and are listed in the British National Formulary.\n\nAmend existing legislation to allow Healthy Start vitamins to be more widely distributed and sold. This includes encouraging manufacturers to sell them direct to pharmacies.\n\nEncourage manufacturers of multivitamin food supplements to include the recommended reference nutrient intake for vitamin D in their preparations.\n\n# Recommendation 2 Clarify existing guidance\n\nPublic Health England and the Department of Health should:\n\nConsider whether there are any risks to infants from taking a supplement containing the RNI when they are consuming more than 500\xa0ml of infant formula per day. Be aware that the complexity of existing advice (based on feeding type and maternal supplementation) may hinder uptake.\n\nMake it clear which type of supplement most people would benefit from. Be aware that people may be more likely to take a vitamin D-only supplement than one that is combined with calcium. Supplements containing vitamin D and calcium may be harder to swallow and cause side effects such as constipation.\n\n# Recommendation 3 Develop national activities to increase awareness about vitamin D\n\nPublic Health England should:\n\nLead development of national action to raise the population's awareness of the importance of vitamin\xa0D. This should start as soon as existing recommendations on vitamin D have been clarified and made consistent (see recommendation 2). Awareness-raising activities should:\n\n\n\nEmphasise the importance of vitamin\xa0D for good health.\n\nEmphasise the limitations of other UK sources of vitamin D (it is only contained in a few foods and sunlight is only effective from the beginning of April to October).\n\nEmphasise the importance of a daily supplement providing the reference nutrient intake.\n\nExplain existing advice as clearly as possible, particularly if it may be misinterpreted. This includes making clear: what a term such as 'low sun exposure' means; who is covered by 'dark skin'; which women and children are at risk (note that children aged 4 to 5\xa0years are not usually eligible for Healthy Start supplements).\n\n\n\nLet people know where they can get vitamin D supplements free or as cheaply as possible.\n\nDevelop resources that are accessible and easy to adapt for local use by a range of agencies, to ensure a consistent message and to minimise duplication of effort.\n\n# Recommendation 4 Ensure a consistent multiagency approach\n\nDirectors of public health should:\n\nEnsure a consistent, multiagency approach is adopted to improve the vitamin D status of the local population. This should include commissioners and senior managers in local authorities and the NHS, council leaders, elected members, public health teams and voluntary and community organisations. They should:\n\n\n\naddress local needs, as identified by the joint strategic needs assessment and other local data\n\ntarget specific population groups\n\ntarget health, social care and other practitioners in contact with specific population groups\n\nwork with relevant community and voluntary groups\n\nensure mechanisms are in place to increase the availability and uptake of supplements\n\nensure mechanisms are in place to increase awareness of vitamin\xa0D\n\nensure action is culturally appropriate (for example, involve community organisations and develop messages that resonate with the community or take account of any cultural barriers to taking supplements).\n\n\n\n# Recommendation 5 Increase local availability of vitamin\xa0D supplements for specific population groups\n\nLocal authorities should ensure vitamin\xa0D supplements containing the recommended reference nutrient intake are widely available by:\n\nEstablishing arrangements with a range of settings to promote and distribute them. This could include local pharmacies, children's centres, midwifery and health visiting services and GP reception areas.\n\nConsidering providing free supplements for specific population groups.\n\nEncouraging pharmacies and other outlets selling food supplements (such as supermarkets) to stock the lowest cost vitamin\xa0D supplements and promote them to specific population groups.\n\nEnsure improvements in the availability of vitamin\xa0D supplements are supported by local awareness-raising activities (see recommendations 9 and 10).\n\n# Recommendation 6 Improve access to Healthy Start supplements\n\nLocal authorities should:\n\nReview current accessibility, availability and uptake of Healthy Start supplements.\n\nConsider how accessibility, availability and uptake could be improved. For example:\n\n\n\nEncourage a range of outlets where pregnant and breastfeeding women and families and carers of under-4s may go to stock and promote Healthy Start supplements. This includes high street and supermarket pharmacies, children's centres, schools and clinics with a range of opening times. Many of them should also be accessible by public transport.\n\nConsider offering free Healthy Start supplements to all pregnant and breastfeeding women and children aged under 4\xa0years.\n\nEncourage pharmacies to sell the Healthy Start supplement to:\n\n\n\npregnant and breastfeeding women and children under 4\xa0years\n\nchildren aged over 3 who are in 1 of the other specific population groups\n\nwomen planning a pregnancy and women of child bearing age (see recommendation\xa01).\n\n\n\nSet up a central point for ordering, storing and distributing Healthy Start supplements across the local authority area. Individual distribution sites should be encouraged to order supplements from the central distribution point, rather than managing their own stock.\n\nConsider using an electronic card system to distribute supplements and use the data collected to improve the supply chain and for system monitoring.\n\n\n\n# Recommendation 7 Only test vitamin D status if someone has symptoms of deficiency or is at very high risk\n\nHealth professionals should not routinely test people's vitamin D status unless:\n\nthey have symptoms of deficiency\n\nthey are considered to be at particularly high risk of deficiency (for example, they have very low exposure to sunlight)\n\nthere is a clinical reason to do so (for example, they have osteomalacia or have had a fall).\n\n# Recommendation 8 Ensure health professionals recommend vitamin\xa0D supplements\n\nLocal authorities, primary care, and clinical commissioning groups should:\n\nEnsure computerised prompts on vitamin\xa0D are integrated into health and social care systems.\n\nEnsure health professionals recommend and record vitamin\xa0D supplement use among specific population groups (and other family members, as appropriate) whenever possible. This could take place during registration appointments with new patients in general practice, flu, other vaccine and screening appointments. It could also take place during routine appointments and health checks including, for example:\n\n\n\nNHS Health Check\n\ndiabetes check-ups\n\nfalls appointments and check-ups\n\nhealth assessments for looked-after children\n\nthe first contact with someone who is pregnant\n\nantenatal and postnatal appointments\n\nmedicine use and prescription reviews\n\nhealth visitor appointments\n\ndevelopmental checks for infants and children.\n\n\n\nDevelopers of standardised electronic and handheld maternity notes and developers of personal child health records (the 'red book') should:\n\n\n\nadd specific questions about the use of vitamin\xa0D supplements.\n\n\n\n# Recommendation 9 Raise awareness among health, social care and other relevant practitioners of the importance of vitamin\xa0D\n\nHealth Education England, Public Health England, clinical commissioning groups, health and wellbeing boards and local authorities should:\n\nEnsure health and social care practitioners receive information on the following as part of their registration and post-registration training and continuing professional development:\n\n\n\nthe importance of vitamin\xa0D for good health\n\nsources of vitamin\xa0D in the UK (from safe sun exposure, supplements and limited dietary sources)\n\ngroups at risk of low vitamin\xa0D status\n\nsupplement recommendations for different groups (this should address any confusion about, for example, age groups or the type of supplement to recommend)\n\nhow to encourage people to start and continue taking supplements (see medicines adherence NICE guideline CG76).\n\n\n\nEnsure health, social care and other relevant practitioners in contact with specific population groups are made aware of the following:\n\n\n\nlocal policies and procedures in relation to vitamin\xa0D\n\nlocal sources of vitamin\xa0D supplements (including Healthy Start)\n\neligibility for Healthy Start vitamin supplements.\n\n\n\n# Recommendation 10 Raise awareness of the importance of vitamin\xa0D supplements among the local population\n\nLocal public health teams, health and social care practitioners and voluntary and community groups working with specific population groups (see who should take action?) should:\n\nIncrease people's awareness of:\n\n\n\nthe importance of vitamin\xa0D for good health\n\nsources of vitamin\xa0D in the UK (from safe sun exposure, supplements and limited dietary sources)\n\nspecific population groups and the importance of a daily vitamin\xa0D supplement for some of those groups\n\nlocal sources of vitamin\xa0D supplements (including Healthy Start)\n\neligibility for Healthy Start vitamin supplements\n\nsources of further information.\n\n\n\nAdapt any national resources for local use to minimise the risk of inconsistent advice (see recommendation 3).\n\nEnsure awareness-raising activities meet the needs of all specific population groups. This includes:\n\n\n\naddressing any misconceptions specific groups may have about their risk\n\nworking with local practitioners, role models and peers to tailor national messages for local communities to ensure information about vitamin\xa0D is culturally appropriate.\n\n\n\nShare vitamin D messages and information with specific population groups using:\n\n\n\nlocal newspapers, social media and local radio channels targeted at these groups\n\nlocal shops and businesses\n\ncommunity workers, groups and events\n\nsocial establishments\n\nnurseries and educational institutions\n\nworkplaces\n\nplaces of worship\n\nlocal health care establishments, for example, community health facilities, hospitals and urgent care centres.\n\n\n\n# Recommendation 11 Monitor and evaluate the provision and uptake of vitamin\xa0D supplements\n\nThe Department of Health, Public Health England and local authority commissioners should:\n\nMonitor national and local awareness of, access to, and uptake of, vitamin\xa0D supplements among specific population groups (including those covered by Healthy Start).\n\nUse a range of sources to assess local uptake, for example, orders for supplements and information collected in personal child health records, maternal antenatal notes and computerised prompts (see recommendation\xa08).\n\nUse monitoring data to improve activities related to the awareness of, access to and uptake of vitamin D supplements.", 'Who should take action?': "# Introduction\n\nThe guideline is for: commissioners, managers and other professionals with public health as part of their remit working within the NHS, local authorities and the wider public, private, voluntary and community sectors. It is also aimed at the suppliers and providers of vitamin\xa0D supplements.\n\nIn addition, it may be of interest to people at risk of vitamin\xa0D deficiency, their families and carers and other members of the public.\n\nWho should take action?\n\nRecommendation\n\nClinical commissioning groups\n\n, 9\n\nCommissioners and senior managers in local authorities and the NHS\n\n, 5, 6, 8, 9, 11\n\nCouncil leaders and elected members\n\n\n\nDepartment of Health\n\n, 2, 11\n\nDevelopers of standardised medical notes\n\n\n\nDirectors of public health\n\n\n\nHealth and social care practitioners\n\n, 8, 10\n\nHealth and wellbeing boards\n\n\n\nHealth Education England\n\n\n\nPrimary care practitioners\n\n\n\nPublic health teams\n\n, 10\n\nPublic Heath England\n\n, 3, 9, 11\n\nSupplement manufacturers\n\n\n\nVoluntary and community organisations\n\n, 10\n\n# Who should take action in detail\n\n## Recommendation 1\n\nDepartment of Health; supplement manufacturers\n\n## Recommendation 2\n\nPublic Health England, the Department of Health\n\n## Recommendation 3\n\nPublic Heath England\n\n## Recommendation 4\n\nCouncil leaders; elected members; directors of public health; public health teams; commissioners and senior managers in local authorities and NHS trusts; and voluntary and community organisations\n\n## Recommendation 5\n\nLocal authorities\n\n## Recommendation 6\n\nLocal authorities\n\n## Recommendation 7\n\nHealth professionals\n\n## Recommendation 8\n\nDevelopers of standardised medical notes; developers of personal child health records; health professionals; local authorities; primary care; clinical commissioning groups\n\n## Recommendation 9\n\nPublic Health England; Health Education England; clinical commissioning groups; health and wellbeing boards; local authorities\n\n## Recommendation 10\n\nLocal public health teams; voluntary and community groups; health, social care and other practitioners working with specific population groups. This includes: dietitians, district nurses, GPs, health visitors, midwives, nursing assistants, pharmacists, physiotherapists, practice nurses, registered nutritionists and social workers. It also includes people working in nursing or care homes, nurseries, schools, children's centres, and secure settings such as prisons\n\n## Recommendation 11\n\nDepartment of Health; Public Health England; local authority commissioners", 'Context': "# Background\n\nVitamin\xa0D is essential for skeletal growth and bone health. Dietary sources in the UK are very limited and oily fish is the only significant source. Small amounts are provided by egg yolk, red meat and fortified foods, such as formula milks for infants and toddlers, some breakfast cereals and fat spreads (margarine). The major natural source is from skin synthesis following exposure to sunlight.\n\nFrom October to the beginning of April in the UK there is no ambient ultraviolet sunlight of the appropriate wavelength for skin synthesis of vitamin D. During this time, the population relies on both body stores from sun exposure in the summer and dietary sources to maintain vitamin\xa0D status (Scientific Advisory Committee on Nutrition's update on vitamin D 2007).\n\nThe National Diet and Nutrition Survey: results from Years 1 to 4 (combined) of the rolling programme for 2008 and 2009 to 2011 and 2012 (Public Health England and Food Standards Agency) shows that vitamin D status is highest among all age groups in the summer months and lowest in the winter. For example, only 8% of adults aged 19–64 had a low vitamin D status in July to September, compared with 39% in January to March. Similarly, around 2% of children aged 4 to 10 years had a low vitamin D status in July to September, compared to 32% in January to March.\n\nSevere vitamin\xa0D deficiency can result in rickets among children: there has been concern that rickets may be re-emerging among children in the UK (Pearce and Cheetham 2010). It can also result in osteomalacia (soft bones, among children and adults) and hypocalaemia (low levels of calcium in the blood) in children. In addition, low vitamin D status has been associated with some diseases and other long-term conditions such as osteoporosis, diabetes and some cancers, although the evidence is inconclusive (Update on vitamin\xa0D).\n\n# People at risk\n\nThe National Diet and Nutrition Survey suggests that almost a fifth of UK adults have a low vitamin D status. This means they have less than 25\xa0nmol/litre of the main circulating form of vitamin D in their body – 25\xa0hydroxyvitamin\xa0D (25[OH]D) ('National Diet and Nutrition Survey: results from Years\xa01 to 4 (combined) of the rolling programme for 2008 and 2009 to 2011 and 2012').\n\nA newborn baby's vitamin\xa0D status is largely determined by the mother's level of vitamin\xa0D during pregnancy.\n\nBreast milk is not a significant source of vitamin D. Formula milks for infants have to be fortified with vitamin D (this is voluntary for formula milks for toddlers).\n\nInfants who are exclusively breastfed, or have less than 500\xa0ml a day of infant formula, may not get enough vitamin\xa0D to meet their needs. (See NICE guidance on antenatal care and maternal and child nutrition.) Infants from Asian families are at particular risk. The Asian Feeding Survey (Infant feeding in Asian families, 1994–1996 Office for National Statistics) found that up to a third of Indian, Bangladeshi or Pakistani children had low vitamin D status at age\xa02.\n\nPeople with dark skin are at increased risk of deficiency as their skin is less efficient at synthesising vitamin D. In other words, they need to expose their skin to sunlight for longer to make the same amount of vitamin D as people with paler skin. People of African, African-Caribbean and South Asian family origin, and those who remain covered when outside, are at particular risk. Almost 75% of Asian adults may have low vitamin D status in the winter. (For more details see the expert paper Vitamin D intakes and status.)\n\nOlder people are also at increased risk, particularly if they are frail, because they may spend more time indoors and have limited sun exposure.\n\nPeople who are housebound and others who have limited exposure to the sun all year round (for example, those in prison) are also at increased risk (the SACN update on vitamin\xa0D). For example, the National Diet and Nutrition survey suggests that between 10 and 20% of older adults have low vitamin\xa0D status. This can increase up to 38% among people living in institutions.\n\nThere is substantial variation in vitamin\xa0D status across England, with people living in more southerly regions tending to have a better vitamin\xa0D status. London is the exception.\n\nThe Health Survey for England (NHS Information Centre for Health and Social Care 2010) found that 35% of adults in London had low status compared to the national average of 24%. (For more details see the expert paper 'Vitamin\xa0D intakes and status'). This may reflect the higher number of people from the minority ethnic groups at risk of vitamin\xa0D deficiency living in London, compared to other parts of England.\n\n# UK recommendations on vitamin\xa0D supplements\n\nAll UK health departments (for example, see the 2012 Chief Medical Officers' report Vitamin\xa0D – advice on supplements for at risk groups) and NICE (see our pathways on antenatal care and maternal and child nutrition) have issued evidence-based guidance on vitamin\xa0D supplements for various population groups. They have also provided guidance on how to distribute free Healthy Start supplements (that contain vitamin\xa0D) to eligible families.\n\nThe 4 UK chief medical officers have also flagged that health professionals could make 'a significant difference' if they ensure those at risk of vitamin\xa0D deficiency understand how important the vitamin is and how to get a daily supplement. They say that all at‑risk groups should be made aware of how they can obtain the vitamins locally ('Vitamin\xa0D – advice on supplements for at risk groups').\n\nThe Chief Medical Officers also stress the need to ensure people who may be eligible for the Healthy Start scheme know how they can apply. Note: this scheme provides vouchers that can be used to buy infant formula, cow's milk and plain fresh or frozen fruit and vegetables. People also receive coupons that can be exchanged for vitamin supplements that include the recommended amounts of vitamin\xa0D.\n\nEvidence suggests implementation of these recommendations has been limited ('Vitamin\xa0D – advice on supplements for at risk groups'). For example, a report commissioned by the Department of Health's Policy Research Programme (Healthy start: understanding the use of vouchers and vitamins) found that parents find it difficult to access Healthy Start vitamins, health professionals do not promote the scheme and eligible families are often unaware of it. It also found that the distribution system is complex, confused and weak, and mothers are not motivated to take the vitamins or to give them to their children.\n\nThe cost effectiveness of implementing interventions to prevent vitamin\xa0D deficiency also remains unclear. Testing for vitamin\xa0D insufficiency has been reported to have increased 2-\xa0to\xa06-fold in recent years and, at approximately £20 a test, is likely to be a considerable cost for the NHS (Sattar et al. 2012). Primary care spending on treatments for vitamin\xa0D deficiency rose from £28\xa0million in 2004 to £76\xa0million in 2011 (Treating vitamin\xa0D deficiency GP, 13\xa0February\xa02012; Prescription cost analysis England 2011 Health and Social Care Information Centre). In 2006, it cost an estimated £2500 to treat each child identified with symptomatic vitamin\xa0D deficiency (Zipitis et al. 2006).\n\n# How to get vitamin\xa0D supplements\n\nSupplements containing vitamin\xa0D are available on prescription or for sale from pharmacies or shops. However, there is wide variation in the content and price and some supplements may not be suitable for particular at‑risk groups. (For example many multivitamins contain vitamin\xa0A, which pregnant women should avoid during pregnancy.)\n\nHealthy Start vitamins tend to be available from health clinics, children's centres, Sure Start centres, outreach programmes or GP surgeries, although there have been national and local supply problems. Manufacturers have not made them directly available to pharmacies.\n\nIn 2013, the Chief Medical Officer for England recommended a review of the cost effectiveness of extending the provision of free Healthy Start vitamins to every child. This was due to concerns that 'providing free vitamins to targeted groups has not led to high enough levels of uptake' (CMO's annual report 2012: our children deserve better Department of Health).\n\nUp to April 2013, people not eligible for Healthy Start were able to buy the supplements at a much lower cost than commercial preparations. However, this option was encouraged in only a limited number of areas (Help pregnant women, new mothers and children get their free healthy start vitamins Department of Health). Since April 2013, following a change in health and social care legislation, these supplements can no longer be sold.", 'Considerations': "The Public Health Advisory Committee (PHAC) took account of a number of factors and issues when developing the recommendations, as follows. Please note: this section does not contain recommendations. (See recommendations.)\n\n# Background\n\nThe PHAC considered only the implementation of existing recommendations on vitamin\xa0D to prevent deficiency. The evidence base on which existing recommendations were made – and the contribution of dietary intake (including fortified foods) and sunlight exposure to vitamin\xa0D status – was outside its remit. Whether older adults should take vitamin D alone, or with calcium, was also outside its remit. Members were aware that the Scientific Advisory Committee on Nutrition (SACN) was considering many of these issues. Wherever possible, the guidance is consistent with SACN's advice and ongoing work in this area. NICE is also developing an associated guideline on the benefits and risks of sunlight exposure. It is hoped that these 3 pieces of work will provide the basis for clear, consistent advice to reduce the risk of low vitamin\xa0D status among all specific population groups.\n\nA number of fundamental issues hinder the uptake of existing guidance among specific population groups. For example, many health professionals and the public may be unaware that the skin cannot synthesise vitamin\xa0D from sunlight during winter months in the UK. They may also be unaware that a balanced diet alone will not provide sufficient vitamin\xa0D. In addition, they do not know enough about the importance of vitamin\xa0D supplements for specific population groups. The availability of suitable low cost supplements may also be limited – and health professionals and the public may not know where they can get them locally. The PHAC decided that there will only be significant increases in uptake if all these issues are addressed. Members also discussed and made recommendations on other actions to prevent any further confusion about the existing guidance. This includes having a viable distribution policy to reach specific population groups before carrying out further awareness-raising activities.\n\n# Communications\n\nAdvice on the use of vitamin\xa0D supplements to maintain good bone health has been available since 1991. (Dietary reference values for food energy and nutrients for the United Kingdom. Report of the panel on dietary reference values of the Committee on Medical Aspects of Food Policy Department of Health.) This includes existing recommendations on vitamin D from SACN, the 4 UK chief medical officers and NICE. However, awareness and implementation of the advice has been poor. The PHAC noted that, although existing recommendations are broadly consistent, the complexity of the advice and poor communications may have been the cause of confusion among both health professionals and the public. Members also noted the lack of clarity about who is 'at risk'. For example, health professionals and the public alike may question what constitutes 'a low exposure' to sunlight or 'dark' skin. Similarly, the disparity between those who are eligible for the Healthy Start scheme and the recommendations on vitamin D supplements for women and children appear to be another source of confusion.\n\n# Availability of vitamin D supplements\n\nThe PHAC discussed the importance of increasing the availability of vitamin\xa0D supplements for all specific population groups. Members were unable to recommend free supplements for these groups, due to a lack of evidence on the effect that differential costs have on uptake. They did recognise that free provision had contributed to increased uptake in some areas. Members also noted the strong economic case for offering free or low cost supplements to specific population groups to prevent deficiency, when compared to the cost of widespread testing for vitamin\xa0D deficiency. They felt it was important to determine the effectiveness and cost effectiveness of providing free supplements to specific population groups and made a recommendation for research on this. Allied to this, the PHAC discussed the potential for confusion among the public if free or low cost supplements were available in some areas but not others. Members agreed that this issue cannot be ignored by areas considering such a policy.\n\nUntil recently, low cost vitamin\xa0D-only supplements containing 100% of the reference nutrient intake were not widely available for sale. The PHAC noted that many vitamin\xa0D supplements also contain calcium (which may be poorly tolerated) and that some people may be deterred by the cost of supplements. Members agreed that there is unlikely to be a significant increase in the number of people in specific populations taking a vitamin supplement unless a free or low cost vitamin\xa0D-only supplement is widely available. This may be particularly true for lower income groups. The PHAC also noted that there is little point in awareness-raising activities to promote vitamin\xa0D supplements if affordable supplements are not widely available.\n\n# Evidence\n\nThe evidence reviews identified very little data on how existing guidance on vitamin\xa0D supplements has been implemented. The evidence available tends to be relatively poor and usually focuses on groups targeted by the Healthy Start initiative. No evidence was identified for interventions aimed at increasing the uptake of vitamin\xa0D supplements among: people aged 65 or older, people who have low or no exposure to the sun, or people who have dark skin. In addition, only very limited information was available on the views of those taking supplements or in specific population groups. The effectiveness of specific interventions was also difficult to determine. For example, it was difficult to quantify the relative impact of: training for health professionals; making vitamin\xa0D or Healthy Start supplements more widely available (including the impact of cost); and activities to increase awareness of the importance of taking them among specific population groups.\n\nThe evidence on the implementation of existing vitamin\xa0D guidance was very limited. As a result, following discussion with PHAC, NICE commissioned an additional review of reviews on effective implementation of a range of public health and clinical guidelines. Several key themes emerged. For example, the PHAC noted that implementation of any health intervention is likely to be more effective if health professionals are made aware of the issue and are prompted to raise it. Other 'effectiveness' factors include consistent guidance and advice and simple, inexpensive interventions.\n\nThe PHAC noted the importance of ongoing monitoring and evaluation of the availability and uptake of vitamin\xa0D supplements among specific population groups, at a national and local level. Members were also aware that data collection may involve using limited resources. Nevertheless, monitoring and evaluation appears to have been insufficient and inconsistent to date and there has been little opportunity to learn from good practice.\n\n# Healthy Start\n\nThe limited evidence available points to extremely low uptake of Healthy Start supplements among eligible pregnant and breastfeeding women and children younger than 4\xa0years. One study of 13 primary care trusts across all regions of England reported uptake to be below 10% (Jessiman et al. 2013). Another reported it to be less than 3% (Moonan et al. 2012). Variation between areas suggests that action can be taken to improve uptake. (For example, members discussed increasing the number of outlets providing the supplement and providing training for health professionals.)\n\nThe PHAC was aware that uptake of Healthy Start vouchers for infant formula, cow's milk and fruit and vegetables was good (at around 77% of those eligible) (Jessiman et al. 2013). Members noted that this could be because the voucher can be used at a variety of outlets as part of everyday shopping.\n\nThe PHAC discussed the need to give people eligible for Healthy Start support a clear explanation of the different benefits gained by taking Healthy Start supplements and consuming the milk, fruit and vegetables provided. Members were concerned that users of the scheme may be unaware of the importance of taking the supplement.\n\nThe PHAC was aware that numerous aspects of the system for distributing Healthy Start vitamins may hinder implementation. For example a report commissioned by the Department of Health's Policy Research Programme Healthy start: understanding the use of vouchers and vitamins identified that senior public health practitioners may spend considerable time administering the scheme. In addition, the order and reimbursement processes are slow and complex, and there are ongoing concerns about shelf-life and storage. The study's authors also reported that the voucher format and the process for getting supplements are confusing for the public.\n\nThe PHAC discussed the fact that universal free provision of Healthy Start vitamins can improve uptake, but that without wider action the impact may be limited. One study suggests uptake may almost treble with universal free provision, but only to around 4% for children's drops and 7.7% for women's tablets. Another study showed a year-on-year increase in uptake to 23% for women's tablets and 20% for children's drops when universal free supplementation was supported by action to increase awareness (McGee and Shaw 2013). No studies were identified that compared universal free provision of vitamin\xa0D supplements with universal provision of supplements that have to be paid for (albeit at a low cost). This prevented the committee from commenting on the relative benefits of these approaches and members felt that this is an important area for future research.\n\nThe PHAC was concerned that most mothers and children at risk of vitamin\xa0D deficiency are not eligible for the Healthy Start scheme. The lack of a similar alternative, or the cost of commercial supplements, may deter them from taking a supplement (particularly those from lower income groups). Some areas had made local arrangements to sell Healthy Start vitamins. But health and social care legislation, introduced in April 2013, means this is no longer possible. Furthermore, the Department of Health's existing arrangements with manufacturers mean it is not possible to get Healthy Start supplements from many places where people might expect to find them. (For example, they are not available in high street or supermarket pharmacies.)\n\n# Training\n\nThe PHAC agreed that health, social care and other practitioners in contact with specific population groups need training to provide robust, consistent advice – and that this is essential if vitamin\xa0D supplementation is to increase. But members also recognised that this would have limited impact if the availability of supplements and inconsistencies in current guidelines are not resolved.\n\n# Cost effectiveness\n\nThe main question asked in the economic model was: 'What is the most cost‑effective way of providing vitamin\xa0D supplements to specific population groups?'. Because of the focus of the guideline, 'What is the cost effectiveness of vitamin\xa0D supplementation among specific population groups?' was a subsidiary question for pregnant and breastfeeding women, and for children under 5\xa0years. Modelling was based on 4 specific population groups: pregnant women and breastfeeding women, children aged under 5\xa0years, people aged 65 or over and people whose skin is darker. There were not enough data to model this question for 'people whose skin is not sufficiently exposed to the sun'. (We do not know how many people in the population this affects, nor the extent of the deficiency among this group.) The cost of giving everyone in each group a daily supplement was compared with the cost of testing everyone and giving vitamin\xa0D supplements only to those with an identified deficiency. The model included estimated costs of intervention administration and delivery, based on an intervention in Birmingham (McGee and Shaw 2013).\n\nThe economic model found that it is cost saving to give everyone in each group a daily vitamin\xa0D supplement, rather than testing them all and supplementing only those who are deficient. It was assumed that the cost of a test is fixed at £16.50.\n\nA potential limitation of the modelling analysis is that it assumes everyone is given a prophylactic supplement without being tested. This may mean that less emphasis is given to finding people who are severely deficient and who may need a higher dose of vitamin\xa0D. However, people showing the symptoms of severe deficiency may well be tested. Aspects of this situation are explored in a sensitivity analysis in the cost effectiveness report. The model did not consider any risks associated with taking a supplement containing the reference nutrient intake for vitamin\xa0D. The PHAC agreed that there is a negligible risk associated with taking the prophylactic dose.\n\nThe subsidiary analysis looked at increasing the uptake of vitamin\xa0D supplements among pregnant and breastfeeding women and children aged 5\xa0years and younger. The estimated cost of supplementation for each additional woman who is pregnant or breastfeeding was £10.15. This resulted in an estimated cost per deficiency averted of £2859. For children aged 5 or younger, the estimated cost of supplementation per additional child was £4.62. This resulted in an estimated cost per deficiency averted of £1229.\n\nA limitation of the subsidiary analysis (see 4.19) is that people with a vitamin\xa0D deficiency are defined in the model in terms of the symptoms of deficiency, rather than by their vitamin\xa0D status. So if someone had a low vitamin\xa0D status but did not show any symptoms of deficiency, the model assumed they would not benefit from a supplement. Because people with symptoms of deficiency are likely to be a relatively small subset of those defined as having a low vitamin\xa0D status, the model almost certainly overstates the cost of averting a 'deficiency'.", 'Recommendations for research': "The Public Health Advisory Committee (PHAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nAll the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.\n\nOutcomes for all the questions below may include vitamin\xa0D status, user adherence or any unintentional consequences. The recommendations apply to all specific population groups, but there is a particular need for research in people over\xa065, people with dark skin and people living in institutions.\n\nHow effective and cost effective are interventions to increase vitamin D access, uptake, adherence or status among identified specific population groups? Does effectiveness vary by age, gender, ethnicity, socioeconomic or other specific population characteristics (such as depression or a disability)? The following could be considered:\n\navailability and uptake of supplements (including the impact of the cost of supplements)\n\ntype of supplements provided and how that impacts on adherence\n\nknowledge and attitudes (of both the public and health and social care practitioners).\n\nHow cost effective are preventive approaches to vitamin\xa0D deficiency among all specific population groups, compared with the cost of testing and treatment? This should include a comparison of universal provision of free supplements with the provision of low or standard cost supplements for different specific population groups. (If there is any new legislation allowing for the sale of Healthy Start supplements, this would provide an opportunity to test this question.)\n\nHow can a multiagency approach to improving awareness, availability and uptake of vitamin\xa0D supplements best be established, improved and sustained? For example, what are the key components, who are the key partners and how does the local context affect effectiveness? The latter may include local population characteristics (such as age, ethnicity or levels of deprivation), setting and the approach to commissioning. Research should be conceived, developed and implemented as a collaboration between academics and local practitioners or the local community.\n\nWhat type of training and awareness-raising can improve how health and social care practitioners:\n\npromote vitamin\xa0D supplements among specific population groups\n\nimprove the local population's awareness of, and attitudes towards, vitamin\xa0D supplements\n\nuptake of vitamin\xa0D supplements?\n\nWhat is the best way of monitoring the local system for distributing vitamin\xa0D supplements? Assessments of methods that enable robust data collection – such as computerised data capture systems – would be particularly useful. (The aim would be to use that data to improve the service.)\n\nMore detail identified during development of this guideline is provided in gaps in the evidence.", 'Related NICE guidance': 'Physical health of people in prison NICE guideline 57 (2016)\n\nSunlight exposure: risks and benefits NICE guideline 34 (2016)\n\nFalls: assessment and prevention of falls in older people NICE guideline CG161 (2013).\n\nBehaviour change – individual approaches NICE guideline PH49 (2014).\n\nSkin cancer prevention: information, resources and environmental changes NICE guideline PH32 (2010).\n\nWeight management before, during and after pregnancy NICE guideline PH27 (2010).\n\nMaternal and child nutrition NICE guideline PH11 (2008).\n\nAntenatal care NICE guideline CG62 (2008).\n\nPostnatal care NICE guideline CG37 (2006).', 'Glossary ': "# At-risk groups\n\nAlthough the entire UK population is at risk of having a low vitamin D status, these population groups are at higher risk:\n\nPeople who have low or no exposure to the sun. For example, those who cover their skin for cultural reasons, who are housebound or confided indoors for long periods.\n\nPeople who have dark skin, for example, people of African, African-Caribbean and South Asian origin.\n\n# Culturally appropriate\n\nCulturally appropriate interventions take account of the community's cultural or religious beliefs and language and literacy skills by:\n\nUsing community resources to improve awareness of, and increase access to, interventions. For example, they involve community organisations and leaders early in the development stage, use media, plan events or make use of community-specific festivals.\n\nUnderstanding the target community and the messages that resonate with them.\n\nIdentifying and addressing barriers to access and participation, for example, keeping costs low to ensure affordability and taking account of working patterns and education levels.\n\nDeveloping communication strategies that are sensitive to language use and information needs. For example, involve staff who can speak the languages used by the community, and provide information in different languages and for varying levels of literacy (for example, using colour-coded visual aids and spoken rather than written information).\n\nTaking account of cultural or religious values, for example, in relation to body image, separate physical activity sessions for men and women, beliefs and practices about hospitality and food, or dates, days, settings, or timings considered unsuitable for community events or interventions.\n\nProviding opportunities to discuss how interventions would work in the context of people's lives.\n\nConsidering how closely aligned people are to their ethnic group or religion and whether they are exposed to influences from both the mainstream and their community in relation to diet and physical activity.\n\n# Dietary reference values\n\nDietary reference values is a collective term for reference nutrient intake, estimated average requirement and lower reference nutrient intakes. Dietary reference values reflect the amount of energy and nutrients needed by healthy people according to their age and gender. For certain nutrients, set increments reflect the increased demands associated with pregnancy and lactation.\n\n# Existing recommendations on vitamin\xa0D\n\nThe UK Health Departments, the Scientific Advisory Committee on Nutrition and NICE have all issued evidence-based guidance on vitamin\xa0D supplements for various specific population groups. (See the NICE guideline on antenatal care and maternal and child nutrition.) They have also provided advice on how to distribute free Healthy Start supplements (containing vitamin\xa0D) to eligible families.\n\n# Halal\n\nHalal refers to foods or non-food items such as cosmetics or pharmaceuticals permitted by and prepared according to Islamic law.\n\n# Healthy Start\n\nHealthy Start is a UK-wide government scheme that provides a 'nutritional safety net' for pregnant women and families on benefits and tax credits. Women who are at least 10\xa0weeks pregnant and families with children younger than 4\xa0years qualify if the family receives the relevant benefits:\n\npregnant women get 1 Healthy Start voucher a week worth £3.10\n\nbabies younger than 1\xa0year get 2 vouchers a week worth £6.20\n\nchildren over 1 and under 4\xa0years of age get 1 voucher a week worth £3.10.\n\nVouchers are posted every 4\xa0weeks. They can be spent on plain cow's milk, plain fresh or frozen fruit and vegetables, or infant formula milk at retail outlets registered to accept them. These include supermarkets, grocery stores, chemists and milk rounds.\n\nEvery 8\xa0weeks, beneficiaries get vitamin coupons to swap for Healthy Start vitamins. It is the responsibility of NHS England until October 2015 – and from then on, local areas – to provide or arrange the provision of Healthy Start vitamins. The vitamin tablets for mothers contain folic acid and vitamins\xa0C and D. Healthy start vitamin drops for children contain vitamins\xa0A, C and D.\n\n# Kosher\n\nKosher refers to food (or premises where food is sold, cooked or eaten), cosmetics and pharmaceuticals that comply with Jewish law.\n\n# Low vitamin\xa0D status\n\nLow vitamin\xa0D status (sometimes called vitamin\xa0D deficiency) is defined by the Department of Health as a plasma concentration of 25\xa0hydroxyvitamin\xa0D (the main circulating form of the vitamin) of below 25\xa0nmol/litre (equal to 10\xa0ng/ml).\n\n# Reference nutrient intake\n\nReference nutrient intake is the amount of a nutrient needed to meet the needs of 97.5% of individuals in a group. Reference nutrient intake for a given nutrient may vary by gender, age and physiological status (for example during pregnancy and lactation). The reference nutrient intake is not a minimum target that all people need to achieve, but the risk of deficiency is minimised if the average population intake exceeds it.\n\nThe current reference nutrient intakes (µg/day) for vitamin\xa0D are:\n\nmicrograms of vitamin D per day, throughout the year, for everyone in the general population aged 4 years and older\n\nmicrograms of vitamin D per day for pregnant and lactating women and population groups at increased risk of vitamin D deficiency.\n\n# Safe intake\n\nSafe intakes are different to RNIs. A safe intake is used where there is insufficient evidence to set a RNI. The safe intake is the amount judged to be enough for almost everyone, but below a level that could have undesirable effects.\n\na 'safe intake' of 8.5 to 10 micrograms per day for all infants from birth to 1 year of age\n\na 'safe intake' of 10 micrograms per day for children aged 1 to 4 years.\n\nAll population groups are currently advised to take a supplement that meets 100% of the reference nutrient intake for their age group (as above). The reference nutrient intake for population groups is 10\xa0micrograms/day (1\xa0microgram=40 international units, so 10\xa0micrograms=400\xa0IU).\n\n# Specific population groups\n\nAlthough the entire population of the UK are at risk of having a low vitamin D status, evidence was only considered in regard to increasing the supplement use for these specific population groups:\n\nAll pregnant and breastfeeding women, particularly teenagers and young women.\n\nInfants and children under 4\xa0years (breast fed, non-breast fed and mixed fed).\n\nPeople over 65.\n\nPeople who have low or no exposure to the sun. For example, those who cover their skin for cultural reasons, who are housebound or confined indoors for long periods.\n\nPeople who have dark skin, for example, people of African, African–Caribbean and South Asian origin.\n\nAll population groups are currently advised to take a supplement that meets 100% of the reference nutrient intake for their age group. The reference nutrient intake levels are noted above.\n\nAll infants and young children aged 6\xa0months to 3\xa0years are advised to take a daily supplement containing vitamin\xa0D in the form of vitamin drops. But infants who are fed infant formula will not need them until they have less than 500\xa0ml of infant formula a day, because these products are fortified with vitamin\xa0D. Breastfed infants may need drops containing vitamin\xa0D from 1\xa0month of age if their mother has not taken vitamin\xa0D supplements throughout pregnancy. ('Vitamin D – advice for supplements for at risk groups – letter from the UK Chief Medical Officers' Department of Health).\n\n# Vegan\n\nPeople who follow a vegan diet consume only plant products. They avoid all food, drink and non-food items, such as pharmaceuticals that contain any animal products.\n\n# Vitamin\xa0D\n\nVitamin\xa0D is a fat soluble pro-hormone. It is obtained through the action of sunlight on skin and from dietary sources. The action of sunlight (ultraviolet radiation of wavelength 290–310\xa0nm) on skin converts 7‑dehydrocholesterol to previtamin\xa0D3, which is then metabolised to vitamin\xa0D3.\n\nDietary vitamin\xa0D exists as either ergocalciferol (vitamin\xa0D2) or cholecalciferol (vitamin\xa0D3).\n\nThe liver 25-hydroxylase enzymes convert vitamin\xa0D2 and D3 (from diet or from the action of sunlight on skin) to the main circulating form of the vitamin, 25\xa0hydroxyvitamin\xa0D – also known as 25(OH)D. This is then converted by the kidney and other tissues to the active form of the vitamin 1,25-dihydroxyvitamin D.", 'References': 'Jessiman T, Cameron A, Wiggins M et al. (2013) A qualitative study of uptake of free vitamins in England. Archives of Disease in Childhood 98: 587–91\n\nMcGee E, Shaw N (2013) Vitamin D supplementation: Putting recommendations into practice. Journal of Health Visiting 1 (3): 138–43\n\nMoonan M, Hanratty B, Whitehead M (2012) Which is more effective, a universal or targeted approach, to implementing the National Healthy Start Programme? A mixed methods study. Journal of Epidemiology and Community Health 66: A44–5\n\nPearce SHS, Cheetham TD (2010) Diagnosis and management of vitamin\xa0D deficiency. BMJ 340: b5664\n\nSattar N, Welsh P, Panarelli M et al. (2012) Increasing requests for vitamin D measurement: costly, confusing, and without credibility The Lancet 379 (9811): 95–6\n\nZipitis CS, Markides GA, Swann IL (2006) Vitamin D deficiency: prevention or treatment? Archives of Disease in Childhood 91: 1011–4', 'Summary of the methods used to develop this guideline': "# Introduction\n\nThe review and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the Public Health Advisory Committee (PHAC) meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\n# Guideline development\n\nThe stages involved in developing public health guidelines are outlined in the box below.\n\n. Draft scope released for consultation\n\n. Stakeholder meeting about the draft scope\n\n. Stakeholder comments used to revise the scope\n\n. Final scope and responses to comments published on website\n\n. Effectiveness reviews and economic modelling undertaken and submitted to PHAC\n\n. PHAC produces draft recommendations\n\n. Draft guideline (and evidence) released for consultation\n\n. PHAC amends recommendations\n\n. Final guideline published on website\n\n. Responses to comments published on website\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PHAC to help develop the recommendations. The overarching questions were:\n\n. How effective and cost effective are interventions to increase awareness and implementation of existing guidance on vitamin\xa0D among health professionals or others working with specific population groups? What are the implications for professional training and practice?\n\n. How effective and cost effective are interventions to increase awareness and uptake of existing guidance on vitamin\xa0D among specific population groups (with special consideration given to those eligible for the Healthy Start scheme)?\n\n. What helps or hinders the implementation of existing guidance on vitamin\xa0D by commissioners, providers, practitioners, those working with specific population groups and people in specific population groups?\n\n. What local provision is made to ensure vitamin\xa0D supplements are available for different specific population groups (including Healthy Start, prescriptions and over-the-counter sales)?\n\nThese questions were made more specific for the effectiveness review 'Vitamin\xa0D: a systematic review of effectiveness and cost-effectiveness of activities to increase awareness, uptake and provision of vitamin\xa0D supplements in specific population groups'.\n\n# Reviewing the evidence\n\n## Effectiveness review\n\nOne effectiveness review was conducted.\n\nSeveral databases were searched in June 2013 for evidence of any type published from 2000 onwards. See review 1: Vitamin\xa0D: a systematic review of effectiveness and cost-effectiveness of activities to increase awareness, uptake and provision of vitamin\xa0D supplements in at-risk groups for details.\n\nEvidence was also identified through:\n\ncitation searches of papers identified for inclusion\n\na search for additional studies by authors of papers identified for inclusion\n\na search of identified webpages\n\na call for evidence issued by NICE in March 2013.\n\nStudies were included in the effectiveness review if they:\n\nwere undertaken in the UK\n\naddressed at least 1 of the key questions.\n\nStudies were excluded if they focused on:\n\nthe management of vitamin\xa0D deficiency or conditions that may increase the risk\n\nfortification of food and drinks with vitamin\xa0D\n\nvitamin\xa0D for different population groups.\n\nSee review 1 for details.\n\n## Review of systematic review\n\nOne review of systematic reviews was conducted.\n\nReview 2 Review of systematic reviews exploring guideline uptake/implementation\n\nSeveral systematic review databases were searched in November\xa02013 for systematic reviews published from 2004 onwards.\n\nStudies were included if they were systematic reviews and addressed at least 1 of the key questions. Studies were excluded if they were not systematic reviews. See review\xa02.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in Methods for the development of NICE public health guidance. A checklist developed by Cardiff University was used for the cross-sectional studies and survey reports. Systematic reviews were assessed using the AMSTAR checklist. Each study was graded (++, +, −) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n− Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\n## Summarising the evidence and making evidence statements\n\nThe review data were summarised in evidence tables (see review 1 and review 2).\n\nThe findings from the review were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractor (see Supporting evidence). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\n\nThis was conducted as part of the effectiveness reviews (see above).\n\n## Economic modelling\n\nAn economic model was constructed, incorporating data from the reviews of effectiveness and cost effectiveness. The results are reported in: An economic evaluation of interventions to improve the uptake of vitamin D supplements in England.\n\n# How the PHAC formulated the recommendations\n\nAt its meetings in September and October 2013, the Public Health Advisory Committee (PHAC) considered the evidence, expert testimony and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme or activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect\n\nwhether the evidence is applicable to the target groups and context covered by the guideline.\n\nThe PHAC developed recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to an evidence statement (see The evidence for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).", 'The evidence ': "# Introduction\n\nThe evidence statements from 1 review are provided by external contractors (see Supporting evidence).\n\nThis section lists how the evidence statements and expert papers link to the recommendations and sets out a brief summary of findings from the economic analysis.\n\n# How the evidence links to the recommendations\n\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from.\n\nEvidence statement number 1.1 indicates that the linked statement is numbered 1 in review 1.\n\nEM indicates that the economic modelling report is linked to a recommendation.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements 1.11, 1.14, 1.15, 1.16\n\nRecommendation 2: evidence statements 1.10, 2.12; IDE\n\nRecommendation 3: evidence statements 1.1, 1.10, 1.11; 2.12; IDE\n\nRecommendation 4: evidence statements 1.1, 1.3, 1.10, 1.11, 1.14, 1.15, 2.10, 2.13\n\nRecommendation 5: evidence statements 1.1, 1.3, 1.5, 1.7, 1.9, 1.11, 1.14, 1.15, 1.16, 2.10; EM\n\nRecommendation 6: evidence statements 1.1, 1.3, 1.5, 1.7, 1.8, 1.9, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 2.2; EM\n\nRecommendation 7: evidence statements 1.7; EM; IDE\n\nRecommendation 8: evidence statements 1.10, 1.11, 2.2, 2.9\n\nRecommendation 9: evidence statements 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.10, 1.11, 2.3, 2.4, 2.5, 2.13\n\nRecommendation 10: evidence statements 1.10, 1.11, 1.12, 2.14\n\nRecommendation 11: evidence statement 2.6; IDE\n\n# Economic modelling\n\nThe economic model addressed the question: 'What is the most cost-effective way of providing vitamin D to specific population groups (pregnant women, children under 5 years, people aged 65 or over and people whose skin is darker)?' There were not enough data to model this question for 'people whose skin is not sufficiently exposed to the sun'.\n\nThere were 2 sets of analysis. The first compared the cost of providing each group with a daily supplement (without testing for deficiency) with the cost of testing everyone and giving those with a deficiency a supplement.\n\nThe second analysis looked at increasing uptake of supplements among pregnant and breastfeeding women, and among children up to the age of 5.\n\nSee An economic evaluation of interventions to improve the uptake of vitamin D supplements in England.", 'Gaps in the evidence': "The Public Health Advisory Committee (PHAC) identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence, expert and stakeholder comment. These gaps are set out below.\n\n. There is a lack of good quality interventions aiming to increase Vitamin\xa0D supplement use among specific population groups in England.\n\n. There is a lack of good quality evidence on the relative impact of the following on the uptake of vitamin\xa0D supplements among specific population groups: awareness-raising activities, health professional training and supplement provision.\n\n. There is a lack of good quality evidence on whether making a free or low cost vitamin\xa0D‑only supplement available affects uptake among specific population groups.\n\n. There is a lack of evidence on whether the following affect the effectiveness of interventions to increase vitamin\xa0D supplement use among specific population groups: sexual orientation, disability, religion, place of residence, occupation, education, socioeconomic position or a sense of community (or 'social capital').\n\n. There is a lack of evidence on what strategies may encourage people to take a vitamin\xa0D supplement on a regular basis.\n\n. There is a lack of evidence on whether health professional training leads to more effective interventions to improve uptake of vitamin\xa0D supplements among specific population groups.\n\n(Source: review 1 and review 2)\n\nThe Committee made 5 recommendations for research into areas that it believes will be a priority for developing future guidelines. These are listed in recommendations for research.", 'About this guideline': "# What does this guideline cover?\n\nThe Department of Health asked the National Institute for Health and Care Excellence (NICE) to produce a guideline on how to increase supplement use to prevent vitamin D deficiency among specific population groups. The guideline focuses on supplement use (see the scope).\n\nThis guideline is a partial update of maternal and child nutrition, NICE guideline PH11 (2008). The recommendations will replace recommendation 3 in 'Maternal and child nutrition'.\n\nThis guideline does not provide detail on the benefits and risks of sunlight exposure or management of vitamin\xa0D deficiency. (See related NICE guidance for other recommendations that may be relevant to the prevention or management of vitamin\xa0D deficiency.)\n\nThis guideline does not examine the cost effectiveness of extending the Healthy Start vitamin programme from the current targeted offering to a universal offering. NICE is working on a separate report on this issue. This will be forwarded to the Chief Medical Officer in 2015.\n\nThe absence of any recommendations on interventions that fall within the scope of this guideline is a result of lack of evidence. It should not be taken as a judgement on whether they are cost effective.\n\n# Other guidance and policies\n\nThe guideline should be implemented alongside other guidance and regulations including:\n\nScientific Advisory Committee on Nutrition report on vitamin\xa0D (expected 2015).\n\n# How was this guideline developed?\n\nThe recommendations are based on the best available evidence. They were developed by the Public Health Advisory Committee (PHAC).\n\nMembers of the PHAC are listed in membership of the Public Health Advisory Committee and the NICE project team.\n\nFor information on how NICE public health guidelines are developed, see the NICE public health guidance process and methods guides.\n\n# What evidence is the guideline based on?\n\nThe evidence that the PHAC considered included:\n\nEvidence reviews:\n\n\n\nReview 1 'Vitamin\xa0D: a systematic review of effectiveness and cost-effectiveness of activities to increase awareness, uptake and provision of vitamin\xa0D supplements in at‑risk groups', was carried out by York Health Economics Consortium. The principal authors were: Anne Morgan, Danielle Varley, Mick Arber, Maria Cikalo, Victoria Burley, Anita Fitzgerald and Julie Glanville.\n\nReview 2 'Review of systematic reviews exploring guideline uptake/ implementation' was carried out by York Health Economics Consortium. The principal authors were: Anita Fitzgerald, Anne Lethaby, Maria Cikalo, Julie Glanville and Hannah Wood.\n\nEconomic modelling 'An economic evaluation of interventions to improve the uptake of vitamin D supplements in England' was carried out by York Health Economics Consortium. The principal authors were: Alexandra Filby, Lily Lewis and Matthew Taylor.\n\n\n\nExpert paper: 'Vitamin D intakes and status' by Gillian Swan, Public Health England.\n\nNote: the views expressed in the expert papers above are the views of the authors and not those of NICE.\n\nIn some cases the evidence was insufficient and the PHAC has made recommendations for future research. For the research recommendations and gaps in research, see Recommendations for research and Gaps in the evidence.\n\n# Status of this guideline\n\nThe draft guideline, including the recommendations, was released for consultation in May and June 2014. At its meeting in September 2014, the PHAC amended the guideline in light of comments from stakeholders and experts and the fieldwork. The guideline was signed off by the NICE Guidance Executive in November 2014.\n\nThe guideline complements the NICE guideline on sunlight exposure and replaces recommendation 3 in the NICE guideline on maternal and child nutrition. (For further details, see Related NICE guidance).\n\nThe recommendations should be read in conjunction with existing NICE guidance unless explicitly stated otherwise. They should be implemented in light of duties set out in the Equality Act 2010.\n\nThe guideline is available on NICE's website. The recommendations are also available in the NICE Pathway on vitamin D: supplement use for specific population groups, for professionals whose remit includes public health and for interested members of the public.\n\nNICE produces guidance, standards and information on commissioning and providing high‑quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government and the Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\n\n# Implementation\n\nNICE guidance can help:\n\nCommissioners and providers of NHS services to meet the requirements of the NHS outcomes framework 2013–14. This includes helping them to deliver against domain 1: preventing people from dying prematurely.\n\nLocal health and wellbeing boards to meet the requirements of the Health and Social Care Act (2012) and the Public health outcomes framework for England 2013–16.\n\nLocal authorities, NHS services and local organisations determine how to improve health outcomes and reduce health inequalities during the joint strategic needs assessment process.\n\nNICE has developed tools to help organisations put this guideline into practice. Details will be available on our website after the guideline has been issued.\n\nISBN: 978-1-4731-0853-0"}
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https://www.nice.org.uk/guidance/ph56
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This guideline covers vitamin D supplement use. It aims to prevent vitamin D deficiency among specific population groups including infants and children aged under 4, pregnant and breastfeeding women, particularly teenagers and young women, people over 65, people who have low or no exposure to the sun and people with dark skin.
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Radiofrequency treatment for haemorrhoids
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Radiofrequency treatment for haemorrhoids
Evidence-based recommendations on radiofrequency treatment for haemorrhoids in adults. This involves using radiofrequency energy to shrink the haemorrhoids.
# Recommendations
Current evidence on the safety and efficacy of radiofrequency treatment for haemorrhoids is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
Clinicians wishing to do radiofrequency treatment for haemorrhoids should:
Inform the clinical governance leads in their NHS trusts.
Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.
Audit and review clinical outcomes of all patients having radiofrequency treatment for haemorrhoids (see section 7.1).
NICE encourages further research into radiofrequency treatment for haemorrhoids, preferably randomised controlled trials. It may update the guidance on publication of further evidence. Outcomes should include pain, secondary haemorrhage, recurrence rate, the need for repeat procedures and quality-of-life measures. Details of patient selection should also be reported.# Indications and current treatments
Haemorrhoids happen when the vascular anal cushions become enlarged. Some patients may be asymptomatic, but others have symptoms of bleeding, itching or discomfort. Small symptomatic haemorrhoids are classified as grade I. If the haemorrhoids are large, they may prolapse out of the anus. Haemorrhoids that prolapse may reduce spontaneously after defaecation (grade II); they may need to be reduced digitally (grade III); or they may not be reducible, remaining continually prolapsed (grade IV).
Grade I and II haemorrhoids may be managed by changes in diet or using laxatives, or treated with topical applications (such as corticosteroid creams or local anaesthetics). Established interventional treatments include rubber band ligation, sclerosant injections, infrared coagulation or bipolar electrocoagulation using diathermy.
Established treatments for symptomatic grade III and IV haemorrhoids include haemorrhoidectomy, stapled haemorrhoidopexy or haemorrhoidal artery ligation and bipolar electrocoagulation using diathermy.
Electrotherapy is another treatment option, which is used for grade I to IV haemorrhoids.# The procedure
Radiofrequency treatment for haemorrhoids is usually done under local anaesthetic, with or without sedation. A lubricated proctoscope is inserted into the anus to allow good visualisation of the anal canal and to expose the haemorrhoids. Local anaesthetic is injected into tissue surrounding the haemorrhoid. Details of the procedure vary according to the specific device being used. A specially designed probe connected to a radiofrequency generator is inserted into the haemorrhoid, or a ball electrode is rolled over the surface of the haemorrhoid. The tissue within the haemorrhoid heats up and the haemorrhoid shrinks. The haemorrhoids may be treated in several sessions, each taking up to 20 minutes.
Radiofrequency treatment for haemorrhoids is claimed to be faster and less painful than other treatment methods, with a shorter recovery time.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
In a randomised controlled trial (RCT) of 80 patients with grade II haemorrhoids treated by radiofrequency or rubber band ligation, the mean time taken to return to work was 2 and 5 days respectively (p=0.051). In an RCT of 40 patients with grade III or IV haemorrhoids, the time off work was 5 days for patients who had radiofrequency treatment and 21 days for patients who had haemorrhoidectomy. In a case series of 50 patients with grade III or IV haemorrhoids, 44% (22/50) of patients returned to work within 5 days and the remaining 56% (28/50) returned within 1 week of the procedure.
In the RCT of 80 patients, recurrence of bleeding was reported in 14% (5/36) of patients who had radiofrequency treatment and 7% (3/44) of patients who had rubber band ligation (p=0.105) at 1‑year follow‑up. Recurrence of haemorrhoid prolapse was reported in 1 patient, who had radiofrequency treatment, in the same study. Recurrence of symptoms was reported in 14% (4/28) and 6% (2/32) of patients respectively (p<0.05) in an RCT of 60 patients with grade II haemorrhoids treated by radiofrequency or rubber band ligation. Recurrence of bleeding was reported in 16% (33/209) of patients in a case series of 240 patients with grade I or II haemorrhoids treated by radiofrequency, at a mean follow‑up of 18 months. Recurrence of bleeding was reported in 4% (8/210) of patients in a case series of 210 patients with grade I or II haemorrhoids treated by radiofrequency, at a mean follow‑up of 12 months. In an RCT of 100 patients who had radiofrequency or infrared coagulation, recurrence of bleeding was reported in 8% and 14% of patients respectively, at 12‑month follow‑up.
In the case series of 50 patients with grade III or IV haemorrhoids, asymptomatic recurrence (diagnosed on proctoscopy) was reported in 9% (4/44) of patients at 12‑month follow‑up. In the RCT of 80 patients, obliteration of treated haemorrhoids (confirmed by anoscopy) was reported in 82% of patients who had radiofrequency and 93% of patients who had rubber band ligation (p=0.004) at 1‑year follow‑up.
In the RCT of 60 patients, the mean satisfaction scores (using a visual analogue scale of 0 to 10, where higher scores show more satisfaction) were 9.1 for radiofrequency treatment and 8.2 for rubber band ligation (p<0.05; follow‑up period not reported). In the RCT of 100 patients, 89% of patients who had radiofrequency treatment were satisfied compared with 83% of patients who had infrared coagulation (p value not reported). In the case series of 50 patients, all of the patients expressed satisfaction with the results of the treatment.
The specialist adviser listed the key efficacy outcomes as symptomatic and clinical resolution of haemorrhoids.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
The postoperative pain score (measured on a visual analogue scale of 0 to 10, where higher scores show more pain) in the first week after the procedure ranged from 0 to 2 for patients who had radiofrequency treatment and from 2 to 4 for patients who had rubber band ligation in a randomised controlled trial (RCT) of 80 patients. Duration of post-defaecation pain in the first week was 6 minutes in the radiofrequency treatment group compared with 13 minutes in the rubber band ligation group (p=0.01) in the same study. Pain in the anal region was reported in 12% (29/240) of patients in a case series of 240 patients. The pain intensity was scored 1 to 2 on the visual analogue scale and the patients were treated with analgesics. Anal pain (not further described) was reported in 7% (2/28) of patients who had radiofrequency treatment and 50% (16/32) of patients who had rubber band ligation in an RCT of 60 patients (p<0.05). Pain was reported by all patients in a case series of 50 patients; this subsided within 10 days after surgery in 43 patients and no patients complained of pain at the end of 1 month. Post-defaecation pain continued for 6 days after radiofrequency treatment and 13 days after haemorrhoidectomy in an RCT of 40 patients.
Bleeding after the procedure was reported in 19% (7/36) of patients who had radiofrequency treatment (reported mostly between 5 and 10 days after the procedure) and 5% (2/44) of patients who had rubber band ligation (reported between 7 and 9 days after the procedure) in the RCT of 80 patients. Bleeding, associated with defaecation, in the first 2 weeks was reported in 10% (23/240) of patients in the case series of 240 patients. Heavy bleeding in the first week after the procedure was reported in 2% (4/240) of patients in the same study; the bleeding was spontaneous and not associated with defaecation. The patients were admitted to hospital and 3 of the 4 had resolution of symptoms after conservative treatment. One patient needed to be examined under general anaesthesia; the active bleeding source was located and secured. Bleeding (not further described) was reported in 21% (6/28) of patients who had radiofrequency treatment and 13% (4/32) of patients who had rubber band ligation (p<0.05) in the RCT of 60 patients. Bleeding within 4 weeks of the procedure was reported in 14% (7/50) of patients in the case series of 50 patients; this was associated with defaecation and no treatment was needed. Post-defaecation bleeding continued for 7 days after radiofrequency treatment and for 24 days after haemorrhoidectomy in the RCT of 40 patients. Heavy bleeding, treated by a second procedure, was reported in 1 patient in a case series of 210 patients.
Urinary retention was reported in 4% (2/50) of patients in the case series of 50 patients; 1 patient had an enlarged prostate, the other had a large prolapsing haemorrhoid. It is thought that the treatment may have caused urethral spasm, leading to retention of urine. Both patients were catheterised, which relieved the symptoms. Urinary retention was reported in 1 patient in the case series of 210 patients; the patient had an enlarged prostate and was catheterised to relieve the symptoms.
Rectal tenesmus was reported in 6% (2/36) of patients who had radiofrequency treatment and 16% (7/44) of patients who had rubber band ligation (p=0.019) at 1‑week follow‑up in the RCT of 80 patients. Rectal tenesmus was reported in 4% (1/28) of patients who had radiofrequency treatment and 19% (6/32) of patients who had rubber band ligation (p<0.05) in the RCT of 60 patients.
Skin tag formation at 12‑month follow‑up was reported in 7 patients who had external haemorrhoids, in the case series of 50 patients.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, the specialist adviser did not list any additional anecdotal adverse events. They considered that the following were theoretical adverse events: infection and abscess.# Further information
This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
Patient commentary was sought but none was received.
For related NICE guidance, see the NICE website.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2639-8
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{'Recommendations': "Current evidence on the safety and efficacy of radiofrequency treatment for haemorrhoids is inadequate in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to do radiofrequency treatment for haemorrhoids should:\n\nInform the clinical governance leads in their NHS trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.\n\nAudit and review clinical outcomes of all patients having radiofrequency treatment for haemorrhoids (see section\xa07.1).\n\nNICE encourages further research into radiofrequency treatment for haemorrhoids, preferably randomised controlled trials. It may update the guidance on publication of further evidence. Outcomes should include pain, secondary haemorrhage, recurrence rate, the need for repeat procedures and quality-of-life measures. Details of patient selection should also be reported.", 'Indications and current treatments': 'Haemorrhoids happen when the vascular anal cushions become enlarged. Some patients may be asymptomatic, but others have symptoms of bleeding, itching or discomfort. Small symptomatic haemorrhoids are classified as grade\xa0I. If the haemorrhoids are large, they may prolapse out of the anus. Haemorrhoids that prolapse may reduce spontaneously after defaecation (grade\xa0II); they may need to be reduced digitally (grade\xa0III); or they may not be reducible, remaining continually prolapsed (grade\xa0IV).\n\nGrade\xa0I and II haemorrhoids may be managed by changes in diet or using laxatives, or treated with topical applications (such as corticosteroid creams or local anaesthetics). Established interventional treatments include rubber band ligation, sclerosant injections, infrared coagulation or bipolar electrocoagulation using diathermy.\n\nEstablished treatments for symptomatic grade\xa0III and\xa0IV haemorrhoids include haemorrhoidectomy, stapled haemorrhoidopexy or haemorrhoidal artery ligation and bipolar electrocoagulation using diathermy.\n\nElectrotherapy is another treatment option, which is used for grade\xa0I to IV haemorrhoids.', 'The procedure': 'Radiofrequency treatment for haemorrhoids is usually done under local anaesthetic, with or without sedation. A lubricated proctoscope is inserted into the anus to allow good visualisation of the anal canal and to expose the haemorrhoids. Local anaesthetic is injected into tissue surrounding the haemorrhoid. Details of the procedure vary according to the specific device being used. A specially designed probe connected to a radiofrequency generator is inserted into the haemorrhoid, or a ball electrode is rolled over the surface of the haemorrhoid. The tissue within the haemorrhoid heats up and the haemorrhoid shrinks. The haemorrhoids may be treated in several sessions, each taking up to 20\xa0minutes.\n\nRadiofrequency treatment for haemorrhoids is claimed to be faster and less painful than other treatment methods, with a shorter recovery time.', 'Efficacy': 'This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nIn a randomised controlled trial (RCT) of 80\xa0patients with grade\xa0II haemorrhoids treated by radiofrequency or rubber band ligation, the mean time taken to return to work was 2\xa0and 5\xa0days respectively (p=0.051). In an RCT of 40\xa0patients with grade\xa0III or IV haemorrhoids, the time off work was 5\xa0days for patients who had radiofrequency treatment and 21\xa0days for patients who had haemorrhoidectomy. In a case series of 50\xa0patients with grade\xa0III or IV haemorrhoids, 44% (22/50) of patients returned to work within 5\xa0days and the remaining 56% (28/50) returned within 1\xa0week of the procedure.\n\nIn the RCT of 80\xa0patients, recurrence of bleeding was reported in 14% (5/36) of patients who had radiofrequency treatment and 7% (3/44) of patients who had rubber band ligation (p=0.105) at 1‑year follow‑up. Recurrence of haemorrhoid prolapse was reported in 1\xa0patient, who had radiofrequency treatment, in the same study. Recurrence of symptoms was reported in 14% (4/28) and 6% (2/32) of patients respectively (p<0.05) in an RCT of 60\xa0patients with grade\xa0II haemorrhoids treated by radiofrequency or rubber band ligation. Recurrence of bleeding was reported in 16% (33/209) of patients in a case series of 240\xa0patients with grade\xa0I or II haemorrhoids treated by radiofrequency, at a mean follow‑up of 18\xa0months. Recurrence of bleeding was reported in 4% (8/210) of patients in a case series of 210\xa0patients with grade\xa0I or II haemorrhoids treated by radiofrequency, at a mean follow‑up of 12\xa0months. In an RCT of 100\xa0patients who had radiofrequency or infrared coagulation, recurrence of bleeding was reported in 8% and 14% of patients respectively, at 12‑month follow‑up.\n\nIn the case series of 50\xa0patients with grade\xa0III or IV haemorrhoids, asymptomatic recurrence (diagnosed on proctoscopy) was reported in 9% (4/44) of patients at 12‑month follow‑up. In the RCT of 80\xa0patients, obliteration of treated haemorrhoids (confirmed by anoscopy) was reported in 82% of patients who had radiofrequency and 93% of patients who had rubber band ligation (p=0.004) at 1‑year follow‑up.\n\nIn the RCT of 60\xa0patients, the mean satisfaction scores (using a visual analogue scale of 0\xa0to\xa010, where higher scores show more satisfaction) were 9.1\xa0for radiofrequency treatment and 8.2\xa0for rubber band ligation (p<0.05; follow‑up period not reported). In the RCT of 100\xa0patients, 89% of patients who had radiofrequency treatment were satisfied compared with 83% of patients who had infrared coagulation (p\xa0value not reported). In the case series of 50\xa0patients, all of the patients expressed satisfaction with the results of the treatment.\n\nThe specialist adviser listed the key efficacy outcomes as symptomatic and clinical resolution of haemorrhoids.', 'Safety': 'This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nThe postoperative pain score (measured on a visual analogue scale of 0\xa0to\xa010, where higher scores show more pain) in the first week after the procedure ranged from 0\xa0to\xa02 for patients who had radiofrequency treatment and from 2\xa0to\xa04 for patients who had rubber band ligation in a randomised controlled trial (RCT) of 80\xa0patients. Duration of post-defaecation pain in the first week was 6\xa0minutes in the radiofrequency treatment group compared with 13\xa0minutes in the rubber band ligation group (p=0.01) in the same study. Pain in the anal region was reported in 12% (29/240) of patients in a case series of 240\xa0patients. The pain intensity was scored 1\xa0to\xa02 on the visual analogue scale and the patients were treated with analgesics. Anal pain (not further described) was reported in 7% (2/28) of patients who had radiofrequency treatment and 50% (16/32) of patients who had rubber band ligation in an RCT of 60\xa0patients (p<0.05). Pain was reported by all patients in a case series of 50\xa0patients; this subsided within 10\xa0days after surgery in 43\xa0patients and no patients complained of pain at the end of 1\xa0month. Post-defaecation pain continued for 6\xa0days after radiofrequency treatment and 13\xa0days after haemorrhoidectomy in an RCT of 40\xa0patients.\n\nBleeding after the procedure was reported in 19% (7/36) of patients who had radiofrequency treatment (reported mostly between 5\xa0and 10\xa0days after the procedure) and 5% (2/44) of patients who had rubber band ligation (reported between 7\xa0and 9\xa0days after the procedure) in the RCT of 80\xa0patients. Bleeding, associated with defaecation, in the first 2\xa0weeks was reported in 10% (23/240) of patients in the case series of 240\xa0patients. Heavy bleeding in the first week after the procedure was reported in 2% (4/240) of patients in the same study; the bleeding was spontaneous and not associated with defaecation. The patients were admitted to hospital and 3\xa0of the\xa04 had resolution of symptoms after conservative treatment. One patient needed to be examined under general anaesthesia; the active bleeding source was located and secured. Bleeding (not further described) was reported in 21% (6/28) of patients who had radiofrequency treatment and 13% (4/32) of patients who had rubber band ligation (p<0.05) in the RCT of 60\xa0patients. Bleeding within 4\xa0weeks of the procedure was reported in 14% (7/50) of patients in the case series of 50\xa0patients; this was associated with defaecation and no treatment was needed. Post-defaecation bleeding continued for 7\xa0days after radiofrequency treatment and for 24\xa0days after haemorrhoidectomy in the RCT of 40\xa0patients. Heavy bleeding, treated by a second procedure, was reported in 1\xa0patient in a case series of 210\xa0patients.\n\nUrinary retention was reported in 4% (2/50) of patients in the case series of 50\xa0patients; 1\xa0patient had an enlarged prostate, the other had a large prolapsing haemorrhoid. It is thought that the treatment may have caused urethral spasm, leading to retention of urine. Both patients were catheterised, which relieved the symptoms. Urinary retention was reported in 1\xa0patient in the case series of 210\xa0patients; the patient had an enlarged prostate and was catheterised to relieve the symptoms.\n\nRectal tenesmus was reported in 6% (2/36) of patients who had radiofrequency treatment and 16% (7/44) of patients who had rubber band ligation (p=0.019) at 1‑week follow‑up in the RCT of 80\xa0patients. Rectal tenesmus was reported in 4% (1/28) of patients who had radiofrequency treatment and 19% (6/32) of patients who had rubber band ligation (p<0.05) in the RCT of 60\xa0patients.\n\nSkin tag formation at 12‑month follow‑up was reported in 7\xa0patients who had external haemorrhoids, in the case series of 50\xa0patients.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, the specialist adviser did not list any additional anecdotal adverse events. They considered that the following were theoretical adverse events: infection and abscess.', 'Further information': 'This guidance requires that clinicians doing the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nPatient commentary was sought but none was received.\n\nFor related NICE guidance, see the NICE website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2639-8'}
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https://www.nice.org.uk/guidance/ipg589
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Evidence-based recommendations on radiofrequency treatment for haemorrhoids in adults. This involves using radiofrequency energy to shrink the haemorrhoids.
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fa0547ee93c26e50585ece8bd67338ae3fa449ce
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nice
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Holoclar for treating limbal stem cell deficiency after eye burns
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Holoclar for treating limbal stem cell deficiency after eye burns
Evidence-based recommendations on Holoclar (a layer of cells grown from cells taken from your own eye) for treating limbal stem cell deficiency in adults with eye burns.
# Recommendations
Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells) is recommended as an option in people with moderate to severe limbal stem cell deficiency after eye burns, only if:
it is only used to treat 1 eye and
people have already had a conjunctival limbal autograft or
there is not enough tissue for a conjunctival limbal autograft or it is contraindicated and
the company provides it with the discount agreed in the patient access scheme.Moderate to severe limbal stem cell deficiency is defined by the presence of superficial corneal neovascularisation in at least 2 corneal quadrants, with central corneal involvement, and severely impaired visual acuity.
Holoclar is recommended in people with moderate to severe limbal stem cell deficiency after eye burns for treating both eyes only:
in the context of research and
when there is not enough tissue for a conjunctival limbal autograft.Such research should be designed to generate robust evidence of the clinical- and cost-effectiveness of Holoclar in treating 2 eyes in people who do not have enough tissue for a conjunctival limbal autograft.
These recommendations are not intended to affect treatment with Holoclar that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
# Description of the technology
The technology is ex vivo expanded autologous human corneal epithelial cells containing stem cells (Holoclar, Holostem Terapie Avanzate). It is a treatment used in the eye to replace damaged cells on the corneal surface.
# Marketing authorisation
It has a conditional marketing authorisation for 'the treatment of adult patients with moderate to severe limbal stem cell deficiency (defined by the presence of superficial corneal neovascularisation in at least 2 corneal quadrants, with central corneal involvement, and severely impaired visual acuity), unilateral or bilateral, due to physical or chemical ocular burns'. At least 1 mm2 to 2 mm2 of undamaged limbus is needed for biopsy before it can be used.
# Adverse reactions
For full details of adverse reactions and contraindications, see the summary of product characteristics.
# Recommended dose and schedule
The exact dosage depends on the size of the corneal surface: the recommended dose is 79,000 to 316,000 cells/cm2. A biopsy is first taken of the eye, which needs at least 1 mm2 to 2 mm2 of undamaged tissue. The treatment is then implanted in the eye.
# Price
According to the company's submission, a single treatment for 1 eye costs £80,000 excluding VAT. The company has a commercial arrangement. This makes Holoclar available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Evidence
The appraisal committee (section 7) considered evidence submitted by Chiesi Farmaceutici and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells), having considered evidence on the nature of moderate to severe limbal stem cell deficiency after eye burns and the value placed on the benefits of the treatment by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Treatment pathway and unmet need
The committee was aware that limbal stem cell deficiency (LSCD) is caused by an injury (such as a chemical or physical burn) to the source of limbal stem cells, which interrupts the renewal and replacement of the surface of the cornea. LSCD can either be unilateral (in 1 eye) or bilateral (in both eyes). The committee heard from the clinical experts that LSCD can be life-changing: in addition to visual impairment, the condition is associated with high levels of pain and photophobia. LSCD also represents a major psychological burden, both from the trauma of the original incident and the ongoing management of eye disfigurement. The highly visible nature of the injury can also impair a person's confidence and cause social isolation. Some people with LSCD are unable to continue working because of the physical or psychological effects. The committee agreed that LSCD can be a life-changing and severely debilitating condition.
The committee heard from the clinical experts that the aim of treatment for LSCD is to restore the surface of the eye, achieve corneal clarity and improve visual acuity. Current practice usually starts with supportive care treatments such as lubrication, autologous serum eye drops, and therapeutic soft and scleral contact lenses. Conservative surgery such as corneal scraping may also be offered before attempting limbal stem cell transplantation. Limbal stem cell transplantation includes a number of invasive surgical options to transplant stem cells to the affected eye which differ in terms of where the cells come from and how they are transferred, specifically:
conjunctival limbal autograft, in which stem cells are taken from the patient's healthy eye
conjunctival limbal allograft, in which stem cells are taken from a living, related donor or dead donor
keratolimbal allograft, in which the entire limbus may be transplanted from a dead donor, using the cornea as carrier tissue.
The committee heard from the clinical experts that successfully treating LSCD could be life-changing. However, current treatments are associated with many disadvantages. Conjunctival limbal autograft needs a relatively large amount of donor tissue from the healthy eye (equivalent to around 40% of the available reserves of the donor tissue). This increases the risk of damage to the donor eye: the clinical experts stated that 3% to 5% of patients having an autograft would have permanent serious damage. The clinical experts also estimated a transplant success rate with conjunctival limbal autograft of only 50%. Therefore, patients often choose to not have the treatment because their perceived risk of damage to the donor eye was not worth the chance of the procedure being a success in the affected eye. The committee assumed that people would have a conjunctival limbal autograft before approaching a living, related donor. One clinical expert stated they no longer did conjunctival limbal autografts because of the risks, although they acknowledged that the procedure is still used in clinical practice. Because both conjunctival limbal and keratolimbal allografts rely on external donors, they need immunosuppression which is in itself associated with several side effects. Even when treatment is successful, most allografts fail within 5 years. The clinical experts explained that finding a source of donor tissue can also be problematic.
The committee asked the clinical experts if patients with bilateral LSCD would have treatment in 1 or both eyes. It heard that ideally both eyes would be treated, but in practice it is likely for 1 eye to be worse than the other and that only the worst eye would be treated. The committee also asked if any of the procedures could be done more than once in the same eye. The clinical experts stated this would be unlikely for existing procedures, but that Holoclar represents a more viable option for retreatment because it needs a smaller amount of tissue. The smaller biopsy also means a much lower risk of damage to the donor eye; 1 clinical expert stated that in data for around 1,000 Holoclar procedures, they were unaware of any instances of damage to the patient's donor eye. The clinical experts stated that there is a subgroup of patients who have had conjunctival limbal autograft previously whose only option for further treatment was Holoclar. The committee concluded that the company had used the most appropriate comparators in its submission (that is: conjunctival limbal autograft, conjunctival limbal allograft, keratolimbal allograft and best supportive care), and Holoclar offered several advantages over these treatments.
# Clinical effectiveness
The committee noted that the evidence for Holoclar comprised 3 studies with follow-up of 12 months or less (HLSTM01, HLSTM02 and HLSTM04) and 5 studies with follow-up of 12 months up to 14.5 years (Rama 2001 and 2010, Pellegrini 1997 and 2013, Marchini 2012). The comparator evidence consisted of 23 smaller studies with high levels of heterogeneity, which the company, ERG and committee agreed made them unsuitable for data pooling. The 8 main studies were mostly case series, which offer poor quality evidence because they do not contain a comparison group, but the committee noted that data for Holoclar were available for a reasonably high number of patients given the rarity of the condition (n=219 across all studies). However, the company had run statistical analyses on the available data despite case series not being designed for this purpose (they are intended to be descriptive only). The committee also noted that the clinical evidence for Holoclar was limited to treating 1 eye only (of the 13 patients with bilateral disease, only 1 had treatment in both eyes). In the absence of stronger evidence in this disease area, the committee accepted this clinical evidence for its decision-making. However, it agreed that when making its recommendations it would need to take into account that no clinical evidence had been presented for using Holoclar in 2 eyes when both eyes are affected.
## Clinical evidence results
The primary outcome of the pivotal HLSTM01 study was treatment success, defined as stable corneal epithelium without significant recurrence of neovascularisation 12 months after treatment. The main secondary outcomes included symptom resolution (pain, burning and photophobia), inflammation, neovascularisation, visual acuity, number of successful keratoplasties and safety.
The results from HLSTM01 showed that 72.1% of patients had a successful Holoclar transplant. For the comparators, transplant success varied between 60.0% and 100.0%. Given its concerns with the quality of evidence, the committee asked the clinical experts if these success rates were likely to be reflective of those in clinical practice. The experts stated that the results for Holoclar were plausible, but that the results for the comparators should be interpreted with more caution. They considered the studies of conjunctival limbal autograft to be poorly conducted and biased, and the rates to be overestimated (in their experience, success rates were closer to 50%). The committee concluded that the evidence showed Holoclar to be an effective treatment in terms of the outcomes described in section 4.6. However, there was uncertainty about the comparator success rates and the effectiveness of Holoclar compared with them.
# Cost effectiveness
## Model structure
The company presented 2 separate models: a 'unilateral' and a 'bilateral' model. The models were similar, with both consisting of a decision tree followed by a Markov model, but the bilateral model assumed that patients had treatment in both eyes (and so included an additional year without treatment before treating the second eye). The evidence review group (ERG) considered the model to be reasonably well constructed. However, the committee noted that the company had not actually presented separate results for unilateral and bilateral populations. The 2 models did not, in fact, distinguish between unilateral and bilateral disease; both models included exactly the same population (that is, both included patients with unilateral and bilateral disease). Instead, the main difference was that only 1 eye was treated in the unilateral model, whereas both eyes were treated in the bilateral model. The committee agreed that it would be more informative to consider the company's unilateral model as the '1-eye treatment' model and the bilateral model as the '2-eye treatment' model. The committee concluded that the model structures were acceptable for its decision-making. It would take into account treatment between 1 eye and 2 eyes but it would be difficult to distinguish between unilateral and bilateral populations in the cost-effectiveness modelling when making its final recommendations.
## Discount rate
The company had deviated from the reference case by using a discount rate for future costs and benefits of 1.5%, rather than 3.5% as outlined in NICE's guide to the methods of technology appraisal. The company justified this by explaining that it believed Holoclar to have a prolonged effect (over 30 years), and that it could return patients to a high utility state. The committee was aware that the NICE methods guide states that when appraising treatments that 'restore people who would otherwise die or have severely impaired life to full or near full health, and when this is sustained over a very long period (normally at least 30 years)', non-reference case rates may be considered. However, the committee noted that it is rarely considered appropriate to change the discount rate and that LSCD was very different from the fatal and near-fatal conditions implied by the methods guide. The committee therefore concluded that the company should have used a 3.5% discount rate.
## Modelled long-term success rates
The committee noted that if treatment with Holoclar were successful at 1 year, it remained successful for the lifetime of the model. When questioned about the plausibility of this assumption, the clinical experts stated that there currently was not enough evidence to support strong assumptions about the long-term effectiveness of Holoclar. However, the transplant being successful at 1 year would demonstrate that the patient's body has regenerated the cornea 3 to 4 times, suggesting there may be some scientific merit to this model assumption. The committee accepted the company assumption about long-term success in the model, but agreed that this was subject to a high level of uncertainty that could increase the incremental cost-effectiveness ratio (ICER).
## Model parameters
The committee noted that the clinical-effectiveness assumptions in the model were taken from HLSTM01 for Holoclar, and from the literature for the comparators. For Holoclar, the committee had previously heard that the estimated transplant success rates were plausible. However, for the comparators, the committee noted that the company had pooled the data, despite the company and ERG agreeing that pooling these data would not be appropriate. The company had presented a limited exploration of different success rates for the comparators, but these scenarios included changes in other assumptions and so did not explore the effect of this rate change alone. Furthermore, only 1 alternative rate for each comparator had been explored. The committee agreed that it would have been more useful to explore a range of different success rates (between 50% and 80%) because there was no comparative evidence for Holoclar and the clinical experts considered the comparator success rates to be overestimated. The committee concluded that there was a substantial level of uncertainty in the clinical-effectiveness assumptions in the company's model.
In response to consultation, the company provided additional sensitivity analyses which included the committee's preferred assumptions (a discount rate of 3.5%, a utility value of 0.84 and a utility decrement for disfigurement of 0.140). The company varied the probability of initial transplant success and long-term probability of transplant failure for each comparator separately. The sensitivity analyses showed that the ICERs for Holoclar were sensitive to the annual failure probability and initial success rates for the comparator treatments; a higher probability of transplant success increased the ICERs. The committee recalled that the company's model may overestimate comparator success rates (section 4.7). It concluded that lower transplant success rates would decrease the ICER, but agreed that this was subject to a high level of uncertainty.
## Utility values
The committee was aware that conjunctival limbal autograft needs a substantial amount of tissue from the donor eye. It queried whether the potentially negative effect on the donor eye had been captured, and heard from the company, ERG and clinical experts that it had not. The committee noted further that the effect on the donor in the event of a transplant from a living, relative donor had also not been captured. It assumed that if donor disutility had been taken into account, the ICER would likely decrease. The committee agreed that it would have preferred to have seen analyses including the effect on the donor eye when comparing with conjunctival limbal autograft and the effect on the donor when comparing with conjunctival limbal allograft from a living, relative donor. The committee noted that the utility values used in the model were extraordinarily low: the values were far lower than any used in previous appraisals for eye treatments, with some lower than those for people in the last 3 months of life having palliative treatment for various cancers. The committee noted that the main reason for these low values appeared to be the utility decrement of 0.318 applied to patients experiencing disfigurement. This was over 100-times higher than the utility decrement applied to people experiencing any pain, burning or photophobia (the highest decrement was 0.019). The committee highlighted that company's 0.318 decrement was derived from non-reference case methods, which were likely to generate exaggerated results. The committee asked the clinical experts about the plausibility of these values. The clinical experts found the low overall utility difficult to quantify, but stated that LSCD has a long-term substantial negative effect on quality of life. For the high utility decrement for disfigurement, the committee heard varied reports about the relative importance of disfigurement. The clinical experts stated that for people with unilateral disease, contrary to conventional wisdom, visual acuity was not the most important outcome: because of its lasting and significant effect on their day-to-day lives, these people often prioritise disfigurement. For people with bilateral disease, disfigurement would be less of a priority than visual acuity because of the risk of complete loss of sight. The committee agreed that it was difficult to resolve this inconsistency in the relative importance of disfigurement. Furthermore, this was not the approach taken in the model, with utility values applying equally irrespective of whether disease was unilateral or bilateral. The committee agreed that the utility values used were implausibly low, noting that the ERG had used alternative values. For visual acuity, the ERG used a range with a more plausible maximum value of 0.861 (rather than the company's assumption of 0.706). For disfigurement, it used a decrement of 0.140 (rather than the company's assumption of 0.318), using cataracts as a proxy. The ERG noted that the decrement associated with cataracts also includes a loss of utility from both disfigurement and vision loss. The committee recognised that cataract disutilities were used as a proxy for disfigurement although uncertainty remained in the utility values, the ERG's values were a more realistic reflection of the impact on quality of life.
## Resource use and costs
The committee noted that the cost of autologous serum eye drops were a substantial driver of cost-effectiveness results in the model. The company had assumed in the model that patients having the comparators needed these drops after treatment and for flare-ups, but patients having Holoclar did not. The committee heard from the clinical experts that autologous serum eye drops are essential after treatment with the comparators, but less so with Holoclar because the stem cells are cultivated in a laboratory and not on the patient's eye. However, some clinicians may still choose to use them with Holoclar. The clinical experts also stated that drops would rarely be used for flare-ups because they take up to 6 weeks to prepare. Although alternative eye drops are available that would be ready for immediate use (allogenic serum eye drops), the committee heard from the ERG that using these drops would not make much difference to the model results because they were similarly priced. The committee agreed that the costs of eye drops for Holoclar had been underestimated in the model, but that the effect of this was difficult to quantify. It also agreed that eye drops after treatment were more necessary for the comparators than for Holoclar. It therefore concluded that it could cautiously accept the company's assumptions about eye drops, but remained aware that any increase in the use of eye drops would make Holoclar less cost effective.
## Cost-effectiveness results and conclusions
The committee considered the estimates of cost effectiveness calculated by the company. The base-case results were:
Conjunctival limbal autograft dominated (that is, was both less costly and more effective than) all treatments including Holoclar in both models.
The ICERs for Holoclar compared with conjunctival limbal allograft from a living, related donor were £7,185 per quality-adjusted life year (QALY) gained in the 1-eye treatment model, and £12,438 per QALY gained in the 2-eye treatment model.
The ICERs for Holoclar compared with keratolimbal allograft were £2,255 per QALY gained in the 1-eye treatment model and £6,533 per QALY gained in the 2-eye treatment model.
Holoclar dominated best supportive care in both models.None of these ICERs took into account the committee's preferred assumptions about utility values (section 4.13) and discount rate (section 4.9). However, the ERG had presented scenarios using both of these assumptions. In these scenarios, the ICERs became less favourable:
Conjunctival limbal autograft remained dominant in the 1-eye treatment model (the ERG did not compare Holoclar with conjunctival limbal autograft in the 2-eye treatment model).
The ICERs for Holoclar compared with conjunctival limbal allograft from a living, related donor were £42,139 per QALY gained in the 1-eye treatment model, and £63,047 per QALY gained in the 2-eye treatment model.
The ICERs for Holoclar compared with keratolimbal allograft were £30,415 per QALY gained in the 1-eye treatment model and £69,455 per QALY gained in the 2-eye treatment model.
The ICERs for Holoclar compared with best supportive care were £6,948 per QALY gained in the 1-eye treatment model and £12,669 per QALY gained in the 2-eye treatment model.Using the committee's preferred assumptions, Holoclar was not cost effective except compared with best supportive care.
The committee was aware that there were uncertainties in the assumptions about the comparators' long-term success rates and the use of eye drops. It noted that the success rates for conjunctival limbal allograft from a living, related donor and keratolimbal allograft in particular were likely to have been overestimated. Furthermore, if the effect on the donor were taken into account, the ICERs for Holoclar would likely decrease and fall within the range of £20,000 to £30,000 per QALY gained. Given the patient need (section 4.1) and innovative nature of the treatment (section 4.17), the committee agreed that it would pragmatically accept this as a demonstration of cost effectiveness. The committee noted that Holoclar was only cost effective for treating 1 eye. It recalled that there was almost no evidence concerning Holoclar's clinical effectiveness for treating both eyes, and agreed that it could not recommend Holoclar for routine use in the NHS to treat both eyes. However, it agreed that its recommendations for treating a single eye should apply equally to unilateral and bilateral disease. The committee therefore concluded that it could recommend Holoclar as a cost-effective use of NHS resources in people with moderate to severe LSCD after eye burns, only if it is used to treat 1 eye and they have already had a conjunctival limbal autograft or there is not enough tissue for a conjunctival limbal autograft, or it is contraindicated, and the company provides it with the discount agreed in the patient access scheme.
The committee took several factors into account when considering if Holoclar could be recommended to treat both eyes. Firstly, the clinical experts explained that usually only the worst eye would be treated in practice. Secondly, the committee discussed the very limited clinical evidence for this group; only 1 patient with bilateral disease had treatment in both eyes, which the committee considered to be uninformative. Thirdly, the ERG's clinical experts stated that there are plausible reasons why Holoclar would not be as effective when used in both eyes. Specifically, the biopsy must be taken from a damaged eye where it may be more difficult to locate and extract healthy limbal cells, and it may not be possible to take the same number of biopsies from a damaged eye in the case of transplant failure. Fourthly, the company's economic model analysis showed that treating both eyes gave ICERs for Holoclar that were too high for it to be considered a cost-effective use of NHS resources. The 2-eye economic model also included several limitations such as not accounting for differential effectiveness of a second Holoclar treatment and using a population of both unilateral and bilateral patients. Finally, the committee considered that for a patient with bilateral disease, there are treatment options available in current clinical practice to treat the second eye (conjunctival limbal allograft and keratolimbal allograft). Taking all of this into account, the committee recommended Holoclar for treating both eyes only in the context of clinical research.
The committee recommended that further research should be designed to generate robust evidence of the clinical- and cost-effectiveness of Holoclar in treating both eyes in people who do not have enough tissue for a conjunctival limbal autograft. The study should recruit people with bilateral disease and evaluate the effectiveness of treatment in both eyes. Outcomes should include transplant success and assessments of health-related quality of life using a generic preference-based measure.
# Innovation
The committee considered the innovative nature of the technology. It noted that the company had won the UK Prix Galien Orphan Product award for innovation and research. In addition, the European Medicines Agency had recognised Holoclar as the first approved stem cell medicine in Europe. The committee also agreed that the company had presented evidence to show that it offered several advantages over existing treatments. Taking all of this into account, the committee concluded that Holoclar could be considered innovative. It also agreed that most of the benefits of treatment with Holoclar were likely to have been captured in the QALY calculation.
Because Holoclar is a regenerative technology for an ultra-orphan condition, the company argued that the modelling was more challenging and suggested that the standard NICE reference case may be inappropriate. However, the committee was aware that NICE had worked with the Centre for Reviews and Dissemination and Centre for Health Economics, University of York, which produced an extensive independent report. This report looked at the appraisals methods and whether they are fit for purpose for regenerative medicines and cell therapies, and it found that the appraisal methods and decision framework was applicable to these treatments. The committee concluded that the standard NICE reference case was appropriate for appraising Holoclar.
# Summary of appraisal committee's key conclusions
TA467
Appraisal title: Holoclar for treating limbal stem cell deficiency after eye burns
Section
Key conclusion
Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells) is recommended as an option in people with moderate to severe limbal stem cell deficiency after eye burns, only if:
it is only used to treat 1 eye and
people have already had a conjunctival limbal autograft or
there is not enough tissue for a conjunctival limbal autograft or it is contraindicated and
the company provides it with the discount agreed in the patient access scheme.
Moderate to severe limbal stem cell deficiency is defined by the presence of superficial corneal neovascularisation in at least 2 corneal quadrants, with central corneal involvement, and severely impaired visual acuity.
Holoclar is recommended in people with moderate to severe limbal stem cell deficiency after eye burns for treating both eyes only:
in the context of research and
when there is not enough tissue for a conjunctival limbal autograft.
Such research should be designed to generate robust evidence of the clinical and cost-effectiveness of Holoclar in treating 2 eyes in people who do not have enough tissue for a conjunctival limbal autograft.
Using the committee's preferred assumptions, Holoclar did not demonstrate cost effectiveness compared with the comparators other than best supportive care. The committee noted that the success rates for conjunctival limbal allograft from a living, related donor and keratolimbal allograft in particular were likely to have been overestimated. Furthermore, if the effect on the donor were taken into account, the ICERs for Holoclar would likely decrease and fall within the range of £20,000 to £30,000 per QALY gained.
Given the patient need and innovative nature of the treatment, the committee agreed that it would pragmatically accept this as a demonstration of cost effectiveness in the circumstances outlined in the recommendation.
The committee took several factors into account when considering if Holoclar could be recommended to treat both eyes and concluded that more robust evidence was needed.
, 4.14 to 4.17
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee heard from the clinical experts that LSCD can be life-changing: in addition to visual impairment, the condition is associated with high levels of pain and photophobia and represents a major psychological burden. The committee agreed that LSCD can be a life-changing and severely debilitating condition.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee recognised that patients would greatly value a new treatment which successfully treated LSCD, particularly if it reduced the need for external donors and damage to the donor eye.
The committee noted that the company had won the UK Prix Galien Orphan Product award for innovation and research. In addition, the European Medicines Agency had recognised Holoclar as the first approved stem cell medicine in Europe. The committee concluded that Holoclar could be considered innovative.
to 4.3, 4.19 to 4.20
What is the position of the treatment in the pathway of care for the condition?
The committee heard that supportive care treatments would be offered and conservative surgery such as corneal scraping may also be offered before attempting limbal stem cell transplantation.
Adverse reactions
The committee heard from the clinical experts that Holoclar needs a smaller amount of tissue than conjunctival limbal autograft. The smaller biopsy means a much lower risk of damage to the donor eye.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that the evidence for Holoclar comprised 3 studies with follow-up of 12 months or less (HLSTM01, HLSTM02 and HLSTM04) and 5 studies with follow-up of 12 months up to 14.5 years (Rama 2001 and 2010, Pellegrini 1997 and 2013, Marchini 2012). The comparator evidence consisted of 23 smaller studies with high levels of heterogeneity, which the company, ERG and committee agreed made them unsuitable for data pooling. The committee also noted that the clinical evidence for Holoclar was limited to treating 1 eye only.
Relevance to general clinical practice in the NHS
The clinical experts stated that the results for Holoclar were plausible, but that the results for the comparators should be interpreted with more caution. In the absence of stronger evidence in this disease area, the committee accepted this clinical evidence for its decision-making.
Uncertainties generated by the evidence
No clinical evidence had been presented for using Holoclar in 2 eyes when both eyes are affected.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee concluded that it would differentiate between the treatment of 1 or 2 eyes. No clinical evidence had been presented for using Holoclar in 2 eyes when both eyes are affected. Because of the lack of evidence, the committee made a recommendation for Holoclar in both eyes only in the context of research.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The results from HLSTM01 showed that 72.1% of patients had a successful Holoclar transplant. For the comparators, transplant success varied between 60.0% and 100.0%. There were no direct comparative studies.
Evidence for cost effectiveness
Availability and nature of evidence
The company presented 2 separate models: a 'unilateral' and a 'bilateral' model. The models were similar, with both consisting of a decision tree followed by a Markov model, but the bilateral model assumed that patients had treatment in both eyes.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee noted that:
the assumption of long-term success was subject to a high level of uncertainty but accepted this assumption
the company had pooled the comparator data despite the company and ERG agreeing that pooling these data would not be appropriate
uncertainty remained in the utility values, but the ERG values were more realistic than the company value
the costs of eye drops for Holoclar had been underestimated in the model, but that the effect of this was difficult to quantify.
to 4.14
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee heard that the potentially negative effect on the donor (in case of conjunctival limbal allograft transplantation) and donor eye (in case of conjunctival limbal autograft transplantation) had not been captured.
Are there specific groups of people for whom the technology is particularly cost effective?
The committee noted that Holoclar was more cost-effective when treating 1 eye compared with 2 eyes.
What are the key drivers of cost effectiveness?
The committee understood that long-term success, success rate and utility values had an impact on the incremental cost-effectiveness ratio.
to 4.12
Most likely cost-effectiveness estimate (given as an ICER)
Conjunctival limbal autograft remained dominant in the 1-eye treatment model (the ERG did not compare Holoclar with conjunctival limbal autograft in the 2-eye treatment model).
The ICERs for Holoclar compared with conjunctival limbal allograft from a living, related donor were £42,139 per QALY gained in the 1-eye treatment model, and £63,047 per QALY gained in the 2-eye treatment model.
The ICERs for Holoclar compared with keratolimbal allograft were £30,415 per QALY gained in the 1-eye treatment model and £69,455 per QALY gained in the 2-eye treatment model.
The ICERs for Holoclar compared with best supportive care were £6,948 per QALY gained in the 1-eye treatment model and £12,669 per QALY gained in the 2-eye treatment model.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
In its submission the company reiterated a concern raised during scoping that a negative recommendation could disproportionately affect military personnel. However, this was not considered an equalities issue because:
The disability is a consequence of the condition.
The committee's recommendations do not exclude or impact differently on any populations.
–# Recommendations for further research
The committee agreed that further research was needed because there is currently no clinical- or cost-effectiveness evidence evaluating the use of Holoclar in both eyes in bilateral patients. The committee was aware of the ongoing HOLOCORE trial which is recruiting both unilateral and bilateral patients, but only evaluates the success of a second transplant in 1 eye rather than transplant success in both eyes.
The committee recommended that further research should be designed to generate robust evidence of the clinical- and cost-effectiveness of Holoclar for treating both eyes in people with bilateral limbal stem cell deficiency after eye burns if they do not have enough tissue for a conjunctival limbal autograft. The study should recruit people with bilateral disease and evaluate the effectiveness of treatment in both eyes. Outcomes should include transplant success and assessments of health-related quality of life using a generic preference-based measure.
|
{'Recommendations': 'Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells) is recommended as an option in people with moderate to severe limbal stem cell deficiency after eye burns, only if:\n\nit is only used to treat 1 eye and\n\npeople have already had a conjunctival limbal autograft or\n\nthere is not enough tissue for a conjunctival limbal autograft or it is contraindicated and\n\nthe company provides it with the discount agreed in the patient access scheme.Moderate to severe limbal stem cell deficiency is defined by the presence of superficial corneal neovascularisation in at least 2 corneal quadrants, with central corneal involvement, and severely impaired visual acuity.\n\nHoloclar is recommended in people with moderate to severe limbal stem cell deficiency after eye burns for treating both eyes only:\n\nin the context of research and\n\nwhen there is not enough tissue for a conjunctival limbal autograft.Such research should be designed to generate robust evidence of the clinical- and cost-effectiveness of Holoclar in treating 2 eyes in people who do not have enough tissue for a conjunctival limbal autograft.\n\nThese recommendations are not intended to affect treatment with Holoclar that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "# Description of the technology\n\nThe technology is ex vivo expanded autologous human corneal epithelial cells containing stem cells (Holoclar, Holostem Terapie Avanzate). It is a treatment used in the eye to replace damaged cells on the corneal surface.\n\n# Marketing authorisation\n\nIt has a conditional marketing authorisation for 'the treatment of adult patients with moderate to severe limbal stem cell deficiency (defined by the presence of superficial corneal neovascularisation in at least 2\xa0corneal quadrants, with central corneal involvement, and severely impaired visual acuity), unilateral or bilateral, due to physical or chemical ocular burns'. At least 1\xa0mm2 to 2\xa0mm2 of undamaged limbus is needed for biopsy before it can be used.\n\n# Adverse reactions\n\nFor full details of adverse reactions and contraindications, see the summary of product characteristics.\n\n# Recommended dose and schedule\n\nThe exact dosage depends on the size of the corneal surface: the recommended dose is 79,000 to 316,000\xa0cells/cm2. A biopsy is first taken of the eye, which needs at least 1\xa0mm2 to 2\xa0mm2 of undamaged tissue. The treatment is then implanted in the eye.\n\n# Price\n\nAccording to the company's submission, a single treatment for 1\xa0eye costs £80,000 excluding VAT. The company has a commercial arrangement. This makes Holoclar available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Evidence': 'The appraisal committee (section 7) considered evidence submitted by Chiesi Farmaceutici and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells), having considered evidence on the nature of moderate to severe limbal stem cell deficiency after eye burns and the value placed on the benefits of the treatment by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Treatment pathway and unmet need\n\nThe committee was aware that limbal stem cell deficiency (LSCD) is caused by an injury (such as a chemical or physical burn) to the source of limbal stem cells, which interrupts the renewal and replacement of the surface of the cornea. LSCD can either be unilateral (in 1 eye) or bilateral (in both eyes). The committee heard from the clinical experts that LSCD can be life-changing: in addition to visual impairment, the condition is associated with high levels of pain and photophobia. LSCD also represents a major psychological burden, both from the trauma of the original incident and the ongoing management of eye disfigurement. The highly visible nature of the injury can also impair a person's confidence and cause social isolation. Some people with LSCD are unable to continue working because of the physical or psychological effects. The committee agreed that LSCD can be a life-changing and severely debilitating condition.\n\nThe committee heard from the clinical experts that the aim of treatment for LSCD is to restore the surface of the eye, achieve corneal clarity and improve visual acuity. Current practice usually starts with supportive care treatments such as lubrication, autologous serum eye drops, and therapeutic soft and scleral contact lenses. Conservative surgery such as corneal scraping may also be offered before attempting limbal stem cell transplantation. Limbal stem cell transplantation includes a number of invasive surgical options to transplant stem cells to the affected eye which differ in terms of where the cells come from and how they are transferred, specifically:\n\nconjunctival limbal autograft, in which stem cells are taken from the patient's healthy eye\n\nconjunctival limbal allograft, in which stem cells are taken from a living, related donor or dead donor\n\nkeratolimbal allograft, in which the entire limbus may be transplanted from a dead donor, using the cornea as carrier tissue.\n\nThe committee heard from the clinical experts that successfully treating LSCD could be life-changing. However, current treatments are associated with many disadvantages. Conjunctival limbal autograft needs a relatively large amount of donor tissue from the healthy eye (equivalent to around 40% of the available reserves of the donor tissue). This increases the risk of damage to the donor eye: the clinical experts stated that 3% to 5% of patients having an autograft would have permanent serious damage. The clinical experts also estimated a transplant success rate with conjunctival limbal autograft of only 50%. Therefore, patients often choose to not have the treatment because their perceived risk of damage to the donor eye was not worth the chance of the procedure being a success in the affected eye. The committee assumed that people would have a conjunctival limbal autograft before approaching a living, related donor. One clinical expert stated they no longer did conjunctival limbal autografts because of the risks, although they acknowledged that the procedure is still used in clinical practice. Because both conjunctival limbal and keratolimbal allografts rely on external donors, they need immunosuppression which is in itself associated with several side effects. Even when treatment is successful, most allografts fail within 5 years. The clinical experts explained that finding a source of donor tissue can also be problematic.\n\nThe committee asked the clinical experts if patients with bilateral LSCD would have treatment in 1 or both eyes. It heard that ideally both eyes would be treated, but in practice it is likely for 1 eye to be worse than the other and that only the worst eye would be treated. The committee also asked if any of the procedures could be done more than once in the same eye. The clinical experts stated this would be unlikely for existing procedures, but that Holoclar represents a more viable option for retreatment because it needs a smaller amount of tissue. The smaller biopsy also means a much lower risk of damage to the donor eye; 1 clinical expert stated that in data for around 1,000 Holoclar procedures, they were unaware of any instances of damage to the patient's donor eye. The clinical experts stated that there is a subgroup of patients who have had conjunctival limbal autograft previously whose only option for further treatment was Holoclar. The committee concluded that the company had used the most appropriate comparators in its submission (that is: conjunctival limbal autograft, conjunctival limbal allograft, keratolimbal allograft and best supportive care), and Holoclar offered several advantages over these treatments.\n\n# Clinical effectiveness\n\nThe committee noted that the evidence for Holoclar comprised 3 studies with follow-up of 12\xa0months or less (HLSTM01, HLSTM02 and HLSTM04) and 5 studies with follow-up of 12\xa0months up to 14.5 years (Rama 2001 and 2010, Pellegrini 1997 and 2013, Marchini 2012). The comparator evidence consisted of 23 smaller studies with high levels of heterogeneity, which the company, ERG and committee agreed made them unsuitable for data pooling. The 8 main studies were mostly case series, which offer poor quality evidence because they do not contain a comparison group, but the committee noted that data for Holoclar were available for a reasonably high number of patients given the rarity of the condition (n=219 across all studies). However, the company had run statistical analyses on the available data despite case series not being designed for this purpose (they are intended to be descriptive only). The committee also noted that the clinical evidence for Holoclar was limited to treating 1 eye only (of the 13 patients with bilateral disease, only 1 had treatment in both eyes). In the absence of stronger evidence in this disease area, the committee accepted this clinical evidence for its decision-making. However, it agreed that when making its recommendations it would need to take into account that no clinical evidence had been presented for using Holoclar in 2 eyes when both eyes are affected.\n\n## Clinical evidence results\n\nThe primary outcome of the pivotal HLSTM01 study was treatment success, defined as stable corneal epithelium without significant recurrence of neovascularisation 12\xa0months after treatment. The main secondary outcomes included symptom resolution (pain, burning and photophobia), inflammation, neovascularisation, visual acuity, number of successful keratoplasties and safety.\n\nThe results from HLSTM01 showed that 72.1% of patients had a successful Holoclar transplant. For the comparators, transplant success varied between 60.0% and 100.0%. Given its concerns with the quality of evidence, the committee asked the clinical experts if these success rates were likely to be reflective of those in clinical practice. The experts stated that the results for Holoclar were plausible, but that the results for the comparators should be interpreted with more caution. They considered the studies of conjunctival limbal autograft to be poorly conducted and biased, and the rates to be overestimated (in their experience, success rates were closer to 50%). The committee concluded that the evidence showed Holoclar to be an effective treatment in terms of the outcomes described in section\xa04.6. However, there was uncertainty about the comparator success rates and the effectiveness of Holoclar compared with them.\n\n# Cost effectiveness\n\n## Model structure\n\nThe company presented 2 separate models: a 'unilateral' and a 'bilateral' model. The models were similar, with both consisting of a decision tree followed by a Markov model, but the bilateral model assumed that patients had treatment in both eyes (and so included an additional year without treatment before treating the second eye). The evidence review group (ERG) considered the model to be reasonably well constructed. However, the committee noted that the company had not actually presented separate results for unilateral and bilateral populations. The 2 models did not, in fact, distinguish between unilateral and bilateral disease; both models included exactly the same population (that is, both included patients with unilateral and bilateral disease). Instead, the main difference was that only 1 eye was treated in the unilateral model, whereas both eyes were treated in the bilateral model. The committee agreed that it would be more informative to consider the company's unilateral model as the '1-eye treatment' model and the bilateral model as the '2-eye treatment' model. The committee concluded that the model structures were acceptable for its decision-making. It would take into account treatment between 1 eye and 2 eyes but it would be difficult to distinguish between unilateral and bilateral populations in the cost-effectiveness modelling when making its final recommendations.\n\n## Discount rate\n\nThe company had deviated from the reference case by using a discount rate for future costs and benefits of 1.5%, rather than 3.5% as outlined in NICE's guide to the methods of technology appraisal. The company justified this by explaining that it believed Holoclar to have a prolonged effect (over 30 years), and that it could return patients to a high utility state. The committee was aware that the NICE methods guide states that when appraising treatments that 'restore people who would otherwise die or have severely impaired life to full or near full health, and when this is sustained over a very long period (normally at least 30 years)', non-reference case rates may be considered. However, the committee noted that it is rarely considered appropriate to change the discount rate and that LSCD was very different from the fatal and near-fatal conditions implied by the methods guide. The committee therefore concluded that the company should have used a 3.5% discount rate.\n\n## Modelled long-term success rates\n\nThe committee noted that if treatment with Holoclar were successful at 1 year, it remained successful for the lifetime of the model. When questioned about the plausibility of this assumption, the clinical experts stated that there currently was not enough evidence to support strong assumptions about the long-term effectiveness of Holoclar. However, the transplant being successful at 1\xa0year would demonstrate that the patient's body has regenerated the cornea 3 to 4 times, suggesting there may be some scientific merit to this model assumption. The committee accepted the company assumption about long-term success in the model, but agreed that this was subject to a high level of uncertainty that could increase the incremental cost-effectiveness ratio (ICER).\n\n## Model parameters\n\nThe committee noted that the clinical-effectiveness assumptions in the model were taken from HLSTM01 for Holoclar, and from the literature for the comparators. For Holoclar, the committee had previously heard that the estimated transplant success rates were plausible. However, for the comparators, the committee noted that the company had pooled the data, despite the company and ERG agreeing that pooling these data would not be appropriate. The company had presented a limited exploration of different success rates for the comparators, but these scenarios included changes in other assumptions and so did not explore the effect of this rate change alone. Furthermore, only 1 alternative rate for each comparator had been explored. The committee agreed that it would have been more useful to explore a range of different success rates (between 50% and 80%) because there was no comparative evidence for Holoclar and the clinical experts considered the comparator success rates to be overestimated. The committee concluded that there was a substantial level of uncertainty in the clinical-effectiveness assumptions in the company's model.\n\nIn response to consultation, the company provided additional sensitivity analyses which included the committee's preferred assumptions (a discount rate of 3.5%, a utility value of 0.84 and a utility decrement for disfigurement of 0.140). The company varied the probability of initial transplant success and long-term probability of transplant failure for each comparator separately. The sensitivity analyses showed that the ICERs for Holoclar were sensitive to the annual failure probability and initial success rates for the comparator treatments; a higher probability of transplant success increased the ICERs. The committee recalled that the company's model may overestimate comparator success rates (section\xa04.7). It concluded that lower transplant success rates would decrease the ICER, but agreed that this was subject to a high level of uncertainty.\n\n## Utility values\n\nThe committee was aware that conjunctival limbal autograft needs a substantial amount of tissue from the donor eye. It queried whether the potentially negative effect on the donor eye had been captured, and heard from the company, ERG and clinical experts that it had not. The committee noted further that the effect on the donor in the event of a transplant from a living, relative donor had also not been captured. It assumed that if donor disutility had been taken into account, the ICER would likely decrease. The committee agreed that it would have preferred to have seen analyses including the effect on the donor eye when comparing with conjunctival limbal autograft and the effect on the donor when comparing with conjunctival limbal allograft from a living, relative donor. The committee noted that the utility values used in the model were extraordinarily low: the values were far lower than any used in previous appraisals for eye treatments, with some lower than those for people in the last 3\xa0months of life having palliative treatment for various cancers. The committee noted that the main reason for these low values appeared to be the utility decrement of 0.318 applied to patients experiencing disfigurement. This was over 100-times higher than the utility decrement applied to people experiencing any pain, burning or photophobia (the highest decrement was 0.019). The committee highlighted that company's 0.318 decrement was derived from non-reference case methods, which were likely to generate exaggerated results. The committee asked the clinical experts about the plausibility of these values. The clinical experts found the low overall utility difficult to quantify, but stated that LSCD has a long-term substantial negative effect on quality of life. For the high utility decrement for disfigurement, the committee heard varied reports about the relative importance of disfigurement. The clinical experts stated that for people with unilateral disease, contrary to conventional wisdom, visual acuity was not the most important outcome: because of its lasting and significant effect on their day-to-day lives, these people often prioritise disfigurement. For people with bilateral disease, disfigurement would be less of a priority than visual acuity because of the risk of complete loss of sight. The committee agreed that it was difficult to resolve this inconsistency in the relative importance of disfigurement. Furthermore, this was not the approach taken in the model, with utility values applying equally irrespective of whether disease was unilateral or bilateral. The committee agreed that the utility values used were implausibly low, noting that the ERG had used alternative values. For visual acuity, the ERG used a range with a more plausible maximum value of 0.861 (rather than the company's assumption of 0.706). For disfigurement, it used a decrement of 0.140 (rather than the company's assumption of 0.318), using cataracts as a proxy. The ERG noted that the decrement associated with cataracts also includes a loss of utility from both disfigurement and vision loss. The committee recognised that cataract disutilities were used as a proxy for disfigurement although uncertainty remained in the utility values, the ERG's values were a more realistic reflection of the impact on quality of life.\n\n## Resource use and costs\n\nThe committee noted that the cost of autologous serum eye drops were a substantial driver of cost-effectiveness results in the model. The company had assumed in the model that patients having the comparators needed these drops after treatment and for flare-ups, but patients having Holoclar did not. The committee heard from the clinical experts that autologous serum eye drops are essential after treatment with the comparators, but less so with Holoclar because the stem cells are cultivated in a laboratory and not on the patient's eye. However, some clinicians may still choose to use them with Holoclar. The clinical experts also stated that drops would rarely be used for flare-ups because they take up to 6 weeks to prepare. Although alternative eye drops are available that would be ready for immediate use (allogenic serum eye drops), the committee heard from the ERG that using these drops would not make much difference to the model results because they were similarly priced. The committee agreed that the costs of eye drops for Holoclar had been underestimated in the model, but that the effect of this was difficult to quantify. It also agreed that eye drops after treatment were more necessary for the comparators than for Holoclar. It therefore concluded that it could cautiously accept the company's assumptions about eye drops, but remained aware that any increase in the use of eye drops would make Holoclar less cost effective.\n\n## Cost-effectiveness results and conclusions\n\nThe committee considered the estimates of cost effectiveness calculated by the company. The base-case results were:\n\nConjunctival limbal autograft dominated (that is, was both less costly and more effective than) all treatments including Holoclar in both models.\n\nThe ICERs for Holoclar compared with conjunctival limbal allograft from a living, related donor were £7,185 per quality-adjusted life year (QALY) gained in the 1-eye treatment model, and £12,438 per QALY gained in the 2-eye treatment model.\n\nThe ICERs for Holoclar compared with keratolimbal allograft were £2,255 per QALY gained in the 1-eye treatment model and £6,533 per QALY gained in the 2-eye treatment model.\n\nHoloclar dominated best supportive care in both models.None of these ICERs took into account the committee's preferred assumptions about utility values (section\xa04.13) and discount rate (section\xa04.9). However, the ERG had presented scenarios using both of these assumptions. In these scenarios, the ICERs became less favourable:\n\nConjunctival limbal autograft remained dominant in the 1-eye treatment model (the ERG did not compare Holoclar with conjunctival limbal autograft in the 2-eye treatment model).\n\nThe ICERs for Holoclar compared with conjunctival limbal allograft from a living, related donor were £42,139 per QALY gained in the 1-eye treatment model, and £63,047 per QALY gained in the 2-eye treatment model.\n\nThe ICERs for Holoclar compared with keratolimbal allograft were £30,415 per QALY gained in the 1-eye treatment model and £69,455 per QALY gained in the 2-eye treatment model.\n\nThe ICERs for Holoclar compared with best supportive care were £6,948 per QALY gained in the 1-eye treatment model and £12,669 per QALY gained in the 2-eye treatment model.Using the committee's preferred assumptions, Holoclar was not cost effective except compared with best supportive care.\n\nThe committee was aware that there were uncertainties in the assumptions about the comparators' long-term success rates and the use of eye drops. It noted that the success rates for conjunctival limbal allograft from a living, related donor and keratolimbal allograft in particular were likely to have been overestimated. Furthermore, if the effect on the donor were taken into account, the ICERs for Holoclar would likely decrease and fall within the range of £20,000 to £30,000 per QALY gained. Given the patient need (section\xa04.1) and innovative nature of the treatment (section\xa04.17), the committee agreed that it would pragmatically accept this as a demonstration of cost effectiveness. The committee noted that Holoclar was only cost effective for treating 1 eye. It recalled that there was almost no evidence concerning Holoclar's clinical effectiveness for treating both eyes, and agreed that it could not recommend Holoclar for routine use in the NHS to treat both eyes. However, it agreed that its recommendations for treating a single eye should apply equally to unilateral and bilateral disease. The committee therefore concluded that it could recommend Holoclar as a cost-effective use of NHS resources in people with moderate to severe LSCD after eye burns, only if it is used to treat 1 eye and they have already had a conjunctival limbal autograft or there is not enough tissue for a conjunctival limbal autograft, or it is contraindicated, and the company provides it with the discount agreed in the patient access scheme.\n\nThe committee took several factors into account when considering if Holoclar could be recommended to treat both eyes. Firstly, the clinical experts explained that usually only the worst eye would be treated in practice. Secondly, the committee discussed the very limited clinical evidence for this group; only 1 patient with bilateral disease had treatment in both eyes, which the committee considered to be uninformative. Thirdly, the ERG's clinical experts stated that there are plausible reasons why Holoclar would not be as effective when used in both eyes. Specifically, the biopsy must be taken from a damaged eye where it may be more difficult to locate and extract healthy limbal cells, and it may not be possible to take the same number of biopsies from a damaged eye in the case of transplant failure. Fourthly, the company's economic model analysis showed that treating both eyes gave ICERs for Holoclar that were too high for it to be considered a cost-effective use of NHS resources. The 2-eye economic model also included several limitations such as not accounting for differential effectiveness of a second Holoclar treatment and using a population of both unilateral and bilateral patients. Finally, the committee considered that for a patient with bilateral disease, there are treatment options available in current clinical practice to treat the second eye (conjunctival limbal allograft and keratolimbal allograft). Taking all of this into account, the committee recommended Holoclar for treating both eyes only in the context of clinical research.\n\nThe committee recommended that further research should be designed to generate robust evidence of the clinical- and cost-effectiveness of Holoclar in treating both eyes in people who do not have enough tissue for a conjunctival limbal autograft. The study should recruit people with bilateral disease and evaluate the effectiveness of treatment in both eyes. Outcomes should include transplant success and assessments of health-related quality of life using a generic preference-based measure.\n\n# Innovation\n\nThe committee considered the innovative nature of the technology. It noted that the company had won the UK Prix Galien Orphan Product award for innovation and research. In addition, the European Medicines Agency had recognised Holoclar as the first approved stem cell medicine in Europe. The committee also agreed that the company had presented evidence to show that it offered several advantages over existing treatments. Taking all of this into account, the committee concluded that Holoclar could be considered innovative. It also agreed that most of the benefits of treatment with Holoclar were likely to have been captured in the QALY calculation.\n\nBecause Holoclar is a regenerative technology for an ultra-orphan condition, the company argued that the modelling was more challenging and suggested that the standard NICE reference case may be inappropriate. However, the committee was aware that NICE had worked with the Centre for Reviews and Dissemination and Centre for Health Economics, University of York, which produced an extensive independent report. This report looked at the appraisals methods and whether they are fit for purpose for regenerative medicines and cell therapies, and it found that the appraisal methods and decision framework was applicable to these treatments. The committee concluded that the standard NICE reference case was appropriate for appraising Holoclar.\n\n# Summary of appraisal committee's key conclusions\n\nTA467\n\nAppraisal title: Holoclar for treating limbal stem cell deficiency after eye burns\n\nSection\n\nKey conclusion\n\nHoloclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells) is recommended as an option in people with moderate to severe limbal stem cell deficiency after eye burns, only if:\n\nit is only used to treat 1 eye and\n\npeople have already had a conjunctival limbal autograft or\n\nthere is not enough tissue for a conjunctival limbal autograft or it is contraindicated and\n\nthe company provides it with the discount agreed in the patient access scheme.\n\nModerate to severe limbal stem cell deficiency is defined by the presence of superficial corneal neovascularisation in at least 2 corneal quadrants, with central corneal involvement, and severely impaired visual acuity.\n\nHoloclar is recommended in people with moderate to severe limbal stem cell deficiency after eye burns for treating both eyes only:\n\nin the context of research and\n\nwhen there is not enough tissue for a conjunctival limbal autograft.\n\nSuch research should be designed to generate robust evidence of the clinical and cost-effectiveness of Holoclar in treating 2 eyes in people who do not have enough tissue for a conjunctival limbal autograft.\n\nUsing the committee's preferred assumptions, Holoclar did not demonstrate cost effectiveness compared with the comparators other than best supportive care. The committee noted that the success rates for conjunctival limbal allograft from a living, related donor and keratolimbal allograft in particular were likely to have been overestimated. Furthermore, if the effect on the donor were taken into account, the ICERs for Holoclar would likely decrease and fall within the range of £20,000 to £30,000 per QALY gained.\n\nGiven the patient need and innovative nature of the treatment, the committee agreed that it would pragmatically accept this as a demonstration of cost effectiveness in the circumstances outlined in the recommendation.\n\n\n\nThe committee took several factors into account when considering if Holoclar could be recommended to treat both eyes and concluded that more robust evidence was needed.\n\n, 4.14 to 4.17\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the clinical experts that LSCD can be life-changing: in addition to visual impairment, the condition is associated with high levels of pain and photophobia and represents a major psychological burden. The committee agreed that LSCD can be a life-changing and severely debilitating condition.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee recognised that patients would greatly value a new treatment which successfully treated LSCD, particularly if it reduced the need for external donors and damage to the donor eye.\n\nThe committee noted that the company had won the UK Prix Galien Orphan Product award for innovation and research. In addition, the European Medicines Agency had recognised Holoclar as the first approved stem cell medicine in Europe. The committee concluded that Holoclar could be considered innovative.\n\nto 4.3, 4.19 to 4.20\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee heard that supportive care treatments would be offered and conservative surgery such as corneal scraping may also be offered before attempting limbal stem cell transplantation.\n\n\n\nAdverse reactions\n\nThe committee heard from the clinical experts that Holoclar needs a smaller amount of tissue than conjunctival limbal autograft. The smaller biopsy means a much lower risk of damage to the donor eye.\n\n, 4.12\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee noted that the evidence for Holoclar comprised 3 studies with follow-up of 12\xa0months or less (HLSTM01, HLSTM02 and HLSTM04) and 5 studies with follow-up of 12\xa0months up to 14.5 years (Rama 2001 and 2010, Pellegrini 1997 and 2013, Marchini 2012). The comparator evidence consisted of 23 smaller studies with high levels of heterogeneity, which the company, ERG and committee agreed made them unsuitable for data pooling. The committee also noted that the clinical evidence for Holoclar was limited to treating 1 eye only.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe clinical experts stated that the results for Holoclar were plausible, but that the results for the comparators should be interpreted with more caution. In the absence of stronger evidence in this disease area, the committee accepted this clinical evidence for its decision-making.\n\n\n\nUncertainties generated by the evidence\n\nNo clinical evidence had been presented for using Holoclar in 2 eyes when both eyes are affected.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee concluded that it would differentiate between the treatment of 1 or 2 eyes. No clinical evidence had been presented for using Holoclar in 2 eyes when both eyes are affected. Because of the lack of evidence, the committee made a recommendation for Holoclar in both eyes only in the context of research.\n\n, 4.15, 4.17\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe results from HLSTM01 showed that 72.1% of patients had a successful Holoclar transplant. For the comparators, transplant success varied between 60.0% and 100.0%. There were no direct comparative studies.\n\n, 4.7\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented 2 separate models: a 'unilateral' and a 'bilateral' model. The models were similar, with both consisting of a decision tree followed by a Markov model, but the bilateral model assumed that patients had treatment in both eyes.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee noted that:\n\nthe assumption of long-term success was subject to a high level of uncertainty but accepted this assumption\n\nthe company had pooled the comparator data despite the company and ERG agreeing that pooling these data would not be appropriate\n\nuncertainty remained in the utility values, but the ERG values were more realistic than the company value\n\nthe costs of eye drops for Holoclar had been underestimated in the model, but that the effect of this was difficult to quantify.\n\nto 4.14\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee heard that the potentially negative effect on the donor (in case of conjunctival limbal allograft transplantation) and donor eye (in case of conjunctival limbal autograft transplantation) had not been captured.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe committee noted that Holoclar was more cost-effective when treating 1 eye compared with 2 eyes.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee understood that long-term success, success rate and utility values had an impact on the incremental cost-effectiveness ratio.\n\nto 4.12\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nConjunctival limbal autograft remained dominant in the 1-eye treatment model (the ERG did not compare Holoclar with conjunctival limbal autograft in the 2-eye treatment model).\n\nThe ICERs for Holoclar compared with conjunctival limbal allograft from a living, related donor were £42,139 per QALY gained in the 1-eye treatment model, and £63,047 per QALY gained in the 2-eye treatment model.\n\nThe ICERs for Holoclar compared with keratolimbal allograft were £30,415 per QALY gained in the 1-eye treatment model and £69,455 per QALY gained in the 2-eye treatment model.\n\nThe ICERs for Holoclar compared with best supportive care were £6,948 per QALY gained in the 1-eye treatment model and £12,669 per QALY gained in the 2-eye treatment model.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nIn its submission the company reiterated a concern raised during scoping that a negative recommendation could disproportionately affect military personnel. However, this was not considered an equalities issue because:\n\nThe disability is a consequence of the condition.\n\nThe committee's recommendations do not exclude or impact differently on any populations.\n\n–", 'Recommendations for further research': 'The committee agreed that further research was needed because there is currently no clinical- or cost-effectiveness evidence evaluating the use of Holoclar in both eyes in bilateral patients. The committee was aware of the ongoing HOLOCORE trial which is recruiting both unilateral and bilateral patients, but only evaluates the success of a second transplant in 1 eye rather than transplant success in both eyes.\n\nThe committee recommended that further research should be designed to generate robust evidence of the clinical- and cost-effectiveness of Holoclar for treating both eyes in people with bilateral limbal stem cell deficiency after eye burns if they do not have enough tissue for a conjunctival limbal autograft. The study should recruit people with bilateral disease and evaluate the effectiveness of treatment in both eyes. Outcomes should include transplant success and assessments of health-related quality of life using a generic preference-based measure.'}
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https://www.nice.org.uk/guidance/ta467
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Evidence-based recommendations on Holoclar (a layer of cells grown from cells taken from your own eye) for treating limbal stem cell deficiency in adults with eye burns.
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2ca92b852b8472eebc3984fe3bcc02dd21fce02f
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nice
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Advanced breast cancer: diagnosis and treatment
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Advanced breast cancer: diagnosis and treatment
This guideline covers care and support for people with advanced (stage 4) breast cancer. It aims to help them and their healthcare professionals make shared decisions about tests and treatments to improve outcomes and quality of life.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Diagnosis and assessment
## Imaging assessment
Assess the presence and extent of visceral metastases using a combination of plain radiography, ultrasound, computed tomography (CT) scans and magnetic resonance imaging (MRI).
Assess the presence and extent of metastases in the bones of the axial skeleton using bone windows on a CT scan or MRI or bone scintigraphy.
Assess proximal limb bones for the risk of pathological fracture in patients with evidence of bone metastases elsewhere, using bone scintigraphy and/or plain radiography.
Use MRI to assess bony metastases if other imaging is equivocal for metastatic disease or if more information is needed (for example, if there are lytic metastases encroaching on the spinal canal).
Positron emission tomography fused with computed tomography (PET-CT) should only be used to make a new diagnosis of metastases for patients with breast cancer whose imaging is suspicious but not diagnostic of metastatic disease.
## Pathological assessment
On recurrence, consider reassessing oestrogen receptor (ER) and human epidermal growth factor 2 receptor (HER2) status if a change in receptor status will lead to a change in management.
## Monitoring disease status
Do not use bone scintigraphy to monitor the response of bone metastases to treatment.
Do not use PET-CT to monitor advanced breast cancer.
# Providing information and support for decision making
Assess the patient's individual preference for the level and type of information. Reassess this as circumstances change.
On the basis of this assessment, offer patients consistent, relevant information and clear explanations, and provide opportunities for patients to discuss issues and ask questions.
Assess the patient's individual preference for how much they wish to be involved in decision making. Reassess this as circumstances change.
Be aware of the value of decision aids and the range available. Make the most appropriate decision aid available to the patient.
# Systemic disease-modifying therapy
Offer endocrine therapy as first-line treatment for the majority of patients with ER-positive advanced breast cancer.
Offer chemotherapy as first-line treatment for patients with ER positive advanced breast cancer whose disease is imminently life-threatening or requires early relief of symptoms because of significant visceral organ involvement, providing they understand and are prepared to accept the toxicity.
For patients with ER-positive advanced breast cancer who have been treated with chemotherapy as their first-line treatment, offer endocrine therapy following the completion of chemotherapy.
## Endocrine therapy
Offer an aromatase inhibitor (either non-steroidal or steroidal) to:
postmenopausal women with ER-positive breast cancer and no prior history of endocrine therapy
postmenopausal women with ER-positive breast cancer previously treated with tamoxifen.
Offer tamoxifen and ovarian suppression as first-line treatment to premenopausal and perimenopausal women with ER-positive advanced breast cancer not previously treated with tamoxifen.
Offer ovarian suppression to premenopausal and perimenopausal women who have previously been treated with tamoxifen and then experience disease progression.
Offer tamoxifen as first-line treatment to men with ER-positive advanced breast cancer.
## Chemotherapy
On disease progression, offer systemic sequential therapy to the majority of patients with advanced breast cancer who have decided to be treated with chemotherapy.
Consider using combination chemotherapy to treat patients with advanced breast cancer for whom a greater probability of response is important and who understand and are likely to tolerate the additional toxicity.
For patients with advanced breast cancer who are not suitable for anthracyclines (because they are contraindicated or because of prior anthracycline treatment either in the adjuvant or metastatic setting), systemic chemotherapy should be offered in the following sequence:
first line: single-agent docetaxel
second line: single-agent vinorelbine or capecitabine
third line: single-agent capecitabine or vinorelbine (whichever was not used as second-line treatment).
Gemcitabine in combination with paclitaxel, within its licensed indication, is recommended as an option for the treatment of metastatic breast cancer only when docetaxel monotherapy or docetaxel plus capecitabine are also considered appropriate. (This recommendation is from NICE's technology appraisal guidance on gemcitabine for the treatment of metastatic breast cancer.)
## Biological therapy
For patients who are receiving treatment with trastuzumab for advanced breast cancer, discontinue treatment with trastuzumab at the time of disease progression outside the central nervous system. Do not discontinue trastuzumab if disease progression is within the central nervous system alone. (Recommendations on the use of trastuzumab are covered by NICE's technology appraisal guidance on the use of trastuzumab for the treatment of advanced breast cancer).
For all technology appraisal guidance relevant to this section, including genomic biomarker‑based therapy, see the NICE topic page on breast cancer. The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based therapy.
# Supportive care
Healthcare professionals involved in the care of patients with advanced breast cancer should ensure that the organisation and provision of supportive care services comply with the recommendations made in NICE's cancer service guidance on improving outcomes in breast cancer and improving supportive and palliative care for adults with cancer, in particular the following two recommendations:
'Assessment and discussion of patients' needs for physical, psychological, social, spiritual and financial support should be undertaken at key points (such as diagnosis; at commencement, during, and at the end of treatment; at relapse; and when death is approaching).'
'Mechanisms should be developed to promote continuity of care, which might include the nomination of a person to take on the role of "key worker" for individual patients.'
# Managing complications
## Lymphoedema
Discuss with people who have or who are at risk of breast cancer-related lymphoedema that there is no indication that exercise prevents, causes or worsens lymphoedema.
Discuss with people who have or who are at risk of breast cancer-related lymphoedema that exercise may improve their quality of life.
Assess patients with lymphoedema for treatable underlying factors before starting any lymphoedema management programme.
Offer all patients with lymphoedema complex decongestive therapy (CDT) as the first stage of lymphoedema management.
Consider using multilayer lymphoedema bandaging (MLLB) for volume reduction as a first treatment option before compression hosiery.
Provide patients with lymphoedema with at least two suitable compression garments. These should be of the appropriate class and size, and a choice of fabrics and colours should be available.
Provide patients with lymphoedema with clear, written information and the contact details of local and national lymphoedema support groups.
## Cancer-related fatigue
Offer all patients with advanced breast cancer for whom cancer-related fatigue is a significant problem an assessment to identify any treatable causative factors, and offer appropriate management as necessary.
Provide clear, written information about cancer-related fatigue, organisations that offer psychosocial support and patient led groups.
Provide information about and timely access to an exercise programme for all patients with advanced breast cancer experiencing cancer-related fatigue.
## Uncontrolled local disease
A breast cancer multidisciplinary team should assess all patients presenting with uncontrolled local disease and discuss the therapeutic options for controlling the disease and relieving symptoms.
A wound care team should see all patients with fungating tumours to plan a dressing regimen and supervise management with the breast care team.
A palliative care team should assess all patients with uncontrolled local disease in order to plan a symptom management strategy and provide psychological support.
## Bone metastases
Consider offering bisphosphonates to patients newly diagnosed with bone metastases to prevent skeletal-related events and reduce pain.
The choice of bisphosphonate for patients with bone metastases should be a local decision, taking into account patient preference and limited to preparations licensed for this indication.
Use external beam radiotherapy in a single fraction of 8 Gy to treat patients with bone metastases and pain.
An orthopaedic surgeon should assess all patients at risk of a long bone fracture, to consider prophylactic surgery.
## Brain metastases
Offer surgery followed by whole brain radiotherapy to patients who have a single or small number of potentially resectable brain metastases, a good performance status and who have no or well controlled other metastatic disease.
Offer whole brain radiotherapy to patients for whom surgery is not appropriate, unless they have a very poor prognosis.
Offer active rehabilitation to patients who have surgery and/or whole brain radiotherapy.
Offer referral to specialist palliative care to patients for whom active treatment for brain metastases would be inappropriate. # Recommendations for research
The 2014 and 2009 guideline committees made the following recommendations for research.
# Assessment of the role of exercise
What is the role of arm and shoulder specific exercises compared with and/or used as an adjunct to established lymphoedema treatments (such as compression garments and complex decongestive therapy)?
## Why this is important
Well-designed randomised controlled trials should consider differing arm and shoulder-specific aerobic and/or resistive exercises that focus on strength and flexibility to improve local lymph flow, for example, swimming, weight lifting, tai chi and yoga. The studies should have a follow-up period that is sufficient to capture long-term outcomes including changes to current lymphoedema or any new-onset lymphoedema in other parts of the limb. Outcomes for this research should include quality-of-life measures.
# Endocrine therapy
Clinical trials are needed to investigate the most effective endocrine therapy for postmenopausal women with ER-positive tumours who progress on treatment with an aromatase inhibitor.
## Why this is important
Although there is good evidence to support the use of aromatase inhibitors for postmenopausal women with ER-positive tumours, there is little evidence to determine what is the best sequence of alternative hormone treatments when they progress.
# Chemotherapy
Randomised clinical trials should evaluate the clinical and cost effectiveness of different sequences of chemotherapy for advanced breast cancer.
## Why this is important
Most patients with advanced breast cancer who receive chemotherapy will be given at least two different regimens and many will receive three. The available evidence to support decisions about the most clinically and cost effective sequence in which to use these drugs is extremely limited. There is also very little good‑quality evidence about the relative clinical and cost effectiveness of currently recommended treatments, either in combination or in sequence. Following on from the recommendations in this guideline, it would be important to establish clinical trials to investigate this problem in a more systematic fashion than hitherto.
# Biological response modifiers (progressive metastatic disease)
The use of continued trastuzumab in patients with progressive metastatic disease should be investigated as part of a randomised controlled trial. Trial design should incorporate collection of data required for prospective cost-effectiveness analysis.
## Why this is important
There is currently no high-quality published evidence about whether continuing trastuzumab is effective in prolonging survival in patients with HER2-positive advanced breast cancer who develop progressive disease (outside the central nervous system) during or after first-line treatment with trastuzumab and cytotoxic chemotherapy. Any studies should be carefully planned to permit a high quality cost-effectiveness analysis.
# Biological response modifiers (adjuvant trastuzumab)
Randomised controlled trials are needed to assess whether patients who have had adjuvant trastuzumab should be offered further biological response modifiers. Trial design should incorporate collection of data required for prospective cost-effectiveness analysis.
## Why this is important
As more patients with HER2-positive advanced breast cancer have trastuzumab as part of their initial adjuvant treatment following a diagnosis of early breast cancer, an increasing number of patients with advanced breast cancer will have had previous exposure to this agent. There is no evidence currently about whether trastuzumab or other biological therapies are effective in this situation.
# Uncontrolled local disease
The relevant research organisations should be encouraged to address the topic of uncontrolled local disease and devise appropriate research studies. This might include development of a national register.
## Why this is important
The problem of how best to manage uncontrolled local disease is very poorly addressed by the current evidence. Although it is probably quite an uncommon condition, it is likely that across the country there are enough patients to generate evidence from well-coordinated national studies. A national register should be considered as part of this because of the current uncertainties about the frequency of the problem. # Context
Breast cancer is the most common cancer affecting women in England and Wales, with about 40,500 new cases diagnosed and 10,900 deaths recorded in England and Wales each year. In men breast cancer is rare, with about 260 cases diagnosed and 68 deaths in England and Wales each year (Office for National Statistics, Cancer statistics registrations: registrations of cancer diagnosed in 2005, England; Welsh Cancer Intelligence and Surveillance Unit, Cancer incidence in Wales 1992−2002). Of these new cases in women and men, a small proportion is diagnosed in the advanced stages, when the tumour has spread significantly within the breast or to other organs of the body. In addition, there are a significant number of women who have been previously treated with curative intent who subsequently develop either a local recurrence or metastases. Over recent years there have been important developments in the investigation and management of patients with advanced breast cancer, including new chemotherapy, and biological and hormonal agents. There is some evidence of practice variation across the country and of patchy availability of certain treatments and procedures. This clinical guideline helps to address these issues and offers guidance on best practice.
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{'Recommendations': 'People have the right to be involved in discussions and make informed decisions about their care, as described in NICE\'s information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Diagnosis and assessment\n\n## Imaging assessment\n\nAssess the presence and extent of visceral metastases using a combination of plain radiography, ultrasound, computed tomography (CT) scans and magnetic resonance imaging (MRI). \n\nAssess the presence and extent of metastases in the bones of the axial skeleton using bone windows on a CT scan or MRI or bone scintigraphy. \n\nAssess proximal limb bones for the risk of pathological fracture in patients with evidence of bone metastases elsewhere, using bone scintigraphy and/or plain radiography. \n\nUse MRI to assess bony metastases if other imaging is equivocal for metastatic disease or if more information is needed (for example, if there are lytic metastases encroaching on the spinal canal). \n\nPositron emission tomography fused with computed tomography (PET-CT) should only be used to make a new diagnosis of metastases for patients with breast cancer whose imaging is suspicious but not diagnostic of metastatic disease. \n\n## Pathological assessment\n\nOn recurrence, consider reassessing oestrogen receptor (ER) and human epidermal growth factor 2 receptor (HER2) status if a change in receptor status will lead to a change in management. \n\n## Monitoring disease status\n\nDo not use bone scintigraphy to monitor the response of bone metastases to treatment. \n\nDo not use PET-CT to monitor advanced breast cancer. \n\n# Providing information and support for decision making\n\nAssess the patient\'s individual preference for the level and type of information. Reassess this as circumstances change. \n\nOn the basis of this assessment, offer patients consistent, relevant information and clear explanations, and provide opportunities for patients to discuss issues and ask questions. \n\nAssess the patient\'s individual preference for how much they wish to be involved in decision making. Reassess this as circumstances change. \n\nBe aware of the value of decision aids and the range available. Make the most appropriate decision aid available to the patient. \n\n# Systemic disease-modifying therapy\n\nOffer endocrine therapy as first-line treatment for the majority of patients with ER-positive advanced breast cancer. \n\nOffer chemotherapy as first-line treatment for patients with ER positive advanced breast cancer whose disease is imminently life-threatening or requires early relief of symptoms because of significant visceral organ involvement, providing they understand and are prepared to accept the toxicity. \n\nFor patients with ER-positive advanced breast cancer who have been treated with chemotherapy as their first-line treatment, offer endocrine therapy following the completion of chemotherapy. \n\n## Endocrine therapy\n\nOffer an aromatase inhibitor (either non-steroidal or steroidal) to:\n\npostmenopausal women with ER-positive breast cancer and no prior history of endocrine therapy\n\npostmenopausal women with ER-positive breast cancer previously treated with tamoxifen. \n\nOffer tamoxifen and ovarian suppression as first-line treatment to premenopausal and perimenopausal women with ER-positive advanced breast cancer not previously treated with tamoxifen. \n\nOffer ovarian suppression to premenopausal and perimenopausal women who have previously been treated with tamoxifen and then experience disease progression. \n\nOffer tamoxifen as first-line treatment to men with ER-positive advanced breast cancer. \n\n## Chemotherapy\n\nOn disease progression, offer systemic sequential therapy to the majority of patients with advanced breast cancer who have decided to be treated with chemotherapy. \n\nConsider using combination chemotherapy to treat patients with advanced breast cancer for whom a greater probability of response is important and who understand and are likely to tolerate the additional toxicity. \n\nFor patients with advanced breast cancer who are not suitable for anthracyclines (because they are contraindicated or because of prior anthracycline treatment either in the adjuvant or metastatic setting), systemic chemotherapy should be offered in the following sequence:\n\nfirst line: single-agent docetaxel\n\nsecond line: single-agent vinorelbine or capecitabine\n\nthird line: single-agent capecitabine or vinorelbine (whichever was not used as second-line treatment). \n\nGemcitabine in combination with paclitaxel, within its licensed indication, is recommended as an option for the treatment of metastatic breast cancer only when docetaxel monotherapy or docetaxel plus capecitabine are also considered appropriate. (This recommendation is from NICE\'s technology appraisal guidance on gemcitabine for the treatment of metastatic breast cancer.) \n\n## Biological therapy\n\nFor patients who are receiving treatment with trastuzumab for advanced breast cancer, discontinue treatment with trastuzumab at the time of disease progression outside the central nervous system. Do not discontinue trastuzumab if disease progression is within the central nervous system alone. (Recommendations on the use of trastuzumab are covered by NICE\'s technology appraisal guidance on the use of trastuzumab for the treatment of advanced breast cancer). \n\nFor all technology appraisal guidance relevant to this section, including genomic biomarker‑based therapy, see the NICE topic page on breast cancer. The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based therapy.\n\n# Supportive care\n\nHealthcare professionals involved in the care of patients with advanced breast cancer should ensure that the organisation and provision of supportive care services comply with the recommendations made in NICE\'s cancer service guidance on improving outcomes in breast cancer and improving supportive and palliative care for adults with cancer, in particular the following two recommendations:\n\n\'Assessment and discussion of patients\' needs for physical, psychological, social, spiritual and financial support should be undertaken at key points (such as diagnosis; at commencement, during, and at the end of treatment; at relapse; and when death is approaching).\'\n\n\'Mechanisms should be developed to promote continuity of care, which might include the nomination of a person to take on the role of "key worker" for individual patients.\' \n\n# Managing complications\n\n## Lymphoedema\n\nDiscuss with people who have or who are at risk of breast cancer-related lymphoedema that there is no indication that exercise prevents, causes or worsens lymphoedema. \n\nDiscuss with people who have or who are at risk of breast cancer-related lymphoedema that exercise may improve their quality of life. \n\nAssess patients with lymphoedema for treatable underlying factors before starting any lymphoedema management programme. \n\nOffer all patients with lymphoedema complex decongestive therapy (CDT) as the first stage of lymphoedema management. \n\nConsider using multilayer lymphoedema bandaging (MLLB) for volume reduction as a first treatment option before compression hosiery. \n\nProvide patients with lymphoedema with at least two suitable compression garments. These should be of the appropriate class and size, and a choice of fabrics and colours should be available. \n\nProvide patients with lymphoedema with clear, written information and the contact details of local and national lymphoedema support groups. \n\n## Cancer-related fatigue\n\nOffer all patients with advanced breast cancer for whom cancer-related fatigue is a significant problem an assessment to identify any treatable causative factors, and offer appropriate management as necessary. \n\nProvide clear, written information about cancer-related fatigue, organisations that offer psychosocial support and patient led groups. \n\nProvide information about and timely access to an exercise programme for all patients with advanced breast cancer experiencing cancer-related fatigue. \n\n## Uncontrolled local disease\n\nA breast cancer multidisciplinary team should assess all patients presenting with uncontrolled local disease and discuss the therapeutic options for controlling the disease and relieving symptoms. \n\nA wound care team should see all patients with fungating tumours to plan a dressing regimen and supervise management with the breast care team. \n\nA palliative care team should assess all patients with uncontrolled local disease in order to plan a symptom management strategy and provide psychological support. \n\n## Bone metastases\n\nConsider offering bisphosphonates to patients newly diagnosed with bone metastases to prevent skeletal-related events and reduce pain. \n\nThe choice of bisphosphonate for patients with bone metastases should be a local decision, taking into account patient preference and limited to preparations licensed for this indication. \n\nUse external beam radiotherapy in a single fraction of 8\xa0Gy to treat patients with bone metastases and pain. \n\nAn orthopaedic surgeon should assess all patients at risk of a long bone fracture, to consider prophylactic surgery. \n\n## Brain metastases\n\nOffer surgery followed by whole brain radiotherapy to patients who have a single or small number of potentially resectable brain metastases, a good performance status and who have no or well controlled other metastatic disease. \n\nOffer whole brain radiotherapy to patients for whom surgery is not appropriate, unless they have a very poor prognosis. \n\nOffer active rehabilitation to patients who have surgery and/or whole brain radiotherapy. \n\nOffer referral to specialist palliative care to patients for whom active treatment for brain metastases would be inappropriate. ', 'Recommendations for research': 'The 2014 and 2009 guideline committees made the following recommendations for research.\n\n# Assessment of the role of exercise\n\nWhat is the role of arm and shoulder specific exercises compared with and/or used as an adjunct to established lymphoedema treatments (such as compression garments and complex decongestive therapy)?\n\n## Why this is important\n\nWell-designed randomised controlled trials should consider differing arm and shoulder-specific aerobic and/or resistive exercises that focus on strength and flexibility to improve local lymph flow, for example, swimming, weight lifting, tai chi and yoga. The studies should have a follow-up period that is sufficient to capture long-term outcomes including changes to current lymphoedema or any new-onset lymphoedema in other parts of the limb. Outcomes for this research should include quality-of-life measures. \n\n# Endocrine therapy\n\nClinical trials are needed to investigate the most effective endocrine therapy for postmenopausal women with ER-positive tumours who progress on treatment with an aromatase inhibitor.\n\n## Why this is important\n\nAlthough there is good evidence to support the use of aromatase inhibitors for postmenopausal women with ER-positive tumours, there is little evidence to determine what is the best sequence of alternative hormone treatments when they progress. \n\n# Chemotherapy\n\nRandomised clinical trials should evaluate the clinical and cost effectiveness of different sequences of chemotherapy for advanced breast cancer.\n\n## Why this is important\n\nMost patients with advanced breast cancer who receive chemotherapy will be given at least two different regimens and many will receive three. The available evidence to support decisions about the most clinically and cost effective sequence in which to use these drugs is extremely limited. There is also very little good‑quality evidence about the relative clinical and cost effectiveness of currently recommended treatments, either in combination or in sequence. Following on from the recommendations in this guideline, it would be important to establish clinical trials to investigate this problem in a more systematic fashion than hitherto. \n\n# Biological response modifiers (progressive metastatic disease)\n\nThe use of continued trastuzumab in patients with progressive metastatic disease should be investigated as part of a randomised controlled trial. Trial design should incorporate collection of data required for prospective cost-effectiveness analysis.\n\n## Why this is important\n\nThere is currently no high-quality published evidence about whether continuing trastuzumab is effective in prolonging survival in patients with HER2-positive advanced breast cancer who develop progressive disease (outside the central nervous system) during or after first-line treatment with trastuzumab and cytotoxic chemotherapy. Any studies should be carefully planned to permit a high quality cost-effectiveness analysis. \n\n# Biological response modifiers (adjuvant trastuzumab)\n\nRandomised controlled trials are needed to assess whether patients who have had adjuvant trastuzumab should be offered further biological response modifiers. Trial design should incorporate collection of data required for prospective cost-effectiveness analysis.\n\n## Why this is important\n\nAs more patients with HER2-positive advanced breast cancer have trastuzumab as part of their initial adjuvant treatment following a diagnosis of early breast cancer, an increasing number of patients with advanced breast cancer will have had previous exposure to this agent. There is no evidence currently about whether trastuzumab or other biological therapies are effective in this situation. \n\n# Uncontrolled local disease\n\nThe relevant research organisations should be encouraged to address the topic of uncontrolled local disease and devise appropriate research studies. This might include development of a national register.\n\n## Why this is important\n\nThe problem of how best to manage uncontrolled local disease is very poorly addressed by the current evidence. Although it is probably quite an uncommon condition, it is likely that across the country there are enough patients to generate evidence from well-coordinated national studies. A national register should be considered as part of this because of the current uncertainties about the frequency of the problem. ', 'Context': 'Breast cancer is the most common cancer affecting women in England and Wales, with about 40,500 new cases diagnosed and 10,900 deaths recorded in England and Wales each year. In men breast cancer is rare, with about 260 cases diagnosed and 68 deaths in England and Wales each year (Office for National Statistics, Cancer statistics registrations: registrations of cancer diagnosed in 2005, England; Welsh Cancer Intelligence and Surveillance Unit, Cancer incidence in Wales 1992−2002). Of these new cases in women and men, a small proportion is diagnosed in the advanced stages, when the tumour has spread significantly within the breast or to other organs of the body. In addition, there are a significant number of women who have been previously treated with curative intent who subsequently develop either a local recurrence or metastases. Over recent years there have been important developments in the investigation and management of patients with advanced breast cancer, including new chemotherapy, and biological and hormonal agents. There is some evidence of practice variation across the country and of patchy availability of certain treatments and procedures. This clinical guideline helps to address these issues and offers guidance on best practice.'}
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https://www.nice.org.uk/guidance/cg81
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This guideline covers care and support for people with advanced (stage 4) breast cancer. It aims to help them and their healthcare professionals make shared decisions about tests and treatments to improve outcomes and quality of life.
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28e4922f6ee9f24e5dd3337ea66befaf0d925540
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nice
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Pemetrexed for the maintenance treatment of non-small-cell lung cancer
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Pemetrexed for the maintenance treatment of non-small-cell lung cancer
Evidence-based recommendations on pemetrexed disodium (Alimta) for the maintenance treatment of non-small-cell lung cancer.
# Guidance
Pemetrexed is recommended as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.# The technology
Pemetrexed disodium (Alimta, Eli Lilly and Company) is an antifolate agent that works by disrupting folate-dependent metabolic processes that are essential for cancer cell replication and survival. Pemetrexed has a marketing authorisation for the maintenance treatment of locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. The marketing authorisation states that first-line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel. (A platinum doublet is platinum-based chemotherapy plus one other drug).
The summary of product characteristics (SPC) states that the recommended dosage is 500 mg/m2 body surface area, administered as a 10-minute intravenous infusion on the first day of each 21-day cycle. To reduce toxicity, patients treated with pemetrexed should also receive folic acid and vitamin B12 supplements. To reduce the incidence and severity of skin reactions, premedication with a corticosteroid is recommended.
The SPC reports that the most common adverse effects include nausea, vomiting, fatigue, leukopenia (particularly of the neutrophil component), skin rash, mucositis and liver function abnormalities. For full details of side effects and contraindications, see the SPC.
The acquisition cost of pemetrexed is £800 for a 500-mg vial (excluding VAT, 'British national formulary' 57th edition). The cost per patient, assuming an average of 8 cycles and a body surface area of 1.79 m2, is approximately £12,076. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and a review of this submission by the Evidence Review Group (ERG; appendix B).
The manufacturer's submission contained evidence on the clinical effectiveness of pemetrexed maintenance therapy compared with best supportive care. The manufacturer stated that pemetrexed is the only chemotherapy currently licensed for the maintenance treatment of non-small-cell lung cancer in the UK and worldwide. Therefore, the comparator used in the clinical trial was placebo plus best supportive care.
The manufacturer identified one phase III multicentre, double-blind randomised control study (the JMEN trial) which evaluated the efficacy of maintenance treatment with pemetrexed monotherapy in people with advanced or metastatic (stage IIIB and IV) non-small-cell lung cancer whose disease had not progressed following treatment with platinum-based first-line chemotherapy. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial randomised 663 patients with squamous and non-squamous non-small-cell lung cancer to pemetrexed plus best supportive care (n = 441) or placebo plus best supportive care (n = 222). Patients in both arms of the trial received concomitant medication with folic acid, vitamin B12 and dexamethasone. Patients in the pemetrexed arm received pemetrexed 500 mg/m2 on day 1 of each 21-day cycle, administered as a 10-minute infusion, plus best supportive care, until disease progression. Patients in the placebo arm received normal saline (0.9% sodium chloride) on day 1 of each 21-day cycle, administered as a 10-minute infusion, plus best supportive care, until disease progression. The manufacturer presented evidence for the subgroup of non-squamous non-small-cell lung cancer (n = 481) in accordance with the licensed indication. Of this subgroup, 325 patients received pemetrexed plus best supportive care and 156 received placebo plus best supportive care.
The mean number of pemetrexed cycles for the non-squamous population was 8.0 (standard deviation 8.62) and the median was 6.0 cycles (25th–75th percentile 2.5–10.0). There were a few patients who received between 20 and 55 cycles (7–11% of patients received more than 20 cycles).
The primary outcome of the JMEN trial was initially overall survival, but this was changed to progression-free survival during the trial. Median progression-free survival was significantly longer with pemetrexed plus best supportive care compared with placebo plus best supportive care (4.5 months versus 2.6 months, hazard ratio 0.44, 95% confidence interval 0.36 to 0.55, p < 0.00001). A subgroup analysis for patients with adenocarcinoma (a type of non-squamous non-small-cell lung cancer) reported similar improvement in progression-free survival with pemetrexed plus best supportive care compared with placebo plus best supportive care (4.7 months versus 2.6 months, HR 0.45, 95% CI 0.35 to 0.59, p < 0.00001). Secondary outcomes of the JMEN trial included tumour response, disease control rate and time to worsening of symptoms. The JMEN trial demonstrated a statistically significant median overall survival benefit of 5.2 months for the non-squamous population in favour of pemetrexed compared with placebo (15.5 months versus 10.3 months, HR 0.70, 95% CI 0.56 to 0.88, p = 0.002). Similar results were reported for the adenocarcinoma subgroup. For the non-squamous population, 1-year overall survival in the pemetrexed plus best supportive care arm was 60% compared with 42% in the placebo arm. The difference in overall survival was smaller at 2 years (28% for pemetrexed compared with 22% for placebo). The trial reported similar results for the 1- and 2-year overall survival in the adenocarcinoma subgroup. Statistically significant improvements in tumour response, disease control rate and time to worsening of symptoms were reported for pemetrexed plus best supportive care compared with placebo plus best supportive care. The manufacturer's submission noted the absence of trial-based health-related quality-of-life data because many of the patients did not complete quality-of-life surveys.
The manufacturer's submission reported higher rates of grade 3 and 4 adverse events with pemetrexed plus best supportive care than with placebo plus best supportive care (6.3% versus 2.3%). Fatigue and neutropenia were the most commonly reported adverse events. There were significantly higher percentages of patients in the pemetrexed arm who discontinued treatment, required transfusion, erythropoiesis-stimulating agents or hospitalisation because of drug-related toxicity, or withdrew from the study.
The manufacturer developed a trial-based model which included three health states (not progressed, progressed and terminal state). Patients entered the model at the start of maintenance treatment, which was assumed to begin after four cycles of first-line chemotherapy (consisting of a platinum doublet with gemcitabine, paclitaxel or docetaxel) in patients who had no evidence of disease progression. Patients in the placebo arm received 'watch and wait' treatment and best supportive care, and patients in the pemetrexed arm received treatment plus best supportive care in 21-day cycles until disease progression. After disease progression patients were eligible for second-line treatment.
The economic model had a time horizon of 72 months (29-month overall survival data from the JMEN trial extrapolated to 72 months using an exponential survival function). Treatment effects that were included in the model were overall survival, adverse events and health-related quality of life. All effectiveness data used in the model, apart from health-related quality of life, were trial based. Trial data on progression-free survival were not used in the economic model. The number of treatment cycles in the trial was used as a proxy for the time to progression in the pemetrexed arm. The disutility of adverse events was not included in the base-case model but was captured in the sensitivity analyses.
In the JMEN trial, patients received pemetrexed treatment until their disease progressed. Although this resulted in patients receiving up to 55 cycles (with a mean of 8 cycles), the manufacturer's submission noted that clinical specialists suggested that if maintenance treatment were introduced to UK clinical practice, patients would receive a maximum of 10 cycles of pemetrexed maintenance treatment. The manufacturer therefore incorporated a 'capping rule' in which the maximum number of cycles of pemetrexed was set at 1 standard deviation above the mean, equivalent to a maximum of 17 cycles (with a new mean of 5.84) for the non-squamous population, and a maximum of 18 cycles (with a new mean of 6.16) for the adenocarcinoma population. The new means were used in the manufacturer's base case.
In the absence of data on health-related quality of life from the JMEN trial, utility data were taken from literature estimates. The manufacturer mainly used a study on the second-line treatment of non-small-cell lung cancer by Nafees et al. (2008). It involved 100 members of the public interviewed with visual analogue scale and standard gamble techniques to generate societal values on utilities in lung cancer. In addition, the manufacturer also used data from a study by Berthelot et al. (2000). Based on these two studies, the manufacturer assigned a utility of 0.66 to patients on pemetrexed and 0.58 to patients on placebo.
The manufacturer's base-case analysis compared pemetrexed plus best supportive care with placebo plus best supportive care in the non-squamous population. The incremental cost-effectiveness ratio (ICER) for pemetrexed compared with best supportive care in the non-squamous population was calculated to be £33,732 per QALY gained, based on an incremental cost of £9137 and an incremental QALY of 0.27. The ICER for the adenocarcinoma subgroup was £39,364 per QALY gained, based on an incremental cost of £9554 and an incremental QALY of 0.24.
The manufacturer also presented the ICERs for 36 one-way sensitivity analyses and a number of scenarios that explored the effect of per-vial costing and cycle capping, and included a best-case and worst-case scenario. Most of the results in the one-way sensitivity analyses had little effect on the base-case ICERs. However, two results did have a large effect:
When the incremental survival of pemetrexed was reduced from 5.3 months in the base case to 1.15 months, the ICER increased to £105,826 per QALY gained.
When the overall survival advantage was reduced by 9.5%, to allow for the patients excluded with the base-case capping rule, the ICER increased to £48,290 per QALY gained.
The ERG reviewed the evidence submitted for clinical and cost effectiveness, focussing on the non-squamous population in accordance with the licensed indication. The ERG stated that the JMEN trial was reasonably well designed, incorporating blinding, placebo control and independent monitoring of investigator assessments. The clinical outcomes reported from the trial addressed the outcomes that were relevant to the appraisal (overall survival, progression-free survival, tumour response, adverse events and health-related quality of life).
The ERG raised concern about the conduct of the trial, its generalisability to the UK patient population and the uncertainty around the estimates of cost effectiveness. The ERG noted that the inclusion criteria of the JMEN trial were restricted to younger patients with a good performance status (ECOG 0 or 1) and with few comorbidities. Only a relatively small proportion of the total number of non-small-cell lung cancer patients treated in clinical practice in the UK has an ECOG performance status of 0 or 1.
The ERG did not consider that adequate justification was given for changing the primary endpoint of the JMEN trial from overall survival to progression-free survival. It considered that this decision had the effect of truncating the data available for analysis of overall survival, which was of critical importance to the economic evaluation. The ERG also considered the high rate of missing data on health-related quality of life to be a limitation. It was not clear how patients' quality of life would be affected by maintenance treatment with pemetrexed.
The ERG noted that 53% of patients in the pemetrexed arm and 36% of patients in the placebo arm of the JMEN trial received second-line treatments that are not used in UK clinical practice. This may have influenced the overall survival estimates observed in the trial and may mean that the results of the trial do not reflect the survival benefits that might be expected in UK clinical practice.
The ERG was concerned that the key clinical evidence was derived from a histological subgroup of the trial population, but that histology was not included in the stratification for the randomisation procedure.
The ERG assessed the manufacturer's cost-effectiveness analysis. It commented on the version of the model which used the exponential (rather than Weibull) projection as the basis for comparison (this being the manufacturer's base case). The ERG noted that the capping of pemetrexed treatment at 17 cycles was much less than the maximum of 55 cycles in the JMEN trial. The ERG considered that this limited the costs of maintenance treatment with no similar limitation on the benefits accrued from the use of pemetrexed, which led to bias in favour of pemetrexed. The ERG considered that the most appropriate base case should have included the full costs and benefits of maintenance treatment based on the number of cycles received in the JMEN trial. The ERG conducted an analysis in which the number of treatment cycles was not capped. This increased the ICER from £33,732 per QALY gained to £43,179 per QALY gained.
The ERG considered that the discounting applied in the model was based on inappropriate assumptions. All maintenance chemotherapy cycles were assumed to occur in the first year (consistent with the imposed maximum cycles limit but not with the trial data), all second-line chemotherapy took place in the first year, all best supportive care was assumed to occur only in years 1 or 2 and all terminal care was assigned to year 3.
The ERG did not consider the additional monitoring of patients on pemetrexed chemotherapy (who were assessed every two cycles) to be consistent with UK clinical practice. It considered the appropriate follow up to be at 3, 6 and 12 months and every 6 months thereafter until progression for the best supportive care arm, and every four cycles (12 weeks) until progression in the pemetrexed arm. The ERG also noted that the body surface area distribution used in the model was not representative of the UK population because 35% of the trial population was Asian (from China, Korea, Taiwan and India).
The ERG noted that no direct use was made in the model of the primary trial outcome (progression-free survival) and the duration of maintenance therapy was used as a proxy. The ERG also expressed concerns that in the model the overall survival of patients who received second-line treatment was assumed to be the same as those who did not.
The ERG did not consider it appropriate for patients entering the model at randomisation who were in the same health state (without disease progression) to be assigned different utility values (0.66 for patents in the pemetrexed arm and 0.58 for patients in the placebo arm). This was not consistent with data from the JMEN trial in which the rate of grade 3 or 4 fatigue was noticeably higher in the pemetrexed arm (3.66%) than in the placebo arm (0.64%). When the ERG used utility values which incorporated the disutility associated with adverse events (0.6568 in the pemetrexed arm and 0.6628 in the placebo arm) the ICER increased from the base case of £33,732 per QALY gained to £36,798 per QALY gained.
The ERG considered that the manufacturer did not adequately justify the choice of parameters and parameter values used in the one-way sensitivity analyses. The ERG also expressed concern that a probabilistic sensitivity analysis had not been undertaken. When the ERG conducted an approximate probabilistic sensitivity analysis based on the overall survival gain and the mean number of treatment cycles from the individual patient data the cost-effectiveness acceptability curve showed that pemetrexed maintenance treatment would have zero probability of being cost effective at a threshold of £30,000 per QALY gained and 50% probability of being cost effective at a threshold of approximately £51,000 per QALY gained.
The ERG identified other concerns with the cost-effectiveness analysis, including:
The half-cycle correction applied to survival estimates appeared to be inappropriate. The ERG considered that the correct approach would be to use the area under the curve from the trial analysis unaltered, and then calculate 'mid-cycle' corrected estimates for the remainder of the model duration derived from a parametric model.
Post progression costs and survival values had been double discounted.
A minor error in the calculation of the proportion of patients assumed to receive docetaxel or erlotinib as second-line treatment. When this was corrected, the manufacturer's base-case ICER increased slightly.
The ERG investigated the impact of unlimited cycles of treatment, revised utility values, revised discounting assumptions, and increased cost of monitoring based on a model populated with individual patient data. The cumulative effect of these changes was an increase in the ICER for pemetrexed maintenance treatment from the manufacturer's estimated base case of £33,732 per QALY gained to £51,192 per QALY gained. The number of treatment cycles and utility revision had the most impact on the ICER.
The manufacturer presented a revised cost-effectiveness analysis to address the concerns raised by the Committee. The revised analysis included a probabilistic sensitivity analysis with an exponential extrapolation survival function and presented six scenarios in which the duration of treatment and the utility values in the pemetrexed and placebo arms were varied (Three different treatment durations were presented, each with two possible utility assumptions, giving a total of six scenarios). The different treatment durations considered were: 1 year (a maximum of 17 cycles), 2 years (a maximum of 35 cycles) and treatment until disease progression in accordance with the JMEN trial (a maximum of 55 cycles). The survival benefits modelled for each treatment duration were consistent with those seen in trial patients. Utility was either the same in both arms (0.66) or a lower utility was assigned to the pemetrexed arm (0.657) compared with the placebo arm (0.663). The ICERs for pemetrexed compared with best supportive care ranged from £46,137 per QALY gained to £50,286 per QALY gained, with a 46–58% probability of being cost effective at a threshold of £50,000 per QALY gained.
The ERG commented on the manufacturer's revised analysis and examined scenario 5 in detail. This scenario represented treatment until disease progression, used the entire trial population and incorporated a utility of 0.663 for the placebo arm and 0.657 for the pemetrexed arm. The ERG noted that most of the changes made by the manufacturer were those required to accommodate a probabilistic sensitivity analysis. The ERG also noted that the changes were implemented appropriately.
The ERG conducted a probabilistic sensitivity analysis on scenario 5 which incorporated all of the amendments suggested in their original analysis (see section 3.23). The ERG also presented the results of a probabilistic sensitivity analysis using an exponential and a Weibull extrapolation of the trial data. The ICER for pemetrexed compared with best supportive care using the exponential survival function was £56,903 per QALY gained using deterministic analysis and £47,168 per QALY gained using probabilistic analysis, with a 57.71% probability of being cost effective at a threshold of £50,000 per QALY gained. When the Weibull function was applied, the ICER for pemetrexed compared with best supportive care was £57,082 per QALY gained using deterministic analysis and £50,673 per QALY gained using probabilistic analysis, with a 49.70% probability of being cost effective at a threshold of £50,000 per QALY gained.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pemetrexed having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of pemetrexed by clinical specialists. It also took into account the effective use of NHS resources.
# Clinical effectiveness
The Committee considered current UK practice for the treatment of people with non-squamous non-small-cell lung cancer. The Committee heard from clinical specialists that patients undergo induction with a platinum doublet of carboplatin or cisplatin in combination with gemcitabine, paclitaxel, vinorelbine or docetaxel. The Committee was also aware of the NICE technology appraisal that recommended pemetrexed as a treatment option for the first-line treatment of non-small-cell lung cancer (NICE technology appraisal guidance 181). After induction, patients are monitored but receive no chemotherapy until progression. Patients whose disease progresses only receive second-line chemotherapy if they have a good performance status. In the UK, this is normally docetaxel or erlotinib. Patients who do not receive second-line chemotherapy receive best supportive care, which can include palliative radiotherapy.
The Committee heard that maintenance treatment after first-line treatment is a new concept in lung cancer and is not currently practised in the UK. The Committee also heard from clinical specialists that pemetrexed has fewer adverse events associated with its use compared with many other chemotherapies offered for the treatment of non-small-cell lung cancer. The aim of maintenance treatment with pemetrexed is to prolong the period of remission after first-line chemotherapy and possibly increase eligibility for second-line chemotherapy.
The Committee noted that the clinical effectiveness evidence for pemetrexed for the maintenance therapy of non-small-cell lung cancer was based on the JMEN trial, and noted that the overall survival achieved with pemetrexed was higher than for people receiving best supportive care. The Committee considered the trial to be generally well designed but had a number of concerns over the interpretation of the trial results (see section 4.5–10).
The initial primary endpoint was changed from overall survival to progression-free survival during the course of the trial. The Committee heard from the manufacturer that this was done after consultation with regulatory authorities in the USA and the change was implemented before any trial data had been analysed.
The evidence in the manufacturer's submission was from the non-squamous histological subgroup of the trial but histology was not a factor in the randomisation process. However, the Committee heard from the clinical specialists that the histological groups were reasonably balanced between the two arms of the trial and that lack of histological testing as part of the randomisation would not have significantly affected the outcome of the analysis. The clinical specialists also told the Committee that although definitive histological testing is variable in practice, the trial strategy was a reasonable reflection of what would be done in non-trial conditions.
In the trial treatment cycles were only limited by disease progression. The Committee heard from clinical specialists that patients would continue to receive pemetrexed while they were responding to treatment and so the trial did reflect the likely UK clinical practice. Therefore, the Committee was concerned that the capping in the manufacturer's original economic model was not consistent with clinical practice (see section 4.14).
None of the trial centres were located in the UK and one third of the trial population was Asian (from China, Korea, Taiwan and India). The Committee heard from the clinical specialists that although this ethnic group has a relatively favourable prognosis for non-small-cell lung cancer, it would have the same relative benefit from treatment with pemetrexed as the UK population.
There was an imbalance in the use of second-line treatments in the trial, and the Committee was concerned about how this was used in the manufacturer's economic model (see section 4.16).
The Committee was concerned that insufficient health-related quality-of-life data had been collected from the trial to enable their inclusion in the economic modelling. The Committee heard from clinical specialists and the manufacturer that trial patients who are in progressive disease after first- and second-line treatment are less likely to complete quality-of-life surveys, making it hard to get health-related quality-of-life data.
The Committee considered the population eligible for maintenance treatment. The Committee heard from clinical specialists that patients who receive first-line treatment usually have a good performance status, and that approximately one third of patients will progress while on first-line chemotherapy. The Committee also considered how patients are monitored in UK clinical practice. The Committee heard that although computer tomography (CT) scanning is not routinely used to monitor patients in UK clinical practice, it is likely that patients receiving pemetrexed maintenance treatment would undergo more CT scans to confirm that they have not progressed.
# Cost effectiveness
The Committee considered the manufacturer's submitted cost-effectiveness analysis and the ERG's critique. The manufacturer's base case stated that the incremental cost of pemetrexed compared with best supportive care was £9137 and the incremental QALY was 0.27, giving an ICER of pemetrexed compared to best supportive care of £33,732 per QALY gained. However, the Committee was aware of several concerns that the ERG had described in the calculation of this base case. These included: the modelling of overall survival, the capping of the number of treatment cycles but not the associated benefits, the different utilities assigned to patients in the same initial health state, the handling of second-line treatment effects and the absence of a probablistic sensitivity analysis.
The Committee noted the 29-month overall survival data from the trial were extrapolated to 6 years in the model. It noted that the exponential curve applied in the base case did not fit the data well. The Committee noted that the manufacturer's analysis using a Weibull model was also plausible and that the ICERs were higher when Weibull models were used, suggesting that the figure in the base case might be at the lower end of the likely range. The Committee also expressed concern that the primary outcome in the trial (progression-free survival) was not captured in the model and number of cycles of treatment was used as a proxy.
The Committee considered the capping of costs in the manufacturer's original model at a maximum of 17 cycles. The Committee was informed by the manufacturer that clinical advice suggested that most benefit is derived in the first 8–10 cycles of treatment, which informed their decision to cap the cycles at 17 (1 standard deviation above the mean of 8 cycles). However, the Committee heard that in other cancers where patients receive maintenance treatment, cycles are not capped. The Committee considered that when capping was assumed, it had the effect of constraining the costs of maintenance therapy without a corresponding effect on the benefits accrued from use of pemetrexed, therefore building an essential bias in the economic evaluation in favour of pemetrexed.
The Committee considered the utility estimates assigned to patients in different arms of the model. It noted that in the manufacturer's original analysis, patients who entered the trial in the same health state were assigned higher utilities in the pemetrexed arm than in the placebo arm of the model – biasing the model in favour of pemetrexed. The Committee also noted that the disutilities of adverse events associated with pemetrexed were not modelled in the base case. Although the clinical specialists said that a minority of patients may feel better on pemetrexed maintenance treatment because their tumour shrank, the Committee was not persuaded that this justified the manufacturer's difference in utility between the two arms. The Committee considered the ERG's re-analysis of the model, which used a slightly lower utility for progression-free disease in the pemetrexed arm compared with the placebo arm, to be more appropriate. The Committee noted that this approach was adopted by the manufacturer in the revised analysis.
The Committee considered the six scenarios of the revised analysis presented by the manufacturer. The Committee also considered the ERG analysis of scenario 5, which corrected the utility estimates, removed cycle capping, performed an approximate probabilistic sensitivity analysis and also corrected discounting errors. The Committee considered scenario 5 to represent the most plausible assumptions for modelling the cost effectiveness of pemetrexed maintenance treatment compared with best supportive care. The Committee considered that the manufacturer's revised analysis had adequately addressed the main concerns identified in the original model. The Committee considered the updated ICERs presented for scenario 5 by the manufacturer (£47,000 per QALY gained) and the ERG (which ranged from £47,000 per QALY gained with the exponential model to £51,000 per QALY gained with the Weibull model) to be reliable.
The Committee considered the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.
The Committee discussed whether the benefit provided by pemetrexed for the maintenance treatment of non-small-cell lung cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that patients with stage IIIB or IV non-small-cell lung cancer who receive no treatment usually survive for about 7–10 months. The Committee considered the evidence from the pemetrexed randomised controlled trial (the JMEN trial) that showed a median survival benefit of 5.2 months for pemetrexed versus placebo. The Committee agreed that the data from the trial were sufficiently robust and that maintenance treatment with pemetrexed would increase overall survival by more than 3 months. The Committee considered that the estimated population for whom pemetrexed is licensed is currently small enough to allow the end-of-life advice to apply. The Committee concluded that the evidence submitted by the manufacturer was robust enough to show that maintenance treatment with pemetrexed fulfilled the criteria for the supplementary advice from NICE (see section 4.19).
The Committee considered the evidence presented by the manufacturer in the revised analysis to be robust. The Committee also considered the ERG's exploratory analysis, which demonstrated that the ICER for pemetrexed compared with best supportive care was about £47,000 per QALY gained. The Committee was persuaded that the most plausible ICER for pemetrexed compared with best supportive care was approximately £47,000 per QALY gained and, with reasonable certainty, was below £50,000 per QALY gained. The Committee considered this ICER, taking into account the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the QALY benefits for the ICER to fall within the plausible range was acceptable. Therefore, the Committee recommended pemetrexed as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology, if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.# Related NICE guidance
# Published
Pemetrexed for the first-line treatment of non-small-cell lung cancer (2009) NICE technology appraisal guidance 181.
Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal) (2009) NICE technology appraisal guidance175.
Erlotinib for the treatment of non-small-cell lung cancer (2008) NICE technology appraisal guidance 162.
Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal) (2008) NICE technology appraisal guidance 148.
Pemetrexed for the treatment of non-small-cell lung cancer (2007) NICE technology appraisal guidance 124.
Lung cancer: the diagnosis and treatment of lung cancer (2005) NICE clinical guideline 24 .
Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (2010) NICE technology appraisal guidance 192.
Erlotinib monotherapy for maintenance treatment of non-small-cell lung cancer (2010) NICE technology appraisal guidance 227.
# Under development
NICE is developing the following guidance(details available from the NICE website):
Cetuximab for the treatment of advanced non-small-cell lung cancer. NICE technology appraisal guidance(publication date to be confirmed).# Review of guidance
The guidance on this technology will be considered for review in November 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJune 2010# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
ISBN: 978-1-4731-2095-2
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{'Guidance': 'Pemetrexed is recommended as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.', 'The technology ': "Pemetrexed disodium (Alimta, Eli Lilly and Company) is an antifolate agent that works by disrupting folate-dependent metabolic processes that are essential for cancer cell replication and survival. Pemetrexed has a marketing authorisation for the maintenance treatment of locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. The marketing authorisation states that first-line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel. (A platinum doublet is platinum-based chemotherapy plus one other drug).\n\nThe summary of product characteristics (SPC) states that the recommended dosage is 500\xa0mg/m2 body surface area, administered as a 10-minute intravenous infusion on the first day of each 21-day cycle. To reduce toxicity, patients treated with pemetrexed should also receive folic acid and vitamin B12 supplements. To reduce the incidence and severity of skin reactions, premedication with a corticosteroid is recommended.\n\nThe SPC reports that the most common adverse effects include nausea, vomiting, fatigue, leukopenia (particularly of the neutrophil component), skin rash, mucositis and liver function abnormalities. For full details of side effects and contraindications, see the SPC.\n\nThe acquisition cost of pemetrexed is £800 for a 500-mg vial (excluding VAT, 'British national formulary' 57th edition). The cost per patient, assuming an average of 8\xa0cycles and a body surface area of 1.79\xa0m2, is approximately £12,076. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission contained evidence on the clinical effectiveness of pemetrexed maintenance therapy compared with best supportive care. The manufacturer stated that pemetrexed is the only chemotherapy currently licensed for the maintenance treatment of non-small-cell lung cancer in the UK and worldwide. Therefore, the comparator used in the clinical trial was placebo plus best supportive care.\n\nThe manufacturer identified one phase III multicentre, double-blind randomised control study (the JMEN trial) which evaluated the efficacy of maintenance treatment with pemetrexed monotherapy in people with advanced or metastatic (stage IIIB and IV) non-small-cell lung cancer whose disease had not progressed following treatment with platinum-based first-line chemotherapy. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial randomised 663 patients with squamous and non-squamous non-small-cell lung cancer to pemetrexed plus best supportive care (n\xa0=\xa0441) or placebo plus best supportive care (n\xa0=\xa0222). Patients in both arms of the trial received concomitant medication with folic acid, vitamin B12 and dexamethasone. Patients in the pemetrexed arm received pemetrexed 500\xa0mg/m2 on day 1 of each 21-day cycle, administered as a 10-minute infusion, plus best supportive care, until disease progression. Patients in the placebo arm received normal saline (0.9% sodium chloride) on day 1 of each 21-day cycle, administered as a 10-minute infusion, plus best supportive care, until disease progression. The manufacturer presented evidence for the subgroup of non-squamous non-small-cell lung cancer (n\xa0=\xa0481) in accordance with the licensed indication. Of this subgroup, 325 patients received pemetrexed plus best supportive care and 156 received placebo plus best supportive care.\n\nThe mean number of pemetrexed cycles for the non-squamous population was 8.0 (standard deviation 8.62) and the median was 6.0 cycles (25th–75th percentile 2.5–10.0). There were a few patients who received between 20 and 55 cycles (7–11% of patients received more than 20\xa0cycles).\n\nThe primary outcome of the JMEN trial was initially overall survival, but this was changed to progression-free survival during the trial. Median progression-free survival was significantly longer with pemetrexed plus best supportive care compared with placebo plus best supportive care (4.5\xa0months versus 2.6\xa0months, hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.36 to 0.55, p\xa0<\xa00.00001). A subgroup analysis for patients with adenocarcinoma (a type of non-squamous non-small-cell lung cancer) reported similar improvement in progression-free survival with pemetrexed plus best supportive care compared with placebo plus best supportive care (4.7\xa0months versus 2.6\xa0months, HR 0.45, 95% CI\xa00.35 to 0.59, p\xa0<\xa00.00001). Secondary outcomes of the JMEN trial included tumour response, disease control rate and time to worsening of symptoms. The JMEN trial demonstrated a statistically significant median overall survival benefit of 5.2\xa0months for the non-squamous population in favour of pemetrexed compared with placebo (15.5\xa0months versus 10.3\xa0months, HR 0.70, 95% CI 0.56 to 0.88, p\xa0=\xa00.002). Similar results were reported for the adenocarcinoma subgroup. For the non-squamous population, 1-year overall survival in the pemetrexed plus best supportive care arm was 60% compared with 42% in the placebo arm. The difference in overall survival was smaller at 2\xa0years (28% for pemetrexed compared with 22% for placebo). The trial reported similar results for the 1- and 2-year overall survival in the adenocarcinoma subgroup. Statistically significant improvements in tumour response, disease control rate and time to worsening of symptoms were reported for pemetrexed plus best supportive care compared with placebo plus best supportive care. The manufacturer's submission noted the absence of trial-based health-related quality-of-life data because many of the patients did not complete quality-of-life surveys.\n\nThe manufacturer's submission reported higher rates of grade 3 and 4 adverse events with pemetrexed plus best supportive care than with placebo plus best supportive care (6.3% versus 2.3%). Fatigue and neutropenia were the most commonly reported adverse events. There were significantly higher percentages of patients in the pemetrexed arm who discontinued treatment, required transfusion, erythropoiesis-stimulating agents or hospitalisation because of drug-related toxicity, or withdrew from the study.\n\nThe manufacturer developed a trial-based model which included three health states (not progressed, progressed and terminal state). Patients entered the model at the start of maintenance treatment, which was assumed to begin after four cycles of first-line chemotherapy (consisting of a platinum doublet with gemcitabine, paclitaxel or docetaxel) in patients who had no evidence of disease progression. Patients in the placebo arm received 'watch and wait' treatment and best supportive care, and patients in the pemetrexed arm received treatment plus best supportive care in 21-day cycles until disease progression. After disease progression patients were eligible for second-line treatment.\n\nThe economic model had a time horizon of 72\xa0months (29-month overall survival data from the JMEN trial extrapolated to 72\xa0months using an exponential survival function). Treatment effects that were included in the model were overall survival, adverse events and health-related quality of life. All effectiveness data used in the model, apart from health-related quality of life, were trial based. Trial data on progression-free survival were not used in the economic model. The number of treatment cycles in the trial was used as a proxy for the time to progression in the pemetrexed arm. The disutility of adverse events was not included in the base-case model but was captured in the sensitivity analyses.\n\nIn the JMEN trial, patients received pemetrexed treatment until their disease progressed. Although this resulted in patients receiving up to 55 cycles (with a mean of 8 cycles), the manufacturer's submission noted that clinical specialists suggested that if maintenance treatment were introduced to UK clinical practice, patients would receive a maximum of 10\xa0cycles of pemetrexed maintenance treatment. The manufacturer therefore incorporated a 'capping rule' in which the maximum number of cycles of pemetrexed was set at 1 standard deviation above the mean, equivalent to a maximum of 17\xa0cycles (with a new mean of 5.84) for the non-squamous population, and a maximum of 18\xa0cycles (with a new mean of 6.16) for the adenocarcinoma population. The new means were used in the manufacturer's base case.\n\nIn the absence of data on health-related quality of life from the JMEN trial, utility data were taken from literature estimates. The manufacturer mainly used a study on the second-line treatment of non-small-cell lung cancer by Nafees et al. (2008). It involved 100\xa0members of the public interviewed with visual analogue scale and standard gamble techniques to generate societal values on utilities in lung cancer. In addition, the manufacturer also used data from a study by Berthelot et al. (2000). Based on these two studies, the manufacturer assigned a utility of 0.66 to patients on pemetrexed and 0.58 to patients on placebo.\n\nThe manufacturer's base-case analysis compared pemetrexed plus best supportive care with placebo plus best supportive care in the non-squamous population. The incremental cost-effectiveness ratio (ICER) for pemetrexed compared with best supportive care in the non-squamous population was calculated to be £33,732 per QALY gained, based on an incremental cost of £9137 and an incremental QALY of 0.27. The ICER for the adenocarcinoma subgroup was £39,364 per QALY gained, based on an incremental cost of £9554 and an incremental QALY of 0.24.\n\nThe manufacturer also presented the ICERs for 36 one-way sensitivity analyses and a number of scenarios that explored the effect of per-vial costing and cycle capping, and included a best-case and worst-case scenario. Most of the results in the one-way sensitivity analyses had little effect on the base-case ICERs. However, two results did have a large effect:\n\nWhen the incremental survival of pemetrexed was reduced from 5.3\xa0months in the base case to 1.15\xa0months, the ICER increased to £105,826 per QALY gained.\n\nWhen the overall survival advantage was reduced by 9.5%, to allow for the patients excluded with the base-case capping rule, the ICER increased to £48,290 per QALY gained.\n\nThe ERG reviewed the evidence submitted for clinical and cost effectiveness, focussing on the non-squamous population in accordance with the licensed indication. The ERG stated that the JMEN trial was reasonably well designed, incorporating blinding, placebo control and independent monitoring of investigator assessments. The clinical outcomes reported from the trial addressed the outcomes that were relevant to the appraisal (overall survival, progression-free survival, tumour response, adverse events and health-related quality of life).\n\nThe ERG raised concern about the conduct of the trial, its generalisability to the UK patient population and the uncertainty around the estimates of cost effectiveness. The ERG noted that the inclusion criteria of the JMEN trial were restricted to younger patients with a good performance status (ECOG 0 or 1) and with few comorbidities. Only a relatively small proportion of the total number of non-small-cell lung cancer patients treated in clinical practice in the UK has an ECOG performance status of 0 or 1.\n\nThe ERG did not consider that adequate justification was given for changing the primary endpoint of the JMEN trial from overall survival to progression-free survival. It considered that this decision had the effect of truncating the data available for analysis of overall survival, which was of critical importance to the economic evaluation. The ERG also considered the high rate of missing data on health-related quality of life to be a limitation. It was not clear how patients' quality of life would be affected by maintenance treatment with pemetrexed.\n\nThe ERG noted that 53% of patients in the pemetrexed arm and 36% of patients in the placebo arm of the JMEN trial received second-line treatments that are not used in UK clinical practice. This may have influenced the overall survival estimates observed in the trial and may mean that the results of the trial do not reflect the survival benefits that might be expected in UK clinical practice.\n\nThe ERG was concerned that the key clinical evidence was derived from a histological subgroup of the trial population, but that histology was not included in the stratification for the randomisation procedure.\n\nThe ERG assessed the manufacturer's cost-effectiveness analysis. It commented on the version of the model which used the exponential (rather than Weibull) projection as the basis for comparison (this being the manufacturer's base case). The ERG noted that the capping of pemetrexed treatment at 17\xa0cycles was much less than the maximum of 55\xa0cycles in the JMEN trial. The ERG considered that this limited the costs of maintenance treatment with no similar limitation on the benefits accrued from the use of pemetrexed, which led to bias in favour of pemetrexed. The ERG considered that the most appropriate base case should have included the full costs and benefits of maintenance treatment based on the number of cycles received in the JMEN trial. The ERG conducted an analysis in which the number of treatment cycles was not capped. This increased the ICER from £33,732 per QALY gained to £43,179 per QALY gained.\n\nThe ERG considered that the discounting applied in the model was based on inappropriate assumptions. All maintenance chemotherapy cycles were assumed to occur in the first year (consistent with the imposed maximum cycles limit but not with the trial data), all second-line chemotherapy took place in the first year, all best supportive care was assumed to occur only in years 1 or 2 and all terminal care was assigned to year 3.\n\nThe ERG did not consider the additional monitoring of patients on pemetrexed chemotherapy (who were assessed every two cycles) to be consistent with UK clinical practice. It considered the appropriate follow up to be at 3, 6 and 12\xa0months and every 6\xa0months thereafter until progression for the best supportive care arm, and every four cycles (12\xa0weeks) until progression in the pemetrexed arm. The ERG also noted that the body surface area distribution used in the model was not representative of the UK population because 35% of the trial population was Asian (from China, Korea, Taiwan and India).\n\nThe ERG noted that no direct use was made in the model of the primary trial outcome (progression-free survival) and the duration of maintenance therapy was used as a proxy. The ERG also expressed concerns that in the model the overall survival of patients who received second-line treatment was assumed to be the same as those who did not.\n\nThe ERG did not consider it appropriate for patients entering the model at randomisation who were in the same health state (without disease progression) to be assigned different utility values (0.66 for patents in the pemetrexed arm and 0.58 for patients in the placebo arm). This was not consistent with data from the JMEN trial in which the rate of grade 3 or 4 fatigue was noticeably higher in the pemetrexed arm (3.66%) than in the placebo arm (0.64%). When the ERG used utility values which incorporated the disutility associated with adverse events (0.6568 in the pemetrexed arm and 0.6628 in the placebo arm) the ICER increased from the base case of £33,732 per QALY gained to £36,798 per QALY gained.\n\nThe ERG considered that the manufacturer did not adequately justify the choice of parameters and parameter values used in the one-way sensitivity analyses. The ERG also expressed concern that a probabilistic sensitivity analysis had not been undertaken. When the ERG conducted an approximate probabilistic sensitivity analysis based on the overall survival gain and the mean number of treatment cycles from the individual patient data the cost-effectiveness acceptability curve showed that pemetrexed maintenance treatment would have zero probability of being cost effective at a threshold of £30,000 per QALY gained and 50% probability of being cost effective at a threshold of approximately £51,000 per QALY gained.\n\nThe ERG identified other concerns with the cost-effectiveness analysis, including:\n\nThe half-cycle correction applied to survival estimates appeared to be inappropriate. The ERG considered that the correct approach would be to use the area under the curve from the trial analysis unaltered, and then calculate 'mid-cycle' corrected estimates for the remainder of the model duration derived from a parametric model.\n\nPost progression costs and survival values had been double discounted.\n\nA minor error in the calculation of the proportion of patients assumed to receive docetaxel or erlotinib as second-line treatment. When this was corrected, the manufacturer's base-case ICER increased slightly.\n\nThe ERG investigated the impact of unlimited cycles of treatment, revised utility values, revised discounting assumptions, and increased cost of monitoring based on a model populated with individual patient data. The cumulative effect of these changes was an increase in the ICER for pemetrexed maintenance treatment from the manufacturer's estimated base case of £33,732 per QALY gained to £51,192 per QALY gained. The number of treatment cycles and utility revision had the most impact on the ICER.\n\nThe manufacturer presented a revised cost-effectiveness analysis to address the concerns raised by the Committee. The revised analysis included a probabilistic sensitivity analysis with an exponential extrapolation survival function and presented six scenarios in which the duration of treatment and the utility values in the pemetrexed and placebo arms were varied (Three different treatment durations were presented, each with two possible utility assumptions, giving a total of six scenarios). The different treatment durations considered were: 1\xa0year (a maximum of 17 cycles), 2\xa0years (a maximum of 35 cycles) and treatment until disease progression in accordance with the JMEN trial (a maximum of 55 cycles). The survival benefits modelled for each treatment duration were consistent with those seen in trial patients. Utility was either the same in both arms (0.66) or a lower utility was assigned to the pemetrexed arm (0.657) compared with the placebo arm (0.663). The ICERs for pemetrexed compared with best supportive care ranged from £46,137 per QALY gained to £50,286 per QALY gained, with a 46–58% probability of being cost effective at a threshold of £50,000 per QALY gained.\n\nThe ERG commented on the manufacturer's revised analysis and examined scenario 5 in detail. This scenario represented treatment until disease progression, used the entire trial population and incorporated a utility of 0.663 for the placebo arm and 0.657 for the pemetrexed arm. The ERG noted that most of the changes made by the manufacturer were those required to accommodate a probabilistic sensitivity analysis. The ERG also noted that the changes were implemented appropriately.\n\nThe ERG conducted a probabilistic sensitivity analysis on scenario 5 which incorporated all of the amendments suggested in their original analysis (see section 3.23). The ERG also presented the results of a probabilistic sensitivity analysis using an exponential and a Weibull extrapolation of the trial data. The ICER for pemetrexed compared with best supportive care using the exponential survival function was £56,903 per QALY gained using deterministic analysis and £47,168 per QALY gained using probabilistic analysis, with a 57.71% probability of being cost effective at a threshold of £50,000 per QALY gained. When the Weibull function was applied, the ICER for pemetrexed compared with best supportive care was £57,082 per QALY gained using deterministic analysis and £50,673 per QALY gained using probabilistic analysis, with a 49.70% probability of being cost effective at a threshold of £50,000 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pemetrexed having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of pemetrexed by clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee considered current UK practice for the treatment of people with non-squamous non-small-cell lung cancer. The Committee heard from clinical specialists that patients undergo induction with a platinum doublet of carboplatin or cisplatin in combination with gemcitabine, paclitaxel, vinorelbine or docetaxel. The Committee was also aware of the NICE technology appraisal that recommended pemetrexed as a treatment option for the first-line treatment of non-small-cell lung cancer (NICE technology appraisal guidance 181). After induction, patients are monitored but receive no chemotherapy until progression. Patients whose disease progresses only receive second-line chemotherapy if they have a good performance status. In the UK, this is normally docetaxel or erlotinib. Patients who do not receive second-line chemotherapy receive best supportive care, which can include palliative radiotherapy.\n\nThe Committee heard that maintenance treatment after first-line treatment is a new concept in lung cancer and is not currently practised in the UK. The Committee also heard from clinical specialists that pemetrexed has fewer adverse events associated with its use compared with many other chemotherapies offered for the treatment of non-small-cell lung cancer. The aim of maintenance treatment with pemetrexed is to prolong the period of remission after first-line chemotherapy and possibly increase eligibility for second-line chemotherapy.\n\nThe Committee noted that the clinical effectiveness evidence for pemetrexed for the maintenance therapy of non-small-cell lung cancer was based on the JMEN trial, and noted that the overall survival achieved with pemetrexed was higher than for people receiving best supportive care. The Committee considered the trial to be generally well designed but had a number of concerns over the interpretation of the trial results (see section\xa04.5–10).\n\nThe initial primary endpoint was changed from overall survival to progression-free survival during the course of the trial. The Committee heard from the manufacturer that this was done after consultation with regulatory authorities in the USA and the change was implemented before any trial data had been analysed.\n\nThe evidence in the manufacturer's submission was from the non-squamous histological subgroup of the trial but histology was not a factor in the randomisation process. However, the Committee heard from the clinical specialists that the histological groups were reasonably balanced between the two arms of the trial and that lack of histological testing as part of the randomisation would not have significantly affected the outcome of the analysis. The clinical specialists also told the Committee that although definitive histological testing is variable in practice, the trial strategy was a reasonable reflection of what would be done in non-trial conditions.\n\nIn the trial treatment cycles were only limited by disease progression. The Committee heard from clinical specialists that patients would continue to receive pemetrexed while they were responding to treatment and so the trial did reflect the likely UK clinical practice. Therefore, the Committee was concerned that the capping in the manufacturer's original economic model was not consistent with clinical practice (see section\xa04.14).\n\nNone of the trial centres were located in the UK and one third of the trial population was Asian (from China, Korea, Taiwan and India). The Committee heard from the clinical specialists that although this ethnic group has a relatively favourable prognosis for non-small-cell lung cancer, it would have the same relative benefit from treatment with pemetrexed as the UK population.\n\nThere was an imbalance in the use of second-line treatments in the trial, and the Committee was concerned about how this was used in the manufacturer's economic model (see section\xa04.16).\n\nThe Committee was concerned that insufficient health-related quality-of-life data had been collected from the trial to enable their inclusion in the economic modelling. The Committee heard from clinical specialists and the manufacturer that trial patients who are in progressive disease after first- and second-line treatment are less likely to complete quality-of-life surveys, making it hard to get health-related quality-of-life data.\n\nThe Committee considered the population eligible for maintenance treatment. The Committee heard from clinical specialists that patients who receive first-line treatment usually have a good performance status, and that approximately one third of patients will progress while on first-line chemotherapy. The Committee also considered how patients are monitored in UK clinical practice. The Committee heard that although computer tomography (CT) scanning is not routinely used to monitor patients in UK clinical practice, it is likely that patients receiving pemetrexed maintenance treatment would undergo more CT scans to confirm that they have not progressed.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's submitted cost-effectiveness analysis and the ERG's critique. The manufacturer's base case stated that the incremental cost of pemetrexed compared with best supportive care was £9137 and the incremental QALY was 0.27, giving an ICER of pemetrexed compared to best supportive care of £33,732 per QALY gained. However, the Committee was aware of several concerns that the ERG had described in the calculation of this base case. These included: the modelling of overall survival, the capping of the number of treatment cycles but not the associated benefits, the different utilities assigned to patients in the same initial health state, the handling of second-line treatment effects and the absence of a probablistic sensitivity analysis.\n\nThe Committee noted the 29-month overall survival data from the trial were extrapolated to 6\xa0years in the model. It noted that the exponential curve applied in the base case did not fit the data well. The Committee noted that the manufacturer's analysis using a Weibull model was also plausible and that the ICERs were higher when Weibull models were used, suggesting that the figure in the base case might be at the lower end of the likely range. The Committee also expressed concern that the primary outcome in the trial (progression-free survival) was not captured in the model and number of cycles of treatment was used as a proxy.\n\nThe Committee considered the capping of costs in the manufacturer's original model at a maximum of 17\xa0cycles. The Committee was informed by the manufacturer that clinical advice suggested that most benefit is derived in the first 8–10 cycles of treatment, which informed their decision to cap the cycles at 17 (1\xa0standard deviation above the mean of 8\xa0cycles). However, the Committee heard that in other cancers where patients receive maintenance treatment, cycles are not capped. The Committee considered that when capping was assumed, it had the effect of constraining the costs of maintenance therapy without a corresponding effect on the benefits accrued from use of pemetrexed, therefore building an essential bias in the economic evaluation in favour of pemetrexed.\n\nThe Committee considered the utility estimates assigned to patients in different arms of the model. It noted that in the manufacturer's original analysis, patients who entered the trial in the same health state were assigned higher utilities in the pemetrexed arm than in the placebo arm of the model – biasing the model in favour of pemetrexed. The Committee also noted that the disutilities of adverse events associated with pemetrexed were not modelled in the base case. Although the clinical specialists said that a minority of patients may feel better on pemetrexed maintenance treatment because their tumour shrank, the Committee was not persuaded that this justified the manufacturer's difference in utility between the two arms. The Committee considered the ERG's re-analysis of the model, which used a slightly lower utility for progression-free disease in the pemetrexed arm compared with the placebo arm, to be more appropriate. The Committee noted that this approach was adopted by the manufacturer in the revised analysis.\n\nThe Committee considered the six scenarios of the revised analysis presented by the manufacturer. The Committee also considered the ERG analysis of scenario 5, which corrected the utility estimates, removed cycle capping, performed an approximate probabilistic sensitivity analysis and also corrected discounting errors. The Committee considered scenario 5 to represent the most plausible assumptions for modelling the cost effectiveness of pemetrexed maintenance treatment compared with best supportive care. The Committee considered that the manufacturer's revised analysis had adequately addressed the main concerns identified in the original model. The Committee considered the updated ICERs presented for scenario 5 by the manufacturer (£47,000 per QALY gained) and the ERG (which ranged from £47,000 per QALY gained with the exponential model to £51,000 per QALY gained with the Weibull model) to be reliable.\n\nThe Committee considered the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee discussed whether the benefit provided by pemetrexed for the maintenance treatment of non-small-cell lung cancer fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that patients with stage IIIB or IV non-small-cell lung cancer who receive no treatment usually survive for about 7–10\xa0months. The Committee considered the evidence from the pemetrexed randomised controlled trial (the JMEN trial) that showed a median survival benefit of 5.2\xa0months for pemetrexed versus placebo. The Committee agreed that the data from the trial were sufficiently robust and that maintenance treatment with pemetrexed would increase overall survival by more than 3\xa0months. The Committee considered that the estimated population for whom pemetrexed is licensed is currently small enough to allow the end-of-life advice to apply. The Committee concluded that the evidence submitted by the manufacturer was robust enough to show that maintenance treatment with pemetrexed fulfilled the criteria for the supplementary advice from NICE (see section\xa04.19).\n\nThe Committee considered the evidence presented by the manufacturer in the revised analysis to be robust. The Committee also considered the ERG's exploratory analysis, which demonstrated that the ICER for pemetrexed compared with best supportive care was about £47,000 per QALY gained. The Committee was persuaded that the most plausible ICER for pemetrexed compared with best supportive care was approximately £47,000 per QALY gained and, with reasonable certainty, was below £50,000 per QALY gained. The Committee considered this ICER, taking into account the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the QALY benefits for the ICER to fall within the plausible range was acceptable. Therefore, the Committee recommended pemetrexed as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology, if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel.", 'Related NICE guidance': '# Published\n\nPemetrexed for the first-line treatment of non-small-cell lung cancer (2009) NICE technology appraisal guidance 181.\n\nGefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal) (2009) NICE technology appraisal guidance175.\n\nErlotinib for the treatment of non-small-cell lung cancer (2008) NICE technology appraisal guidance 162.\n\nBevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal) (2008) NICE technology appraisal guidance 148.\n\nPemetrexed for the treatment of non-small-cell lung cancer (2007) NICE technology appraisal guidance 124.\n\nLung cancer: the diagnosis and treatment of lung cancer (2005) NICE clinical guideline 24 [Replaced by NICE clinical guideline 121].\n\nGefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (2010) NICE technology appraisal guidance 192.\n\nErlotinib monotherapy for maintenance treatment of non-small-cell lung cancer (2010) NICE technology appraisal guidance 227.\n\n# Under development\n\nNICE is developing the following guidance(details available from the NICE website):\n\nCetuximab for the treatment of advanced non-small-cell lung cancer. NICE technology appraisal guidance(publication date to be confirmed).', 'Review of guidance': 'The guidance on this technology will be considered for review in November 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveJune 2010', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nISBN: 978-1-4731-2095-2'}
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https://www.nice.org.uk/guidance/ta190
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Evidence-based recommendations on pemetrexed disodium (Alimta) for the maintenance treatment of non-small-cell lung cancer.
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95c4b96cb7c56aff6b74687f996ca6b1b41734d1
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Cabozantinib for previously treated advanced renal cell carcinoma
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Cabozantinib for previously treated advanced renal cell carcinoma
Evidence-based recommendations on cabozantinib (Cabometyx) for previously treated advance renal cell carcinoma in adults.
# Recommendations
Cabozantinib is recommended, within its marketing authorisation, as an option for treating advanced renal cell carcinoma in adults after vascular endothelial growth factor (VEGF)-targeted therapy, only if the company provides cabozantinib with the discount agreed in the patient access scheme.# The technology
Description of the technology
Cabozantinib (Cabometyx, Ipsen) is a small molecule that inhibits multiple receptor tyrosine kinases.
Marketing authorisation
Cabozantinib 'is indicated for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy'.
Adverse reactions
The most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%) and nausea (2%). For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Administered orally, 60 mg once daily.
Price
The list price is £5,143.00 per 30‑tab pack applicable to all dosages (20 mg, 40 mg and 60 mg).
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of cabozantinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by Ipsen and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of cabozantinib, having considered evidence on the nature of renal cell carcinoma and the value placed on the benefits of cabozantinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The committee was aware that, despite new treatments recently being recommended by NICE, there remained an unmet clinical need for some people with advanced renal cell carcinoma. It noted that the clinical experts perceived cabozantinib to be more effective than everolimus and axitinib, although it caused more adverse effects. The committee recognised that people with advanced renal cell carcinoma would value any increased life expectancy offered by cabozantinib and may be prepared to tolerate the adverse effects of treatment.
# Treatment pathway
The committee heard from the clinical experts that most people in the NHS with newly diagnosed advanced renal cell carcinoma will first be offered 1 of 2 tyrosine kinase inhibitors (TKIs), pazopanib or sunitinib, as recommended in NICE guidance. If the disease progresses and they are fit enough to have further treatment, most people are then offered axitinib (also a TKI), nivolumab (a programmed cell death protein 1 ), or everolimus (a mammalian target of rapamycin inhibitor), as recommended in NICE guidance. If the disease progresses again, people who previously had axitinib may have nivolumab or everolimus as a third-line treatment; people who had nivolumab may have axitinib or everolimus; and people who had everolimus may have axitinib or nivolumab. The committee was aware that some patients have fourth-line treatment and beyond, but that no accepted treatment pathway exists at this point. It concluded that the current treatment pathway offered options for patients.
The committee was aware of the recent changes in the recommendations for everolimus, and discussed the impact of these on the treatment pathway. At the first committee meeting, it heard from the clinical experts that everolimus could be used after 1 previous treatment (second line), although they would prefer to use it after 2 or 3 previous treatments (third or fourth line). At that time, everolimus was available only through the Cancer Drugs Fund, as a second-line treatment, after 1 TKI for people who cannot have axitinib. So, clinicians could not use everolimus beyond the second-line setting in the NHS. NICE published guidance following the Cancer Drugs Fund reconsideration of everolimus in February 2017, recommending everolimus, with a new patient access scheme (lower price), for routine commissioning. The Cancer Drugs Fund reconsideration of everolimus broadened the population eligible for treatment. It means that everolimus is now recommended after 1 or more lines of vascular endothelial growth factor (VEGF)-targeted therapy (which includes TKIs), rather than after only 1 TKI in those who cannot take axitinib. Given the clinicians' preference to use everolimus later in treatment, the committee appreciated that use of everolimus after the recommendation changes was likely to shift down the treatment pathway. Responses to the second consultation echoed this view. The committee concluded that everolimus was predominantly used in clinical practice after 3 previous treatments (including nivolumab and axitinib), that is as a fourth- or subsequent-line treatment.
# Population and comparators
The clinical experts explained that they would offer cabozantinib to patients who have had 1 or 2 previous treatments. The committee recalled that, at this point, axitinib and nivolumab are also treatment options (see section 4.2), but not everolimus, which would be used after these treatments (see section 4.3). The committee was aware that the final scope of this appraisal included best supportive care as a comparator. It heard from the clinical experts that active treatment is unsuitable for a small group of people who are not fit enough and who will instead have best supportive care. The committee appreciated that, after positive NICE guidance on nivolumab, this group was even smaller, and unlikely to reflect those who would be offered cabozantinib. It concluded that cabozantinib would be used in people who have had 1 or 2 previous treatments, and that the relevant comparators were axitinib and nivolumab.
The committee discussed whether there was merit in considering separately people who have had 1 or 2 previous treatments. It heard from the clinical experts that there was no biological reason for axitinib to work any differently based on people having 1 or 2 previous treatments. In addition, the clinical experts stated that cabozantinib would be expected to work similarly after 1 previous treatment as it would after 2 previous treatments, and that it would also work after other TKIs had failed. The committee concluded that it would consider cabozantinib for the population comprising people who have had either 1 or 2 previous treatments as a whole.
# Clinical effectiveness
The committee noted that the main evidence for cabozantinib came from METEOR, an open-label randomised controlled trial comparing cabozantinib with everolimus. It appreciated that the trial did not allow patients to switch from everolimus to cabozantinib at disease progression. The committee heard from the clinical experts that the results of METEOR were generalisable to the NHS.
The committee noted that METEOR measured progression-free survival in 2 populations:
The primary endpoint intention-to-treat population: the first 375 patients randomised (n=375).
The intention-to-treat population: all patients randomised at baseline (n=658).The committee noted that more events occurred in the intention-to-treat population than in the primary endpoint intention-to-treat population, which resulted in more mature data. It also noted that the intention-to-treat population reflected a longer follow-up than the primary endpoint intention-to-treat population. Because of this, the committee concluded that it would use the intention-to-treat population analysis for its decision-making.
## Clinical trial results
In the intention-to-treat population of METEOR (December 2015 data cut-off):
Progression-free survival improved with cabozantinib compared with everolimus (median 7.4 and 3.9 months respectively; hazard ratio 0.51; 95% confidence interval 0.41 to 0.62; p<0.0001).
Overall survival improved with cabozantinib compared with everolimus (median 21.4 and 16.5 months respectively; hazard ratio 0.66; 95% CI 0.53 to 0.83; p=0.00026).The committee also noted the updated survival data from METEOR, presented by the company in response to the first consultation (based on a cut-off date of October 2016), and welcomed the availability of new, more mature data. It concluded that cabozantinib was more effective than everolimus in METEOR.
## Network meta-analysis
Because there were no head-to-head trials comparing cabozantinib with axitinib or nivolumab, the company did a network meta-analysis to compare the treatments indirectly. The original network linked 6 trials, including TARGET, which compared sorafenib with placebo. Although sorafenib was not a comparator for cabozantinib in this appraisal, the company included TARGET to link together treatments. The committee was concerned about including this trial for 2 reasons. First, none of the patients had previously had VEGF-targeted therapies. Second, the company used immature data from the trial, which censored patients who switched from placebo to sorafenib. This was likely to have underestimated the effect of sorafenib because the placebo data reflected patients whose disease responded relatively well (who were therefore not censored), and this would in turn have underestimated the effect of axitinib. In response to the first consultation, and in line with the committee's preference, the company submitted a revised network that excluded TARGET. This assumed that axitinib was as effective as everolimus in terms of overall and progression-free survival. The committee concluded that the company's simplified network reduced the potential bias associated with using immature data from TARGET.
## Methodology of the network meta-analysis
The committee understood that, to estimate long-term outcomes, the company used a 'family' of related survival curves for cabozantinib and for all of the comparator treatments. The company chose the curves based on how well, on average, they fitted the data on overall or progression-free survival for all the treatments in the network. The committee noted that, because of this simplification, the parametric distribution chosen by the company for both progression-free and overall survival (log-normal for both endpoints) did not fit the data for each individual treatment well. In response to the first consultation, the company used fractional polynomial modelling, as described by Janssen et al. (2011), to fit survival curves. The new method also used a family of related survival curves for all the treatments. However, the committee agreed that it was a more flexible family, which improved the curve fits to the Kaplan–Meier data on overall and progression-free survival for all treatments in the network compared with the original parametric modelling using the log-normal distribution. The committee appreciated that the fractional polynomial modelling did not fit data in the extrapolation period. It noted that the evidence review group (ERG) considered that estimating survival based on the 'average fit' across the network (as opposed to the fit for each individual treatment) was less of an issue with fractional polynomial models than with parametric curve fitting. The committee was satisfied that the company's revised modelling of overall and progression-free survival was more appropriate than the original parametric modelling.
# Cost effectiveness
The company used a 3‑stage, partitioned-survival economic model, which the committee considered appropriate to capture the natural history of the disease. The health states included in the model were pre-progressed disease, progressed disease and death. The company used the model to estimate average delay in time to disease progression, average delay in time to death, and costs and health-related quality of life associated with cabozantinib and its comparators by forecasting beyond the end of the trials. The modelled population reflected the trial population of METEOR in that it included people who had had 1 (71%), or 2 or more (29%), previous treatments. This was consistent with the population who would have cabozantinib in clinical practice (see section 4.4).
In its original submission, the company presented 2 separate cost-effectiveness analyses based on the model:
A trial-based analysis comparing cabozantinib with everolimus using data from METEOR only.
A network meta-analysis-based analysis comparing cabozantinib with axitinib, everolimus, best supportive care and nivolumab using data from the network meta-analysis.In response to the first consultation, the company revised the network meta-analysis to exclude best supportive care, in line with the committee's conclusion about the treatment pathway (see section 4.3). The committee recognised that the trial data were more robust than those estimated from the network meta-analysis because they reflected a direct comparison between 2 treatments. The committee acknowledged that everolimus was not a relevant comparator for cabozantinib for most patients. Nevertheless, it agreed that it could have confidence that the model was suitable for decision-making with respect to axitinib and nivolumab if, based on the network meta-analysis (using fractional polynomial survival modelling), it produced plausible estimates for cabozantinib compared with everolimus that aligned with the analysis based on observed data from METEOR (using parametric survival modelling). Although the company, in response to the first consultation, did not present a trial-based analysis, the committee heard from the ERG that there was little difference between the results of the trial-based and the network meta-analysis-based analyses. The committee was therefore satisfied that the comparisons of cabozantinib with axitinib and nivolumab were reliable.
## Survival modelling
The committee considered the company's revised modelling in response to the first consultation. It noted that, to estimate overall and progression-free survival for cabozantinib and its comparator treatments, the company extrapolated the curves based on fitting fractional polynomial models (see section 4.10) up to the end of the time horizon. As such, to estimate overall and progression-free survival for cabozantinib and its comparator treatments, the company used fractional polynomial modelling during both the trial follow-up and extrapolation. Hereafter, this analysis will be referred to as 'the company's revised base case'.
## Comparison of survival predictions in the company's revised base case with observational data on everolimus (the natural history of the disease)
In its revised base case (see section 4.13), the company predicted that 5% of people in the everolimus arm would be alive 5 years after starting treatment. The committee compared this estimate with 2 sources of observational data submitted during the first consultation:
Registry-based pharmaco-epidemiological data from a publication by Ruiz-Morales et al. (2016) submitted by the company. These data came from the International Metastatic renal cell carcinoma Database Consortium (IMDC) reflecting people initially treated with either pazopanib or sunitinib. Some people then had second-line treatment. The company presented data for people who had second-line treatment after sunitinib (n=2,667) because this group was larger than the group that had second-line treatment after pazopanib (n=260). It noted that, in this group, about 10% were alive 5 years after starting treatment.
Audit data from the Christie Hospital (Manchester, UK) submitted by a clinical expert. These data showed that, among people who had axitinib or everolimus as a second-line treatment (n=282), around 6% were alive 5 years after starting treatment.
The committee discussed whether the Ruiz-Morales et al. (2016) data on were generalisable to patients who would be offered everolimus in the UK. It observed that:
Ruiz-Morales et al. did not include patients from the UK. The committee acknowledged that the company considered that this study included people with similar characteristics at baseline to patients in METEOR, and that the countries from which these people were included had similar socio-economic profiles and health systems to the UK.
As second-line treatment, only 45% of people had everolimus, and some had treatments that were not available in the NHS.
Ruiz-Morales et al. did not report information on the third-line treatments; these treatments may not be available in the NHS, and may have biased the effect of second-line treatment.For these reasons, the committee agreed that the survival estimates from Ruiz-Morales et al. were likely to overestimate the survival of patients who have everolimus in the NHS. It considered the 5‑year survival estimate from the Christie Hospital audit to be unreliable because the numbers were small and there were no observations beyond 3 years 3 months after starting treatment. The committee concluded that survival in the UK was likely to have been overestimated in Ruiz-Morales et al., but it did provide useful data with which to compare the survival prediction of the company's model.
The committee noted that the company presented a scenario analysis to align the revised base-case predictions (see section 4.14) and the data from Ruiz-Morales et al. (2016). In this, the company did not change the modelling of progression-free survival, that is, it continued to use fractional polynomial modelling across the entire time horizon. For overall survival, it used fractional polynomial modelling during the trial follow-up period (as per the revised base case), but used parametric modelling choosing the log-normal distribution during the extrapolation period. The committee noted that this scenario aligned the model's predictions of survival with data from Ruiz-Morales et al. However, the committee did not consider that it was appropriate to base the extrapolation on meeting the 5‑year death rate observed in Ruiz-Morales et al. The committee recalled that survival among people having everolimus was likely to have been overestimated in Ruiz-Morales et al. It concluded that it preferred the company's revised base case, which used fractional polynomial modelling across the entire time horizon for both overall and progression-free survival.
## Duration of cabozantinib's treatment effect
The committee noted that both the company and the ERG assumed that the effect of cabozantinib continued beyond the trial follow-up, even after the disease progressed or patients stopped treatment, but the committee was not presented with evidence to support this. The clinical experts considered that it was not clear whether a survival benefit would continue after stopping treatment. They explained that, in clinical practice, some patients have stable disease for 2 to 3 years after stopping treatment, whereas the disease progresses more quickly in others. Also, some patients have a prolonged response after a short length of treatment and others do not. The committee concluded that assuming the effect of cabozantinib continues for up to 30 years, based on a trial with a median follow-up of under 2 years for overall survival, was highly uncertain.
## Modelling of nivolumab
The committee noted that, for nivolumab, the company's revised base case (see section 4.13) estimated a longer progression-free survival than overall survival. It understood that, in the model, disease progression could occur until the point where overall and progression-free survival curves cross (around 5 years after starting treatment), after which people whose disease had not progressed followed the overall survival curve. This meant that the company assumed that the disease would never progress at that point, instead people would die of causes other than their cancer. It also meant that they would accrue the utility associated with pre-progressed disease during their remaining time in the model. The committee was not presented with any evidence that people who are alive and on treatment 5 years after starting treatment remain progression-free until they die. The company did not consider it plausible that progression-free survival would be longer than overall survival, and conducted a scenario analysis. In this, it continued to use fractional polynomial modelling for overall survival across the entire time horizon as in the revised base case. For progression-free survival, it used parametric modelling using the log-normal distribution during both the trial follow-up and extrapolation periods. The committee recalled that the log-normal distribution did not fit the data for the individual treatments well (see section 4.10). Because of this, the committee did not consider this analysis further. It recognised the uncertainties in the company's revised base case with respect to the modelling of nivolumab, but concluded it could use it for decision-making.
The committee noted that the company presented a further scenario analysis that, as in the previous scenario (see section 4.18), used the log-normal distribution to model progression-free survival across the entire time horizon. However, it differed in that of those who were alive 5 years after starting treatment and still having nivolumab, the company assumed that half had the same mortality as the age-matched general population. The committee recalled that using the log-normal distribution to model progression-free survival did not produce robust estimates (see section 4.18). Furthermore, the committee noted that this scenario had little impact on the mean overall survival associated with nivolumab, which it did not expect. The company suggested that this may have been because the risk of death estimated by the log-normal curve was similar to that of the general population. The committee recalled from the NICE technology appraisal on nivolumab that the committee preferred to base its decision on a mixed model that relied 50% on a single generalised gamma model and 50% on a model that assumed a greater long-term survival benefit than in the single generalised gamma model for nivolumab. The committee concluded that the scenario analysis was unrealistic, but appreciated that the company had explored predictions of better survival for nivolumab.
## Utility values
The committee was aware that METEOR collected health-related quality-of-life data using the EQ‑5D‑5L measure, which the company adjusted for age, as requested by the committee, and used in its revised base case. The committee considered these data, together with data from other studies, including those used in previous appraisals of renal cell carcinoma. It noted that the available utility values varied widely, particularly those used for the post-progression state. The ERG explained that the utility values collected from METEOR were higher than those clinicians would expect to see in clinical practice and, notably, the utility value before disease progression was higher than that of the age-matched general population. Because of this, the ERG explored using utility values from the AXIS trial. The committee accepted that the new, more detailed version of the EQ‑5D (EQ‑5D‑5L) used in METEOR could explain the relatively high utility values reported in this trial. It also heard from the company that there was evidence showing that utility estimates were higher using EQ‑5D‑5L. Another possible explanation was greater attrition bias in METEOR, in which unhealthy people were less likely to continue filling in quality-of-life questionnaires. The committee was also aware that AXIS and METEOR differed in whether they allowed patients to switch between treatment arms, the number and type of therapies that patients took before enrolling in the trial or after the disease progressed during the trial, and the prognostic scores at baseline of the study populations. In response to the second consultation, the company argued that the utility from AXIS was not the most relevant because patients in the trial had had either a cytokine or a VEGF-targeted therapy, and it was unclear what the effect was of having previous cytokines on the patient's health. The committee generally preferred sourcing utility and effectiveness from the same trial. However, it agreed that some of the utility values from METEOR appeared high, particularly the utility value before disease progression. The committee concluded that it would take into account both sets of utility values in its decision-making.
## Analyses used for decision-making
The committee considered the cost-effectiveness results incorporating the revisions to the models in response to the first consultation, the new data from METEOR (cut-off of October 2016), and the confidential discounts for all technologies applied by the ERG. It was presented with results with and without everolimus included in the analysis but, because the committee concluded that everolimus was not a relevant comparator for cabozantinib, it considered only the analyses excluding everolimus. In its consideration of the cost-effectiveness estimates, the committee took into account:
the company's revised base case (see section 4.10)
the company's scenario analysis using fractional polynomial modelling during the trial follow-up period, and parametric modelling using the log-normal distribution during the extrapolation period (see section 4.16)
the ERG's revised base case (which reflected minor changes with minimal impact on the results compared with the company's revised base case)
the ERG's scenario analysis exploring utility values from AXIS.
# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.
The committee considered the life expectancy of people with previously treated advanced renal cell carcinoma having each of the 2 comparator treatments, axitinib or nivolumab (see section 4.3). The committee noted that the mean life expectancy, based on the revised model in response to the first consultation, and the updated dataset from METEOR, was about 24 months among people with advanced renal cell carcinoma having axitinib, but not among those having nivolumab.
The committee discussed whether cabozantinib extended life by at least 3 months. It agreed that the results of the cost-effectiveness analyses (see section 4.21) suggested that cabozantinib was likely to extend mean overall survival by more than 3 months compared with axitinib, but not compared with nivolumab. The committee therefore concluded that cabozantinib met the end-of-life criteria when compared with axitinib, but did not meet the end-of-life criteria when compared with nivolumab.
# Results of cost-effectiveness analyses
The committee noted that, excluding everolimus as a comparator, in the revised base-case analysis, the incremental analysis showed that cabozantinib was associated with an incremental cost-effectiveness ratio (ICER) that was below £50,000 per quality-adjusted life year (QALY) gained compared with axitinib. It also noted that, in the incremental analyses, cabozantinib dominated nivolumab (that is, it was more effective and less expensive).
The committee discussed how the remaining uncertainties in the model could affect the results. It recalled that the cost effectiveness of cabozantinib would:
improve (that is, cabozantinib's ICER would decrease) if:
the long-term survival rate were higher than predicted by the model.
worsen (that is, cabozantinib's ICER would increase) if:
cabozantinib had no effect or a diminishing effect over time
nivolumab were associated with better long-term survival than assumed in the base case
the utility values from AXIS better represented the quality of life of people in the NHS than the utility values from METEOR (the ICER could increase by as much as £8,000 per QALY but would still remain below £50,000 per QALY).The committee was satisfied that the remaining uncertainties in the model were unlikely to change the results to a degree where the incremental ICER for cabozantinib from the company's revised base case would not be cost effective compared with axitinib.
The committee was aware that, in line with the population included in METEOR, the cost-effectiveness analysis related mostly to people who had 1 or 2 previous treatments (see section 4.11), whereas the marketing authorisation for cabozantinib does not specify the number of previous treatments. The committee discussed whether the effectiveness and cost effectiveness of cabozantinib could be generalised to people who have had 3 previous treatments. It noted that, at this point, everolimus was likely to be an option, and that cabozantinib was not cost effective compared with everolimus, with ICERs exceeding £50,000 per QALY gained. The committee was aware that, according to NICE guidance, axitinib and nivolumab may also be used as fourth-line treatments. It recalled that cabozantinib would be expected to work similarly after 1 previous treatment and after 2 previous treatments, and that it would also work after other TKIs had failed (see section 4.5). It considered that it was plausible that cabozantinib would also work similarly after 3 previous treatments. The committee acknowledged that some people in the NHS will likely have had everolimus second- or third-line, and if they remain fit for fourth-line treatment, have limited options available. Taking account of these reasons, and even though cabozantinib is not cost effective compared with everolimus, the committee agreed to keep options for this small and likely diminishing group by extending its recommendations to people who have had more than 2 previous treatments. The committee concluded that cabozantinib could be considered a cost-effective use of NHS resources for treating advanced renal cell carcinoma in adults after VEGF-targeted therapy.
# Innovation
The committee considered whether cabozantinib was an innovative treatment. It heard from the clinical experts that, because of its multi-targeted approach, cabozantinib would likely have additional benefits for some patients and so could be considered innovative. The committee also heard that cabozantinib would be highly valued in patients whose disease is resistant to standard TKIs and may or may not have responded to nivolumab. The committee agreed that cabozantinib could fulfil the unmet need in these patients. However, it did not consider cabozantinib to reflect a 'step change' in treatment nor did it identify a benefit to utility that was not otherwise accounted for in the modelling.
# Pharmaceutical Price Regulation Scheme (PPRS) 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Summary of appraisal committee's key conclusions
TA463
Appraisal title: Cabozantinib for previously treated advanced renal cell carcinoma
Section
Key conclusion
Cabozantinib is recommended within its marketing authorisation for treating advanced renal cell carcinoma in adults after vascular endothelial growth factor (VEGF)-targeted therapy.
In the intention-to-treat population of METEOR, progression-free and overall survival were statistically significantly improved with cabozantinib compared with everolimus.
The committee concluded that the company's simplified network reduced the potential bias associated with using immature data from TARGET. The committee was satisfied that the company's revised modelling of progression-free and overall survival was more appropriate than the original parametric modelling. The committee noted that, excluding everolimus as a comparator, in the revised base-case analysis, the incremental analysis showed that cabozantinib was associated with an incremental cost-effectiveness ratio (ICER) that was below £50,000 per quality-adjusted life year (QALY) gained compared with axitinib. It also noted that, in the incremental analyses, cabozantinib dominated nivolumab.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee was aware that there remained an unmet clinical need for some people with advanced renal cell carcinoma.
Most people fit enough for second-line treatment are offered axitinib, nivolumab or everolimus. If the disease progresses further, people who previously had axitinib may have nivolumab or everolimus as a third-line treatment; people who had nivolumab may have axitinib or everolimus; and people who had everolimus may have axitinib or nivolumab. The committee was aware that some patients have fourth-line treatment and beyond, but that there is no accepted treatment pathway at this point.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The clinical experts perceived cabozantinib to be more effective than everolimus and axitinib, although it caused more adverse effects.
The committee heard from the clinical experts that, because of its multi-targeted approach, cabozantinib could be considered innovative. The committee also heard that cabozantinib would be highly valued in patients whose disease is resistant to standard tyrosine kinase inhibitors and whose disease may or may not have responded to nivolumab.
What is the position of the treatment in the pathway of care for the condition?
Cabozantinib can be used in people who have had 1 or 2 previous treatments.
Adverse reactions
The most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%) and nausea (2%).
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The main evidence came from METEOR, an open-label randomised controlled trial comparing cabozantinib with everolimus. The committee appreciated that the trial did not allow patients to switch from placebo to cabozantinib at disease progression.
The company presented updated survival data from the METEOR trial during the first consultation (based on a cut-off date of October 2016 compared with December 2015 for the original data cut).
Relevance to general clinical practice in the NHS
The committee heard from the clinical experts that the results of METEOR were generalisable to the NHS.
Uncertainties generated by the evidence
The committee noted that the company used fractional polynomial modelling to fit survival curves. The new method used a family of related survival curves for all the treatments. However, it was a more flexible family, which improved the curve fits to the Kaplan–Meier data on overall and progression-free survival for all treatments in the network compared with the original network meta-analysis.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee concluded that it would consider cabozantinib for the population comprising people who have had 1 or 2 previous treatments as a whole.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
In the intention-to-treat population of METEOR, progression-free and overall survival were statistically significantly improved with cabozantinib compared with everolimus.
Evidence for cost effectiveness
Availability and nature of evidence
The company used a 3‑stage, partitioned-survival economic model, which the committee considered appropriate to capture the natural history of the disease.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee concluded that assuming the effect of cabozantinib continues for up to 30 years, based on a trial with a median follow-up of under 2 years for overall survival, was highly uncertain.
The committee suspected that the survival estimates from Ruiz-Morales et al. (2016) were likely to overestimate the survival of patients who have everolimus in the NHS.
The committee recognised the uncertainties in the company's revised base case with respect to the modelling of nivolumab, but concluded it could use it for decision-making.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The evidence review group (ERG) explained that the utility values collected from METEOR were higher than those clinicians would expect to see in clinical practice and, notably, the utility value before disease progression was higher than that of the age-matched general population. The committee concluded that it would also take into account both sets of utility values (AXIS and METEOR) in its decision-making.
The committee did not identify a benefit to utility that was not otherwise accounted for in the modelling.
Are there specific groups of people for whom the technology is particularly cost effective?
No subgroup analyses were presented.
What are the key drivers of cost effectiveness?
the duration of the effect of cabozantinib
the prediction of long-term survival rate with the disease
the survival modelling of nivolumab
Most likely cost-effectiveness estimate (given as an ICER)
The committee noted that, in the revised base-case analysis, excluding everolimus as a comparator, the incremental analysis showed that cabozantinib was associated with an ICER that was below £50,000 per QALY gained compared with axitinib. It also noted that, in the incremental analyses, cabozantinib dominated nivolumab (that is, it was more effective and less expensive).
Additional factors taken into account
Patient access schemes (PPRS)
There are patient access schemes for cabozantinib, axitinib, everolimus and nivolumab. The ERG presented analyses that included the confidential discounts for all technologies.
End-of-life considerations
The committee concluded that cabozantinib met the end-of-life criteria when compared with axitinib and everolimus, but did not meet the end-of-life criteria when compared with nivolumab.
Equalities considerations and social value judgements
No equality issues were identified by consultees or the committee.
|
{'Recommendations': 'Cabozantinib is recommended, within its marketing authorisation, as an option for treating advanced renal cell carcinoma in adults after vascular endothelial growth factor (VEGF)-targeted therapy, only if the company provides cabozantinib with the discount agreed in the patient access scheme.', 'The technology': "Description of the technology\n\nCabozantinib (Cabometyx, Ipsen) is a small molecule that inhibits multiple receptor tyrosine kinases.\n\nMarketing authorisation\n\nCabozantinib 'is indicated for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy'.\n\nAdverse reactions\n\nThe most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%) and nausea (2%). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nAdministered orally, 60\xa0mg once daily.\n\nPrice\n\nThe list price is £5,143.00 per 30‑tab pack applicable to all dosages (20\xa0mg, 40\xa0mg and 60\xa0mg).\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of cabozantinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Ipsen and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of cabozantinib, having considered evidence on the nature of renal cell carcinoma and the value placed on the benefits of cabozantinib by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\nThe committee was aware that, despite new treatments recently being recommended by NICE, there remained an unmet clinical need for some people with advanced renal cell carcinoma. It noted that the clinical experts perceived cabozantinib to be more effective than everolimus and axitinib, although it caused more adverse effects. The committee recognised that people with advanced renal cell carcinoma would value any increased life expectancy offered by cabozantinib and may be prepared to tolerate the adverse effects of treatment.\n\n# Treatment pathway\n\nThe committee heard from the clinical experts that most people in the NHS with newly diagnosed advanced renal cell carcinoma will first be offered 1\xa0of\xa02 tyrosine kinase inhibitors (TKIs), pazopanib or sunitinib, as recommended in NICE guidance. If the disease progresses and they are fit enough to have further treatment, most people are then offered axitinib (also a TKI), nivolumab (a programmed cell death protein\xa01 [PD‑1]), or everolimus (a mammalian target of rapamycin [mTOR] inhibitor), as recommended in NICE guidance. If the disease progresses again, people who previously had axitinib may have nivolumab or everolimus as a third-line treatment; people who had nivolumab may have axitinib or everolimus; and people who had everolimus may have axitinib or nivolumab. The committee was aware that some patients have fourth-line treatment and beyond, but that no accepted treatment pathway exists at this point. It concluded that the current treatment pathway offered options for patients.\n\nThe committee was aware of the recent changes in the recommendations for everolimus, and discussed the impact of these on the treatment pathway. At the first committee meeting, it heard from the clinical experts that everolimus could be used after 1\xa0previous treatment (second line), although they would prefer to use it after 2\xa0or\xa03 previous treatments (third or fourth line). At that time, everolimus was available only through the Cancer Drugs Fund, as a second-line treatment, after 1\xa0TKI for people who cannot have axitinib. So, clinicians could not use everolimus beyond the second-line setting in the NHS. NICE published guidance following the Cancer Drugs Fund reconsideration of everolimus in February 2017, recommending everolimus, with a new patient access scheme (lower price), for routine commissioning. The Cancer Drugs Fund reconsideration of everolimus broadened the population eligible for treatment. It means that everolimus is now recommended after 1\xa0or more lines of vascular endothelial growth factor (VEGF)-targeted therapy (which includes TKIs), rather than after only 1\xa0TKI in those who cannot take axitinib. Given the clinicians' preference to use everolimus later in treatment, the committee appreciated that use of everolimus after the recommendation changes was likely to shift down the treatment pathway. Responses to the second consultation echoed this view. The committee concluded that everolimus was predominantly used in clinical practice after 3\xa0previous treatments (including nivolumab and axitinib), that is as a fourth- or subsequent-line treatment.\n\n# Population and comparators\n\nThe clinical experts explained that they would offer cabozantinib to patients who have had 1\xa0or\xa02 previous treatments. The committee recalled that, at this point, axitinib and nivolumab are also treatment options (see section\xa04.2), but not everolimus, which would be used after these treatments (see section\xa04.3). The committee was aware that the final scope of this appraisal included best supportive care as a comparator. It heard from the clinical experts that active treatment is unsuitable for a small group of people who are not fit enough and who will instead have best supportive care. The committee appreciated that, after positive NICE guidance on nivolumab, this group was even smaller, and unlikely to reflect those who would be offered cabozantinib. It concluded that cabozantinib would be used in people who have had 1\xa0or\xa02 previous treatments, and that the relevant comparators were axitinib and nivolumab.\n\nThe committee discussed whether there was merit in considering separately people who have had 1\xa0or 2\xa0previous treatments. It heard from the clinical experts that there was no biological reason for axitinib to work any differently based on people having 1\xa0or\xa02 previous treatments. In addition, the clinical experts stated that cabozantinib would be expected to work similarly after 1\xa0previous treatment as it would after 2\xa0previous treatments, and that it would also work after other TKIs had failed. The committee concluded that it would consider cabozantinib for the population comprising people who have had either 1\xa0or 2\xa0previous treatments as a whole.\n\n# Clinical effectiveness\n\nThe committee noted that the main evidence for cabozantinib came from METEOR, an open-label randomised controlled trial comparing cabozantinib with everolimus. It appreciated that the trial did not allow patients to switch from everolimus to cabozantinib at disease progression. The committee heard from the clinical experts that the results of METEOR were generalisable to the NHS.\n\nThe committee noted that METEOR measured progression-free survival in 2\xa0populations:\n\nThe primary endpoint intention-to-treat population: the first 375\xa0patients randomised (n=375).\n\nThe intention-to-treat population: all patients randomised at baseline (n=658).The committee noted that more events occurred in the intention-to-treat population than in the primary endpoint intention-to-treat population, which resulted in more mature data. It also noted that the intention-to-treat population reflected a longer follow-up than the primary endpoint intention-to-treat population. Because of this, the committee concluded that it would use the intention-to-treat population analysis for its decision-making.\n\n## Clinical trial results\n\nIn the intention-to-treat population of METEOR (December 2015 data cut-off):\n\nProgression-free survival improved with cabozantinib compared with everolimus (median 7.4\xa0and 3.9\xa0months respectively; hazard ratio\xa00.51; 95% confidence interval [CI] 0.41 to 0.62; p<0.0001).\n\nOverall survival improved with cabozantinib compared with everolimus (median 21.4\xa0and 16.5\xa0months respectively; hazard ratio\xa00.66; 95%\xa0CI 0.53\xa0to\xa00.83; p=0.00026).The committee also noted the updated survival data from METEOR, presented by the company in response to the first consultation (based on a cut-off date of October 2016), and welcomed the availability of new, more mature data. It concluded that cabozantinib was more effective than everolimus in METEOR.\n\n## Network meta-analysis\n\nBecause there were no head-to-head trials comparing cabozantinib with axitinib or nivolumab, the company did a network meta-analysis to compare the treatments indirectly. The original network linked 6\xa0trials, including TARGET, which compared sorafenib with placebo. Although sorafenib was not a comparator for cabozantinib in this appraisal, the company included TARGET to link together treatments. The committee was concerned about including this trial for 2\xa0reasons. First, none of the patients had previously had VEGF-targeted therapies. Second, the company used immature data from the trial, which censored patients who switched from placebo to sorafenib. This was likely to have underestimated the effect of sorafenib because the placebo data reflected patients whose disease responded relatively well (who were therefore not censored), and this would in turn have underestimated the effect of axitinib. In response to the first consultation, and in line with the committee's preference, the company submitted a revised network that excluded TARGET. This assumed that axitinib was as effective as everolimus in terms of overall and progression-free survival. The committee concluded that the company's simplified network reduced the potential bias associated with using immature data from TARGET.\n\n## Methodology of the network meta-analysis\n\nThe committee understood that, to estimate long-term outcomes, the company used a 'family' of related survival curves for cabozantinib and for all of the comparator treatments. The company chose the curves based on how well, on average, they fitted the data on overall or progression-free survival for all the treatments in the network. The committee noted that, because of this simplification, the parametric distribution chosen by the company for both progression-free and overall survival (log-normal for both endpoints) did not fit the data for each individual treatment well. In response to the first consultation, the company used fractional polynomial modelling, as described by Janssen et al. (2011), to fit survival curves. The new method also used a family of related survival curves for all the treatments. However, the committee agreed that it was a more flexible family, which improved the curve fits to the Kaplan–Meier data on overall and progression-free survival for all treatments in the network compared with the original parametric modelling using the log-normal distribution. The committee appreciated that the fractional polynomial modelling did not fit data in the extrapolation period. It noted that the evidence review group (ERG) considered that estimating survival based on the 'average fit' across the network (as opposed to the fit for each individual treatment) was less of an issue with fractional polynomial models than with parametric curve fitting. The committee was satisfied that the company's revised modelling of overall and progression-free survival was more appropriate than the original parametric modelling.\n\n# Cost effectiveness\n\nThe company used a 3‑stage, partitioned-survival economic model, which the committee considered appropriate to capture the natural history of the disease. The health states included in the model were pre-progressed disease, progressed disease and death. The company used the model to estimate average delay in time to disease progression, average delay in time to death, and costs and health-related quality of life associated with cabozantinib and its comparators by forecasting beyond the end of the trials. The modelled population reflected the trial population of METEOR in that it included people who had had 1\xa0(71%), or 2\xa0or more (29%), previous treatments. This was consistent with the population who would have cabozantinib in clinical practice (see section\xa04.4).\n\nIn its original submission, the company presented 2\xa0separate cost-effectiveness analyses based on the model:\n\nA trial-based analysis comparing cabozantinib with everolimus using data from METEOR only.\n\nA network meta-analysis-based analysis comparing cabozantinib with axitinib, everolimus, best supportive care and nivolumab using data from the network meta-analysis.In response to the first consultation, the company revised the network meta-analysis to exclude best supportive care, in line with the committee's conclusion about the treatment pathway (see section\xa04.3). The committee recognised that the trial data were more robust than those estimated from the network meta-analysis because they reflected a direct comparison between 2\xa0treatments. The committee acknowledged that everolimus was not a relevant comparator for cabozantinib for most patients. Nevertheless, it agreed that it could have confidence that the model was suitable for decision-making with respect to axitinib and nivolumab if, based on the network meta-analysis (using fractional polynomial survival modelling), it produced plausible estimates for cabozantinib compared with everolimus that aligned with the analysis based on observed data from METEOR (using parametric survival modelling). Although the company, in response to the first consultation, did not present a trial-based analysis, the committee heard from the ERG that there was little difference between the results of the trial-based and the network meta-analysis-based analyses. The committee was therefore satisfied that the comparisons of cabozantinib with axitinib and nivolumab were reliable.\n\n## Survival modelling\n\nThe committee considered the company's revised modelling in response to the first consultation. It noted that, to estimate overall and progression-free survival for cabozantinib and its comparator treatments, the company extrapolated the curves based on fitting fractional polynomial models (see section\xa04.10) up to the end of the time horizon. As such, to estimate overall and progression-free survival for cabozantinib and its comparator treatments, the company used fractional polynomial modelling during both the trial follow-up and extrapolation. Hereafter, this analysis will be referred to as 'the company's revised base case'.\n\n## Comparison of survival predictions in the company's revised base case with observational data on everolimus (the natural history of the disease)\n\nIn its revised base case (see section\xa04.13), the company predicted that 5% of people in the everolimus arm would be alive 5\xa0years after starting treatment. The committee compared this estimate with 2\xa0sources of observational data submitted during the first consultation:\n\nRegistry-based pharmaco-epidemiological data from a publication by Ruiz-Morales et al. (2016) submitted by the company. These data came from the International Metastatic renal cell carcinoma Database Consortium (IMDC) reflecting people initially treated with either pazopanib or sunitinib. Some people then had second-line treatment. The company presented data for people who had second-line treatment after sunitinib (n=2,667) because this group was larger than the group that had second-line treatment after pazopanib (n=260). It noted that, in this group, about 10% were alive 5\xa0years after starting treatment.\n\nAudit data from the Christie Hospital (Manchester, UK) submitted by a clinical expert. These data showed that, among people who had axitinib or everolimus as a second-line treatment (n=282), around 6% were alive 5\xa0years after starting treatment.\n\nThe committee discussed whether the Ruiz-Morales et al. (2016) data on were generalisable to patients who would be offered everolimus in the UK. It observed that:\n\nRuiz-Morales et al. did not include patients from the UK. The committee acknowledged that the company considered that this study included people with similar characteristics at baseline to patients in METEOR, and that the countries from which these people were included had similar socio-economic profiles and health systems to the UK.\n\nAs second-line treatment, only 45% of people had everolimus, and some had treatments that were not available in the NHS.\n\nRuiz-Morales et al. did not report information on the third-line treatments; these treatments may not be available in the NHS, and may have biased the effect of second-line treatment.For these reasons, the committee agreed that the survival estimates from Ruiz-Morales et al. were likely to overestimate the survival of patients who have everolimus in the NHS. It considered the 5‑year survival estimate from the Christie Hospital audit to be unreliable because the numbers were small and there were no observations beyond 3\xa0years 3\xa0months after starting treatment. The committee concluded that survival in the UK was likely to have been overestimated in Ruiz-Morales et al., but it did provide useful data with which to compare the survival prediction of the company's model.\n\nThe committee noted that the company presented a scenario analysis to align the revised base-case predictions (see section\xa04.14) and the data from Ruiz-Morales et al. (2016). In this, the company did not change the modelling of progression-free survival, that is, it continued to use fractional polynomial modelling across the entire time horizon. For overall survival, it used fractional polynomial modelling during the trial follow-up period (as per the revised base case), but used parametric modelling choosing the log-normal distribution during the extrapolation period. The committee noted that this scenario aligned the model's predictions of survival with data from Ruiz-Morales et al. However, the committee did not consider that it was appropriate to base the extrapolation on meeting the 5‑year death rate observed in Ruiz-Morales et al. The committee recalled that survival among people having everolimus was likely to have been overestimated in Ruiz-Morales et al. It concluded that it preferred the company's revised base case, which used fractional polynomial modelling across the entire time horizon for both overall and progression-free survival.\n\n## Duration of cabozantinib's treatment effect\n\nThe committee noted that both the company and the ERG assumed that the effect of cabozantinib continued beyond the trial follow-up, even after the disease progressed or patients stopped treatment, but the committee was not presented with evidence to support this. The clinical experts considered that it was not clear whether a survival benefit would continue after stopping treatment. They explained that, in clinical practice, some patients have stable disease for 2\xa0to 3\xa0years after stopping treatment, whereas the disease progresses more quickly in others. Also, some patients have a prolonged response after a short length of treatment and others do not. The committee concluded that assuming the effect of cabozantinib continues for up to 30\xa0years, based on a trial with a median follow-up of under 2\xa0years for overall survival, was highly uncertain.\n\n## Modelling of nivolumab\n\nThe committee noted that, for nivolumab, the company's revised base case (see section\xa04.13) estimated a longer progression-free survival than overall survival. It understood that, in the model, disease progression could occur until the point where overall and progression-free survival curves cross (around 5\xa0years after starting treatment), after which people whose disease had not progressed followed the overall survival curve. This meant that the company assumed that the disease would never progress at that point, instead people would die of causes other than their cancer. It also meant that they would accrue the utility associated with pre-progressed disease during their remaining time in the model. The committee was not presented with any evidence that people who are alive and on treatment 5\xa0years after starting treatment remain progression-free until they die. The company did not consider it plausible that progression-free survival would be longer than overall survival, and conducted a scenario analysis. In this, it continued to use fractional polynomial modelling for overall survival across the entire time horizon as in the revised base case. For progression-free survival, it used parametric modelling using the log-normal distribution during both the trial follow-up and extrapolation periods. The committee recalled that the log-normal distribution did not fit the data for the individual treatments well (see section\xa04.10). Because of this, the committee did not consider this analysis further. It recognised the uncertainties in the company's revised base case with respect to the modelling of nivolumab, but concluded it could use it for decision-making.\n\nThe committee noted that the company presented a further scenario analysis that, as in the previous scenario (see section\xa04.18), used the log-normal distribution to model progression-free survival across the entire time horizon. However, it differed in that of those who were alive 5\xa0years after starting treatment and still having nivolumab, the company assumed that half had the same mortality as the age-matched general population. The committee recalled that using the log-normal distribution to model progression-free survival did not produce robust estimates (see section\xa04.18). Furthermore, the committee noted that this scenario had little impact on the mean overall survival associated with nivolumab, which it did not expect. The company suggested that this may have been because the risk of death estimated by the log-normal curve was similar to that of the general population. The committee recalled from the NICE technology appraisal on nivolumab that the committee preferred to base its decision on a mixed model that relied 50% on a single generalised gamma model and 50% on a model that assumed a greater long-term survival benefit than in the single generalised gamma model for nivolumab. The committee concluded that the scenario analysis was unrealistic, but appreciated that the company had explored predictions of better survival for nivolumab.\n\n## Utility values\n\nThe committee was aware that METEOR collected health-related quality-of-life data using the EQ‑5D‑5L measure, which the company adjusted for age, as requested by the committee, and used in its revised base case. The committee considered these data, together with data from other studies, including those used in previous appraisals of renal cell carcinoma. It noted that the available utility values varied widely, particularly those used for the post-progression state. The ERG explained that the utility values collected from METEOR were higher than those clinicians would expect to see in clinical practice and, notably, the utility value before disease progression was higher than that of the age-matched general population. Because of this, the ERG explored using utility values from the AXIS trial. The committee accepted that the new, more detailed version of the EQ‑5D (EQ‑5D‑5L) used in METEOR could explain the relatively high utility values reported in this trial. It also heard from the company that there was evidence showing that utility estimates were higher using EQ‑5D‑5L. Another possible explanation was greater attrition bias in METEOR, in which unhealthy people were less likely to continue filling in quality-of-life questionnaires. The committee was also aware that AXIS and METEOR differed in whether they allowed patients to switch between treatment arms, the number and type of therapies that patients took before enrolling in the trial or after the disease progressed during the trial, and the prognostic scores at baseline of the study populations. In response to the second consultation, the company argued that the utility from AXIS was not the most relevant because patients in the trial had had either a cytokine or a VEGF-targeted therapy, and it was unclear what the effect was of having previous cytokines on the patient's health. The committee generally preferred sourcing utility and effectiveness from the same trial. However, it agreed that some of the utility values from METEOR appeared high, particularly the utility value before disease progression. The committee concluded that it would take into account both sets of utility values in its decision-making.\n\n## Analyses used for decision-making\n\nThe committee considered the cost-effectiveness results incorporating the revisions to the models in response to the first consultation, the new data from METEOR (cut-off of October 2016), and the confidential discounts for all technologies applied by the ERG. It was presented with results with and without everolimus included in the analysis but, because the committee concluded that everolimus was not a relevant comparator for cabozantinib, it considered only the analyses excluding everolimus. In its consideration of the cost-effectiveness estimates, the committee took into account:\n\nthe company's revised base case (see section\xa04.10)\n\nthe company's scenario analysis using fractional polynomial modelling during the trial follow-up period, and parametric modelling using the log-normal distribution during the extrapolation period (see section\xa04.16)\n\nthe ERG's revised base case (which reflected minor changes with minimal impact on the results compared with the company's revised base case)\n\nthe ERG's scenario analysis exploring utility values from AXIS.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods.\n\nThe committee considered the life expectancy of people with previously treated advanced renal cell carcinoma having each of the 2\xa0comparator treatments, axitinib or nivolumab (see section\xa04.3). The committee noted that the mean life expectancy, based on the revised model in response to the first consultation, and the updated dataset from METEOR, was about 24\xa0months among people with advanced renal cell carcinoma having axitinib, but not among those having nivolumab.\n\nThe committee discussed whether cabozantinib extended life by at least 3\xa0months. It agreed that the results of the cost-effectiveness analyses (see section\xa04.21) suggested that cabozantinib was likely to extend mean overall survival by more than 3\xa0months compared with axitinib, but not compared with nivolumab. The committee therefore concluded that cabozantinib met the end-of-life criteria when compared with axitinib, but did not meet the end-of-life criteria when compared with nivolumab.\n\n# Results of cost-effectiveness analyses\n\nThe committee noted that, excluding everolimus as a comparator, in the revised base-case analysis, the incremental analysis showed that cabozantinib was associated with an incremental cost-effectiveness ratio (ICER) that was below £50,000 per quality-adjusted life year (QALY) gained compared with axitinib. It also noted that, in the incremental analyses, cabozantinib dominated nivolumab (that is, it was more effective and less expensive).\n\nThe committee discussed how the remaining uncertainties in the model could affect the results. It recalled that the cost effectiveness of cabozantinib would:\n\nimprove (that is, cabozantinib's ICER would decrease) if:\n\n\n\nthe long-term survival rate were higher than predicted by the model.\n\n\n\nworsen (that is, cabozantinib's ICER would increase) if:\n\n\n\ncabozantinib had no effect or a diminishing effect over time\n\nnivolumab were associated with better long-term survival than assumed in the base case\n\nthe utility values from AXIS better represented the quality of life of people in the NHS than the utility values from METEOR (the ICER could increase by as much as £8,000 per QALY but would still remain below £50,000 per QALY).The committee was satisfied that the remaining uncertainties in the model were unlikely to change the results to a degree where the incremental ICER for cabozantinib from the company's revised base case would not be cost effective compared with axitinib.\n\n\n\nThe committee was aware that, in line with the population included in METEOR, the cost-effectiveness analysis related mostly to people who had 1\xa0or 2\xa0previous treatments (see section\xa04.11), whereas the marketing authorisation for cabozantinib does not specify the number of previous treatments. The committee discussed whether the effectiveness and cost effectiveness of cabozantinib could be generalised to people who have had 3\xa0previous treatments. It noted that, at this point, everolimus was likely to be an option, and that cabozantinib was not cost effective compared with everolimus, with ICERs exceeding £50,000 per QALY gained. The committee was aware that, according to NICE guidance, axitinib and nivolumab may also be used as fourth-line treatments. It recalled that cabozantinib would be expected to work similarly after 1\xa0previous treatment and after 2\xa0previous treatments, and that it would also work after other TKIs had failed (see section\xa04.5). It considered that it was plausible that cabozantinib would also work similarly after 3\xa0previous treatments. The committee acknowledged that some people in the NHS will likely have had everolimus second- or third-line, and if they remain fit for fourth-line treatment, have limited options available. Taking account of these reasons, and even though cabozantinib is not cost effective compared with everolimus, the committee agreed to keep options for this small and likely diminishing group by extending its recommendations to people who have had more than 2\xa0previous treatments. The committee concluded that cabozantinib could be considered a cost-effective use of NHS resources for treating advanced renal cell carcinoma in adults after VEGF-targeted therapy.\n\n# Innovation\n\nThe committee considered whether cabozantinib was an innovative treatment. It heard from the clinical experts that, because of its multi-targeted approach, cabozantinib would likely have additional benefits for some patients and so could be considered innovative. The committee also heard that cabozantinib would be highly valued in patients whose disease is resistant to standard TKIs and may or may not have responded to nivolumab. The committee agreed that cabozantinib could fulfil the unmet need in these patients. However, it did not consider cabozantinib to reflect a 'step change' in treatment nor did it identify a benefit to utility that was not otherwise accounted for in the modelling.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA463\n\nAppraisal title: Cabozantinib for previously treated advanced renal cell carcinoma\n\nSection\n\nKey conclusion\n\nCabozantinib is recommended within its marketing authorisation for treating advanced renal cell carcinoma in adults after vascular endothelial growth factor (VEGF)-targeted therapy.\n\n\n\nIn the intention-to-treat population of METEOR, progression-free and overall survival were statistically significantly improved with cabozantinib compared with everolimus.\n\n\n\nThe committee concluded that the company's simplified network reduced the potential bias associated with using immature data from TARGET. The committee was satisfied that the company's revised modelling of progression-free and overall survival was more appropriate than the original parametric modelling. The committee noted that, excluding everolimus as a comparator, in the revised base-case analysis, the incremental analysis showed that cabozantinib was associated with an incremental cost-effectiveness ratio (ICER) that was below £50,000 per quality-adjusted life year (QALY) gained compared with axitinib. It also noted that, in the incremental analyses, cabozantinib dominated nivolumab.\n\n, 4.10, 4.25\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee was aware that there remained an unmet clinical need for some people with advanced renal cell carcinoma.\n\n\n\nMost people fit enough for second-line treatment are offered axitinib, nivolumab or everolimus. If the disease progresses further, people who previously had axitinib may have nivolumab or everolimus as a third-line treatment; people who had nivolumab may have axitinib or everolimus; and people who had everolimus may have axitinib or nivolumab. The committee was aware that some patients have fourth-line treatment and beyond, but that there is no accepted treatment pathway at this point.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe clinical experts perceived cabozantinib to be more effective than everolimus and axitinib, although it caused more adverse effects.\n\n\n\nThe committee heard from the clinical experts that, because of its multi-targeted approach, cabozantinib could be considered innovative. The committee also heard that cabozantinib would be highly valued in patients whose disease is resistant to standard tyrosine kinase inhibitors and whose disease may or may not have responded to nivolumab.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nCabozantinib can be used in people who have had 1\xa0or\xa02 previous treatments.\n\n\n\nAdverse reactions\n\nThe most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%) and nausea (2%).\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe main evidence came from METEOR, an open-label randomised controlled trial comparing cabozantinib with everolimus. The committee appreciated that the trial did not allow patients to switch from placebo to cabozantinib at disease progression.\n\n\n\nThe company presented updated survival data from the METEOR trial during the first consultation (based on a cut-off date of October 2016 compared with December 2015 for the original data cut).\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee heard from the clinical experts that the results of METEOR were generalisable to the NHS.\n\n\n\nUncertainties generated by the evidence\n\nThe committee noted that the company used fractional polynomial modelling to fit survival curves. The new method used a family of related survival curves for all the treatments. However, it was a more flexible family, which improved the curve fits to the Kaplan–Meier data on overall and progression-free survival for all treatments in the network compared with the original network meta-analysis.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee concluded that it would consider cabozantinib for the population comprising people who have had 1\xa0or\xa02 previous treatments as a whole.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nIn the intention-to-treat population of METEOR, progression-free and overall survival were statistically significantly improved with cabozantinib compared with everolimus.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company used a 3‑stage, partitioned-survival economic model, which the committee considered appropriate to capture the natural history of the disease.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee concluded that assuming the effect of cabozantinib continues for up to 30\xa0years, based on a trial with a median follow-up of under 2\xa0years for overall survival, was highly uncertain.\n\n\n\nThe committee suspected that the survival estimates from Ruiz-Morales et al. (2016) were likely to overestimate the survival of patients who have everolimus in the NHS.\n\n\n\nThe committee recognised the uncertainties in the company's revised base case with respect to the modelling of nivolumab, but concluded it could use it for decision-making.\n\n, 4.19\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe evidence review group (ERG) explained that the utility values collected from METEOR were higher than those clinicians would expect to see in clinical practice and, notably, the utility value before disease progression was higher than that of the age-matched general population. The committee concluded that it would also take into account both sets of utility values (AXIS and METEOR) in its decision-making.\n\n\n\nThe committee did not identify a benefit to utility that was not otherwise accounted for in the modelling.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNo subgroup analyses were presented.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nthe duration of the effect of cabozantinib\n\nthe prediction of long-term survival rate with the disease\n\nthe survival modelling of nivolumab\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee noted that, in the revised base-case analysis, excluding everolimus as a comparator, the incremental analysis showed that cabozantinib was associated with an ICER that was below £50,000 per QALY gained compared with axitinib. It also noted that, in the incremental analyses, cabozantinib dominated nivolumab (that is, it was more effective and less expensive).\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThere are patient access schemes for cabozantinib, axitinib, everolimus and nivolumab. The ERG presented analyses that included the confidential discounts for all technologies.\n\n–\n\nEnd-of-life considerations\n\nThe committee concluded that cabozantinib met the end-of-life criteria when compared with axitinib and everolimus, but did not meet the end-of-life criteria when compared with nivolumab.\n\n\n\nEqualities considerations and social value judgements\n\nNo equality issues were identified by consultees or the committee.\n\n–"}
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https://www.nice.org.uk/guidance/ta463
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Evidence-based recommendations on cabozantinib (Cabometyx) for previously treated advance renal cell carcinoma in adults.
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c004fe5a2c80be421edaeb26f63af5e56e2a094c
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Baricitinib for moderate to severe rheumatoid arthritis
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Baricitinib for moderate to severe rheumatoid arthritis
Evidence-based recommendations on baricitinib (Olumiant) for moderate to severe rheumatoid arthritis in adults.
# Recommendations
Baricitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying antirheumatic drugs (DMARDs), only if:
disease is severe (a disease activity score of more than 5.1) and
the company provides baricitinib with the discount agreed in the patient access scheme.
Baricitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1 biological DMARD, only if:
disease is severe (a DAS28 of more than 5.1) and
they cannot have rituximab and
the company provides baricitinib with the discount agreed in the patient access scheme.
Baricitinib can be used as monotherapy for people who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections 1.1 or 1.2 are met.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. After an initial response within 6 months, withdraw treatment if at least a moderate EULAR response is not maintained.
When using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.
These recommendations are not intended to affect treatment with baricitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trials showed baricitinib plus conventional disease-modifying antirheumatic drugs (DMARDs) to be more effective than conventional DMARDs alone for treating severe active rheumatoid arthritis that has not responded adequately to conventional or biological DMARDs. Some trial evidence also suggests that in people who have not previously had DMARDs, baricitinib works as well when taken alone as it does when taken with conventional DMARDs.
Baricitinib plus conventional DMARDs was also shown to have similar effectiveness to the biological DMARD adalimumab in people whose disease has responded inadequately to conventional DMARDs. Because there are no trials which compare baricitinib with other biological DMARDs, the company did an indirect comparison. Baricitinib was shown to work as well as most of the biological DMARDs which NICE has already recommended in this indication.
Based on the health-related benefits and costs compared with conventional and biological DMARDs, baricitinib plus conventional DMARDs was recommended as a cost-effective treatment, in line with previous recommendations in:
adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (after conventional DMARDs)
tocilizumab
golimumab (after DMARDs)
adalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha inhibitor).# The technology
Marketing authorisation
Baricitinib (Olumiant, Eli Lilly) has a marketing authorisation in the UK for the 'treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs.' Baricitinib can be given as monotherapy or in combination with methotrexate.
Recommended dose and schedule
The recommended dose of baricitinib is 4 mg once daily. A dose of 2 mg once daily is appropriate for patients aged 75 years and over and may be appropriate for patients with a history of chronic or recurrent infections. A dose of 2 mg once daily may also be considered for patients who have achieved sustained control of disease activity with 4 mg once daily and are eligible for dose-tapering.
Price
The list price of a 28-tablet pack of 2 mg or 4 mg baricitinib is £805.56. Each dose will also be available in 84-tablet packs at a pro-rata price from late 2017.
The average cost per patient per year is estimated at £10,501 based on the list price.
The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of baricitinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Committee discussion
The appraisal committee (section 5) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatment pathway
## Baricitinib can be used at 4 different points in the pathway
Baricitinib's marketing authorisation covers its use at 4 points in the treatment pathway, specifically in adults with:
moderate, active rheumatoid arthritis that has not responded adequately to conventional disease-modifying antirheumatic drugs (DMARDs)
severe, active rheumatoid arthritis that has not responded adequately to conventional DMARDs
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1 tumour necrosis factor-alpha (TNF‑alpha) inhibitor
severe, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1 TNF‑alpha inhibitor and when rituximab is contraindicated or withdrawn because of adverse events.The committee also noted that the marketing authorisation includes the use of baricitinib alone or with methotrexate.
## NICE technology appraisal guidance exists for these points in the rheumatoid arthritis treatment pathway
NICE currently recommends the use of the biological DMARDs NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are TNF‑alpha inhibitors), in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, less than 3.2 but more than 2.6 indicates mild disease and less than 2.6 indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that adalimumab, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy.
For people with severe rheumatoid arthritis who have already had at least 1 TNF‑alpha inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept recommends the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. If rituximab is contraindicated or withdrawn because of an adverse event, the guidance recommends abatacept, adalimumab, etanercept or infliximab in combination with methotrexate. NICE also recommends golimumab under the same circumstances in NICE's technology appraisal guidance on golimumab. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept recommends adalimumab or etanercept as monotherapy. NICE technology appraisal guidance on tocilizumab and certolizumab pegol recommend both treatments as alternatives to TNF‑alpha inhibitors in the same circumstances (that is, for people with severe rheumatoid arthritis who have already had at least 1 TNF‑alpha inhibitor that hasn't worked, in combination with methotrexate when rituximab is contraindicated or withdrawn. Certolizumab pegol is also recommended as monotherapy if methotrexate is contraindicated or withdrawn). NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha inhibitors nor rituximab have worked.
## Baricitinib offers a new treatment option
The committee heard from the patient experts that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional DMARDs such as methotrexate are inadequate for many people. They added that the disease sometimes does not respond adequately to the first biological DMARD prescribed, and that there are few tools available to predict response to help decide which treatment to use. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological DMARDs after failure of conventional DMARDs. The clinical and patient experts agreed that methotrexate is often not well tolerated; the clinical experts noted that up to a third of people who are prescribed methotrexate with biological DMARDs do not take methotrexate because of side effects. The clinical experts emphasised that baricitinib is a novel treatment with a different mode of action to the biological DMARDs. They noted that the selective inhibition of Janus kinase 1 and 2 will affect a broad range of cytokines involved in the pathogenesis of rheumatoid arthritis. The clinical experts also noted the fast kinetic action of baricitinib compared with biological DMARDs. Both the clinical and patient experts also highlighted that baricitinib is given orally, which has major benefits for both patients and the health system. The patient experts emphasised that this is an important factor for people who have difficulty injecting themselves because of the disease affecting their hands. The patient experts also noted that some current treatments have to be stopped if the person gets an infection, and that some treatments may cause injection site reactions. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological DMARDs.
# Subgroups
## The company's subgroups and comparators were appropriate
The committee was aware that the company had analysed 4 distinct subgroups in which baricitinib could be used:
People with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.
People with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.
People with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option.
People with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated.The relevant comparators varied by subgroup. The committee concluded that it was appropriate to consider the 4 groups separately and that the company had broadly included the appropriate comparators.
# Clinical effectiveness
## The trials were adequate and suitable for decision-making
The company's clinical evidence came from 4 phase III randomised controlled trials and 1 long-term safety and tolerability study. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.2. The trials were:
RA‑BEAM, which included people whose disease responded inadequately to methotrexate and who had not had biological DMARDs. Baricitinib 4 mg was given once daily and the comparators were placebo and adalimumab. Background methotrexate was given to all the groups.
RA‑BUILD, which included people whose disease responded inadequately to conventional DMARDs and who had not had biological DMARDs. Baricitinib 2 mg or 4 mg was given once daily and the comparator was placebo. People taking conventional DMARDs with or without methotrexate before the study continued to take background therapy.
RA‑BEACON, which included people whose disease responded inadequately to TNF‑alpha inhibitors. Baricitinib 2 mg or 4 mg was given once daily and the comparator was placebo. Background conventional DMARDs were given to all the groups.
RA-BEGIN, which included people who had not had any conventional or biological DMARDs. Baricitinib 4 mg was given once daily, with or without methotrexate. The comparator was methotrexate. The committee was aware that the marketing authorisation for baricitinib does not include the treatment of rheumatoid arthritis in people who have not had any conventional or biological DMARDs (that is, this subgroup).The long-term safety and tolerability study, RA-BEYOND, included people with moderate or severe rheumatoid arthritis who took part in a separate phase IIb study or 1 of the 4 trials described above. Baricitinib 2 mg or 4 mg was given once daily, with or without conventional DMARDs.
The primary outcome of all the randomised controlled trials was the proportion of people achieving a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 12 or 24. Secondary outcomes included the proportion of people achieving a 50% or 70% improvement in the response criteria (ACR50 and ACR70 respectively), and the proportion of people meeting the European League Against Rheumatism (EULAR) response criteria. The committee concluded that the trials were relevant and adequate for its decision-making.
## Baricitinib is more clinically effective than conventional DMARDs alone and as effective as adalimumab for moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs
The committee considered RA‑BEAM and RA‑BUILD, which included people with moderate to severe rheumatoid arthritis which responded inadequately to conventional DMARDs. In RA‑BEAM, there was a significant increase in the proportion of people meeting the ACR20 criteria at 12 weeks with 4 mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (odds ratio 3.6; 95% confidence interval 2.7 to 4.7, p=0.001). A smaller response was seen with 4 mg baricitinib plus conventional DMARDs compared with adalimumab plus conventional DMARDs (OR 1.5; 95% CI 1.1 to 2.0, p=0.014 for ACR20). Significant improvements in ACR20 and EULAR good and moderate responses were also seen in RA‑BUILD for 4 mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (OR 2.5; 95% CI 1.7 to 3.7, p=0.001 for ACR20 and OR 3.5; 95% CI 2.3 to 5.4, p=0.001 for EULAR). The committee also noted that in RA‑BUILD, 2 mg baricitinib plus conventional DMARDs improved ACR20 and EULAR responses in this population compared with conventional DMARDs alone (OR 3.0; 95% CI 2.0 to 4.4, p=0.001 for ACR20 and OR 3.3; 95% CI 2.2 to 5.0, p=0.001 for EULAR good and moderate response). The committee concluded that 4 mg baricitinib plus conventional DMARDs has similar efficacy to adalimumab plus conventional DMARDs, and is more effective than conventional DMARDs alone in people with moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs.
## Baricitinib is more clinically effective than conventional DMARDs alone for moderate to severe rheumatoid arthritis which has responded inadequately to biological DMARDs
The committee considered RA‑BEACON, which included people with moderate to severe rheumatoid arthritis which responded inadequately to TNF‑alpha inhibitors. There was a significant increase in the proportion of people meeting the ACR20 criteria and having a EULAR moderate or good response rate at 12 weeks for 4 mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (OR 3.4; 95% CI 2.2 to 5.4, p=0.001 for ACR20 and OR 3.6; 95% CI 2.3 to 5.7, p=0.001 for EULAR moderate and good response). The committee also noted that 2 mg baricitinib plus conventional DMARDs also improved ACR20 and EULAR response rates in this population compared with conventional DMARDs alone (OR 2.7; 95% CI 1.7 to 4.2, p=0.001 for ACR20 OR 2.7; 95% CI 1.8 to 4.2, p=0.001 for EULAR moderate and good response). The committee concluded that both dosages of baricitinib, when given with conventional DMARDs, are more effective than conventional DMARDs alone in people with moderate to severe rheumatoid arthritis which has responded inadequately to TNF‑alpha inhibitors.
## Baricitinib has a similar safety profile to conventional DMARDs and adalimumab
The committee noted that across all 3 randomised controlled trials in which patients had previously had conventional or biological DMARDs (RA‑BEAM, RA‑BUILD and RA‑BEACON), the safety profile of baricitinib was similar to that of the conventional DMARDs. In addition, it noted that the safety profiles were found to be similar in the head-to-head comparison of baricitinib and adalimumab (RA‑BEAM).
# Indirect comparison
## Network meta-analyses show that baricitinib works as well as biological DMARDs
The committee was aware that other than the direct comparison with adalimumab, the only evidence available on the comparative effectiveness of baricitinib and the biological DMARDs was from the company's network meta-analyses. The company did separate analyses for patients whose disease inadequately responded to either conventional or biological DMARDs, using ACR and EULAR outcome measures.At 24 weeks' follow-up, for patients whose disease inadequately responded to conventional DMARDs, the network meta-analysis showed:
Baricitinib plus conventional DMARDs gave better EULAR response rates than conventional DMARDs alone.
Baricitinib plus conventional DMARDs gave similar EULAR response rates to the biological DMARDs plus conventional DMARDs.The exception to this was tocilizumab plus conventional DMARDs, which gave better EULAR result than all the other treatments. However, the clinical experts noted that the trials of tocilizumab had slightly different characteristics than the trials of the other technologies, and they considered tocilizumab to have similar effectiveness to the other biological DMARDs. Tocilizumab monotherapy showed similar results to baricitinib and the biological DMARDs when used with conventional DMARDs.At 24 weeks' follow-up, for patients whose disease inadequately responded to biological DMARDs, the network meta-analysis showed:
Baricitinib (2 mg and 4 mg) plus conventional DMARDs gave better EULAR response rates than conventional DMARDs alone. A dose response was seen, with 4 mg baricitinib having a better EULAR response than 2 mg baricitinib.
Rituximab plus conventional DMARDs gave a better point estimate of the EULAR response rate than baricitinib (2 mg and 4 mg) plus conventional DMARDs.
## The company's and ERG's network meta-analysis results were broadly comparable
The committee heard from the ERG that there were problems with the methods used in the company's network meta-analysis. These included the conversion of ACR data to EULAR data before synthesis, the use of simultaneous models for baseline and treatment effects, the use of a random effects model for 1 population and a fixed effects model for the other, and poor model fit. In addition, the company had pooled the control data inappropriately. The ERG corrected the errors in the company's network meta-analysis. Having reviewed both analyses, the committee concluded that the results of the corrected network meta-analysis and the company's network meta-analysis were broadly comparable.
# Cost effectiveness
## The cost-effectiveness studies presented by the company were appropriate
The company identified 9 UK-based cost-effectiveness studies. The committee was aware that 8 of these were associated with previous NICE technology appraisals guidance; 1 was an independent published review. The company did not identify any studies that included baricitinib, but the committee noted that the studies were nonetheless relevant and appropriate.
# Economic model
## The model structure was appropriate for decision-making
The company used an individual patient-based discrete event simulation model for its economic evaluation. The model simulates patients' disease progression through the sequences of treatments being compared. It was based on the model used by the assessment group during the production of NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The model categorised patients based on their EULAR response (good, moderate or no response) at 6 months. Response rates were based on the company's network meta-analysis. The company analysed cost effectiveness for each of the subgroups described in section 3.5. The committee concluded that the model structure was appropriate for its decision-making.
## There were some concerns with how costs were calculated
The company's model included costs associated with drug acquisition, drug administration and monitoring, and hospitalisation. The committee was aware that baricitinib and several of the biological DMARDs have patient access schemes. It noted that the company had incorporated the patient access scheme prices for baricitinib, certolizumab pegol and golimumab in the model, but not the confidential patient access schemes for abatacept and tocilizumab. The incremental cost-effectiveness ratios (ICERs) that incorporated these confidential patient access schemes cannot be reported here, but the range of ICERs usually considered to be cost effective is from £20,000 to £30,000 per quality-adjusted life year (QALY) gained. The company had also calculated the average cost of drug doses using the average weight, rather than the distribution of the weight of the modelled patient population. The committee was also aware that the company overestimated the number of doses and therefore the costs of infliximab.
## The company is likely to have overestimated how well biological DMARDs work after an inadequate response to biological DMARDs and when rituximab is not an option
The company did not identify any evidence on the effectiveness of adalimumab, certolizumab pegol, etanercept or infliximab plus conventional DMARDs in patients with severe active rheumatoid arthritis which has responded inadequately to biological DMARDs when rituximab is contraindicated or not tolerated. In the absence of these data, the company used the same efficacy estimates for these treatments as those in patients with severe active rheumatoid arthritis which has responded inadequately to conventional DMARDs. The EULAR responses for all treatments were higher in these patients than in those with an inadequate response to biological DMARDs. The committee heard from the ERG that because of this, the company's base case is likely to have overestimated the efficacy of adalimumab, certolizumab pegol, etanercept and infliximab plus conventional DMARDs in patients with active rheumatoid arthritis which has responded inadequately to biological DMARDs when rituximab is contraindicated or not tolerated. The committee accepted this in the absence of any other evidence.
# Utility values
## The different approaches used to calculate utility were unlikely to change the overall conclusions
Health-related quality of life data were collected using a health assessment questionnaire (HAQ) in RA‑BEAM, RA‑BUILD and RA‑BEACON. Patient-level responses were converted to utility index-based EQ-5D-5L scores using the UK-specific scoring algorithm reported by Hernandez Alava et al. (2012). The committee was aware this was not in line with the analysis done during NICE's technology appraisal on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept, but it heard from the ERG that this approach was unlikely to change the overall conclusions.
## The model was adequate for decision-making
The ERG identified several issues with the company's economic analyses including:
Limitations with the company's network meta-analysis because an inappropriate random effects model was assumed for the baselines. In addition, simultaneous baseline and treatment effect models were used without ensuring that information in the baseline model did not propagate to the relative treatment effect model. Furthermore, studies that reported EULAR responses were synthesised along with converted EULAR response outcomes from studies that only reported ACR responses.
A lack of face validity in several of the scenario analyses, partly because of transcription and programming errors.
Limitations with the probabilistic sensitivity analyses because of programming errors, including an error which resulted in patients having some biological DMARDs never achieving a good or moderate EULAR response.
Using the efficacy of treatments in the population with an inadequate response to conventional DMARDs for all biological DMARDs in the treatment sequence, regardless of their position in the sequence.
Rounding HAQ scores to the nearest valid HAQ score, rather than allowing HAQ scores to be sampled based on a continuous HAQ value.
Incorrect implementation of the HAQ trajectory classes by assigning each patient to a single class based on the probability of class membership, instead of using an average weighted by the probability of class membership.
Assuming that patients who achieve a moderate or good EULAR response at 24 weeks had an instant reduction in HAQ score when starting treatment.
Averaging HAQ across large time periods, which may lead to inaccurate results because the relationships between HAQ score and EQ-5D and between HAQ score and hospitalisation costs are not linear.
Excluding intravenous abatacept and subcutaneous tocilizumab from the list of comparators.
Using a less accurate method to map HAQ scores to EQ-5D (Malottki et al. 2011) than that used during the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (Hernandez Alava et al. 2013).
Assuming that baricitinib would be used before intensive therapy with conventional DMARDs for patients with moderate rheumatoid arthritis (this was not supported by the clinical experts).
Re-estimating the age of death at every event, which resulted in slightly different expected life years, which would be exacerbated by sequences of different lengths.
Using the average weight of the population in the relevant trials to calculate average dose, which assumes there is a linear relationship between weight and dose costing and does not take into account drug wastage, for example.
Overestimating the average number of doses, and thereby the cost, of infliximab that would be given in a year.The ERG stated that these errors were unlikely to change the broad conclusions of the company's model. The committee concluded that although there were several errors in the company's economic model, it was adequate for its decision-making.
## Baricitinib was comparable to other biological DMARDs in all of the company's scenario analyses
The company carried out several scenario analyses. In one, the company assumed that patients having conventional DMARDs or palliative care had a linear increase in their HAQ scores at a yearly rate of 0.045 and 0.060 respectively (based on Malottki et al. 2011), instead of using the latent class approach. For the moderate rheumatoid arthritis population, the ICER for baricitinib plus conventional DMARDs compared with intensive conventional DMARDs alone decreased from £37,420 to £20,965 per QALY gained. In the severe rheumatoid arthritis population, the ICERs were slightly lower for the most effective drugs. The company also:
adjusted the HAQ score for baricitinib plus methotrexate so that it deteriorated at half of the rate assumed for conventional DMARDs
used HAQ score improvements for baricitinib calculated from trial data rather than the UK rheumatoid arthritis database
used a different time to treatment discontinuation for patients on baricitinib
used alternative methods to map HAQ scores to the EQ-5D
accounted for serious adverse events
tapered baricitinib from 4 mg once daily to 2 mg once daily.The committee heard from the ERG that these scenarios were unlikely to change the results of the cost-effectiveness analysis. The committee agreed that any exploratory analyses would not change its conclusion that baricitinib is broadly comparable to the other biological DMARDs recommended by NICE.
# Cost-effectiveness results
## Baricitinib is not cost effective for moderate disease after conventional DMARDs
In the moderate active rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the company's base-case ICER for the baricitinib sequence compared with the conventional DMARD sequence was £37,420 per QALY. The committee noted that the company used a different sequence for this population to that used in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept. The ERG did not correct this or the errors in the model because they were unlikely to change the conclusions, and it could use the model from the other appraisal as a reference. The ERG noted that the median ICER of biological DMARDs in the NICE appraisal of adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept was around £50,000 per QALY gained. Taking into account the cost-effectiveness evidence for baricitinib in patients with moderate active rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, the committee considered that baricitinib plus conventional DMARDs did not have plausible potential to be cost effective in this population.
## Baricitinib is cost effective for severe active rheumatoid arthritis after conventional DMARDs
In the company's base-case analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, baricitinib plus conventional DMARDs dominated all its comparators (that is, it was both less costly and more effective). The exception to this was certolizumab pegol plus conventional DMARDs, which had an ICER of £18,400 per QALY compared with baricitinib plus conventional DMARDs. The committee noted that there are confidential patient access schemes in place for subcutaneous abatacept and intravenous tocilizumab, which the company did not include in its analysis. The ERG calculated new ICERs using the confidential comparator prices. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness, and concluded to recommend baricitinib plus conventional DMARDs as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.
## Baricitinib is not cost effective for severe disease after biological DMARDs if rituximab is a treatment option
In the company's base-case analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option, baricitinib plus conventional DMARDs was dominated by rituximab plus conventional DMARDs (that is, it was more costly and less effective). The committee concluded that baricitinib plus conventional DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs if rituximab is a treatment option.
## Baricitinib is cost effective for severe disease after biological DMARDs if rituximab is not a treatment option
In the pairwise analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated, baricitinib plus conventional DMARDs was dominated by golimumab plus conventional DMARDs. Compared with all other comparators, the ICERs ranged from £16,201 to £484,782. In the full incremental analysis, baricitinib plus conventional DMARDs dominated or extendedly dominated all comparators except for certolizumab pegol plus conventional DMARDs, which had an ICER of £16,201 per QALY gained. The ICERs for biosimilar etanercept plus conventional DMARDs compared with baricitinib plus conventional DMARDs, and adalimumab plus conventional DMARDs compared with baricitinib plus conventional DMARDs, were also less than £30,000 per QALY gained. The committee again noted the confidential patient access schemes in place for subcutaneous abatacept and intravenous tocilizumab, which the company did not include in its analysis. The ERG calculated new ICERs using the confidential comparator prices. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness, and concluded to recommend baricitinib plus conventional DMARDs as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is not a treatment option.
## The recommendations also apply to baricitinib monotherapy
The committee was aware that the marketing authorisation for baricitinib includes its use as a monotherapy, but that the company did not present an economic analysis for baricitinib alone for patients who cannot have methotrexate. The committee noted that the only available evidence for baricitinib alone is in people who have not had conventional DMARDs, which is outside of its marketing authorisation. The committee recognised the considerable uncertainty about the effectiveness of baricitinib alone in people whose rheumatoid arthritis has had an inadequate response to conventional or biological DMARDs. The committee heard from the ERG that data from RA-BEGIN showed that the addition of methotrexate to 4 mg baricitinib produced similar ACR scores compared with baricitinib alone. The committee agreed that baricitinib monotherapy provides similar clinical efficacy to baricitinib plus conventional DMARDs. It concluded that its recommendations for baricitinib plus conventional DMARDs should also apply to baricitinib alone.
|
{'Recommendations': 'Baricitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with a combination of conventional disease-modifying antirheumatic drugs (DMARDs), only if:\n\ndisease is severe (a disease activity score [DAS28] of more than 5.1) and\n\nthe company provides baricitinib with the discount agreed in the patient access scheme.\n\nBaricitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to or who cannot have other DMARDs, including at least 1\xa0biological DMARD, only if:\n\ndisease is severe (a DAS28 of more than 5.1) and\n\nthey cannot have rituximab and\n\nthe company provides baricitinib with the discount agreed in the patient access scheme.\n\nBaricitinib can be used as monotherapy for people who cannot take methotrexate because it is contraindicated or because of intolerance, when the criteria in sections 1.1 or 1.2 are met.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. After an initial response within 6\xa0months, withdraw treatment if at least a moderate EULAR response is not maintained.\n\nWhen using the DAS28, healthcare professionals should take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with baricitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trials showed baricitinib plus conventional disease-modifying antirheumatic drugs (DMARDs) to be more effective than conventional DMARDs alone for treating severe active rheumatoid arthritis that has not responded adequately to conventional or biological DMARDs. Some trial evidence also suggests that in people who have not previously had DMARDs, baricitinib works as well when taken alone as it does when taken with conventional DMARDs.\n\nBaricitinib plus conventional DMARDs was also shown to have similar effectiveness to the biological DMARD adalimumab in people whose disease has responded inadequately to conventional DMARDs. Because there are no trials which compare baricitinib with other biological DMARDs, the company did an indirect comparison. Baricitinib was shown to work as well as most of the biological DMARDs which NICE has already recommended in this indication.\n\nBased on the health-related benefits and costs compared with conventional and biological DMARDs, baricitinib plus conventional DMARDs was recommended as a cost-effective treatment, in line with previous recommendations in:\n\n\n\nadalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept (after conventional DMARDs)\n\ntocilizumab\n\ngolimumab (after DMARDs)\n\nadalimumab, etanercept, infliximab, rituximab and abatacept (after a TNF-alpha\xa0inhibitor).', 'The technology': "Marketing authorisation\n\nBaricitinib (Olumiant, Eli Lilly) has a marketing authorisation in the UK for the 'treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs.' Baricitinib can be given as monotherapy or in combination with methotrexate.\n\nRecommended dose and schedule\n\nThe recommended dose of baricitinib is 4\xa0mg once daily. A dose of 2\xa0mg once daily is appropriate for patients aged 75 years and over and may be appropriate for patients with a history of chronic or recurrent infections. A dose of 2\xa0mg once daily may also be considered for patients who have achieved sustained control of disease activity with 4\xa0mg once daily and are eligible for dose-tapering.\n\nPrice\n\nThe list price of a 28-tablet pack of 2\xa0mg or 4\xa0mg baricitinib is £805.56. Each dose will also be available in 84-tablet packs at a pro-rata price from late 2017.\n\nThe average cost per patient per year is estimated at £10,501 based on the list price.\n\nThe company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of baricitinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", 'Committee discussion': "The appraisal committee (section 5) considered evidence submitted by Eli Lilly and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Baricitinib can be used at 4\xa0different points in the pathway\n\nBaricitinib's marketing authorisation covers its use at 4\xa0points in the treatment pathway, specifically in adults with:\n\nmoderate, active rheumatoid arthritis that has not responded adequately to conventional disease-modifying antirheumatic drugs (DMARDs)\n\nsevere, active rheumatoid arthritis that has not responded adequately to conventional DMARDs\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1\xa0tumour necrosis factor-alpha (TNF‑alpha) inhibitor\n\nsevere, active rheumatoid arthritis that has not responded adequately to biological DMARDs, including at least 1\xa0TNF‑alpha\xa0inhibitor and when rituximab is contraindicated or withdrawn because of adverse events.The committee also noted that the marketing authorisation includes the use of baricitinib alone or with methotrexate.\n\n## NICE technology appraisal guidance exists for these points in the rheumatoid arthritis treatment pathway\n\nNICE currently recommends the use of the biological DMARDs NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab\xa0pegol, etanercept, golimumab and infliximab are TNF‑alpha\xa0inhibitors), in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, less than 3.2 but more than 2.6 indicates mild disease and less than 2.6 indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that adalimumab, certolizumab\xa0pegol, etanercept or tocilizumab may be used as monotherapy.\n\nFor people with severe rheumatoid arthritis who have already had at least 1\xa0TNF‑alpha\xa0inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept recommends the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. If rituximab is contraindicated or withdrawn because of an adverse event, the guidance recommends abatacept, adalimumab, etanercept or infliximab in combination with methotrexate. NICE also recommends golimumab under the same circumstances in NICE's technology appraisal guidance on golimumab. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept recommends adalimumab or etanercept as monotherapy. NICE technology appraisal guidance on tocilizumab and certolizumab\xa0pegol recommend both treatments as alternatives to TNF‑alpha\xa0inhibitors in the same circumstances (that is, for people with severe rheumatoid arthritis who have already had at least 1\xa0TNF‑alpha\xa0inhibitor that hasn't worked, in combination with methotrexate when rituximab is contraindicated or withdrawn. Certolizumab\xa0pegol is also recommended as monotherapy if methotrexate is contraindicated or withdrawn). NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha\xa0inhibitors nor rituximab have worked.\n\n## Baricitinib offers a new treatment option\n\nThe committee heard from the patient experts that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional DMARDs such as methotrexate are inadequate for many people. They added that the disease sometimes does not respond adequately to the first biological DMARD prescribed, and that there are few tools available to predict response to help decide which treatment to use. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological DMARDs after failure of conventional DMARDs. The clinical and patient experts agreed that methotrexate is often not well tolerated; the clinical experts noted that up to a third of people who are prescribed methotrexate with biological DMARDs do not take methotrexate because of side effects. The clinical experts emphasised that baricitinib is a novel treatment with a different mode of action to the biological DMARDs. They noted that the selective inhibition of Janus kinase 1 and 2 will affect a broad range of cytokines involved in the pathogenesis of rheumatoid arthritis. The clinical experts also noted the fast kinetic action of baricitinib compared with biological DMARDs. Both the clinical and patient experts also highlighted that baricitinib is given orally, which has major benefits for both patients and the health system. The patient experts emphasised that this is an important factor for people who have difficulty injecting themselves because of the disease affecting their hands. The patient experts also noted that some current treatments have to be stopped if the person gets an infection, and that some treatments may cause injection site reactions. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological DMARDs.\n\n# Subgroups\n\n## The company's subgroups and comparators were appropriate\n\nThe committee was aware that the company had analysed 4\xa0distinct subgroups in which baricitinib could be used:\n\nPeople with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.\n\nPeople with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.\n\nPeople with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option.\n\nPeople with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated.The relevant comparators varied by subgroup. The committee concluded that it was appropriate to consider the 4\xa0groups separately and that the company had broadly included the appropriate comparators.\n\n# Clinical effectiveness\n\n## The trials were adequate and suitable for decision-making\n\nThe company's clinical evidence came from 4\xa0phase III randomised controlled trials and 1\xa0long-term safety and tolerability study. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.2. The trials were:\n\nRA‑BEAM, which included people whose disease responded inadequately to methotrexate and who had not had biological DMARDs. Baricitinib 4\xa0mg was given once daily and the comparators were placebo and adalimumab. Background methotrexate was given to all the groups.\n\nRA‑BUILD, which included people whose disease responded inadequately to conventional DMARDs and who had not had biological DMARDs. Baricitinib 2\xa0mg or 4\xa0mg was given once daily and the comparator was placebo. People taking conventional DMARDs with or without methotrexate before the study continued to take background therapy.\n\nRA‑BEACON, which included people whose disease responded inadequately to TNF‑alpha\xa0inhibitors. Baricitinib 2\xa0mg or 4\xa0mg was given once daily and the comparator was placebo. Background conventional DMARDs were given to all the groups.\n\nRA-BEGIN, which included people who had not had any conventional or biological DMARDs. Baricitinib 4\xa0mg was given once daily, with or without methotrexate. The comparator was methotrexate. The committee was aware that the marketing authorisation for baricitinib does not include the treatment of rheumatoid arthritis in people who have not had any conventional or biological DMARDs (that is, this subgroup).The long-term safety and tolerability study, RA-BEYOND, included people with moderate or severe rheumatoid arthritis who took part in a separate phase\xa0IIb study or 1 of the 4\xa0trials described above. Baricitinib 2\xa0mg or 4\xa0mg was given once daily, with or without conventional DMARDs.\n\nThe primary outcome of all the randomised controlled trials was the proportion of people achieving a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 12 or 24. Secondary outcomes included the proportion of people achieving a 50% or 70% improvement in the response criteria (ACR50 and ACR70 respectively), and the proportion of people meeting the European League Against Rheumatism (EULAR) response criteria. The committee concluded that the trials were relevant and adequate for its decision-making.\n\n## Baricitinib is more clinically effective than conventional DMARDs alone and as effective as adalimumab for moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs\n\nThe committee considered RA‑BEAM and RA‑BUILD, which included people with moderate to severe rheumatoid arthritis which responded inadequately to conventional DMARDs. In RA‑BEAM, there was a significant increase in the proportion of people meeting the ACR20 criteria at 12\xa0weeks with 4\xa0mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (odds ratio [OR] 3.6; 95%\xa0confidence interval [CI] 2.7\xa0to\xa04.7, p=0.001). A smaller response was seen with 4\xa0mg baricitinib plus conventional DMARDs compared with adalimumab plus conventional DMARDs (OR\xa01.5; 95%\xa0CI\xa01.1\xa0to\xa02.0, p=0.014 for ACR20). Significant improvements in ACR20 and EULAR good and moderate responses were also seen in RA‑BUILD for 4\xa0mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (OR\xa02.5; 95%\xa0CI\xa01.7\xa0to\xa03.7, p=0.001 for ACR20 and OR\xa03.5; 95%\xa0CI\xa02.3\xa0to\xa05.4, p=0.001 for EULAR). The committee also noted that in RA‑BUILD, 2\xa0mg baricitinib plus conventional DMARDs improved ACR20 and EULAR responses in this population compared with conventional DMARDs alone (OR\xa03.0; 95%\xa0CI\xa02.0\xa0to\xa04.4, p=0.001 for ACR20 and OR\xa03.3; 95%\xa0CI\xa02.2\xa0to\xa05.0, p=0.001 for EULAR good and moderate response). The committee concluded that 4\xa0mg baricitinib plus conventional DMARDs has similar efficacy to adalimumab plus conventional DMARDs, and is more effective than conventional DMARDs alone in people with moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs.\n\n## Baricitinib is more clinically effective than conventional DMARDs alone for moderate to severe rheumatoid arthritis which has responded inadequately to biological DMARDs\n\nThe committee considered RA‑BEACON, which included people with moderate to severe rheumatoid arthritis which responded inadequately to TNF‑alpha\xa0inhibitors. There was a significant increase in the proportion of people meeting the ACR20 criteria and having a EULAR moderate or good response rate at 12\xa0weeks for 4\xa0mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (OR\xa03.4; 95%\xa0CI\xa02.2\xa0to\xa05.4, p=0.001 for ACR20 and OR\xa03.6; 95%\xa0CI\xa02.3\xa0to\xa05.7, p=0.001 for EULAR moderate and good response). The committee also noted that 2\xa0mg baricitinib plus conventional DMARDs also improved ACR20 and EULAR response rates in this population compared with conventional DMARDs alone (OR\xa02.7; 95%\xa0CI\xa01.7\xa0to\xa04.2, p=0.001 for ACR20 OR\xa02.7; 95%\xa0CI\xa01.8\xa0to\xa04.2, p=0.001 for EULAR moderate and good response). The committee concluded that both dosages of baricitinib, when given with conventional DMARDs, are more effective than conventional DMARDs alone in people with moderate to severe rheumatoid arthritis which has responded inadequately to TNF‑alpha\xa0inhibitors.\n\n## Baricitinib has a similar safety profile to conventional DMARDs and adalimumab\n\nThe committee noted that across all 3\xa0randomised controlled trials in which patients had previously had conventional or biological DMARDs (RA‑BEAM, RA‑BUILD and RA‑BEACON), the safety profile of baricitinib was similar to that of the conventional DMARDs. In addition, it noted that the safety profiles were found to be similar in the head-to-head comparison of baricitinib and adalimumab (RA‑BEAM).\n\n# Indirect comparison\n\n## Network meta-analyses show that baricitinib works as well as biological DMARDs\n\nThe committee was aware that other than the direct comparison with adalimumab, the only evidence available on the comparative effectiveness of baricitinib and the biological DMARDs was from the company's network meta-analyses. The company did separate analyses for patients whose disease inadequately responded to either conventional or biological DMARDs, using ACR and EULAR outcome measures.At 24\xa0weeks' follow-up, for patients whose disease inadequately responded to conventional DMARDs, the network meta-analysis showed:\n\nBaricitinib plus conventional DMARDs gave better EULAR response rates than conventional DMARDs alone.\n\nBaricitinib plus conventional DMARDs gave similar EULAR response rates to the biological DMARDs plus conventional DMARDs.The exception to this was tocilizumab plus conventional DMARDs, which gave better EULAR result than all the other treatments. However, the clinical experts noted that the trials of tocilizumab had slightly different characteristics than the trials of the other technologies, and they considered tocilizumab to have similar effectiveness to the other biological DMARDs. Tocilizumab monotherapy showed similar results to baricitinib and the biological DMARDs when used with conventional DMARDs.At 24\xa0weeks' follow-up, for patients whose disease inadequately responded to biological DMARDs, the network meta-analysis showed:\n\nBaricitinib (2\xa0mg and 4\xa0mg) plus conventional DMARDs gave better EULAR response rates than conventional DMARDs alone. A dose response was seen, with 4\xa0mg baricitinib having a better EULAR response than 2\xa0mg baricitinib.\n\nRituximab plus conventional DMARDs gave a better point estimate of the EULAR response rate than baricitinib (2\xa0mg and 4\xa0mg) plus conventional DMARDs.\n\n## The company's and ERG's network meta-analysis results were broadly comparable\n\nThe committee heard from the ERG that there were problems with the methods used in the company's network meta-analysis. These included the conversion of ACR data to EULAR data before synthesis, the use of simultaneous models for baseline and treatment effects, the use of a random effects model for 1 population and a fixed effects model for the other, and poor model fit. In addition, the company had pooled the control data inappropriately. The ERG corrected the errors in the company's network meta-analysis. Having reviewed both analyses, the committee concluded that the results of the corrected network meta-analysis and the company's network meta-analysis were broadly comparable.\n\n# Cost effectiveness\n\n## The cost-effectiveness studies presented by the company were appropriate\n\nThe company identified 9\xa0UK-based cost-effectiveness studies. The committee was aware that 8 of these were associated with previous NICE technology appraisals guidance; 1\xa0was an independent published review. The company did not identify any studies that included baricitinib, but the committee noted that the studies were nonetheless relevant and appropriate.\n\n# Economic model\n\n## The model structure was appropriate for decision-making\n\nThe company used an individual patient-based discrete event simulation model for its economic evaluation. The model simulates patients' disease progression through the sequences of treatments being compared. It was based on the model used by the assessment group during the production of NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The model categorised patients based on their EULAR response (good, moderate or no response) at 6\xa0months. Response rates were based on the company's network meta-analysis. The company analysed cost effectiveness for each of the subgroups described in section 3.5. The committee concluded that the model structure was appropriate for its decision-making.\n\n## There were some concerns with how costs were calculated\n\nThe company's model included costs associated with drug acquisition, drug administration and monitoring, and hospitalisation. The committee was aware that baricitinib and several of the biological DMARDs have patient access schemes. It noted that the company had incorporated the patient access scheme prices for baricitinib, certolizumab\xa0pegol and golimumab in the model, but not the confidential patient access schemes for abatacept and tocilizumab. The incremental cost-effectiveness ratios (ICERs) that incorporated these confidential patient access schemes cannot be reported here, but the range of ICERs usually considered to be cost effective is from £20,000 to £30,000 per quality-adjusted life year (QALY) gained. The company had also calculated the average cost of drug doses using the average weight, rather than the distribution of the weight of the modelled patient population. The committee was also aware that the company overestimated the number of doses and therefore the costs of infliximab.\n\n## The company is likely to have overestimated how well biological DMARDs work after an inadequate response to biological DMARDs and when rituximab is not an option\n\nThe company did not identify any evidence on the effectiveness of adalimumab, certolizumab\xa0pegol, etanercept or infliximab plus conventional DMARDs in patients with severe active rheumatoid arthritis which has responded inadequately to biological DMARDs when rituximab is contraindicated or not tolerated. In the absence of these data, the company used the same efficacy estimates for these treatments as those in patients with severe active rheumatoid arthritis which has responded inadequately to conventional DMARDs. The EULAR responses for all treatments were higher in these patients than in those with an inadequate response to biological DMARDs. The committee heard from the ERG that because of this, the company's base case is likely to have overestimated the efficacy of adalimumab, certolizumab\xa0pegol, etanercept and infliximab plus conventional DMARDs in patients with active rheumatoid arthritis which has responded inadequately to biological DMARDs when rituximab is contraindicated or not tolerated. The committee accepted this in the absence of any other evidence.\n\n# Utility values\n\n## The different approaches used to calculate utility were unlikely to change the overall conclusions\n\nHealth-related quality of life data were collected using a health assessment questionnaire (HAQ) in RA‑BEAM, RA‑BUILD and RA‑BEACON. Patient-level responses were converted to utility index-based EQ-5D-5L scores using the UK-specific scoring algorithm reported by Hernandez Alava\xa0et\xa0al.\xa0(2012). The committee was aware this was not in line with the analysis done during NICE's technology appraisal on adalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept, but it heard from the ERG that this approach was unlikely to change the overall conclusions.\n\n## The model was adequate for decision-making\n\nThe ERG identified several issues with the company's economic analyses including:\n\nLimitations with the company's network meta-analysis because an inappropriate random effects model was assumed for the baselines. In addition, simultaneous baseline and treatment effect models were used without ensuring that information in the baseline model did not propagate to the relative treatment effect model. Furthermore, studies that reported EULAR responses were synthesised along with converted EULAR response outcomes from studies that only reported ACR responses.\n\nA lack of face validity in several of the scenario analyses, partly because of transcription and programming errors.\n\nLimitations with the probabilistic sensitivity analyses because of programming errors, including an error which resulted in patients having some biological DMARDs never achieving a good or moderate EULAR response.\n\nUsing the efficacy of treatments in the population with an inadequate response to conventional DMARDs for all biological DMARDs in the treatment sequence, regardless of their position in the sequence.\n\nRounding HAQ scores to the nearest valid HAQ score, rather than allowing HAQ scores to be sampled based on a continuous HAQ value.\n\nIncorrect implementation of the HAQ trajectory classes by assigning each patient to a single class based on the probability of class membership, instead of using an average weighted by the probability of class membership.\n\nAssuming that patients who achieve a moderate or good EULAR response at 24\xa0weeks had an instant reduction in HAQ score when starting treatment.\n\nAveraging HAQ across large time periods, which may lead to inaccurate results because the relationships between HAQ score and EQ-5D and between HAQ score and hospitalisation costs are not linear.\n\nExcluding intravenous abatacept and subcutaneous tocilizumab from the list of comparators.\n\nUsing a less accurate method to map HAQ scores to EQ-5D (Malottki\xa0et\xa0al.\xa02011) than that used during the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept (Hernandez Alava\xa0et\xa0al.\xa02013).\n\nAssuming that baricitinib would be used before intensive therapy with conventional DMARDs for patients with moderate rheumatoid arthritis (this was not supported by the clinical experts).\n\nRe-estimating the age of death at every event, which resulted in slightly different expected life years, which would be exacerbated by sequences of different lengths.\n\nUsing the average weight of the population in the relevant trials to calculate average dose, which assumes there is a linear relationship between weight and dose costing and does not take into account drug wastage, for example.\n\nOverestimating the average number of doses, and thereby the cost, of infliximab that would be given in a year.The ERG stated that these errors were unlikely to change the broad conclusions of the company's model. The committee concluded that although there were several errors in the company's economic model, it was adequate for its decision-making.\n\n## Baricitinib was comparable to other biological DMARDs in all of the company's scenario analyses\n\nThe company carried out several scenario analyses. In one, the company assumed that patients having conventional DMARDs or palliative care had a linear increase in their HAQ scores at a yearly rate of 0.045 and 0.060 respectively (based on Malottki\xa0et\xa0al.\xa02011), instead of using the latent class approach. For the moderate rheumatoid arthritis population, the ICER for baricitinib plus conventional DMARDs compared with intensive conventional DMARDs alone decreased from £37,420 to £20,965 per QALY gained. In the severe rheumatoid arthritis population, the ICERs were slightly lower for the most effective drugs. The company also:\n\nadjusted the HAQ score for baricitinib plus methotrexate so that it deteriorated at half of the rate assumed for conventional DMARDs\n\nused HAQ score improvements for baricitinib calculated from trial data rather than the UK rheumatoid arthritis database\n\nused a different time to treatment discontinuation for patients on baricitinib\n\nused alternative methods to map HAQ scores to the EQ-5D\n\naccounted for serious adverse events\n\ntapered baricitinib from 4\xa0mg once daily to 2\xa0mg once daily.The committee heard from the ERG that these scenarios were unlikely to change the results of the cost-effectiveness analysis. The committee agreed that any exploratory analyses would not change its conclusion that baricitinib is broadly comparable to the other biological DMARDs recommended by NICE.\n\n# Cost-effectiveness results\n\n## Baricitinib is not cost effective for moderate disease after conventional DMARDs\n\nIn the moderate active rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the company's base-case ICER for the baricitinib sequence compared with the conventional DMARD sequence was £37,420 per QALY. The committee noted that the company used a different sequence for this population to that used in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept. The ERG did not correct this or the errors in the model because they were unlikely to change the conclusions, and it could use the model from the other appraisal as a reference. The ERG noted that the median ICER of biological DMARDs in the NICE appraisal of adalimumab, etanercept, infliximab, certolizumab\xa0pegol, golimumab, tocilizumab and abatacept was around £50,000 per QALY gained. Taking into account the cost-effectiveness evidence for baricitinib in patients with moderate active rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, the committee considered that baricitinib plus conventional DMARDs did not have plausible potential to be cost effective in this population.\n\n## Baricitinib is cost effective for severe active rheumatoid arthritis after conventional DMARDs\n\nIn the company's base-case analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, baricitinib plus conventional DMARDs dominated all its comparators (that is, it was both less costly and more effective). The exception to this was certolizumab\xa0pegol plus conventional DMARDs, which had an ICER of £18,400 per QALY compared with baricitinib plus conventional DMARDs. The committee noted that there are confidential patient access schemes in place for subcutaneous abatacept and intravenous tocilizumab, which the company did not include in its analysis. The ERG calculated new ICERs using the confidential comparator prices. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness, and concluded to recommend baricitinib plus conventional DMARDs as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.\n\n## Baricitinib is not cost effective for severe disease after biological DMARDs if rituximab is a treatment option\n\nIn the company's base-case analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option, baricitinib plus conventional DMARDs was dominated by rituximab plus conventional DMARDs (that is, it was more costly and less effective). The committee concluded that baricitinib plus conventional DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs if rituximab is a treatment option.\n\n## Baricitinib is cost effective for severe disease after biological DMARDs if rituximab is not a treatment option\n\nIn the pairwise analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated, baricitinib plus conventional DMARDs was dominated by golimumab plus conventional DMARDs. Compared with all other comparators, the ICERs ranged from £16,201 to £484,782. In the full incremental analysis, baricitinib plus conventional DMARDs dominated or extendedly dominated all comparators except for certolizumab\xa0pegol plus conventional DMARDs, which had an ICER of £16,201 per QALY gained. The ICERs for biosimilar etanercept plus conventional DMARDs compared with baricitinib plus conventional DMARDs, and adalimumab plus conventional DMARDs compared with baricitinib plus conventional DMARDs, were also less than £30,000 per QALY gained. The committee again noted the confidential patient access schemes in place for subcutaneous abatacept and intravenous tocilizumab, which the company did not include in its analysis. The ERG calculated new ICERs using the confidential comparator prices. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness, and concluded to recommend baricitinib plus conventional DMARDs as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is not a treatment option.\n\n## The recommendations also apply to baricitinib monotherapy\n\nThe committee was aware that the marketing authorisation for baricitinib includes its use as a monotherapy, but that the company did not present an economic analysis for baricitinib alone for patients who cannot have methotrexate. The committee noted that the only available evidence for baricitinib alone is in people who have not had conventional DMARDs, which is outside of its marketing authorisation. The committee recognised the considerable uncertainty about the effectiveness of baricitinib alone in people whose rheumatoid arthritis has had an inadequate response to conventional or biological DMARDs. The committee heard from the ERG that data from RA-BEGIN showed that the addition of methotrexate to 4\xa0mg baricitinib produced similar ACR scores compared with baricitinib alone. The committee agreed that baricitinib monotherapy provides similar clinical efficacy to baricitinib plus conventional DMARDs. It concluded that its recommendations for baricitinib plus conventional DMARDs should also apply to baricitinib alone."}
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https://www.nice.org.uk/guidance/ta466
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Evidence-based recommendations on baricitinib (Olumiant) for moderate to severe rheumatoid arthritis in adults.
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79a04a012fccdceb181b714b40d34be8d93799be
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nice
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Developmental follow-up of children and young people born preterm
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Developmental follow-up of children and young people born preterm
This guideline covers the developmental follow-up of babies, children and young people under 18 years who were born preterm (before 37+0 weeks of pregnancy). It explains the risk of different developmental problems and disorders, and specifies what extra assessments and support children born preterm might need during their growth and development.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information and support for parents and carers of all preterm babies
## Providing information and support
Be aware that the majority of children and young people born preterm have a good developmental outcome and good quality of life.
Provide information about the risk and prevalence of developmental problems and disorders in babies born preterm (see section 1.2) to parents or carers, and offer to discuss this with them.
Provide information to parents or carers of preterm babies that is tailored to their individual circumstances, taking into account:
their child's potential developmental needs
their level of education
any social care needs they have
any cultural, spiritual or religious beliefs
the need for consistency in information sharing among healthcare professionals.
Follow the principles in the NICE guidelines on patient experience in NHS services and babies, children and young people's experience of healthcare in relation to communication (including different formats and languages), information and continuity of care. Also see NICE's guideline on shared decision making.
Provide emotional and psychological support to parents or carers of preterm babies as needed, recognising the significant potential impact of having a preterm baby on all the family. Times when support may be particularly valuable include:
when the baby is transferred between units or hospitals
leading up to and on discharge home.
Provide information to parents or carers of preterm babies about opportunities for peer support.
## Information and support leading up to and on discharge home
Start discharge planning as soon as possible after the birth of a preterm baby, and involve parents or carers at all stages.
Before discharging a preterm baby:
agree a discharge plan with the parents or carers
ensure that the discharge plan includes clear information about any antenatal and perinatal risk factors for developmental problems and disorders (see section 1.2)
share the written discharge plan with parents or carers and with primary and secondary healthcare teams.
Help parents or carers to gain the knowledge, skills and confidence they need to look after their baby at home and to support the baby's developmental needs, taking into account that they are likely to be anxious about caring for their baby after discharge. This may relate to:
interaction with the baby
managing feeding
patterns of sleeping
physical positioning of the baby, including safe sleeping
impact on day-to-day living, such as social isolation because of fear of infection.
Involve the social support networks (which may include partners, grandparents or other family members) of parents or carers of a baby born preterm when planning discharge and during follow-up.
Inform parents or carers of all preterm babies about the routine postnatal care and support available, as described in the NICE guideline on postnatal care up to 8 weeks after birth.
Explain to parents and carers of preterm babies about:
universal services and national recommendations for assessing the development of all children through screening (for example, newborn hearing screening) and surveillance (including social, emotional, behavioural and language development) and
whether their baby will also be offered enhanced developmental support and surveillance (see section 1.3) and plans for follow-up.For more information on universal screening and surveillance services in England, see the Healthy Child Programme.
Explain to parents or carers that their child's developmental (corrected) age, which is calculated from their original due date (and not the date they were born), will be used for the first 2 years when assessing their functional and developmental skills (such as walking and talking).
Advise parents or carers to talk to their health visitor or GP if they have any concerns about their child's development at any stage of childhood or adolescence.
Healthcare professionals providing postnatal care and support in the community for babies born preterm should have the skills and knowledge to recognise and manage problems in these babies, including:
providing feeding support
addressing concerns about sleeping
helping parents or carers to interact with their baby.
# Risk and prevalence of developmental problems and disorders
Be aware that children and young people born preterm are at increased risk of developmental problems and disorders.
Be aware that for recommendations in this section:
for some developmental problems and disorders there was an absence of evidence about overall risk and prevalence in children born preterm
there was limited evidence about developmental problems and disorders in 11–18-year-olds
for some developmental problems and disorders the evidence was underpowered to detect an effect
some studies described specific gestational ages at birth, from which the committee was unable to extrapolate to other gestational ages
-ther gestational ages and other factors not listed here might also be associated with increased risk of developmental problems and disorders.
## Cerebral palsy
Be aware that children born preterm are at increased risk of cerebral palsy, and that:
the following are independent risk factors:
grade 3 or 4 intraventricular haemorrhage
cystic periventricular leukomalacia
neonatal sepsis
bronchopulmonary dysplasia for which mechanical ventilation was still needed at 36 weeks' postmenstrual age
antenatal steroids not given
postnatal steroids given to babies born before 32+0 weeks' gestation
prevalence increases with decreasing gestational age.
See also the NICE guideline on cerebral palsy in under 25s: assessment and management.
## Motor function problems
Be aware that children born preterm are at increased risk of motor function problems, and that the following are independent risk factors:
brain lesions (for example, grade 3 or 4 intraventricular haemorrhage, periventricular leukomalacia, infarct)
necrotising enterocolitis that needed surgery
neonatal sepsis
severe retinopathy of prematurity.
Be aware that there is an increased prevalence of developmental coordination disorder in children born preterm compared with the general population.
## Learning disability (intellectual disability)
Be aware that children born preterm are at increased risk of learning disability (intellectual disability), and that:
the following are independent risk factors:
grade 3 or 4 intraventricular haemorrhage
cystic periventricular leukomalacia
neonatal sepsis in babies born before 28+0 weeks' gestation
necrotising enterocolitis that needed surgery in babies born before 33+0 weeks' gestation
bronchopulmonary dysplasia for which mechanical ventilation was still needed at 36 weeks' postmenstrual age in babies born before 28+0 weeks' gestation
severe retinopathy of prematurity in babies born before 28+0 weeks' gestation
small for gestational age
postnatal steroids given to babies born before 33+0 weeks' gestation
mother from a low-income or disadvantaged background
prevalence increases with decreasing gestational age.
## Special educational needs and educational attainment
Be aware that children born preterm are at increased risk of having special educational needs, and that the following are independent risk factors:
brain lesions detected by ultrasound
male sex.
Be aware that children born preterm are at increased risk of low educational attainment at the end of the Early Years Foundation stage and at key stage 1 (age up to 7 years), and that:
prevalence of low educational attainment increases with decreasing gestational age
children born preterm are at increased risk of low attainment for reading and maths, and this risk is greater in children born before 26+0 weeks' gestation
the following are independent risk factors for low attainment in maths in children born before 32+0 weeks' gestation:
intraventricular haemorrhage
bronchopulmonary dysplasia for which mechanical ventilation was still needed at 36 weeks' postmenstrual age.
## Executive function problems
Be aware that children born before 32+0 weeks' gestation are at increased risk of executive function problems at preschool and school ages, and that prevalence increases with decreasing gestational age.
## Speech, language and communication
Be aware that children born preterm are at increased risk of speech, language and communication problems and disorders, and that the following are independent risk factors for language disorder:
grade 3 or 4 intraventricular haemorrhage
cystic periventricular leukomalacia
male sex.
## Attention, impulsivity and hyperactivity
Be aware that children born before 33+0 weeks' gestation are at increased risk of symptoms of hyperactivity, impulsivity and particularly inattention at preschool and school ages.
Be aware that children born before 28+0 weeks' gestation are at increased risk of attention deficit hyperactivity disorder (ADHD), and that male sex is an independent risk factor.
## Autism spectrum disorder
Be aware that children born before 28+0 weeks' gestation are at increased risk of symptoms of social communication impairment, which may suggest a problem in the autism spectrum.
Be aware that children born preterm are at increased risk of autism spectrum disorder, and that the following are independent risk factors:
intraventricular haemorrhage in babies born before 34+0 weeks' gestation
male sex.
## Emotional and behavioural problems
Be aware that children born preterm are at increased risk of emotional and behavioural problems, particularly internalising behaviours and passivity, at preschool and school ages, and that the following are independent risk factors:
major brain lesions (for example, periventricular leukomalacia, parenchymal lesions)
mother with mental health problems
mother younger than 25 years
mother from a low-income or disadvantaged background.
## Feeding problems
Be aware that children born preterm are at increased risk of oro-motor feeding problems (for example, problems with sucking and chewing), and that this increased risk persists until at least 6 years of age in children born before 26+0 weeks' gestation.
## Sleep problems
Be aware that children born preterm are at increased risk of sleep apnoea up to 6 years of age.
## Visual impairment
Be aware that the prevalence of visual impairment increases with decreasing gestational age in children born preterm, and that the following are independent risk factors:
grade 3 or 4 intraventricular haemorrhage with a shunt
neonatal sepsis in babies born before 33+0 weeks' gestation
retinopathy of prematurity needing treatment.
## Hearing impairment
Be aware that the prevalence of hearing impairment increases with decreasing gestational age in children born preterm, and that neonatal sepsis is an independent risk factor in babies born before 28+0 weeks' gestation.
## Developmental delay
Be aware that children born preterm are at increased risk of developmental delay (identified using a range of tools), and that the following are independent risk factors:
small for gestational age
male sex
mother from a low-income or disadvantaged background
black, Asian or other minority ethnic group
multiple pregnancy.
# Enhanced developmental support and surveillance
## Criteria for enhanced developmental support and surveillance up to 2 years (corrected age)
Provide enhanced developmental support and surveillance by a multidisciplinary team (see section 1.4) up to 2 years (corrected age) for children born preterm who:
have a developmental problem or disorder or
are at increased risk of developmental problems or disorders, based on the following criteria:
born before 30+0 weeks' gestation or
born between 30+0 and 36+6 weeks' gestation and has or had 1 or more of the following risk factors:
a brain lesion on neuroimaging likely to be associated with developmental problems or disorders (for example, grade 3 or 4 intraventricular haemorrhage or cystic periventricular leukomalacia)
grade 2 or 3 hypoxic ischaemic encephalopathy in the neonatal period
neonatal bacterial meningitis
herpes simplex encephalitis in the neonatal period.
Consider enhanced developmental support and surveillance by a multidisciplinary team up to 2 years (corrected age) for children born preterm who do not meet the criteria in recommendation 1.3.1 but are suspected of being at increased risk of developmental problems or disorders, taking into account the presence and severity of risk factors (see recommendations 1.2.3 to 1.2.20).
## Criteria for enhanced developmental support and surveillance at 4 years (uncorrected age)
Provide a face-to-face developmental assessment at 4 years (uncorrected age) for all children born before 28+0 weeks' gestation (see recommendation 1.3.13).
## Providing enhanced developmental support
Provide parents or carers of a preterm baby having enhanced developmental support with a single point of contact within the neonatal service for outreach care after discharge.
Use a range of approaches when providing enhanced developmental support and tailor the support to take account of individual preferences and needs. Approaches may include:
face-to-face meetings, in clinics or in the home
a telephone helpline
text messages, emails or similar.
## Providing enhanced developmental surveillance up to 2 years (corrected age)
For all children born preterm who are having enhanced developmental surveillance, provide as a minimum:
face-to-face follow-up visits in the first year that focus on development, at the following corrected ages:
between 3 and 5 months and
by 12 monthsand
a detailed face-to-face developmental assessment at 2 years (corrected age) (see recommendation 1.3.11).
## Checks at each developmental visit and assessment
At each face-to-face follow-up visit and developmental assessment (see recommendations 1.3.6, 1.3.11 and 1.3.13) for a child born preterm who is having enhanced developmental surveillance, professionals with appropriate skills (see section 1.4) should:
discuss with parents or carers whether they have any concerns about their child's development
include checks for developmental problems and disorders (see recommendation 1.3.8)
measure length or height, weight and head circumference
carefully evaluate and review any developmental concerns reported by parents or carers or noted during the visit or assessment
correct for gestational age up to 2 years when assessing development
consider further investigation or referral if a developmental problem or disorder is suspected or present
refer the child to the appropriate local pathway if needed.
At each face-to-face follow-up visit and developmental assessment for a child born preterm who is having enhanced developmental surveillance, check for signs and symptoms of developmental problems and disorders as appropriate, such as:
cerebral palsy (see recommendation 1.3.9)
global developmental delay and learning disability (intellectual disability)
autism spectrum disorder (see recommendation 1.3.10)
visual impairment
hearing impairment
feeding problems
sleep problems, including sleep apnoea
speech, language and communication problems
motor problems
problems with inattention, impulsivity or hyperactivity
emotional and behavioural problems
executive function problems
potential special educational needs.
Recognise the following as possible early motor signs of cerebral palsy:
delayed motor milestones, such as late sitting, crawling or walking (correcting for gestational age)
unusual (abnormal or absent) fidgety movements or other abnormalities of movement, including asymmetry or paucity of movement
abnormalities of tone, including hypotonia (floppiness) or spasticity (stiffness)
persisting feeding difficulties.
See also the NICE guideline on cerebral palsy in under 25s: assessment and management.
For guidance on recognising signs and symptoms of possible autism spectrum disorder, see the NICE guideline on autism spectrum disorder in under 19s: recognition, referral and diagnosis.
## Developmental assessment at 2 years (corrected age)
Provide a face-to-face developmental assessment at 2 years (corrected age) for children born preterm who are having enhanced developmental surveillance. This assessment should include as a minimum:
all aspects listed in recommendation 1.3.7
using the Parent Report of Children's Abilities – Revised (PARCA-R) to identify if the child is at risk of global developmental delay, learning disability (intellectual disability) or language problems:
if the PARCA-R is not suitable (for example, because of poor English language comprehension or the child being outside the validated age range of 22 to 26 months), use a suitable alternative parent questionnaire
Gross Motor Function Classification System (GMFCS) score if cerebral palsy has been diagnosed
ensuring that checks of vision and hearing have been carried out in line with national recommendations.
## Follow-up and assessment after 2 years (corrected age)
After the developmental assessment at 2 years (corrected age):
advise parents or carers of all children that their child should continue to be followed up by universal screening and surveillance services for all children and young people and
advise parents or carers of children born before 28+0 weeks' gestation that their child will also be offered a further developmental assessment at 4 years (uncorrected age). For more information on universal screening and surveillance services in England, see the Healthy Child Programme.
## Further developmental assessment at 4 years (uncorrected age) for children born before 28+0 weeks' gestation
Provide a face-to-face developmental assessment at 4 years (uncorrected age) for all children born before 28+0 weeks' gestation that includes as a minimum:
all aspects listed in recommendation 1.3.7
using the following parent questionnaires, to be completed by parents or carers beforehand and the results discussed during the assessment:
the Strengths and Difficulties Questionnaire (SDQ), to check for social, attentional, emotional and behavioural problems
the Ages and Stages Questionnaire (ASQ) 48-month questionnaire, to check for various aspects of development
reviewing previous assessments and information from all other relevant sources
using a standardised test to assess IQ, such as the Wechsler Preschool and Primary Scales of Intelligence 4th Edition (WPPSI) test
GMFCS score if cerebral palsy has been diagnosed
ensuring that the child has been offered orthoptic vision screening as recommended by the National Screening Committee.
After the 4-year assessment, provide a comprehensive summary of the child's strengths and difficulties, including any developmental problems and disorders, that:
is in a format that is accessible to parents and carers
if needed, informs the development of a plan for intervention and support, including educational support
should be shared with the neonatal consultant.
## Information sharing and referral
If findings at any stage of developmental surveillance, including the assessments at 2 years (corrected age) and 4 years (uncorrected age) (see recommendations 1.3.11 and 1.3.13), suggest any developmental problems or disorders:
share information with:
parents or carers
primary and secondary healthcare teams
refer the child to an appropriate local pathway for further assessment
ask parents or carers for permission to share the information with:
education services
social care services as appropriate.
## Later presentation of learning or behavioural problems
Primary and secondary education professionals should be aware that:
preterm birth may be a factor in learning or behavioural problems
these problems can emerge at any point during a child or young person's education
prompt referral to educational support services may be needed.
# Delivering enhanced developmental support and surveillance
Enhanced developmental support and surveillance for children born preterm who meet the defined criteria (see recommendations 1.3.1 to 1.3.3) should:
be provided as an integral part of a neonatal service working together with local health services
empower parents and carers to be involved in decisions about their child's care
be delivered by a multidisciplinary team with the necessary skills (see recommendation 1.4.2)
record outcomes at specified time points for national audit (see section 1.5)
be monitored by checking adherence to the recommendations in this guideline, including follow-up rates and outcomes, as part of the routine provision of neonatal care by neonatal operational delivery networks and commissioners.
Multidisciplinary teams delivering enhanced developmental support and surveillance for children born preterm should include professionals with knowledge and expertise in the following areas:
neonatal care
development of children born preterm, including developmental problems and disorders (see recommendation 1.3.8)
providing support in the community, for example for feeding problems
administering and interpreting results from questionnaires and standardised tests (for example, the PARCA-R, SDQ, ASQ and IQ tests such as the WPPSI)
collating information from a range of sources to facilitate decision-making and writing reports
local care pathways, including Early Years education.
Multidisciplinary teams delivering enhanced developmental support and surveillance for children born preterm should include the following professionals:
for enhanced developmental support:
neonatologist or paediatrician with an understanding of neonatal care and child development
-utreach nurse or nurse with expertise in the development of babies born preterm
for the surveillance assessments up to and including 2 years (corrected age) (see recommendation 1.3.6):
neonatologist or paediatrician with an understanding of neonatal care and child development
at least one of occupational therapist, physiotherapist and speech and language therapist
for the surveillance assessment at 4 years (uncorrected age) (see recommendation 1.3.13):
educational or clinical psychologist
paediatrician with expertise in neurodevelopment.
Multidisciplinary teams delivering enhanced developmental support and surveillance for children born preterm should have access to the following professionals:
community nurse or health visitor
-ccupational therapist
physiotherapist
speech and language therapist
paediatric neurologist
dietitian.
# Neonatal audit
Record the following information, as applicable, in the National Neonatal Research Database for every child born preterm who has enhanced developmental surveillance:
whether the child had specialist neonatal care and if so, relevant details
the reasons for enhanced surveillance (see recommendations 1.3.1 to 1.3.3)
at the assessment at 2 years (corrected age) (see recommendation 1.3.11):
diagnosis of cerebral palsy
GMFCS score if cerebral palsy is present
PARCA-R score
epilepsy that is currently being treated
impairments of hearing, vision, speech and language, and motor skills (as defined in Figure 3 in Classification of health status at 2 years as a perinatal outcome, report of a BAPM/RCPCH working group, version 1.0, 8 January 2008)
at the assessment at 4 years (uncorrected age) (see recommendation 1.3.13):
diagnosis of cerebral palsy
GMFCS score if cerebral palsy is present
full scale IQ score
SDQ total difficulty score, subscale scores and impact score
any formal clinical diagnoses of a developmental disorder (for example, autism spectrum disorder)
epilepsy that is currently being treated
the presence of a hearing impairment, defined as profound deafness or impairment severe enough to need hearing aids or cochlear implant
results of national orthoptic vision screening.
Record routine educational measures at Key Stage 2 (including special educational needs and disability ) on an operational delivery network-wide basis, to allow educational outcomes at 11 years to be linked to neonatal information.
# Terms used in this guideline
## Developmental problems and disorders
A group of problems that become apparent during child development and often occur together. They are characterised by impairments of personal, social, academic or occupational functioning, ranging from very specific limitations to global impairments of social skills or cognition, as measured by parent or teacher reports and surveillance tools. The term 'disorder' applies if the condition is severe, persistent and pervasive enough to meet the criteria for a disorder in the International statistical classification of diseases and related health problems (ICD) or the Diagnostic and statistical manual of mental disorders (DSM).
## Enhanced developmental support
Additional advice and interventions with skilled professionals for children and young people born preterm and their parents and carers. The aim is to support them after discharge from hospital, respond to their concerns, and reduce the impact of any developmental problems and disorders.
## Enhanced developmental surveillance
Active monitoring of a child's development, at set times and using specific tools, to detect developmental problems and disorders.
## Executive function
Executive functions are a set of inter-related cognitive processes that are used to organise and regulate thoughts and actions. These processes are important for guiding learning and behaviour, and comprise skills such as inhibition, impulse control, emotional control, working memory, cognitive flexibility and planning.
## Learning disability (Intellectual disability)
Learning disability (intellectual disability) is characterised by deficits in general cognitive abilities (such as reasoning and abstract thinking) and impairment of adaptive function that affects several aspects of daily life. In the ICD-10 this is defined as an IQ score more than 2 standard deviations below the mean.
## Neonatal sepsis
Blood culture-positive sepsis that is treated with antibiotics for more than 5 days.
## Small for gestational age
Birth weight less than the 10th percentile for gestational age.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
One issue was highlighted that might need specific thought when implementing the recommendations. This was raised during the development of this guideline. The issue is service organisation for implementing the developmental assessment at 4 years (uncorrected age).
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.# Context
This guideline focuses on the specialist developmental support and surveillance needed for the early identification of developmental problems and disorders in children born preterm.
The proportion of babies born preterm in the UK, defined as birth before 37 weeks' gestation, has remained steady for several years at 7.4%. In 2014 this amounted to 48,985 from a total of 656,957 live births, of which 2438 (5% of preterm births and 0.4% of all births) were before 28 weeks' gestation.
Preterm birth is associated with an increased risk of developmental problems and disorders. These include developmental challenges, physical, sensory, cognitive and learning disorders, and emotional and behavioural problems. These may extend into adolescence and, in some cases, be lifelong. In particular, the risk and prevalence of impairments that affect educational attainment rise sharply in children born before 28 weeks' gestation. Although most major disorders are detectable in the first 2 years of life, several developmental disorders and problems, particularly those that have an impact on the child's ability to participate and on their educational attainment, may not be apparent until they are older.
This guideline aims to improve the identification of developmental problems and disorders in children born preterm by setting standards for follow-up. This is expected to improve outcomes for these children by reducing variation in follow-up and enabling benchmarking of neonatal care. Developmental surveillance up to and at 2 years (corrected age) is recommended for identifying major problems and disorders. A later developmental assessment for children at high risk aims to identify problems that are more apparent at school age, with a view to supporting education plans for the child.
To find out what NICE has said on topics related to this guideline, see our web pages on intrapartum care, postnatal care, cerebral palsy, spasticity, autism and mental health and wellbeing.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Predictive accuracy of the WPPSI-IV at age 4 years (uncorrected) for children born preterm
What is the accuracy of a Wechsler Preschool and Primary Scale of Intelligence 4th Edition (WPPSI-IV) assessment at age 4 years (uncorrected) for predicting later educational difficulties in children of primary school age who were born before 28+0 weeks' gestation?
## Why this is important
Children born before 28+0 weeks' gestation are at increased risk of learning disability (intellectual disability), which may have an adverse impact on their learning and achievement at school, but may not be apparent at the 2-year developmental assessment. Determining the predictive accuracy of a WPPSI-IV assessment is key to providing parents or carers with accurate information about their child's likely development, so that educational support can be provided in order to reduce the risk of long-term learning disability (intellectual disability).
# Predictive accuracy of the PARCA-R for children born preterm
What is the accuracy of the parent-completed Parent Report of Children's Abilities – Revised (PARCA-R) questionnaire carried out at age 2 years (corrected) for predicting learning disability (intellectual disability), language impairment and special educational needs at age 4 years (uncorrected) for children born preterm?
## Why this is important
Parent-completed questionnaires such as the PARCA-R are used to identify children at risk of developmental problems and disorders. Although the PARCA-R has good diagnostic accuracy for identifying children at risk of concurrent developmental problems at age 2 years (corrected), its accuracy for predicting later risk of learning disability (intellectual disability), language impairment and learning difficulties is not known. Improved identification and provision of interventions are expected to lead to improved developmental outcomes for children born preterm.
# Predictive accuracy of the ASQ-3 for children born preterm
What is the concurrent and predictive accuracy of the parent-completed Ages and Stages Questionnaire, 3rd edition (ASQ-3) for detecting concurrent learning disability (intellectual disability) and motor impairment between the ages of 2 years (corrected) and 4 years (uncorrected) in children born preterm?
## Why this is important
The ASQ is widely used to identify children at risk of developmental problems and disorders, and there are many versions of the questionnaire that span the preschool years. If the ASQ-3 was found to have sufficient concurrent and predictive accuracy for detecting learning disability (intellectual disability) and motor impairment between the ages of 2 years (corrected) and 4 years (uncorrected), this developmental check could be considered for use in enhanced developmental surveillance.
# Accuracy of the SDQ for predicting social, attentional, emotional and behavioural problems in children born before 28+0 weeks' gestation
What is the accuracy of the parent-completed Strengths and Difficulties Questionnaire (SDQ) for predicting social, attentional, emotional and behavioural problems in children born before 28+0 weeks' gestation?
## Why this is important
Social, attentional, emotional and behavioural problems in children born preterm may go unnoticed, yet can have an adverse impact on a child's health and wellbeing, quality of life and school performance, as well as on their family. Identifying children at risk of these problems will enable intervention and family support to be provided in order to reduce their impact. In particular, identifying problems before school entry will support education planning and promote social and emotional development and attainment at school.
# Impact of enhanced developmental support and surveillance for children born preterm on parents and carers
Does enhanced developmental support and surveillance improve outcomes for the parents and carers of children born preterm?
## Why this is important
Enhanced developmental support and surveillance up to 4 years (uncorrected age) for children born preterm who fulfil the necessary criteria is expected to increase the detection of developmental problems and disorders and improve outcomes for these children. However, the acceptability of this approach to parents, carers and families also needs to be taken into consideration. A study that looks at the impact of enhanced developmental support and surveillance on parents and carers (for outcomes such as experience of services, satisfaction and anxiety) may help to identify where improvements can be made to future support and surveillance.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and support for parents and carers of all preterm babies\n\n## Providing information and support\n\nBe aware that the majority of children and young people born preterm have a good developmental outcome and good quality of life.\n\nProvide information about the risk and prevalence of developmental problems and disorders in babies born preterm (see section 1.2) to parents or carers, and offer to discuss this with them.\n\nProvide information to parents or carers of preterm babies that is tailored to their individual circumstances, taking into account:\n\ntheir child's potential developmental needs\n\ntheir level of education\n\nany social care needs they have\n\nany cultural, spiritual or religious beliefs\n\nthe need for consistency in information sharing among healthcare professionals.\n\nFollow the principles in the NICE guidelines on patient experience in NHS services\xa0and babies, children and young people's experience of healthcare in relation to communication (including different formats and languages), information and continuity of care. Also see NICE's guideline on shared decision making.\n\nProvide emotional and psychological support to parents or carers of preterm babies as needed, recognising the significant potential impact of having a preterm baby on all the family. Times when support may be particularly valuable include:\n\nwhen the baby is transferred between units or hospitals\n\nleading up to and on discharge home.\n\nProvide information to parents or carers of preterm babies about opportunities for peer support.\n\n## Information and support leading up to and on discharge home\n\nStart discharge planning as soon as possible after the birth of a preterm baby, and involve parents or carers at all stages.\n\nBefore discharging a preterm baby:\n\nagree a discharge plan with the parents or carers\n\nensure that the discharge plan includes clear information about any antenatal and perinatal risk factors for developmental problems and disorders (see section 1.2)\n\nshare the written discharge plan with parents or carers and with primary and secondary healthcare teams.\n\nHelp parents or carers to gain the knowledge, skills and confidence they need to look after their baby at home and to support the baby's developmental needs, taking into account that they are likely to be anxious about caring for their baby after discharge. This may relate to:\n\ninteraction with the baby\n\nmanaging feeding\n\npatterns of sleeping\n\nphysical positioning of the baby, including safe sleeping\n\nimpact on day-to-day living, such as social isolation because of fear of infection.\n\nInvolve the social support networks (which may include partners, grandparents or other family members) of parents or carers of a baby born preterm when planning discharge and during follow-up.\n\nInform parents or carers of all preterm babies about the routine postnatal care and support available, as described in the NICE guideline on postnatal care up to 8 weeks after birth.\n\nExplain to parents and carers of preterm babies about:\n\nuniversal services and national recommendations for assessing the development of all children through screening (for example, newborn hearing screening) and surveillance (including social, emotional, behavioural and language development) and\n\nwhether their baby will also be offered enhanced developmental support and surveillance (see section 1.3) and plans for follow-up.For more information on universal screening and surveillance services in England, see the Healthy Child Programme.\n\nExplain to parents or carers that their child's developmental (corrected) age, which is calculated from their original due date (and not the date they were born), will be used for the first 2 years when assessing their functional and developmental skills (such as walking and talking).\n\nAdvise parents or carers to talk to their health visitor or GP if they have any concerns about their child's development at any stage of childhood or adolescence.\n\nHealthcare professionals providing postnatal care and support in the community for babies born preterm should have the skills and knowledge to recognise and manage problems in these babies, including:\n\nproviding feeding support\n\naddressing concerns about sleeping\n\nhelping parents or carers to interact with their baby.\n\n# Risk and prevalence of developmental problems and disorders\n\nBe aware that children and young people born preterm are at increased risk of developmental problems and disorders.\n\nBe aware that for recommendations in this section:\n\nfor some developmental problems and disorders there was an absence of evidence about overall risk and prevalence in children born preterm\n\nthere was limited evidence about developmental problems and disorders in 11–18-year-olds\n\nfor some developmental problems and disorders the evidence was underpowered to detect an effect\n\nsome studies described specific gestational ages at birth, from which the committee was unable to extrapolate to other gestational ages\n\nother gestational ages and other factors not listed here might also be associated with increased risk of developmental problems and disorders.\n\n## Cerebral palsy\n\nBe aware that children born preterm are at increased risk of cerebral palsy, and that:\n\nthe following are independent risk factors:\n\n\n\ngrade 3 or 4 intraventricular haemorrhage\n\ncystic periventricular leukomalacia\n\nneonatal sepsis\n\nbronchopulmonary dysplasia for which mechanical ventilation was still needed at 36 weeks' postmenstrual age\n\nantenatal steroids not given\n\npostnatal steroids given to babies born before 32+0 weeks' gestation\n\n\n\nprevalence increases with decreasing gestational age.\n\nSee also the NICE guideline on cerebral palsy in under 25s: assessment and management.\n\n## Motor function problems\n\nBe aware that children born preterm are at increased risk of motor function problems, and that the following are independent risk factors:\n\nbrain lesions (for example, grade 3 or 4 intraventricular haemorrhage, periventricular leukomalacia, infarct)\n\nnecrotising enterocolitis that needed surgery\n\nneonatal sepsis\n\nsevere retinopathy of prematurity.\n\nBe aware that there is an increased prevalence of developmental coordination disorder in children born preterm compared with the general population.\n\n## Learning disability (intellectual disability)\n\nBe aware that children born preterm are at increased risk of learning disability (intellectual disability), and that:\n\nthe following are independent risk factors:\n\n\n\ngrade 3 or 4 intraventricular haemorrhage\n\ncystic periventricular leukomalacia\n\nneonatal sepsis in babies born before 28+0 weeks' gestation\n\nnecrotising enterocolitis that needed surgery in babies born before 33+0\xa0weeks' gestation\n\nbronchopulmonary dysplasia for which mechanical ventilation was still needed at 36 weeks' postmenstrual age in babies born before 28+0\xa0weeks' gestation\n\nsevere retinopathy of prematurity in babies born before 28+0\xa0weeks' gestation\n\nsmall for gestational age\n\npostnatal steroids given to babies born before 33+0\xa0weeks' gestation\n\nmother from a low-income or disadvantaged background\n\n\n\nprevalence increases with decreasing gestational age.\n\n## Special educational needs and educational attainment\n\nBe aware that children born preterm are at increased risk of having special educational needs, and that the following are independent risk factors:\n\nbrain lesions detected by ultrasound\n\nmale sex.\n\nBe aware that children born preterm are at increased risk of low educational attainment at the end of the Early Years Foundation stage and at key stage 1 (age up to 7 years), and that:\n\nprevalence of low educational attainment increases with decreasing gestational age\n\nchildren born preterm are at increased risk of low attainment for reading and maths, and this risk is greater in children born before 26+0 weeks' gestation\n\nthe following are independent risk factors for low attainment in maths in children born before 32+0 weeks' gestation:\n\n\n\nintraventricular haemorrhage\n\nbronchopulmonary dysplasia for which mechanical ventilation was still needed at 36 weeks' postmenstrual age.\n\n\n\n## Executive function problems\n\nBe aware that children born before 32+0 weeks' gestation are at increased risk of executive function problems at preschool and school ages, and that prevalence increases with decreasing gestational age.\n\n## Speech, language and communication\n\nBe aware that children born preterm are at increased risk of speech, language and communication problems and disorders, and that the following are independent risk factors for language disorder:\n\ngrade 3 or 4 intraventricular haemorrhage\n\ncystic periventricular leukomalacia\n\nmale sex.\n\n## Attention, impulsivity and hyperactivity\n\nBe aware that children born before 33+0\xa0weeks' gestation are at increased risk of symptoms of hyperactivity, impulsivity and particularly inattention at preschool and school ages.\n\nBe aware that children born before 28+0 weeks' gestation are at increased risk of attention deficit hyperactivity disorder (ADHD), and that male sex is an independent risk factor.\n\n## Autism spectrum disorder\n\nBe aware that children born before 28+0\xa0weeks' gestation are at increased risk of symptoms of social communication impairment, which may suggest a problem in the autism spectrum.\n\nBe aware that children born preterm are at increased risk of autism spectrum disorder, and that the following are independent risk factors:\n\nintraventricular haemorrhage in babies born before 34+0\xa0weeks' gestation\n\nmale sex.\n\n## Emotional and behavioural problems\n\nBe aware that children born preterm are at increased risk of emotional and behavioural problems, particularly internalising behaviours and passivity, at preschool and school ages, and that the following are independent risk factors:\n\nmajor brain lesions (for example, periventricular leukomalacia, parenchymal lesions)\n\nmother with mental health problems\n\nmother younger than 25 years\n\nmother from a low-income or disadvantaged background.\n\n## Feeding problems\n\nBe aware that children born preterm are at increased risk of oro-motor feeding problems (for example, problems with sucking and chewing), and that this increased risk persists until at least 6 years of age in children born before 26+0 weeks' gestation.\n\n## Sleep problems\n\nBe aware that children born preterm are at increased risk of sleep apnoea up to 6 years of age.\n\n## Visual impairment\n\nBe aware that the prevalence of visual impairment increases with decreasing gestational age in children born preterm, and that the following are independent risk factors:\n\ngrade 3 or 4 intraventricular haemorrhage with a shunt\n\nneonatal sepsis in babies born before 33+0 weeks' gestation\n\nretinopathy of prematurity needing treatment.\n\n## Hearing impairment\n\nBe aware that the prevalence of hearing impairment increases with decreasing gestational age in children born preterm, and that neonatal sepsis is an independent risk factor in babies born before 28+0\xa0weeks' gestation.\n\n## Developmental delay\n\nBe aware that children born preterm are at increased risk of developmental delay (identified using a range of tools), and that the following are independent risk factors:\n\nsmall for gestational age\n\nmale sex\n\nmother from a low-income or disadvantaged background\n\nblack, Asian or other minority ethnic group\n\nmultiple pregnancy.\n\n# Enhanced developmental support and surveillance\n\n## Criteria for enhanced developmental support and surveillance up to 2\xa0years (corrected age)\n\nProvide enhanced developmental support and surveillance by a multidisciplinary team (see section 1.4) up to 2\xa0years (corrected age) for children born preterm who:\n\nhave a developmental problem or disorder or\n\nare at increased risk of developmental problems or disorders, based on the following criteria:\n\n\n\nborn before 30+0\xa0weeks' gestation or\n\nborn between 30+0 and 36+6\xa0weeks' gestation and has or had 1 or more of the following risk factors:\n\n\n\na brain lesion on neuroimaging likely to be associated with developmental problems or disorders (for example, grade 3 or 4 intraventricular haemorrhage or cystic periventricular leukomalacia)\n\ngrade 2 or 3 hypoxic ischaemic encephalopathy in the neonatal period\n\nneonatal bacterial meningitis\n\nherpes simplex encephalitis in the neonatal period.\n\n\n\n\n\nConsider enhanced developmental support and surveillance by a multidisciplinary team up to 2 years (corrected age) for children born preterm who do not meet the criteria in recommendation 1.3.1 but are suspected of being at increased risk of developmental problems or disorders, taking into account the presence and severity of risk factors (see recommendations 1.2.3 to 1.2.20).\n\n## Criteria for enhanced developmental support and surveillance at 4\xa0years (uncorrected age)\n\nProvide a face-to-face developmental assessment at 4 years (uncorrected age) for all children born before 28+0\xa0weeks' gestation (see recommendation 1.3.13).\n\n## Providing enhanced developmental support\n\nProvide parents or carers of a preterm baby having enhanced developmental support with a single point of contact within the neonatal service for outreach care after discharge.\n\nUse a range of approaches when providing enhanced developmental support and tailor the support to take account of individual preferences and needs. Approaches may include:\n\nface-to-face meetings, in clinics or in the home\n\na telephone helpline\n\ntext messages, emails or similar.\n\n## Providing enhanced developmental surveillance up to 2 years (corrected age)\n\nFor all children born preterm who are having enhanced developmental surveillance, provide as a minimum:\n\nface-to-face follow-up visits in the first year that focus on development, at the following corrected ages:\n\n\n\nbetween 3 and 5 months and\n\nby 12 monthsand\n\n\n\na detailed face-to-face developmental assessment at 2 years (corrected age) (see recommendation 1.3.11).\n\n## Checks at each developmental visit and assessment\n\nAt each face-to-face follow-up visit and developmental assessment (see recommendations 1.3.6, 1.3.11 and 1.3.13) for a child born preterm who is having enhanced developmental surveillance, professionals with appropriate skills (see section 1.4) should:\n\ndiscuss with parents or carers whether they have any concerns about their child's development\n\ninclude checks for developmental problems and disorders (see recommendation 1.3.8)\n\nmeasure length or height, weight and head circumference\n\ncarefully evaluate and review any developmental concerns reported by parents or carers or noted during the visit or assessment\n\ncorrect for gestational age up to 2\xa0years when assessing development\n\nconsider further investigation or referral if a developmental problem or disorder is suspected or present\n\nrefer the child to the appropriate local pathway if needed.\n\nAt each face-to-face follow-up visit and developmental assessment for a child born preterm who is having enhanced developmental surveillance, check for signs and symptoms of developmental problems and disorders as appropriate, such as:\n\ncerebral palsy (see recommendation 1.3.9)\n\nglobal developmental delay and learning disability (intellectual disability)\n\nautism spectrum disorder (see recommendation 1.3.10)\n\nvisual impairment\n\nhearing impairment\n\nfeeding problems\n\nsleep problems, including sleep apnoea\n\nspeech, language and communication problems\n\nmotor problems\n\nproblems with inattention, impulsivity or hyperactivity\n\nemotional and behavioural problems\n\nexecutive function problems\n\npotential special educational needs.\n\nRecognise the following as possible early motor signs of cerebral palsy:\n\ndelayed motor milestones, such as late sitting, crawling or walking (correcting for gestational age)\n\nunusual (abnormal or absent) fidgety movements or other abnormalities of movement, including asymmetry or paucity of movement\n\nabnormalities of tone, including hypotonia (floppiness) or spasticity (stiffness)\n\npersisting feeding difficulties.\n\nSee also the NICE guideline on cerebral palsy in under 25s: assessment and management.\n\nFor guidance on recognising signs and symptoms of possible autism spectrum disorder, see the NICE guideline on autism spectrum disorder in under 19s: recognition, referral and diagnosis.\n\n## Developmental assessment at 2\xa0years (corrected age)\n\nProvide a face-to-face developmental assessment at 2 years (corrected age) for children born preterm who are having enhanced developmental surveillance. This assessment should include as a minimum:\n\nall aspects listed in recommendation 1.3.7\n\nusing the Parent Report of Children's Abilities – Revised (PARCA-R) to identify if the child is at risk of global developmental delay, learning disability (intellectual disability) or language problems:\n\n\n\nif the PARCA-R is not suitable (for example, because of poor English language comprehension or the child being outside the validated age range of 22 to 26 months), use a suitable alternative parent questionnaire\n\n\n\nGross Motor Function Classification System (GMFCS) score if cerebral palsy has been diagnosed\n\nensuring that checks of vision and hearing have been carried out in line with national recommendations.\n\n## Follow-up and assessment after 2 years (corrected age)\n\nAfter the developmental assessment at 2 years (corrected age):\n\nadvise parents or carers of all children that their child should continue to be followed up by universal screening and surveillance services for all children and young people and\n\nadvise parents or carers of children born before 28+0 weeks' gestation that their child will also be offered a further developmental assessment at 4 years (uncorrected age). For more information on universal screening and surveillance services in England, see the Healthy Child Programme.\n\n## Further developmental assessment at 4 years (uncorrected age) for children born before 28+0 weeks' gestation\n\nProvide a face-to-face developmental assessment at 4 years (uncorrected age) for all children born before 28+0\xa0weeks' gestation that includes as a minimum:\n\nall aspects listed in recommendation 1.3.7\n\nusing the following parent questionnaires, to be completed by parents or carers beforehand and the results discussed during the assessment:\n\n\n\nthe Strengths and Difficulties Questionnaire (SDQ), to check for social, attentional, emotional and behavioural problems\n\nthe Ages and Stages Questionnaire (ASQ) 48-month questionnaire, to check for various aspects of development\n\n\n\nreviewing previous assessments and information from all other relevant sources\n\nusing a standardised test to assess IQ, such as the Wechsler Preschool and Primary Scales of Intelligence 4th Edition (WPPSI) test\n\nGMFCS score if cerebral palsy has been diagnosed\n\nensuring that the child has been offered orthoptic vision screening as recommended by the National Screening Committee.\n\nAfter the 4-year assessment, provide a comprehensive summary of the child's strengths and difficulties, including any developmental problems and disorders, that:\n\nis in a format that is accessible to parents and carers\n\nif needed, informs the development of a plan for intervention and support, including educational support\n\nshould be shared with the neonatal consultant.\n\n## Information sharing and referral\n\nIf findings at any stage of developmental surveillance, including the assessments at 2 years (corrected age) and 4 years (uncorrected age) (see recommendations 1.3.11 and 1.3.13), suggest any developmental problems or disorders:\n\nshare information with:\n\n\n\nparents or carers\n\nprimary and secondary healthcare teams\n\n\n\nrefer the child to an appropriate local pathway for further assessment\n\nask parents or carers for permission to share the information with:\n\n\n\neducation services\n\nsocial care services as appropriate.\n\n\n\n## Later presentation of learning or behavioural problems\n\nPrimary and secondary education professionals should be aware that:\n\npreterm birth may be a factor in learning or behavioural problems\n\nthese problems can emerge at any point during a child or young person's education\n\nprompt referral to educational support services may be needed.\n\n# Delivering enhanced developmental support and surveillance\n\nEnhanced developmental support and surveillance for children born preterm who meet the defined criteria (see recommendations 1.3.1 to 1.3.3) should:\n\nbe provided as an integral part of a neonatal service working together with local health services\n\nempower parents and carers to be involved in decisions about their child's care\n\nbe delivered by a multidisciplinary team with the necessary skills (see recommendation 1.4.2)\n\nrecord outcomes at specified time points for national audit (see section 1.5)\n\nbe monitored by checking adherence to the recommendations in this guideline, including follow-up rates and outcomes, as part of the routine provision of neonatal care by neonatal operational delivery networks and commissioners.\n\nMultidisciplinary teams delivering enhanced developmental support and surveillance for children born preterm should include professionals with knowledge and expertise in the following areas:\n\nneonatal care\n\ndevelopment of children born preterm, including developmental problems and disorders (see recommendation 1.3.8)\n\nproviding support in the community, for example for feeding problems\n\nadministering and interpreting results from questionnaires and standardised tests (for example, the PARCA-R, SDQ, ASQ and IQ tests such as the WPPSI)\n\ncollating information from a range of sources to facilitate decision-making and writing reports\n\nlocal care pathways, including Early Years education.\n\nMultidisciplinary teams delivering enhanced developmental support and surveillance for children born preterm should include the following professionals:\n\nfor enhanced developmental support:\n\n\n\nneonatologist or paediatrician with an understanding of neonatal care and child development\n\noutreach nurse or nurse with expertise in the development of babies born preterm\n\n\n\nfor the surveillance assessments up to and including 2 years (corrected age) (see recommendation 1.3.6):\n\n\n\nneonatologist or paediatrician with an understanding of neonatal care and child development\n\nat least one of occupational therapist, physiotherapist and speech and language therapist\n\n\n\nfor the surveillance assessment at 4 years (uncorrected age) (see recommendation 1.3.13):\n\n\n\neducational or clinical psychologist\n\npaediatrician with expertise in neurodevelopment.\n\n\n\nMultidisciplinary teams delivering enhanced developmental support and surveillance for children born preterm should have access to the following professionals:\n\ncommunity nurse or health visitor\n\noccupational therapist\n\nphysiotherapist\n\nspeech and language therapist\n\npaediatric neurologist\n\ndietitian.\n\n# Neonatal audit\n\nRecord the following information, as applicable, in the National Neonatal Research Database for every child born preterm who has enhanced developmental surveillance:\n\nwhether the child had specialist neonatal care and if so, relevant details\n\nthe reasons for enhanced surveillance (see recommendations 1.3.1 to 1.3.3)\n\nat the assessment at 2 years (corrected age) (see recommendation 1.3.11):\n\n\n\ndiagnosis of cerebral palsy\n\nGMFCS score if cerebral palsy is present\n\nPARCA-R score\n\nepilepsy that is currently being treated\n\nimpairments of hearing, vision, speech and language, and motor skills (as defined in Figure 3 in Classification of health status at 2 years as a perinatal outcome, report of a BAPM/RCPCH working group, version 1.0, 8 January 2008)\n\n\n\nat the assessment at 4 years (uncorrected age) (see recommendation 1.3.13):\n\n\n\ndiagnosis of cerebral palsy\n\nGMFCS score if cerebral palsy is present\n\nfull scale IQ score\n\nSDQ total difficulty score, subscale scores and impact score\n\nany formal clinical diagnoses of a developmental disorder (for example, autism spectrum disorder)\n\nepilepsy that is currently being treated\n\nthe presence of a hearing impairment, defined as profound deafness or impairment severe enough to need hearing aids or cochlear implant\n\nresults of national orthoptic vision screening.\n\n\n\nRecord routine educational measures at Key Stage 2 (including special educational needs and disability [SEND]) on an operational delivery network-wide basis, to allow educational outcomes at 11 years to be linked to neonatal information.\n\n# Terms used in this guideline\n\n## Developmental problems and disorders\n\nA group of problems that become apparent during child development and often occur together. They are characterised by impairments of personal, social, academic or occupational functioning, ranging from very specific limitations to global impairments of social skills or cognition, as measured by parent or teacher reports and surveillance tools. The term 'disorder' applies if the condition is severe, persistent and pervasive enough to meet the criteria for a disorder in the International statistical classification of diseases and related health problems (ICD) or the Diagnostic and statistical manual of mental disorders (DSM).\n\n## Enhanced developmental support\n\nAdditional advice and interventions with skilled professionals for children and young people born preterm and their parents and carers. The aim is to support them after discharge from hospital, respond to their concerns, and reduce the impact of any developmental problems and disorders.\n\n## Enhanced developmental surveillance\n\nActive monitoring of a child's development, at set times and using specific tools, to detect developmental problems and disorders.\n\n## Executive function\n\nExecutive functions are a set of inter-related cognitive processes that are used to organise and regulate thoughts and actions. These processes are important for guiding learning and behaviour, and comprise skills such as inhibition, impulse control, emotional control, working memory, cognitive flexibility and planning.\n\n## Learning disability (Intellectual disability)\n\nLearning disability (intellectual disability) is characterised by deficits in general cognitive abilities (such as reasoning and abstract thinking) and impairment of adaptive function that affects several aspects of daily life. In the ICD-10 this is defined as an IQ score more than 2 standard deviations below the mean.\n\n## Neonatal sepsis\n\nBlood culture-positive sepsis that is treated with antibiotics for more than 5\xa0days.\n\n## Small for gestational age\n\nBirth weight less than the 10th percentile for gestational age.", 'Putting this guideline into practice': 'NICE has produced tools and resources to help you put this guideline into practice.\n\nOne issue was highlighted that might need specific thought when implementing the recommendations. This was raised during the development of this guideline. The issue is service organisation for implementing the developmental assessment at 4\xa0years (uncorrected age).\n\nPutting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.\n\nChanges recommended for clinical practice that can be done quickly – like changes in prescribing practice – should be shared quickly. This is because healthcare professionals should use guidelines to guide their work – as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.\n\nChanges should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).\n\nDifferent organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.\n\nHere are some pointers to help organisations put NICE guidelines into practice:\n\n. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.\n\n. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.\n\n. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.\n\n. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.\n\n. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.\n\n. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.\n\n. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.\n\n. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.\n\nNICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.\n\nAlso see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care – practical experience from NICE. Chichester: Wiley.', 'Context': "This guideline focuses on the specialist developmental support and surveillance needed for the early identification of developmental problems and disorders in children born preterm.\n\nThe proportion of babies born preterm in the UK, defined as birth before 37\xa0weeks' gestation, has remained steady for several years at 7.4%. In 2014 this amounted to 48,985 from a total of 656,957 live births, of which 2438 (5% of preterm births and 0.4% of all births) were before 28 weeks' gestation.\n\nPreterm birth is associated with an increased risk of developmental problems and disorders. These include developmental challenges, physical, sensory, cognitive and learning disorders, and emotional and behavioural problems. These may extend into adolescence and, in some cases, be lifelong. In particular, the risk and prevalence of impairments that affect educational attainment rise sharply in children born before 28 weeks' gestation. Although most major disorders are detectable in the first 2\xa0years of life, several developmental disorders and problems, particularly those that have an impact on the child's ability to participate and on their educational attainment, may not be apparent until they are older.\n\nThis guideline aims to improve the identification of developmental problems and disorders in children born preterm by setting standards for follow-up. This is expected to improve outcomes for these children by reducing variation in follow-up and enabling benchmarking of neonatal care. Developmental surveillance up to and at 2 years (corrected age) is recommended for identifying major problems and disorders. A later developmental assessment for children at high risk aims to identify problems that are more apparent at school age, with a view to supporting education plans for the child.\n\nTo find out what NICE has said on topics related to this guideline, see our web pages on intrapartum care, postnatal care, cerebral palsy, spasticity, autism and mental health and wellbeing.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Predictive accuracy of the WPPSI-IV at age 4 years (uncorrected) for children born preterm\n\nWhat is the accuracy of a Wechsler Preschool and Primary Scale of Intelligence 4th Edition (WPPSI-IV) assessment at age 4 years (uncorrected) for predicting later educational difficulties in children of primary school age who were born before 28+0 weeks' gestation?\n\n## Why this is important\n\nChildren born before 28+0 weeks' gestation are at increased risk of learning disability (intellectual disability), which may have an adverse impact on their learning and achievement at school, but may not be apparent at the 2-year developmental assessment. Determining the predictive accuracy of a WPPSI-IV assessment is key to providing parents or carers with accurate information about their child's likely development, so that educational support can be provided in order to reduce the risk of long-term learning disability (intellectual disability).\n\n# Predictive accuracy of the PARCA-R for children born preterm\n\nWhat is the accuracy of the parent-completed Parent Report of Children's Abilities – Revised (PARCA-R) questionnaire carried out at age 2 years (corrected) for predicting learning disability (intellectual disability), language impairment and special educational needs at age 4 years (uncorrected) for children born preterm?\n\n## Why this is important\n\nParent-completed questionnaires such as the PARCA-R are used to identify children at risk of developmental problems and disorders. Although the PARCA-R has good diagnostic accuracy for identifying children at risk of concurrent developmental problems at age 2 years (corrected), its accuracy for predicting later risk of learning disability (intellectual disability), language impairment and learning difficulties is not known. Improved identification and provision of interventions are expected to lead to improved developmental outcomes for children born preterm.\n\n# Predictive accuracy of the ASQ-3 for children born preterm\n\nWhat is the concurrent and predictive accuracy of the parent-completed Ages and Stages Questionnaire, 3rd edition (ASQ-3) for detecting concurrent learning disability (intellectual disability) and motor impairment between the ages of 2 years (corrected) and 4 years (uncorrected) in children born preterm?\n\n## Why this is important\n\nThe ASQ is widely used to identify children at risk of developmental problems and disorders, and there are many versions of the questionnaire that span the preschool years. If the ASQ-3 was found to have sufficient concurrent and predictive accuracy for detecting learning disability (intellectual disability) and motor impairment between the ages of 2 years (corrected) and 4 years (uncorrected), this developmental check could be considered for use in enhanced developmental surveillance.\n\n# Accuracy of the SDQ for predicting social, attentional, emotional and behavioural problems in children born before 28+0 weeks' gestation\n\nWhat is the accuracy of the parent-completed Strengths and Difficulties Questionnaire (SDQ) for predicting social, attentional, emotional and behavioural problems in children born before 28+0 weeks' gestation?\n\n## Why this is important\n\nSocial, attentional, emotional and behavioural problems in children born preterm may go unnoticed, yet can have an adverse impact on a child's health and wellbeing, quality of life and school performance, as well as on their family. Identifying children at risk of these problems will enable intervention and family support to be provided in order to reduce their impact. In particular, identifying problems before school entry will support education planning and promote social and emotional development and attainment at school.\n\n# Impact of enhanced developmental support and surveillance for children born preterm on parents and carers\n\nDoes enhanced developmental support and surveillance improve outcomes for the parents and carers of children born preterm?\n\n## Why this is important\n\nEnhanced developmental support and surveillance up to 4 years (uncorrected age) for children born preterm who fulfil the necessary criteria is expected to increase the detection of developmental problems and disorders and improve outcomes for these children. However, the acceptability of this approach to parents, carers and families also needs to be taken into consideration. A study that looks at the impact of enhanced developmental support and surveillance on parents and carers (for outcomes such as experience of services, satisfaction and anxiety) may help to identify where improvements can be made to future support and surveillance."}
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https://www.nice.org.uk/guidance/ng72
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This guideline covers the developmental follow-up of babies, children and young people under 18 years who were born preterm (before 37+0 weeks of pregnancy). It explains the risk of different developmental problems and disorders, and specifies what extra assessments and support children born preterm might need during their growth and development.
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80852b3fc220a93094ddbbb3907bc34d9b7cdbcf
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nice
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moorLDI2-BI: a laser doppler blood flow imager for burn wound assessment
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moorLDI2-BI: a laser doppler blood flow imager for burn wound assessment
Evidence-based recommendations on moorLDI2-BI: a laser doppler blood flow imager for burn wound assessment.
# Recommendations
NICE medical technology guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
The case for adopting the moorLDI2-BI in the NHS is supported when it is used to guide treatment decisions for patients in whom there is uncertainty about the depth and healing potential of burn wounds that have been assessed by experienced clinicians.
There is evidence of benefit for patients and for the NHS when the moorLDI2-BI is used in addition to clinical evaluation compared with clinical evaluation alone, in burn wounds of intermediate (also known as indeterminate) depth. By demonstrating which areas of any burn wound require surgical treatment and which do not, the moorLDI2-BI enables decisions about surgery to be made earlier and for surgery to be avoided in some patients.
The estimated average cost saving when the moorLDI2-BI is used in addition to clinical evaluation is £1,281 per patient scanned (if the equipment is purchased) or £1,274 per patient scanned (if the equipment is leased). This is based on an assumption of a 17% reduction in the number of skin graft operations at a cost of £2,319 each. # The technology
# Description of the technology
The moorLDI2-BI (Moor Instruments Ltd) is a laser doppler blood flow imaging system for the non-invasive mapping of blood flow in an area of skin that has been burned. This can be used in addition to clinical evaluation to guide decisions about the need for surgical treatment of burn wounds.
The moorLDI2-BI includes a scan head, scan controller and a touch-screen panel computer, all mounted on a mobile stand that can be used in a ward, operating theatre or consulting room as well as in rooms designed specifically for laser equipment.
The moorLDI2-BI uses a low-power laser beam, directed at the burn wound using a mirror. The laser beam scans across the burn wound by rotating the mirror and there is no direct contact with the burned skin. Laser light scattered from moving blood cells in the tissue undergoes a doppler frequency shift, proportional to the average speed of the blood cells. Some of the scattered laser light is focused onto photodiode detectors and the resulting photocurrent is processed to calculate the blood flow in the tissue. Results are displayed as a colour-coded blood flow image and a colour video image of the burn wound. Depending on the size of the burn wound and required resolution of the image, the scan takes from 80 seconds to about 5 minutes. Healing potential results based on the blood-flow image are calculated and reported in three categories: less than 14 days, 14–21 days and more than 21 days.
The moorLDI2-BI can be purchased at a cost of approximately £53,942 with an annual servicing cost of approximately £8,301, or it can be leased at an inclusive cost of approximately £22,000 per year.
# Current management
Current provision for inpatient treatment of burn injuries within England and Wales, based on the recommendation of the National Burn Care Review, is by specialised burn care services which consist of burn centres, burn units and burn facilities.
The assessment of burn wound depth and healing potential is fundamental in planning burn wound management. An experienced clinician can easily identify a burn that is epidermal and will heal without surgery, or a full thickness burn that requires surgical excision and grafting. However, it is often difficult to distinguish the superficial dermal burns that will heal well, from deep dermal burns, when a prolonged healing time will result in hypertrophic scarring (when the scar is swollen and red). It is difficult to assess burn wound depth and healing time in children because of the prevalence of mixed-depth scald burns and their thin skin.
Diagnosis of burn wound depth and healing potential is also difficult in patients with dark skin (including those with suntan, birthmarks or tattoos). Identifying the level of burn injury can be complicated by other factors such as oedema, tissue hypoxia and burn wound conversion, when superficial burns progress into deeper wounds because of the death of severely injured cells.
Clinical evaluation is the most widely used method of assessing burn wound depth and healing potential. This method is based on visual and tactile assessment of the external characteristics of the burn. The accuracy of clinical examination depends on the experience of the clinician. Other less widely used methods such as thermography and fluoroscein injections are also available for burn wound assessment.
The surgical procedure for treatment of burn wounds usually involves removing the damaged skin (using excision or debridement) followed by skin grafting. Skin grafting is the transplantation of skin from a healthy part of the body. This procedure is used for deep dermal wounds because it reduces the wound healing time and wound complications. Even after excision and skin grafting there will be scarring, and hypertrophic scarring may occur.# Clinical evidence
# Summary of clinical evidence
The key outcome for moorLDI2-BI laser doppler blood flow imaging is the development of an appropriate treatment plan based on an accurate assessment of burn wound depth and healing potential. Other performance measures are the sensitivity, specificity, negative predictive value and positive predictive value of the wound healing potential before 14 or 21 days. Clinical utility outcomes associated with the technology are avoiding unnecessary operations, extent of surgery, number of dressing changes, complications and length of stay in hospital. Longer-term outcomes are extent and type of scarring and the recovery of pre-injury function.
## Accuracy of the moorLDI2-BI
The accuracy of the moorLDI2-BI in the assessment of burn wounds was examined in eight studies with a variety of criteria including ability to predict healing within 14 or 21 days. Comparisons were made with clinical and histological evaluation of burn wound depth.
Pape et al. (2001) reported an audit of wound healing at 21 days for 76 intermediate depth wounds in 48 patients. Results showed the moorLDI2-BI to be 97% accurate (74/76) in predicting wound healing at 21 days compared with 70% (53/76) for clinical evaluation (no statistical comparison reported).
Hoeksema et al. (2009) investigated the changing accuracies of laser doppler imaging and clinical evaluation over days 0, 1, 3, 5 and 8 after injury. Forty patients with intermediate depth burn wounds were scanned using the moorLDI2-BI. The final assessment of wound depth showed a deep partial or full thickness burn in 14 patients, 12 of whom had a skin graft, and a superficial dermal burn in 26 patients. Accuracies on days 0, 1, 3, 5 and 8 were 41%, 62%, 53%, 71% and 100% respectively by clinical evaluation, and 55%, 80%, 95%, 97% and 100% respectively by laser doppler imaging. The burn wound depth accuracy using the moorLDI2-BI was significantly higher than clinical evaluation on day 3 (p < 0.001) and day 5 (p = 0.005) but not on days 0, 1 or 8.
Jeng et al. (2003) described a prospective blinded trial comparing laser doppler imaging using the moorLDI2-BI versus clinical evaluation by an experienced burn wound surgeon to decide whether or not to operate. Forty-one wounds of intermediate depth were analysed. Biopsy confirmation was obtained for 21 wounds. There was agreement on wound depth between laser doppler imaging and clinical evaluation in 56% (23/41) of cases. The surgeon's determination of burn wound depth was accurate in 71% (15/21) of wounds biopsied. The moorLDI2-BI was 100% (7/7) accurate in wounds for which it indicated a need for excision.
Monstrey et al. (2011) compared healing prediction based on interpretation of a moorLDI2-BI scan with actual wound healing as recorded photographically for 433 burn wounds in 139 patients. This assessment found an overall accuracy for the moorLDI2-BI of 96.3% with sensitivity 94.5%, specificity 97.2%, positive predictive value 94.5% and negative predictive value 97.2%.
La Hei et al. (2006) scanned 50 burns in 31 paediatric patients. Two experienced burn wound surgeons independently reviewed the scans, photographs and a basic patient history, without meeting the patient. One surgeon identified 82 areas of differing depth, the other identified 76 areas, and both surgeons predicted healing times (superficial heal: less than 14 days or deep heal: more than 14 days or graft). Overall, 97% (154/158) of predicted healing times were correct with four deep burn areas incorrectly predicted to heal within 14 days. No superficial wounds were reported as deep.
Holland et al. (2002) investigated the ability of laser doppler imaging to evaluate burn wound depth in children by scanning 58 patients and comparing the predicted outcome (from either the scan or from clinical evaluation) with the subsequent wound outcome at 12 days. One patient was excluded because there was too much movement for the scan to be interpreted. Clinical evaluation correctly identified 66% (19/29) of deep partial or full thickness burns between 36 and 72 hours after injury compared with 90% (26/29) using moorLDI2-BI scans. Scans using moorLDI2-BI were also more specific, correctly diagnosing 96% (27/28) of superficial partial thickness burns compared with 71% (20/28) from clinical evaluation alone (no statistical comparison reported).
Niazi et al. (1993) reported results from a pilot study that analysed 17 burn wounds on 13 patients. Punch biopsies were used to confirm burn wound depth at 72 hours after injury. Clinical evaluation was correct for 41% (7/17) of the burns, overestimated depth in 41% (7/17) and underestimated depth in 18% (3/17). Burn wound depth assessed from moorLDI2-BI scans was correct for 100% (17/17) of burn wounds (no statistical comparison reported).
Mill et al. (2009) compared moorLDI2-BI image colours with wound outcomes in 85 burns on 48 children. Analysis of the image colour regions was found to be significantly related to re-epithelialisation (p < 0.003), grafting (p < 0.001) and active scar management (p = 0.003).
## Clinical utility outcomes
Two studies evaluated whether or not using the moorLDI2-BI enabled appropriate skin grafting decisions to be made earlier than using clinical evaluation alone. Jeng et al. (2003) described a prospective blinded trial that compared laser doppler imaging versus clinical evaluation by an experienced burn wound surgeon, in deciding whether to operate or not on 41 burn wounds of intermediate depth. There was agreement on wound depth between the imaging and clinical evaluation in 56% (23/41) of cases. In these cases the moorLDI2-BI determined wound depth a median of 2 days (minimum = 0, maximum = 4) earlier than clinical evaluation alone (no statistical comparison reported). Kim et al. (2010) described a non-randomised cohort study of 196 children with an acute burn injury who required surgical treatment. Laser doppler imaging was used in addition to clinical evaluation on 49% (96/196), and 51% (100/196) were assessed by clinical evaluation alone. The mean time from date of injury to the decision to graft was 8.9 days in the moorLDI2-BI group compared with 11.6 days in the group assessed by clinical evaluation alone (p = 0.01).
# Committee considerations
The Committee considered that there was good clinical evidence that information from moorLDI2-BI scans increases the accuracy of predicting burn wound healing and also that this information can be used to facilitate treatment plans. Using the moorLDI2-BI in addition to clinical evaluation can enable earlier surgical treatment in some patients and avoid the need for surgery in others. It may also reduce the extent of surgery.
Burn wounds on dark skin can be difficult to assess clinically. The Committee considered that the moorLDI2-BI offers particular advantages for assessing burn wounds on dark skin.
The Committee was advised that additional patient and system benefit could be obtained by using the moorLDI2-BI to define accurately the margins of surgical areas for the skin graft operations, so helping to limit the extent of excision and grafting in some patients.
There are many factors that are known to have a detrimental effect on moorLDI2-BI images or their interpretation, including infected wounds, patient movement, old scars and tattoos. These are acknowledged in the published studies and also recognised by the manufacturer in its user guide. It was therefore considered important that moorLDI2-BI images should only be taken and interpreted by a clinician trained in use of the technique.
The Committee was advised that the moorLDI2-BI can be used to assess burns treated by biological and semi-biological dressings.
The Committee considered that there was no evidence to suggest patients were likely to be harmed by the moorLDI2-BI used by trained clinicians.# NHS considerations
# System impact
System benefits associated with the moorLDI2-BI for burn wound assessment are based on reducing the length of hospital stay and avoiding unnecessary skin grafting operations.
Timing of moorLDI2-BI imaging is important because burn wounds change rapidly in the first 48 hours after injury. The evidence suggested that the best time for imaging is 48–72 hours after the injury, but the device can be used up to 5 days after injury.
Wound assessment using the moorLDI2-BI needs a trained clinician to operate the device and to interpret the results. In a study to assess clinical benefit, La Hei et al. (2006) reported an increase in accuracy of interpretation of the laser doppler images by a new assessor from 83% (15/18) to 96% (73/76) over a 6 month period.
# Committee considerations
The Committee considered that earlier and more accurate prediction of the need (or lack of need) for surgery using the moorLDI2-BI would benefit the system by reducing unnecessary operations and by saving on inpatient care. These are considered further in the cost modelling (see section 5.2).
The Committee was advised that training is important for all staff to operate this device and interpret the images. The cost model includes costs for 2 days' training for one consultant, two registrars and three nurses every 2 years for each device.# Cost considerations
# Cost evidence
The evidence comprised a cost analysis to assess the costs and savings to the NHS from use of the moorLDI2-BI for the assessment of burn wounds of intermediate depth, as described in the manufacturer's submission. The costs and savings from using the moorLDI2-BI in addition to clinical evaluation were compared with those from using clinical evaluation alone. The cost analysis balanced the additional equipment and staff costs of burn wound assessment with the moorLDI2-BI against the cost benefits from earlier more appropriate treatment decisions based on information from moorLDI2-BI images.
The cost model assumed 10,000 patients, based on Enoch et al. (2009), admitted each year to 28 'burns centres' in England and Wales. For the purposes of the cost model the term 'burns centre' encompasses burns centres, units and facilities (as defined in the National Burn Care review).
The cost model assumed that 70% of the admitted patients were likely to have intermediate burn wounds and be scanned. To calculate a per patient cost in the base case, each burns centre was assumed to have one imager with annual staff training costs of £5,160. Nurse scanning time per patient was 1 hour and clinician time per patient for interpreting results was 15 minutes. The cost savings included were based on a reduction of 17% in the number of skin graft operations and a 2-day reduction in the length of hospital stay. These parameter values were based on evidence from clinical studies. In the model the cost per hour for an operation to treat burn wounds was £4,593, based on the figures presented in Hemington-Gorse et al. (2009). Expert advice to the External Assessment Centre was that this hourly cost was high, so it derived a lower figure of £2,043, this has been adjusted for inflation to £2,319 per hour.
A range of scenario analyses were done, including best- and worst-case scenarios using the ranges for the proportion of patients scanned, number of bed days saved and operating time. Additional analyses were done by the External Assessment Centre to assess the impact of changing the hourly cost for an operation to £2,043, this has been adjusted for inflation to £2,319.
The cost saving per patient scanned from using the moorLDI2-BI in addition to clinical evaluation compared with clinical evaluation alone for the base case was £1,281 for the purchase option and £1,274 for the lease option (both based on an hourly cost of £2,043 per operation). The worst-case scenario for the purchase option, based on 2011 prices resulted in a cost saving of £734 per patient and the best-case scenario resulted in a saving of £2,860 per patient scanned. All analyses presented in the assessment report showed that the total cost saving from reducing length of hospital stay and number of operations was greater than the costs associated with the purchase and operation of the moorLDI2-BI.
An area of uncertainty in the cost analyses was the impact on the cost per patient scanned of the assumption that all patients scanned would achieve on average a 2-day reduction in length of hospital stay. An additional analysis was undertaken that modelled the assumption that there was no length of stay reduction from using the moorLDI2-BI. This demonstrated that the moorLDI2-BI would still achieve a cost saving of £159 per patient scanned when a 17% reduction in operations was assumed (based on the purchase option and an hourly cost of £2,043 per operation).
# Committee considerations
The Committee considered the implications of purchasing the moorLD12 BI for use in units or facilities, which may deal with smaller numbers of burns patients and with less specialised resources. All units and facilities should have access to a trained specialist to interpret the scan, and to break even, the cost model for the base case showed a minimum of 21 burns patients a year needed to be admitted to a burns centre, of which 70% would be scanned.
The Committee was informed that the device had been available to the NHS for a number of years and was already used routinely in some burn care services.
The base case in the manufacturer's submission included costs of 1 hour scanning time and 1 hour skin graft procedure associated with an average intermediate burn. The Committee was advised that 30 minutes scanning time is more appropriate for burn wounds requiring a 1 hour skin grafting procedure. Using this time for a scan, the cost saving per patient scanned in the base case was recalculated as £1,254 for the purchase option and £1,270 for the lease option.
The cost analysis focused on cost savings associated with inpatient care. The Committee was advised that additional savings, including avoidance of hospital admission, might be obtained by using the device as an aid to clinical decision-making for outpatients with small burns of uncertain depth.
The time horizon for the cost analysis was the initial period of hospitalisation, and no longer-term cost consequences were included. The manufacturer described but did not quantify the longer-term cost benefits from improved treatment decisions. Avoiding unnecessary grafting or making earlier decisions to graft could avoid the need for long durations of prophylactic anti-scar therapy or any therapy. Anti-scar therapy includes fitting pressure garments and follow-up hospital appointments.# Conclusions
The Committee concluded that the available evidence supported a clinical benefit and a cost saving when the moorLDI2-BI is used to guide treatment decisions for patients in whom there is uncertainty about the depth and healing potential of burn wounds that have been assessed by experienced clinicians.# About this guidance
NICE medical technology guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.
This guidance was developed using the NICE medical technologies guidance process.
We have produced a summary of this guidance for the public. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
ISBN: 978-1-4731-1137-0
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{'Recommendations': "NICE medical technology guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThe case for adopting the moorLDI2-BI in the NHS is supported when it is used to guide treatment decisions for patients in whom there is uncertainty about the depth and healing potential of burn wounds that have been assessed by experienced clinicians.\n\nThere is evidence of benefit for patients and for the NHS when the moorLDI2-BI is used in addition to clinical evaluation compared with clinical evaluation alone, in burn wounds of intermediate (also known as indeterminate) depth. By demonstrating which areas of any burn wound require surgical treatment and which do not, the moorLDI2-BI enables decisions about surgery to be made earlier and for surgery to be avoided in some patients.\n\nThe estimated average cost saving when the moorLDI2-BI is used in addition to clinical evaluation is £1,281 per patient scanned (if the equipment is purchased) or £1,274 per patient scanned (if the equipment is leased). This is based on an assumption of a 17% reduction in the number of skin graft operations at a cost of £2,319 each. ", 'The technology': '# Description of the technology\n\nThe moorLDI2-BI (Moor Instruments Ltd) is a laser doppler blood flow imaging system for the non-invasive mapping of blood flow in an area of skin that has been burned. This can be used in addition to clinical evaluation to guide decisions about the need for surgical treatment of burn wounds.\n\nThe moorLDI2-BI includes a scan head, scan controller and a touch-screen panel computer, all mounted on a mobile stand that can be used in a ward, operating theatre or consulting room as well as in rooms designed specifically for laser equipment.\n\nThe moorLDI2-BI uses a low-power laser beam, directed at the burn wound using a mirror. The laser beam scans across the burn wound by rotating the mirror and there is no direct contact with the burned skin. Laser light scattered from moving blood cells in the tissue undergoes a doppler frequency shift, proportional to the average speed of the blood cells. Some of the scattered laser light is focused onto photodiode detectors and the resulting photocurrent is processed to calculate the blood flow in the tissue. Results are displayed as a colour-coded blood flow image and a colour video image of the burn wound. Depending on the size of the burn wound and required resolution of the image, the scan takes from 80\xa0seconds to about 5\xa0minutes. Healing potential results based on the blood-flow image are calculated and reported in three categories: less than\xa014\xa0days, 14–21\xa0days and more than\xa021\xa0days.\n\nThe moorLDI2-BI can be purchased at a cost of approximately £53,942 with an annual servicing cost of approximately £8,301, or it can be leased at an inclusive cost of approximately £22,000 per year. \n\n# Current management\n\nCurrent provision for inpatient treatment of burn injuries within England and Wales, based on the recommendation of the National Burn Care Review, is by specialised burn care services which consist of burn centres, burn units and burn facilities.\n\nThe assessment of burn wound depth and healing potential is fundamental in planning burn wound management. An experienced clinician can easily identify a burn that is epidermal and will heal without surgery, or a full thickness burn that requires surgical excision and grafting. However, it is often difficult to distinguish the superficial dermal burns that will heal well, from deep dermal burns, when a prolonged healing time will result in hypertrophic scarring (when the scar is swollen and red). It is difficult to assess burn wound depth and healing time in children because of the prevalence of mixed-depth scald burns and their thin skin.\n\nDiagnosis of burn wound depth and healing potential is also difficult in patients with dark skin (including those with suntan, birthmarks or tattoos). Identifying the level of burn injury can be complicated by other factors such as oedema, tissue hypoxia and burn wound conversion, when superficial burns progress into deeper wounds because of the death of severely injured cells.\n\nClinical evaluation is the most widely used method of assessing burn wound depth and healing potential. This method is based on visual and tactile assessment of the external characteristics of the burn. The accuracy of clinical examination depends on the experience of the clinician. Other less widely used methods such as thermography and fluoroscein injections are also available for burn wound assessment.\n\nThe surgical procedure for treatment of burn wounds usually involves removing the damaged skin (using excision or debridement) followed by skin grafting. Skin grafting is the transplantation of skin from a healthy part of the body. This procedure is used for deep dermal wounds because it reduces the wound healing time and wound complications. Even after excision and skin grafting there will be scarring, and hypertrophic scarring may occur.', 'Clinical evidence': "# Summary of clinical evidence\n\nThe key outcome for moorLDI2-BI laser doppler blood flow imaging is the development of an appropriate treatment plan based on an accurate assessment of burn wound depth and healing potential. Other performance measures are the sensitivity, specificity, negative predictive value and positive predictive value of the wound healing potential before 14 or 21\xa0days. Clinical utility outcomes associated with the technology are avoiding unnecessary operations, extent of surgery, number of dressing changes, complications and length of stay in hospital. Longer-term outcomes are extent and type of scarring and the recovery of pre-injury function.\n\n## Accuracy of the moorLDI2-BI\n\nThe accuracy of the moorLDI2-BI in the assessment of burn wounds was examined in eight studies with a variety of criteria including ability to predict healing within 14 or 21\xa0days. Comparisons were made with clinical and histological evaluation of burn wound depth.\n\nPape et al. (2001) reported an audit of wound healing at 21\xa0days for 76 intermediate depth wounds in 48\xa0patients. Results showed the moorLDI2-BI to be 97% accurate (74/76) in predicting wound healing at 21\xa0days compared with 70% (53/76) for clinical evaluation (no statistical comparison reported).\n\nHoeksema et al. (2009) investigated the changing accuracies of laser doppler imaging and clinical evaluation over days 0, 1, 3, 5 and 8 after injury. Forty patients with intermediate depth burn wounds were scanned using the moorLDI2-BI. The final assessment of wound depth showed a deep partial or full thickness burn in 14\xa0patients, 12 of whom had a skin graft, and a superficial dermal burn in 26\xa0patients. Accuracies on days 0, 1, 3, 5 and 8 were 41%, 62%, 53%, 71% and 100% respectively by clinical evaluation, and 55%, 80%, 95%, 97% and 100% respectively by laser doppler imaging. The burn wound depth accuracy using the moorLDI2-BI was significantly higher than clinical evaluation on day\xa03 (p\xa0<\xa00.001) and day\xa05 (p\xa0=\xa00.005) but not on days 0, 1 or 8.\n\nJeng et al. (2003) described a prospective blinded trial comparing laser doppler imaging using the moorLDI2-BI versus clinical evaluation by an experienced burn wound surgeon to decide whether or not to operate. Forty-one wounds of intermediate depth were analysed. Biopsy confirmation was obtained for 21 wounds. There was agreement on wound depth between laser doppler imaging and clinical evaluation in 56% (23/41) of cases. The surgeon's determination of burn wound depth was accurate in 71% (15/21) of wounds biopsied. The moorLDI2-BI was 100% (7/7) accurate in wounds for which it indicated a need for excision.\n\nMonstrey et al. (2011) compared healing prediction based on interpretation of a moorLDI2-BI scan with actual wound healing as recorded photographically for 433 burn wounds in 139\xa0patients. This assessment found an overall accuracy for the moorLDI2-BI of 96.3% with sensitivity 94.5%, specificity 97.2%, positive predictive value 94.5% and negative predictive value\xa097.2%.\n\nLa Hei et al. (2006) scanned 50 burns in 31 paediatric patients. Two experienced burn wound surgeons independently reviewed the scans, photographs and a basic patient history, without meeting the patient. One surgeon identified 82 areas of differing depth, the other identified 76 areas, and both surgeons predicted healing times (superficial heal: less than\xa014\xa0days or deep heal: more than\xa014\xa0days or graft). Overall, 97% (154/158) of predicted healing times were correct with four deep burn areas incorrectly predicted to heal within 14\xa0days. No superficial wounds were reported as deep.\n\nHolland et al. (2002) investigated the ability of laser doppler imaging to evaluate burn wound depth in children by scanning 58\xa0patients and comparing the predicted outcome (from either the scan or from clinical evaluation) with the subsequent wound outcome at 12\xa0days. One patient was excluded because there was too much movement for the scan to be interpreted. Clinical evaluation correctly identified 66% (19/29) of deep partial or full thickness burns between 36 and 72\xa0hours after injury compared with 90% (26/29) using moorLDI2-BI scans. Scans using moorLDI2-BI were also more specific, correctly diagnosing 96% (27/28) of superficial partial thickness burns compared with 71% (20/28) from clinical evaluation alone (no statistical comparison reported).\n\nNiazi et al. (1993) reported results from a pilot study that analysed 17 burn wounds on 13\xa0patients. Punch biopsies were used to confirm burn wound depth at 72\xa0hours after injury. Clinical evaluation was correct for 41% (7/17) of the burns, overestimated depth in 41% (7/17) and underestimated depth in 18% (3/17). Burn wound depth assessed from moorLDI2-BI scans was correct for 100% (17/17) of burn wounds (no statistical comparison reported).\n\nMill et al. (2009) compared moorLDI2-BI image colours with wound outcomes in 85\xa0burns on 48\xa0children. Analysis of the image colour regions was found to be significantly related to re-epithelialisation (p\xa0<\xa00.003), grafting (p\xa0<\xa00.001) and active scar management (p\xa0=\xa00.003).\n\n## Clinical utility outcomes\n\nTwo studies evaluated whether or not using the moorLDI2-BI enabled appropriate skin grafting decisions to be made earlier than using clinical evaluation alone. Jeng et al. (2003) described a prospective blinded trial that compared laser doppler imaging versus clinical evaluation by an experienced burn wound surgeon, in deciding whether to operate or not on 41\xa0burn wounds of intermediate depth. There was agreement on wound depth between the imaging and clinical evaluation in 56% (23/41) of cases. In these cases the moorLDI2-BI determined wound depth a median of 2\xa0days (minimum\xa0=\xa00, maximum\xa0=\xa04) earlier than clinical evaluation alone (no statistical comparison reported). Kim et al. (2010) described a non-randomised cohort study of 196 children with an acute burn injury who required surgical treatment. Laser doppler imaging was used in addition to clinical evaluation on 49% (96/196), and 51% (100/196) were assessed by clinical evaluation alone. The mean time from date of injury to the decision to graft was 8.9\xa0days in the moorLDI2-BI group compared with 11.6\xa0days in the group assessed by clinical evaluation alone (p\xa0=\xa00.01).\n\n# Committee considerations\n\nThe Committee considered that there was good clinical evidence that information from moorLDI2-BI scans increases the accuracy of predicting burn wound healing and also that this information can be used to facilitate treatment plans. Using the moorLDI2-BI in addition to clinical evaluation can enable earlier surgical treatment in some patients and avoid the need for surgery in others. It may also reduce the extent of surgery.\n\nBurn wounds on dark skin can be difficult to assess clinically. The Committee considered that the moorLDI2-BI offers particular advantages for assessing burn wounds on dark skin.\n\nThe Committee was advised that additional patient and system benefit could be obtained by using the moorLDI2-BI to define accurately the margins of surgical areas for the skin graft operations, so helping to limit the extent of excision and grafting in some patients.\n\nThere are many factors that are known to have a detrimental effect on moorLDI2-BI images or their interpretation, including infected wounds, patient movement, old scars and tattoos. These are acknowledged in the published studies and also recognised by the manufacturer in its user guide. It was therefore considered important that moorLDI2-BI images should only be taken and interpreted by a clinician trained in use of the technique.\n\nThe Committee was advised that the moorLDI2-BI can be used to assess burns treated by biological and semi-biological dressings.\n\nThe Committee considered that there was no evidence to suggest patients were likely to be harmed by the moorLDI2-BI used by trained clinicians.", 'NHS considerations': "# System impact\n\nSystem benefits associated with the moorLDI2-BI for burn wound assessment are based on reducing the length of hospital stay and avoiding unnecessary skin grafting operations.\n\nTiming of moorLDI2-BI imaging is important because burn wounds change rapidly in the first 48\xa0hours after injury. The evidence suggested that the best time for imaging is 48–72\xa0hours after the injury, but the device can be used up to 5\xa0days after injury.\n\nWound assessment using the moorLDI2-BI needs a trained clinician to operate the device and to interpret the results. In a study to assess clinical benefit, La Hei et al. (2006) reported an increase in accuracy of interpretation of the laser doppler images by a new assessor from 83% (15/18) to 96% (73/76) over a 6\xa0month period.\n\n# Committee considerations\n\nThe Committee considered that earlier and more accurate prediction of the need (or lack of need) for surgery using the moorLDI2-BI would benefit the system by reducing unnecessary operations and by saving on inpatient care. These are considered further in the cost modelling (see section 5.2).\n\nThe Committee was advised that training is important for all staff to operate this device and interpret the images. The cost model includes costs for 2\xa0days' training for one consultant, two registrars and three nurses every 2\xa0years for each device.", 'Cost considerations': "# Cost evidence\n\nThe evidence comprised a cost analysis to assess the costs and savings to the NHS from use of the moorLDI2-BI for the assessment of burn wounds of intermediate depth, as described in the manufacturer's submission. The costs and savings from using the moorLDI2-BI in addition to clinical evaluation were compared with those from using clinical evaluation alone. The cost analysis balanced the additional equipment and staff costs of burn wound assessment with the moorLDI2-BI against the cost benefits from earlier more appropriate treatment decisions based on information from moorLDI2-BI images.\n\nThe cost model assumed 10,000 patients, based on Enoch et al. (2009), admitted each year to 28 'burns centres' in England and Wales. For the purposes of the cost model the term 'burns centre' encompasses burns centres, units and facilities (as defined in the National Burn Care review).\n\nThe cost model assumed that 70% of the admitted patients were likely to have intermediate burn wounds and be scanned. To calculate a per patient cost in the base case, each burns centre was assumed to have one imager with annual staff training costs of £5,160. Nurse scanning time per patient was 1 hour and clinician time per patient for interpreting results was 15 minutes. The cost savings included were based on a reduction of 17% in the number of skin graft operations and a 2-day reduction in the length of hospital stay. These parameter values were based on evidence from clinical studies. In the model the cost per hour for an operation to treat burn wounds was £4,593, based on the figures presented in Hemington-Gorse et al. (2009). Expert advice to the External Assessment Centre was that this hourly cost was high, so it derived a lower figure of £2,043, this has been adjusted for inflation to £2,319 per hour. \n\nA range of scenario analyses were done, including best- and worst-case scenarios using the ranges for the proportion of patients scanned, number of bed days saved and operating time. Additional analyses were done by the External Assessment Centre to assess the impact of changing the hourly cost for an operation to £2,043, this has been adjusted for inflation to £2,319. \n\nThe cost saving per patient scanned from using the moorLDI2-BI in addition to clinical evaluation compared with clinical evaluation alone for the base case was £1,281 for the purchase option and £1,274 for the lease option (both based on an hourly cost of £2,043 per operation). The worst-case scenario for the purchase option, based on 2011 prices resulted in a cost saving of £734 per patient and the best-case scenario resulted in a saving of £2,860 per patient scanned. All analyses presented in the assessment report showed that the total cost saving from reducing length of hospital stay and number of operations was greater than the costs associated with the purchase and operation of the moorLDI2-BI. \n\nAn area of uncertainty in the cost analyses was the impact on the cost per patient scanned of the assumption that all patients scanned would achieve on average a 2-day reduction in length of hospital stay. An additional analysis was undertaken that modelled the assumption that there was no length of stay reduction from using the moorLDI2-BI. This demonstrated that the moorLDI2-BI would still achieve a cost saving of £159 per patient scanned when a 17% reduction in operations was assumed (based on the purchase option and an hourly cost of £2,043 per operation).\n\n# Committee considerations\n\nThe Committee considered the implications of purchasing the moorLD12 BI for use in units or facilities, which may deal with smaller numbers of burns patients and with less specialised resources. All units and facilities should have access to a trained specialist to interpret the scan, and to break even, the cost model for the base case showed\xa0a minimum\xa0of 21 burns patients a year needed to be admitted to a burns centre, of which 70% would be scanned.\n\nThe Committee was informed that the device had been available to the NHS for a number of years and was already used routinely in some burn care services.\n\nThe base case in the manufacturer's submission included costs of 1\xa0hour scanning time and 1\xa0hour skin graft procedure associated with an average intermediate burn. The Committee was advised that 30\xa0minutes scanning time is more appropriate for burn wounds requiring a 1\xa0hour skin grafting procedure. Using this time for a scan, the cost saving per patient scanned in the base case was recalculated as £1,254 for the purchase option and £1,270 for the lease option.\n\nThe cost analysis focused on cost savings associated with inpatient care. The Committee was advised that additional savings, including avoidance of hospital admission, might be obtained by using the device as an aid to clinical decision-making for outpatients with small burns of uncertain depth.\n\nThe time horizon for the cost analysis was the initial period of hospitalisation, and no longer-term cost consequences were included. The manufacturer described but did not quantify the longer-term cost benefits from improved treatment decisions. Avoiding unnecessary grafting or making earlier decisions to graft could avoid the need for long durations of prophylactic anti-scar therapy or any therapy. Anti-scar therapy includes fitting pressure garments and follow-up hospital appointments.", 'Conclusions': 'The Committee concluded that the available evidence supported a clinical benefit and a cost saving when the moorLDI2-BI is used to guide treatment decisions for patients in whom there is uncertainty about the depth and healing potential of burn wounds that have been assessed by experienced clinicians.', 'About this guidance': "NICE medical technology guidance addresses specific technologies notified to NICE by manufacturers. The 'case for adoption' is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This 'case' is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.\n\nThis guidance was developed using the NICE medical technologies guidance process.\n\nWe have produced a summary of this guidance for the public. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nISBN: 978-1-4731-1137-0"}
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https://www.nice.org.uk/guidance/mtg2
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Evidence-based recommendations on moorLDI2-BI: a laser doppler blood flow imager for burn wound assessment.
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93f68b821e4059de8c0f3c911dcaab5c338a0677
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nice
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Nutrition support for adults: oral nutrition support, enteral tube feeding and parenteral nutrition
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Nutrition support for adults: oral nutrition support, enteral tube feeding and parenteral nutrition
This guideline covers identifying and caring for adults who are malnourished or at risk of malnutrition in hospital or in their own home or a care home. It offers advice on how oral, enteral tube feeding and parenteral nutrition support should be started, administered and stopped. It aims to support healthcare professionals identify malnourished people and help them to choose the most appropriate form of support.
# Introduction
Malnutrition is a state in which a deficiency of nutrients such as energy, protein, vitamins and minerals causes measurable adverse effects on body composition, function or clinical outcome. In this guideline, we do not use the term to cover excess nutrient provision.
Malnutrition is both a cause and a consequence of ill health. It is common and increases a patient's vulnerability to disease. Methods to improve or maintain nutritional intake are known as nutrition support. These include:
-ral nutrition support – for example, fortified food, additional snacks and/or sip feeds
enteral tube feeding – the delivery of a nutritionally complete feed directly into the gut via a tube
parenteral nutrition – the delivery of nutrition intravenously.
These methods can improve outcomes, but decisions on the most effective and safe methods are complex.
Currently, knowledge of the causes, effects and treatment of malnutrition among healthcare professionals in the UK is poor. This guideline aims to help healthcare professionals correctly identify people in hospital and the community who need nutrition support, and enable them to choose and deliver the most appropriate nutrition support at the most appropriate time.# Recommendations
# Organisation of nutrition support in hospital and the community
All healthcare professionals who are directly involved in patient care should receive education and training, relevant to their post, on the importance of providing adequate nutrition. Education and training should cover:
nutritional needs and indications for nutrition support
-ptions for nutrition support (oral, enteral and parenteral)
ethical and legal concepts
potential risks and benefits
when and where to seek expert advice.
Healthcare professionals should ensure that care provides:
food and fluid of adequate quantity and quality in an environment conducive to eating
appropriate support, for example, modified eating aids, for people who can potentially chew and swallow but are unable to feed themselves.
Healthcare professionals should ensure that all people who need nutrition support receive coordinated care from a multidisciplinary team. The composition of this team may differ according to setting and local arrangements.
All acute hospital trusts should have a multidisciplinary nutrition support team, which may include: doctors (for example, gastroenterologists, gastrointestinal surgeons, intensivists or others with a specific interest in nutrition support), dietitians, a specialist nutrition nurse, other nurses, pharmacists, biochemistry and microbiology laboratory support staff, and other allied healthcare professionals (for example, speech and language therapists).
All hospital trusts should have a nutrition steering committee working within the clinical governance framework.
Members of the nutrition steering committee should be drawn from trust management, and include senior representation from medical staff, catering, nursing, dietetics, pharmacy and other healthcare professionals as appropriate, for example, speech and language therapists.
All acute hospital trusts should employ at least 1 specialist nutrition support nurse.
The specialist nutrition support nurse should work alongside nursing staff, as well as dietitians and other experts in nutrition support, to:
minimise complications related to enteral tube feeding and parenteral nutrition
ensure optimal ward-based training of nurses
ensure adherence to nutrition support protocols
support coordination of care between the hospital and the community.
# Screening for malnutrition and the risk of malnutrition in hospital and the community
Screening for malnutrition and the risk of malnutrition should be carried out by healthcare professionals with appropriate skills and training.
All hospital inpatients on admission and all outpatients at their first clinic appointment should be screened. Screening should be repeated weekly for inpatients and when there is clinical concern for outpatients.
Hospital departments who identify groups of patients with low risk of malnutrition may opt out of screening these groups. Opt-out decisions should follow an explicit process via the local clinical governance structure involving experts in nutrition support.
People in care homes should be screened on admission and when there is clinical concern. Clinical concern includes, for example, unintentional weight loss, fragile skin, poor wound healing, apathy, wasted muscles, poor appetite, altered taste sensation, impaired swallowing, altered bowel habit, loose fitting clothes or prolonged intercurrent illness.
Screening should take place on initial registration at general practice surgeries and when there is clinical concern. Clinical concern includes, for example, unintentional weight loss, fragile skin, poor wound healing, apathy, wasted muscles, poor appetite, altered taste sensation, impaired swallowing, altered bowel habit, loose fitting clothes or prolonged intercurrent illness. Screening should also be considered at other opportunities (for example, health checks, flu injections).
Screening should assess body mass index (BMI) and percentage unintentional weight loss and should also consider the time over which nutrient intake has been unintentionally reduced and/or the likelihood of future impaired nutrient intake. The Malnutrition Universal Screening Tool (MUST), for example, may be used to do this. BMI is weight in kilograms divided by height in metres squared.
# Indications for nutrition support in hospital and the community
Nutrition support should be considered in people who are malnourished, as defined by any of the following:
a BMI of less than 18.5 kg/m2
unintentional weight loss greater than 10% within the last 3 to 6 months
a BMI of less than 20 kg/m2 and unintentional weight loss greater than 5% within the last 3 to 6 months.
Nutrition support should be considered in people at risk of malnutrition who, as defined by any of the following:
have eaten little or nothing for more than 5 days and/or are likely to eat little or nothing for the next 5 days or longer
have a poor absorptive capacity, and/or have high nutrient losses and/or have increased nutritional needs from causes such as catabolism.
Healthcare professionals should consider using oral, enteral or parenteral nutrition support, alone or in combination, for people who are either malnourished or at risk of malnutrition, as defined in recommendations 1.3.1 and 1.3.2. Potential swallowing problems should be taken into account.
Healthcare professionals involved in starting or stopping nutrition support should:
-btain consent from the patient if he or she is competent
act in the patient's best interest if he or she is not competent to give consent
be aware that the provision of nutrition support is not always appropriate. Decisions on withholding or withdrawing of nutrition support require a consideration of both ethical and legal principles (both at common law and statute including the Human Rights Act 1998). When such decisions are being made, follow the General Medical Council's Treatment and care towards the end of life: good practice in decision making and the Department of Health and Social Care's Reference guide to consent for examination or treatment, second edition (2009).
Healthcare professionals should ensure that people having nutrition support, and their carers, are kept fully informed about their treatment. They should also have access to appropriate information and be given the opportunity to discuss diagnosis and treatment options.
# What to give in hospital and the community
Healthcare professionals who are skilled and trained in nutritional requirements and methods of nutrition support should ensure that the total nutrient intake of people prescribed nutrition support accounts for:
energy, protein, fluid, electrolyte, mineral, micronutrients and fibre needs
activity levels and the underlying clinical condition – for example, catabolism, pyrexia
gastrointestinal tolerance, potential metabolic instability and risk of refeeding problems
the likely duration of nutrition support. Total intake includes intake from any food, oral fluid, oral nutritional supplements, enteral and/or parenteral nutrition support and intravenous fluid. The term 'micronutrient' is used throughout to include all essential vitamins and trace elements.
For people who are not severely ill or injured, nor at risk of refeeding syndrome, the suggested nutritional prescription for total intake should provide all of the following:
to 35 kcal/kg/day total energy (including that derived from protein); this level may need to be lower in people who are overweight, with a BMI over 25; when using parenteral nutrition, it is often necessary to adjust total energy values listed on the manufacturer's information, which may not include protein energy values
to 1.5 g protein (0.13 to 0.24 g nitrogen)/kg/day
to 35 ml fluid/kg (with allowance for extra losses from drains and fistulae, for example, and extra input from other sources – for example, intravenous drugs)
adequate electrolytes, minerals, micronutrients (allowing for any pre-existing deficits, excessive losses or increased demands) and fibre if appropriate.Total intake includes intake from any food, oral fluid, oral nutritional supplements, enteral and/or parenteral nutrition support and intravenous fluid.
The prescription should be reviewed according to the person's progress, and care should be taken when:
using food fortification that tends to supplement energy and/or protein without adequate micronutrients and minerals
using feeds and supplements that meet full energy and nitrogen needs, as they may not provide adequate micronutrients and minerals when only used in a supplementary role
using pre-mixed parenteral nutrition bags that have not had tailored additions from pharmacy.
Nutrition support should be cautiously introduced in seriously ill or injured people requiring enteral tube feeding or parenteral nutrition. It should be started at no more than 50% of the estimated target energy and protein needs. It should be built up to meet full needs over the first 24 to 48 hours according to metabolic and gastrointestinal tolerance. Full requirements of fluid, electrolytes, vitamins and minerals should be provided from the outset of feeding.
People who have eaten little or nothing for more than 5 days should have nutrition support introduced at no more than 50% of requirements for the first 2 days, before increasing feed rates to meet full needs if clinical and biochemical monitoring reveals no refeeding problems.
People who meet the criteria in box 1 should be considered to be at high risk of developing refeeding problems.
Patient has 1 or more of the following:
BMI less than 16 kg/m2
unintentional weight loss greater than 15% within the last 3 to 6 months
little or no nutritional intake for more than 10 days
low levels of potassium, phosphate or magnesium before feeding.
Or patient has 2 or more of the following:
BMI less than 18.5 kg/m2
unintentional weight loss greater than 10% within the last 3 to 6 months
little or no nutritional intake for more than 5 days
a history of alcohol abuse or drugs including insulin, chemotherapy, antacids or diuretics.
People at high risk of developing refeeding problems (box 1) should be cared for by healthcare professionals who are appropriately skilled and trained and have expert knowledge of nutritional requirements and nutrition support.
The prescription for people at high risk of developing refeeding problems should consider:
starting nutrition support at a maximum of 10 kcal/kg/day, increasing levels slowly to meet or exceed full needs by 4 to 7 days
using only 5 kcal/kg/day in extreme cases (for example, BMI less than 14 kg/m2 or negligible intake for more than 15 days) and monitoring cardiac rhythm continually in these people and any others who already have or develop any cardiac arrythmias
restoring circulatory volume and monitoring fluid balance and overall clinical status closely
providing immediately before and during the first 10 days of feeding: oral thiamin 200 to 300 mg daily, vitamin B co strong 1 or 2 tablets, 3 times a day (or full dose daily intravenous vitamin B preparation, if necessary) and a balanced multivitamin or trace element supplement once daily
providing oral, enteral or intravenous supplements of potassium (likely requirement 2 to 4 mmol/kg/day), phosphate (likely requirement 0.3 to 0.6 mmol/kg/day) and magnesium (likely requirement 0.2 mmol/kg/day intravenous, 0.4 mmol/kg/day oral) unless pre-feeding plasma levels are high; pre-feeding correction of low plasma levels is unnecessary.
# Monitoring of nutrition support in hospital and the community
Healthcare professionals should review the indications, route, risks, benefits and goals of nutrition support at regular intervals. The time between reviews depends on the patient, care setting and duration of nutrition support. Intervals may increase as the patient is stabilised on nutrition support.
People having nutrition support in hospital should be monitored by healthcare professionals with the relevant skills and training in nutritional monitoring.
Healthcare professionals should refer to the protocols for nutritional, anthropometric and clinical monitoring, shown in table 1, when monitoring people having nutrition support in hospital.
Healthcare professionals should refer to the protocols for laboratory monitoring, shown in table 2, when monitoring people having nutrition support in hospital. Table 2 is particularly relevant to parenteral nutrition. It could also be selectively applied when enteral or oral nutrition support is used, particularly for people who are metabolically unstable or at risk of refeeding syndrome. The frequency and extent of the observations given may need to be adapted in acutely ill or metabolically unstable people.
People having parenteral nutrition in the community need regular assessment and monitoring. This should be carried out by home care specialists and by experienced hospital teams (initially at least weekly), using observations marked - in table 1. In addition, they should be reviewed at a specialist hospital clinic every 3 to 6 months. Monitoring should be more frequent during the early months of home parenteral nutrition, or if there is a change in clinical condition, when the full range of tests in tables 1 and 2 should be performed. Some of the clinical observations may be checked by patients or carers.
People having oral nutrition support and/or enteral tube feeding in the community should be monitored by healthcare professionals with the relevant skills and training in nutritional monitoring. This group of people should be monitored every 3 to 6 months or more frequently if there is any change in their clinical condition. A limited number of observations and tests from table 1 should be performed. Some of the clinical observations may be checked by patients or carers. If clinical progress is satisfactory, laboratory tests are rarely needed.
If long-term nutrition support is needed patients and carers should be trained to recognise and respond to adverse changes in both their well-being and in the management of their nutritional delivery system.
Monitoring of nutrition support
Parameter
Frequency
Rationale
Nutritional
Nutrient intake from oral, enteral or parenteral nutrition (including any change in conditions that are affecting food intake)
Daily initially, reducing to twice weekly when stable
To ensure that patient is receiving nutrients to meet requirements and that current method of feeding is still the most appropriate. To allow alteration of intake as indicated
Nutritional
Actual volume of feed delivered*
Daily initially, reducing to twice weekly when stable
To ensure that patient is receiving correct volume of feed. To allow troubleshooting
Nutritional
Fluid balance charts (enteral and parenteral)
Daily initially, reducing to twice weekly when stable
To ensure patient is not becoming over or under hydrated
Anthropometric
Weight*
Daily if concerns regarding fluid balance, otherwise weekly reducing to monthly
To assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle
Anthropometric
Body mass index (BMI)*
Start of feeding and then monthly
To assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle
Anthropometric
Mid-arm circumference*
Monthly, if weight cannot be obtained or is difficult to interpret
To assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle
Anthropometric
Triceps skinfold thickness
Monthly, if weight cannot be obtained or is difficult to interpret
To assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle
Gastrointestinal (GI) function
Nausea or vomiting*
Daily initially, reducing to twice weekly
To ensure tolerance of feed
GI function
Diarrhoea*
Daily initially, reducing to twice weekly
To rule out any other causes of diarrhoea and then assess tolerance of feeds
GI function
Constipation*
Daily initially, reducing to twice weekly
To rule out other causes of constipation and then assess tolerance of feeds
GI function
Abdominal distension
As necessary
Assess tolerance of feed
Enteral tube – nasally inserted
Gastric tube position (pH less than or equal to 5.5 using pH paper – or noting position of markers on tube once initial position has been confirmed)
Before each feed begins
To ensure tube in correct position
Enteral tube – nasally inserted
Nasal erosion
Daily
To ensure tolerance of tube
Enteral tube – nasally inserted
Fixation (is it secure?)
Daily
To help prevent tube becoming dislodged
Enteral tube – nasally inserted
Is tube in working order (all pieces intact, tube not blocked or kinked)?
Daily
To ensure tube is in working order
Gastrostomy or jejunostomy
Stoma site
Daily
To ensure site not infected or red, no signs of gastric leakage
Gastrostomy or jejunostomy
Tube position (length at external fixation)
Daily
To ensure tube has not migrated from or into stomach and external over granulation
Gastrostomy or jejunostomy
Tube insertion and rotation (gastrostomy without jejunal extension only)
Weekly
Prevent internal overgranulation or prevention of buried bumper syndrome
Gastrostomy or jejunostomy
Balloon water volume (balloon retained gastrostomies only)
Weekly
To prevent tube falling out
Gastrostomy or jejunostomy
Jejunostomy tube position by noting position of external markers
Daily
Confirmation of position
Parenteral nutrition
Catheter entry site*
Daily
Signs of infection or inflammation
Parenteral nutrition
Skin over position of catheter tip (peripherally fed people)*
Daily
Signs of thrombophlebitis
Clinical condition
General condition*
Daily
To ensure that patient is tolerating feed and that feeding and route continue to be appropriate
Clinical condition
Temperature or blood pressure
Daily initially, then as needed
Sign of infection or fluid balance
Clinical condition
Drug therapy*
Daily initially, reducing to monthly when stable
Appropriate preparation of drug (to reduce incidence of tube blockage). To prevent or reduce drug nutrient interactions
Long- or short-term goals
Are goals being met?*
Daily initially, reducing to twice weekly and then progressively to 3- to 6‑monthly, unless clinical condition changes
To ensure that feeding is appropriate to overall care of patient
Long- or short-term goals
Are goals still appropriate?*
Daily initially, reducing to twice weekly and then progressively to 3- to 6‑monthly, unless clinical condition changes
To ensure that feeding is appropriate to overall care of patient
People at home having parenteral nutrition should be monitored using observations marked*.
Parameter
Frequency
Rationale
Interpretation
Sodium (Na), potassium (K), urea, creatinine
Baseline
Daily until stable
Then 1 or 2 times a week
Assessment of renal function, fluid status, and Na and K status
Interpret with knowledge of fluid balance and medication
Urinary sodium may be helpful in complex cases with gastrointestinal fluid loss
Glucose
Baseline
-r 2 times a day (or more if needed) until stable
Then weekly
Glucose intolerance is common
Good glycaemic control is necessary
Magnesium (Mg), phosphate
Baseline
Daily if risk of refeeding syndrome
Three times a week until stable
Then weekly
Depletion is common and under recognised
Low concentrations indicate poor status
Liver function tests including International Normalised Ratio (INR)
Baseline
Twice weekly until stable
Then weekly
Abnormalities common during parenteral nutrition
Complex; may be due to sepsis, other disease or nutritional intake
Calcium, albumin
Baseline
Then weekly
Hypocalcaemia or hypercalcaemia may occur
Correct measured serum calcium concentration for albumin
Hypocalcaemia may be secondary to Mg deficiency
Low albumin reflects disease not protein status
C-reactive protein
Baseline
Then 2 or 3 times a week until stable
Assists interpretation of protein, trace element and vitamin results
To assess the presence of an acute phase reaction (APR); the trend of results is important
Zinc (Zn), copper (Cu)
Baseline
Then every 2 to 4 weeks, depending on results
Deficiency common, especially when increased losses
People most at risk when anabolic
APR causes Zn decrease and Cu increase
Selenium (Se)
Baseline if risk of depletion
Further testing dependent on baseline
These tests are needed primarily for people having parenteral nutrition in the community
Se deficiency likely in severe illness and sepsis, or long-term nutrition support
APR causes Se decrease
Long-term status better assessed by glutathione peroxidase
Full blood count and mean corpuscular volume (MCV)
Baseline
-r 2 times a week until stable
Then weekly
Anaemia due to iron or folate deficiency is common
Effects of sepsis may be important
Iron (Fe), ferritin
Baseline
Then every 3 to 6 months
Iron deficiency common in long-term parenteral nutrition
Iron status difficult if APR (Fe decrease, ferritin increase)
Folate, B12
Baseline
Then every 2 to 4 weeks
Iron deficiency is common
Serum folate or B12 sufficient, with full blood count
Manganese
Every 3 to 6 months if on home parenteral nutrition
These tests are rarely needed for people having enteral tube feeding (in hospital or in the community), unless there is cause for concern
Excess provision to be avoided, more likely if liver disease
Red blood cell or whole blood better measure of excess than plasma
‑OH vitamin D
‑monthly if on long-term support
These tests are rarely needed for people having enteral tube feeding (in hospital or in the community), unless there is cause for concern
Low if housebound
Requires normal kidney function for effect
Bone densitometry
On starting home parenteral nutrition
Then every 2 years
These tests are rarely needed for people having enteral tube feeding (in hospital or in the community), unless there is cause for concern
Metabolic bone disease diagnosis
Together with lab tests for metabolic bone disease
# Oral nutrition support in hospital and the community
## People with dysphagia
People who present with any obvious or less obvious indicators of dysphagia listed in box 2 should be referred to healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders.
Obvious indicators of dysphagia
difficult, painful chewing or swallowing
regurgitation of undigested food
difficulty controlling food or liquid in the mouth
drooling
hoarse voice
coughing or choking before, during or after swallowing
globus sensation
nasal regurgitation
feeling of obstruction
unintentional weight loss – for example, in people with dementia.
Less obvious indicators of dysphagia
change in respiration pattern
unexplained temperature spikes
wet voice quality
tongue fasciculation (may be indicative of motor neurone disease)
xerostomia
heartburn
change in eating habits – for example, eating slowly or avoiding social occasions
frequent throat clearing
recurrent chest infections
atypical chest pain.
Healthcare professionals should recognise that people with acute and chronic neurological conditions and those who have undergone surgery or radiotherapy to the upper aero-digestive tract are at high risk of developing dysphagia.
When managing dysphagia in people, healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should consider:
the risks and benefits of modified oral nutrition support and/or enteral tube feeding
the factors listed in box 3.
recurrent chest infections
mobility
dependency on others for assistance to eat
perceived palatability and appearance of food or drink
level of alertness
compromised physiology
poor oral hygiene
compromised medical status
metabolic and nutritional requirements
vulnerability (for example, immunocompromised)
comorbidities.
People with dysphagia should have a drug review to ascertain if the current drug formulation, route and timing of administration remains appropriate and is without contraindications for the feeding regimen or swallowing process.
Healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should regularly monitor and reassess people with dysphagia who are having modified food and liquid until they are stable.
## Indications
Healthcare professionals should consider oral nutrition support to improve nutritional intake for people who can swallow safely and are malnourished or at risk of malnutrition, as defined in recommendations 1.3.1 and 1.3.2, respectively. Oral nutrition support includes any of the following methods to improve nutritional intake: fortified food with protein, carbohydrate and/or fat, plus minerals and vitamins; snacks; oral nutritional supplements; altered meal patterns; the provision of dietary advice.
Healthcare professionals should ensure that the overall nutrient intake of oral nutrition support offered contains a balanced mixture of protein, energy, fibre, electrolytes, vitamins and minerals.
If there is concern about the adequacy of micronutrient intake, a complete oral multivitamin and mineral supplement providing the reference nutrient intake for all vitamins and trace elements should be considered by healthcare professionals with the relevant skills and training in nutrition support who are able to determine the nutritional adequacy of a patient's dietary intake.
Oral nutrition support should be stopped when the patient is established on adequate oral intake from normal food.
## Surgical patients
Peri-operative oral nutrition support should be considered for surgical patients who can swallow safely and are malnourished as defined in recommendation 1.3.1.
Healthcare professionals should consider giving post-caesarean or gynaecological surgical patients who can swallow safely, some oral intake within 24 hours of surgery.
Healthcare professionals should consider giving post-abdominal surgery patients who can swallow safely, and in whom there are no specific concerns about gut function or integrity, some oral intake within 24 hours of surgery. The patient should be monitored carefully for any signs of nausea or vomiting.
# Enteral tube feeding in hospital and the community
In this guideline, enteral tube feeding refers to the delivery of a nutritionally complete feed (as specified in section 1.4) via a tube into the stomach, duodenum or jejunum.
## Indications
Healthcare professionals should consider enteral tube feeding in people who are malnourished or at risk of malnutrition, as defined in recommendations 1.3.1 and 1.3.2, respectively, and have:
inadequate or unsafe oral intake and
a functional, accessible gastrointestinal tract.
Enteral tube feeding should not be given to people unless they meet the criteria in recommendation 1.7.1, or they are taking part in a clinical trial.
Enteral tube feeding should be stopped when the patient is established on adequate oral intake.
## Surgical patients
Surgical patients who are malnourished, as defined in recommendation 1.3.1, meet the criteria in recommendation 1.7.1, and are due to undergo major abdominal procedures, should be considered for pre-operative enteral tube feeding.
General surgical patients should not have enteral tube feeding within 48 hours post-surgery unless they meet the criteria in recommendation 1.7.1.
## Route of access
People in general medical, surgical and intensive care wards who meet the criteria in recommendation 1.7.1 should be fed via a tube into the stomach unless there is upper gastrointestinal dysfunction.
People who meet the criteria in recommendation 1.7.1, with upper gastrointestinal dysfunction (or an inaccessible upper gastrointestinal tract) should be considered for post-pyloric (duodenal or jejunal) feeding.
Gastrostomy feeding should be considered in people likely to need long-term (4 weeks or more) enteral tube feeding.
Percutaneous endoscopic gastrostomy (PEG) tubes that have been placed without apparent complications can be used for enteral tube feeding 4 hours after insertion.
## People with dysphagia
In the acute setting, for example, following stroke, people unable to swallow safely or take sufficient energy and nutrients orally should have an initial 2- to 4‑week trial of nasogastric enteral tube feeding. Healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should assess the prognosis and options for future nutrition support.
## Mode of delivery
For people being fed into the stomach, bolus or continuous methods should be considered, taking into account patient preference, convenience and drug administration.
For people in intensive care, nasogastric tube feeding should usually be delivered continuously over 16 to 24 hours daily. If insulin administration is needed, it is safe and more practical to administer feeding continuously over 24 hours.
## Motility agents
For people in intensive care with delayed gastric emptying who are not tolerating enteral tube feeding, a motility agent should be considered, unless there is a pharmacological cause that can be rectified or suspicion of gastrointestinal obstruction.
People in other acute care settings who have delayed gastric emptying and are not tolerating enteral tube feeding should also be offered a motility agent unless there is a pharmacological cause that can be rectified or suspicion of gastrointestinal obstruction.
If delayed gastric emptying is severely limiting feeding into the stomach, despite the use of motility agents, post-pyloric enteral tube feeding and/or parenteral nutrition should be considered.
## Management of tubes
People requiring enteral tube feeding should have their tube inserted by healthcare professionals with the relevant skills and training.
The position of all nasogastric tubes should be confirmed after placement and before each use by aspiration and pH graded paper (with X‑ray if necessary) as per the advice from the National Patient Safety Agency (2011); further patient safety alerts for nasogastric tubes have also been issued in 2013 and 2016. Local protocols should address the clinical criteria that permit enteral tube feeding. These criteria include how to proceed when the ability to make repeat checks of the tube position is limited by the inability to aspirate the tube, or the checking of pH is invalid because of gastric acid suppression.
The initial placement of post-pyloric tubes should be confirmed with an abdominal X‑ray (unless placed radiologically). Agreed protocols setting out the necessary clinical checks need to be in place before this procedure is carried out.
# Parenteral nutrition in hospital and the community
## Indications
Healthcare professionals should consider parenteral nutrition in people who are malnourished or at risk of malnutrition as defined in recommendations 1.3.1 and 1.3.2, respectively, and meet either of the following criteria:
inadequate or unsafe oral and/or enteral nutritional intake
a non-functional, inaccessible or perforated (leaking) gastrointestinal tract.
## Prescription
Parenteral nutrition should be introduced progressively and closely monitored, usually starting at no more than 50% of estimated needs for the first 24 to 48 hours. Parenteral nutrition can be withdrawn once adequate oral or enteral nutrition is tolerated and nutritional status is stable. Withdrawal should be planned and stepwise with a daily review of the patient's progress.
Patients who need parenteral nutrition should have their nutritional requirements determined by healthcare professionals with the relevant skills and training in the prescription of nutrition support. Before using most parenteral nutrition products, micronutrients and trace elements should be added and additional electrolytes and other nutrients may also be needed. Additions should be made under appropriate pharmaceutically controlled environmental conditions before administration.
Parenteral nutrition should be stopped when the patient is established on adequate oral and/or enteral support. There is no minimum length of time for the duration of parenteral nutrition.
## Surgical patients
Healthcare professionals should consider supplementary peri‑operative parenteral nutrition in malnourished surgical patients who meet the criteria in recommendation 1.8.1.
Peri-operative supplementary parenteral nutrition should not be given to surgical patients unless they meet the criteria set out in recommendation 1.8.1.
If intestinal tolerance persistently limits enteral tube feeding in surgical or critical care patients, parenteral nutrition should be used to supplement or replace enteral tube feeding.
## Route of access
In hospital, parenteral nutrition can be given via a dedicated peripherally inserted central catheter as an alternative to a dedicated centrally placed central venous catheter. A free dedicated lumen in a multi-lumen centrally placed catheter may also be used.
Administration of parenteral nutrition via a peripheral venous catheter should be considered for patients who are likely to need short-term parenteral nutrition (less than 14 days) who have no need for central access for other reasons. Care should be taken in catheter choice, and in attention to pH, tonicity and long-term compatibility of the parenteral nutrition formulations in order to avoid administration or stability problems.
Tunnelling subclavian lines is recommended for long-term use (more than 30 days).
Catheters do not have to be tunnelled for short-term use (less than 30 days).
## Mode of delivery
Continuous administration of parenteral nutrition should be offered as the preferred method of infusion in severely ill people who require parenteral nutrition.
Cyclical delivery of parenteral nutrition should be considered when using peripheral venous cannulae with planned routine catheter change.
A gradual change from continuous to cyclical delivery should be considered in patients requiring parenteral nutrition for more than 2 weeks.
## Management of catheters
Only healthcare professionals competent in catheter placement should be responsible for the placement of catheters and they should be aware of the importance of monitoring and managing these safely. See the NICE guideline on healthcare-associated infections: prevention and control in primary and community care.
# Supporting patients in the community
Healthcare professionals should ensure that patients having enteral or parenteral nutrition in the community and their carers:
are kept fully informed and have access to appropriate sources of information in formats, languages and ways that are suited to an individual's requirements; consideration should be given to cognition, gender, physical needs, culture and stage of life of the individual
have the opportunity to discuss diagnosis, treatment options and relevant physical, psychological and social issues
are given contact details for relevant support groups, charities and voluntary organisations.
## Enteral tube feeding
All people in the community having enteral tube feeding should be supported by a coordinated multidisciplinary team, which includes dietitians, district, care home or homecare company nurses, GPs, community pharmacists and other allied healthcare professionals (for example, speech and language therapists) as appropriate. Close liaison between the multidisciplinary team and patients and carers regarding diagnoses, prescription, arrangements and potential problems is essential.
Patients in the community having enteral tube feeding and their carers should receive an individualised care plan which includes overall aims and a monitoring plan.
Patients in the community having enteral tube feeding and their carers, should receive training and information from members of the multidisciplinary team on:
the management of the tubes, delivery systems and the regimen, outlining all procedures related to setting up feeds, using feed pumps, the likely risks and methods for troubleshooting common problems and be provided with an instruction manual (and visual aids if appropriate)
both routine and emergency telephone numbers to contact a healthcare professional who understands the needs and potential problems of people on home enteral tube feeding
the delivery of equipment, ancillaries and feed with appropriate contact details for any homecare company involved.
## Parenteral nutrition
All people in the community having parenteral nutrition should be supported by a coordinated multidisciplinary team, which includes input from specialist nutrition nurses, dietitians, GPs, pharmacists and district and/or homecare company nurses. Close liaison between the multidisciplinary team and patients and carers regarding diagnoses, prescription, arrangements and potential problems is essential.
People in the community having parenteral nutrition and their carers should receive an individualised care plan which includes overall aims and a monitoring plan.
People in the community having parenteral nutrition and their carers should receive training and information from members of the multidisciplinary team on:
the management of the delivery systems and the regimen, outlining all procedures related to setting up feeds, using feed pumps, the likely risks and methods for troubleshooting common problems and be provided with an instruction manual (and visual aids if appropriate)
routine and emergency telephone numbers to contact a healthcare professional with the relevant competencies (specialist nutrition nurse, pharmacist)
the arrangements for the delivery of equipment, ancillaries and feed with appropriate contact details for any homecare company involved.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Research question 1
Further research is needed to ascertain whether an educational intervention (for example, three 1‑week modular courses, over 6 months) for all healthcare professionals, in particular medical and nursing staff including those who work with people with dementia, would have an effect on patient care (that is, effect on nutritional status, length of hospital stay, frequency of GP visits, complications and quality of life) compared with no formal education.
## Why this is important
It is known that healthcare professionals in both the hospital and community setting have a poor knowledge of nutrition. This is partly due to receiving a minimal amount of education in nutrition during their undergraduate or basic training. It is therefore essential to determine whether an organised nutrition support education programme to healthcare professionals would improve the choice made about nutrition support and the consequent care of patients prescribed nutrition support.
# Research question 2
What are the benefits to patients of a nutritional screening programme (using a simple tool such as the Malnutrition Universal Screening Tool ) compared with not screening people in: a) primary care (attending GP clinics); b) care homes; c) hospital inpatients; d) hospital outpatients; e) patients with dementia in terms of determining the number of people at risk of malnutrition, complications, survival, hospital admission rates, length of stay, quality of life and cost effectiveness?
## Why this is important
There is no clear evidence available as to whether screening is really beneficial or how it should be carried out. With the lack of evidence, the committee have considered in detail this problem and have instead carefully developed consensus statements to support recommendations for screening. As a priority, it is important that we determine the need for screening and intervention − in particular, primary care and the wider community.
# Research question 3
Further research is needed to identify which components of nutrition monitoring are clinically and cost effective.
## Why this is important
There is no clear evidence available regarding the long- and short-term benefits of clinical monitoring in terms of prevention of complications and survival. With the lack of evidence, the committee have considered in detail this problem and have instead carefully developed the guidance for monitoring by expert clinical practice and consensus opinion.
# Research question 4
What are the benefits of patients (in hospital or the community, including older people) identified as at high risk of malnutrition by a screening tool such as MUST being offered either oral nutritional supplements compared with: a) dietary modification and/or food fortification; or b) dietary modification and/or food fortification together with dietary counselling, in terms of determining complications, survival, length of hospital stay, quality of life and cost effectiveness?
## Why this is important
This is an essential recommendation for research since there is insufficient evidence on the benefits of intervention used for oral nutrition support – in particular, the benefits of often first line treatment, for example food fortification and/or dietary counselling. It is essential to know this so that the indications on how to treat can be further supported.
# Research question 5
What are the benefits of enteral tube feeding to patients compared with no enteral tube feeding in people with dysphagia and early- to mid-stage dementia in terms of reduced complications associated with swallowing, improved nutritional status, delayed onset of advanced stage dementia, hospital admissions, cost effectiveness and survival?
## Why this is important
Much of the research tends to focus or concentrate on tube feeding people with advanced dementia or those who may be in terminal stages of the disease. Depending on the type of dementia, swallowing disorders may occur at an earlier stage in the disease, for example vascular dementia. The benefits and complications of tube feeding may be quite different in people in the earlier stages than those who are in the advanced stage of dementia.
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{'Introduction': "Malnutrition is a state in which a deficiency of nutrients such as energy, protein, vitamins and minerals causes measurable adverse effects on body composition, function or clinical outcome. In this guideline, we do not use the term to cover excess nutrient provision.\n\nMalnutrition is both a cause and a consequence of ill health. It is common and increases a patient's vulnerability to disease. Methods to improve or maintain nutritional intake are known as nutrition support. These include:\n\noral nutrition support – for example, fortified food, additional snacks and/or sip feeds\n\nenteral tube feeding – the delivery of a nutritionally complete feed directly into the gut via a tube\n\nparenteral nutrition – the delivery of nutrition intravenously.\n\nThese methods can improve outcomes, but decisions on the most effective and safe methods are complex.\n\nCurrently, knowledge of the causes, effects and treatment of malnutrition among healthcare professionals in the UK is poor. This guideline aims to help healthcare professionals correctly identify people in hospital and the community who need nutrition support, and enable them to choose and deliver the most appropriate nutrition support at the most appropriate time.", 'Recommendations': "# Organisation of nutrition support in hospital and the community\n\nAll healthcare professionals who are directly involved in patient care should receive education and training, relevant to their post, on the importance of providing adequate nutrition. Education and training should cover:\n\nnutritional needs and indications for nutrition support\n\noptions for nutrition support (oral, enteral and parenteral)\n\nethical and legal concepts\n\npotential risks and benefits\n\nwhen and where to seek expert advice.\n\nHealthcare professionals should ensure that care provides:\n\nfood and fluid of adequate quantity and quality in an environment conducive to eating\n\nappropriate support, for example, modified eating aids, for people who can potentially chew and swallow but are unable to feed themselves.\n\nHealthcare professionals should ensure that all people who need nutrition support receive coordinated care from a multidisciplinary team. The composition of this team may differ according to setting and local arrangements.\n\nAll acute hospital trusts should have a multidisciplinary nutrition support team, which may include: doctors (for example, gastroenterologists, gastrointestinal surgeons, intensivists or others with a specific interest in nutrition support), dietitians, a specialist nutrition nurse, other nurses, pharmacists, biochemistry and microbiology laboratory support staff, and other allied healthcare professionals (for example, speech and language therapists).\n\nAll hospital trusts should have a nutrition steering committee working within the clinical governance framework.\n\nMembers of the nutrition steering committee should be drawn from trust management, and include senior representation from medical staff, catering, nursing, dietetics, pharmacy and other healthcare professionals as appropriate, for example, speech and language therapists.\n\nAll acute hospital trusts should employ at least 1\xa0specialist nutrition support nurse.\n\nThe specialist nutrition support nurse should work alongside nursing staff, as well as dietitians and other experts in nutrition support, to:\n\nminimise complications related to enteral tube feeding and parenteral nutrition\n\nensure optimal ward-based training of nurses\n\nensure adherence to nutrition support protocols\n\nsupport coordination of care between the hospital and the community.\n\n# Screening for malnutrition and the risk of malnutrition in hospital and the community\n\nScreening for malnutrition and the risk of malnutrition should be carried out by healthcare professionals with appropriate skills and training.\n\nAll hospital inpatients on admission and all outpatients at their first clinic appointment should be screened. Screening should be repeated weekly for inpatients and when there is clinical concern for outpatients.\n\nHospital departments who identify groups of patients with low risk of malnutrition may opt out of screening these groups. Opt-out decisions should follow an explicit process via the local clinical governance structure involving experts in nutrition support.\n\nPeople in care homes should be screened on admission and when there is clinical concern. Clinical concern includes, for example, unintentional weight loss, fragile skin, poor wound healing, apathy, wasted muscles, poor appetite, altered taste sensation, impaired swallowing, altered bowel habit, loose fitting clothes or prolonged intercurrent illness.\n\nScreening should take place on initial registration at general practice surgeries and when there is clinical concern. Clinical concern includes, for example, unintentional weight loss, fragile skin, poor wound healing, apathy, wasted muscles, poor appetite, altered taste sensation, impaired swallowing, altered bowel habit, loose fitting clothes or prolonged intercurrent illness. Screening should also be considered at other opportunities (for example, health checks, flu injections).\n\nScreening should assess body mass index (BMI) and percentage unintentional weight loss and should also consider the time over which nutrient intake has been unintentionally reduced and/or the likelihood of future impaired nutrient intake. The Malnutrition Universal Screening Tool (MUST), for example, may be used to do this. BMI is weight in kilograms divided by height in metres squared.\n\n# Indications for nutrition support in hospital and the community\n\nNutrition support should be considered in people who are malnourished, as defined by any of the following:\n\na BMI of less than 18.5\xa0kg/m2\n\nunintentional weight loss greater than 10% within the last 3\xa0to 6\xa0months\n\na BMI of less than 20\xa0kg/m2 and unintentional weight loss greater than 5% within the last 3\xa0to 6\xa0months.\n\nNutrition support should be considered in people at risk of malnutrition who, as defined by any of the following:\n\nhave eaten little or nothing for more than 5\xa0days and/or are likely to eat little or nothing for the next 5\xa0days or longer\n\nhave a poor absorptive capacity, and/or have high nutrient losses and/or have increased nutritional needs from causes such as catabolism.\n\nHealthcare professionals should consider using oral, enteral or parenteral nutrition support, alone or in combination, for people who are either malnourished or at risk of malnutrition, as defined in recommendations\xa01.3.1 and\xa01.3.2. Potential swallowing problems should be taken into account.\n\nHealthcare professionals involved in starting or stopping nutrition support should:\n\nobtain consent from the patient if he or she is competent\n\nact in the patient's best interest if he or she is not competent to give consent\n\nbe aware that the provision of nutrition support is not always appropriate. Decisions on withholding or withdrawing of nutrition support require a consideration of both ethical and legal principles (both at common law and statute including the Human Rights Act 1998). When such decisions are being made, follow the General Medical Council's Treatment and care towards the end of life: good practice in decision making and the Department of Health and Social Care's Reference guide to consent for examination or treatment, second edition (2009).\n\nHealthcare professionals should ensure that people having nutrition support, and their carers, are kept fully informed about their treatment. They should also have access to appropriate information and be given the opportunity to discuss diagnosis and treatment options.\n\n# What to give in hospital and the community\n\nHealthcare professionals who are skilled and trained in nutritional requirements and methods of nutrition support should ensure that the total nutrient intake of people prescribed nutrition support accounts for:\n\nenergy, protein, fluid, electrolyte, mineral, micronutrients and fibre needs\n\nactivity levels and the underlying clinical condition – for example, catabolism, pyrexia\n\ngastrointestinal tolerance, potential metabolic instability and risk of refeeding problems\n\nthe likely duration of nutrition support. Total intake includes intake from any food, oral fluid, oral nutritional supplements, enteral and/or parenteral nutrition support and intravenous fluid. The term 'micronutrient' is used throughout to include all essential vitamins and trace elements.\n\nFor people who are not severely ill or injured, nor at risk of refeeding syndrome, the suggested nutritional prescription for total intake should provide all of the following:\n\nto 35 kcal/kg/day total energy (including that derived from protein); this level may need to be lower in people who are overweight, with a BMI over 25; when using parenteral nutrition, it is often necessary to adjust total energy values listed on the manufacturer's information, which may not include protein energy values\n\nto 1.5 g protein (0.13\xa0to 0.24\xa0g nitrogen)/kg/day\n\nto 35 ml fluid/kg (with allowance for extra losses from drains and fistulae, for example, and extra input from other sources – for example, intravenous drugs)\n\nadequate electrolytes, minerals, micronutrients (allowing for any pre-existing deficits, excessive losses or increased demands) and fibre if appropriate.Total intake includes intake from any food, oral fluid, oral nutritional supplements, enteral and/or parenteral nutrition support and intravenous fluid.\n\nThe prescription should be reviewed according to the person's progress, and care should be taken when:\n\nusing food fortification that tends to supplement energy and/or protein without adequate micronutrients and minerals\n\nusing feeds and supplements that meet full energy and nitrogen needs, as they may not provide adequate micronutrients and minerals when only used in a supplementary role\n\nusing pre-mixed parenteral nutrition bags that have not had tailored additions from pharmacy.\n\nNutrition support should be cautiously introduced in seriously ill or injured people requiring enteral tube feeding or parenteral nutrition. It should be started at no more than 50% of the estimated target energy and protein needs. It should be built up to meet full needs over the first 24\xa0to 48\xa0hours according to metabolic and gastrointestinal tolerance. Full requirements of fluid, electrolytes, vitamins and minerals should be provided from the outset of feeding.\n\nPeople who have eaten little or nothing for more than 5\xa0days should have nutrition support introduced at no more than 50% of requirements for the first 2\xa0days, before increasing feed rates to meet full needs if clinical and biochemical monitoring reveals no refeeding problems.\n\nPeople who meet the criteria in box\xa01 should be considered to be at high risk of developing refeeding problems.\n\nPatient has 1\xa0or more of the following:\n\nBMI less than 16\xa0kg/m2\n\nunintentional weight loss greater than 15% within the last 3\xa0to 6\xa0months\n\nlittle or no nutritional intake for more than 10\xa0days\n\nlow levels of potassium, phosphate or magnesium before feeding.\n\nOr patient has 2\xa0or more of the following:\n\nBMI less than 18.5\xa0kg/m2\n\nunintentional weight loss greater than 10% within the last 3\xa0to 6\xa0months\n\nlittle or no nutritional intake for more than 5\xa0days\n\na history of alcohol abuse or drugs including insulin, chemotherapy, antacids or diuretics.\n\nPeople at high risk of developing refeeding problems (box\xa01) should be cared for by healthcare professionals who are appropriately skilled and trained and have expert knowledge of nutritional requirements and nutrition support.\n\nThe prescription for people at high risk of developing refeeding problems should consider:\n\nstarting nutrition support at a maximum of 10\xa0kcal/kg/day, increasing levels slowly to meet or exceed full needs by 4\xa0to 7\xa0days\n\nusing only 5\xa0kcal/kg/day in extreme cases (for example, BMI less than 14\xa0kg/m2 or negligible intake for more than 15\xa0days) and monitoring cardiac rhythm continually in these people and any others who already have or develop any cardiac arrythmias\n\nrestoring circulatory volume and monitoring fluid balance and overall clinical status closely\n\nproviding immediately before and during the first 10\xa0days of feeding: oral thiamin 200\xa0to 300\xa0mg daily, vitamin\xa0B co\xa0strong 1\xa0or 2\xa0tablets, 3\xa0times a day (or full dose daily intravenous vitamin\xa0B preparation, if necessary) and a balanced multivitamin or trace element supplement once daily\n\nproviding oral, enteral or intravenous supplements of potassium (likely requirement 2\xa0to 4\xa0mmol/kg/day), phosphate (likely requirement 0.3\xa0to 0.6\xa0mmol/kg/day) and magnesium (likely requirement 0.2\xa0mmol/kg/day intravenous, 0.4\xa0mmol/kg/day oral) unless pre-feeding plasma levels are high; pre-feeding correction of low plasma levels is unnecessary.\n\n# Monitoring of nutrition support in hospital and the community\n\nHealthcare professionals should review the indications, route, risks, benefits and goals of nutrition support at regular intervals. The time between reviews depends on the patient, care setting and duration of nutrition support. Intervals may increase as the patient is stabilised on nutrition support.\n\nPeople having nutrition support in hospital should be monitored by healthcare professionals with the relevant skills and training in nutritional monitoring.\n\nHealthcare professionals should refer to the protocols for nutritional, anthropometric and clinical monitoring, shown in table\xa01, when monitoring people having nutrition support in hospital.\n\nHealthcare professionals should refer to the protocols for laboratory monitoring, shown in table\xa02, when monitoring people having nutrition support in hospital. Table\xa02 is particularly relevant to parenteral nutrition. It could also be selectively applied when enteral or oral nutrition support is used, particularly for people who are metabolically unstable or at risk of refeeding syndrome. The frequency and extent of the observations given may need to be adapted in acutely ill or metabolically unstable people.\n\nPeople having parenteral nutrition in the community need regular assessment and monitoring. This should be carried out by home care specialists and by experienced hospital teams (initially at least weekly), using observations marked * in table\xa01. In addition, they should be reviewed at a specialist hospital clinic every 3\xa0to 6\xa0months. Monitoring should be more frequent during the early months of home parenteral nutrition, or if there is a change in clinical condition, when the full range of tests in tables\xa01 and\xa02 should be performed. Some of the clinical observations may be checked by patients or carers.\n\nPeople having oral nutrition support and/or enteral tube feeding in the community should be monitored by healthcare professionals with the relevant skills and training in nutritional monitoring. This group of people should be monitored every 3\xa0to 6\xa0months or more frequently if there is any change in their clinical condition. A limited number of observations and tests from table\xa01 should be performed. Some of the clinical observations may be checked by patients or carers. If clinical progress is satisfactory, laboratory tests are rarely needed.\n\nIf long-term nutrition support is needed patients and carers should be trained to recognise and respond to adverse changes in both their well-being and in the management of their nutritional delivery system.\n\nMonitoring of nutrition support\n\nParameter\n\nFrequency\n\nRationale\n\nNutritional\n\nNutrient intake from oral, enteral or parenteral nutrition (including any change in conditions that are affecting food intake)\n\nDaily initially, reducing to twice weekly when stable\n\nTo ensure that patient is receiving nutrients to meet requirements and that current method of feeding is still the most appropriate. To allow alteration of intake as indicated\n\nNutritional\n\nActual volume of feed delivered*\n\nDaily initially, reducing to twice weekly when stable\n\nTo ensure that patient is receiving correct volume of feed. To allow troubleshooting\n\nNutritional\n\nFluid balance charts (enteral and parenteral)\n\nDaily initially, reducing to twice weekly when stable\n\nTo ensure patient is not becoming over or under hydrated\n\nAnthropometric\n\nWeight*\n\nDaily if concerns regarding fluid balance, otherwise weekly reducing to monthly\n\nTo assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle\n\nAnthropometric\n\nBody mass index (BMI)*\n\nStart of feeding and then monthly\n\nTo assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle\n\nAnthropometric\n\nMid-arm circumference*\n\nMonthly, if weight cannot be obtained or is difficult to interpret\n\nTo assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle\n\nAnthropometric\n\nTriceps skinfold thickness\n\nMonthly, if weight cannot be obtained or is difficult to interpret\n\nTo assess ongoing nutritional status, determine whether nutritional goals are being achieved and take into account both body fat and muscle\n\nGastrointestinal (GI) function\n\nNausea or vomiting*\n\nDaily initially, reducing to twice weekly\n\nTo ensure tolerance of feed\n\nGI function\n\nDiarrhoea*\n\nDaily initially, reducing to twice weekly\n\nTo rule out any other causes of diarrhoea and then assess tolerance of feeds\n\nGI function\n\nConstipation*\n\nDaily initially, reducing to twice weekly\n\nTo rule out other causes of constipation and then assess tolerance of feeds\n\nGI function\n\nAbdominal distension\n\nAs necessary\n\nAssess tolerance of feed\n\nEnteral tube – nasally inserted\n\nGastric tube position (pH less than or equal to 5.5 using pH paper – or noting position of markers on tube once initial position has been confirmed)\n\nBefore each feed begins\n\nTo ensure tube in correct position\n\nEnteral tube – nasally inserted\n\nNasal erosion\n\nDaily\n\nTo ensure tolerance of tube\n\nEnteral tube – nasally inserted\n\nFixation (is it secure?)\n\nDaily\n\nTo help prevent tube becoming dislodged\n\nEnteral tube – nasally inserted\n\nIs tube in working order (all pieces intact, tube not blocked or kinked)?\n\nDaily\n\nTo ensure tube is in working order\n\nGastrostomy or jejunostomy\n\nStoma site\n\nDaily\n\nTo ensure site not infected or red, no signs of gastric leakage\n\nGastrostomy or jejunostomy\n\nTube position (length at external fixation)\n\nDaily\n\nTo ensure tube has not migrated from or into stomach and external over granulation\n\nGastrostomy or jejunostomy\n\nTube insertion and rotation (gastrostomy without jejunal extension only)\n\nWeekly\n\nPrevent internal overgranulation or prevention of buried bumper syndrome\n\nGastrostomy or jejunostomy\n\nBalloon water volume (balloon retained gastrostomies only)\n\nWeekly\n\nTo prevent tube falling out\n\nGastrostomy or jejunostomy\n\nJejunostomy tube position by noting position of external markers\n\nDaily\n\nConfirmation of position\n\nParenteral nutrition\n\nCatheter entry site*\n\nDaily\n\nSigns of infection or inflammation\n\nParenteral nutrition\n\nSkin over position of catheter tip (peripherally fed people)*\n\nDaily\n\nSigns of thrombophlebitis\n\nClinical condition\n\nGeneral condition*\n\nDaily\n\nTo ensure that patient is tolerating feed and that feeding and route continue to be appropriate\n\nClinical condition\n\nTemperature or blood pressure\n\nDaily initially, then as needed\n\nSign of infection or fluid balance\n\nClinical condition\n\nDrug therapy*\n\nDaily initially, reducing to monthly when stable\n\nAppropriate preparation of drug (to reduce incidence of tube blockage). To prevent or reduce drug nutrient interactions\n\nLong- or short-term goals\n\nAre goals being met?*\n\nDaily initially, reducing to twice weekly and then progressively to 3- to 6‑monthly, unless clinical condition changes\n\nTo ensure that feeding is appropriate to overall care of patient\n\nLong- or short-term goals\n\nAre goals still appropriate?*\n\nDaily initially, reducing to twice weekly and then progressively to 3- to 6‑monthly, unless clinical condition changes\n\nTo ensure that feeding is appropriate to overall care of patient\n\nPeople at home having parenteral nutrition should be monitored using observations marked*.\n\nParameter\n\nFrequency\n\nRationale\n\nInterpretation\n\nSodium (Na), potassium (K), urea, creatinine\n\nBaseline\n\nDaily until stable\n\nThen 1 or 2 times a week\n\nAssessment of renal function, fluid status, and Na and K status\n\nInterpret with knowledge of fluid balance and medication\n\nUrinary sodium may be helpful in complex cases with gastrointestinal fluid loss\n\nGlucose\n\nBaseline\n\nor 2 times a day (or more if needed) until stable\n\nThen weekly\n\nGlucose intolerance is common\n\nGood glycaemic control is necessary\n\nMagnesium (Mg), phosphate\n\nBaseline\n\nDaily if risk of refeeding syndrome\n\nThree times a week until stable\n\nThen weekly\n\nDepletion is common and under recognised\n\nLow concentrations indicate poor status\n\nLiver function tests including International Normalised Ratio (INR)\n\nBaseline\n\nTwice weekly until stable\n\nThen weekly\n\nAbnormalities common during parenteral nutrition\n\nComplex; may be due to sepsis, other disease or nutritional intake\n\nCalcium, albumin\n\nBaseline\n\nThen weekly\n\nHypocalcaemia or hypercalcaemia may occur\n\nCorrect measured serum calcium concentration for albumin\n\nHypocalcaemia may be secondary to Mg deficiency\n\nLow albumin reflects disease not protein status\n\nC-reactive protein\n\nBaseline\n\nThen 2 or 3 times a week until stable\n\nAssists interpretation of protein, trace element and vitamin results\n\nTo assess the presence of an acute phase reaction (APR); the trend of results is important\n\nZinc (Zn), copper (Cu)\n\nBaseline\n\nThen every 2 to 4\xa0weeks, depending on results\n\nDeficiency common, especially when increased losses\n\nPeople most at risk when anabolic\n\nAPR causes Zn decrease and Cu increase\n\nSelenium (Se)\n\nBaseline if risk of depletion\n\nFurther testing dependent on baseline\n\nThese tests are needed primarily for people having parenteral nutrition in the community\n\nSe deficiency likely in severe illness and sepsis, or long-term nutrition support\n\nAPR causes Se decrease\n\nLong-term status better assessed by glutathione peroxidase\n\nFull blood count and mean corpuscular volume (MCV)\n\nBaseline\n\nor 2\xa0times a week until stable\n\nThen weekly\n\nAnaemia due to iron or folate deficiency is common\n\nEffects of sepsis may be important\n\nIron (Fe), ferritin\n\nBaseline\n\nThen every 3 to 6\xa0months\n\nIron deficiency common in long-term parenteral nutrition\n\nIron status difficult if APR (Fe decrease, ferritin increase)\n\nFolate, B12\n\nBaseline\n\nThen every 2 to 4\xa0weeks\n\nIron deficiency is common\n\nSerum folate or B12 sufficient, with full blood count\n\nManganese\n\nEvery 3 to 6\xa0months if on home parenteral nutrition\n\nThese tests are rarely needed for people having enteral tube feeding (in hospital or in the community), unless there is cause for concern\n\nExcess provision to be avoided, more likely if liver disease\n\nRed blood cell or whole blood better measure of excess than plasma\n\n‑OH vitamin\xa0D\n\n‑monthly if on long-term support\n\nThese tests are rarely needed for people having enteral tube feeding (in hospital or in the community), unless there is cause for concern\n\nLow if housebound\n\nRequires normal kidney function for effect\n\nBone densitometry\n\nOn starting home parenteral nutrition\n\nThen every 2\xa0years\n\nThese tests are rarely needed for people having enteral tube feeding (in hospital or in the community), unless there is cause for concern\n\nMetabolic bone disease diagnosis\n\nTogether with lab tests for metabolic bone disease\n\n# Oral nutrition support in hospital and the community\n\n## People with dysphagia\n\nPeople who present with any obvious or less obvious indicators of dysphagia listed in box\xa02 should be referred to healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders.\n\nObvious indicators of dysphagia\n\ndifficult, painful chewing or swallowing\n\nregurgitation of undigested food\n\ndifficulty controlling food or liquid in the mouth\n\ndrooling\n\nhoarse voice\n\ncoughing or choking before, during or after swallowing\n\nglobus sensation\n\nnasal regurgitation\n\nfeeling of obstruction\n\nunintentional weight loss – for example, in people with dementia.\n\nLess obvious indicators of dysphagia\n\nchange in respiration pattern\n\nunexplained temperature spikes\n\nwet voice quality\n\ntongue fasciculation (may be indicative of motor neurone disease)\n\nxerostomia\n\nheartburn\n\nchange in eating habits – for example, eating slowly or avoiding social occasions\n\nfrequent throat clearing\n\nrecurrent chest infections\n\natypical chest pain.\n\nHealthcare professionals should recognise that people with acute and chronic neurological conditions and those who have undergone surgery or radiotherapy to the upper aero-digestive tract are at high risk of developing dysphagia.\n\nWhen managing dysphagia in people, healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should consider:\n\nthe risks and benefits of modified oral nutrition support and/or enteral tube feeding\n\nthe factors listed in box\xa03.\n\nrecurrent chest infections\n\nmobility\n\ndependency on others for assistance to eat\n\nperceived palatability and appearance of food or drink\n\nlevel of alertness\n\ncompromised physiology\n\npoor oral hygiene\n\ncompromised medical status\n\nmetabolic and nutritional requirements\n\nvulnerability (for example, immunocompromised)\n\ncomorbidities.\n\nPeople with dysphagia should have a drug review to ascertain if the current drug formulation, route and timing of administration remains appropriate and is without contraindications for the feeding regimen or swallowing process.\n\nHealthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should regularly monitor and reassess people with dysphagia who are having modified food and liquid until they are stable.\n\n## Indications\n\nHealthcare professionals should consider oral nutrition support to improve nutritional intake for people who can swallow safely and are malnourished or at risk of malnutrition, as defined in recommendations\xa01.3.1 and 1.3.2, respectively. Oral nutrition support includes any of the following methods to improve nutritional intake: fortified food with protein, carbohydrate and/or fat, plus minerals and vitamins; snacks; oral nutritional supplements; altered meal patterns; the provision of dietary advice.\n\nHealthcare professionals should ensure that the overall nutrient intake of oral nutrition support offered contains a balanced mixture of protein, energy, fibre, electrolytes, vitamins and minerals.\n\nIf there is concern about the adequacy of micronutrient intake, a complete oral multivitamin and mineral supplement providing the reference nutrient intake for all vitamins and trace elements should be considered by healthcare professionals with the relevant skills and training in nutrition support who are able to determine the nutritional adequacy of a patient's dietary intake.\n\nOral nutrition support should be stopped when the patient is established on adequate oral intake from normal food.\n\n## Surgical patients\n\nPeri-operative oral nutrition support should be considered for surgical patients who can swallow safely and are malnourished as defined in recommendation\xa01.3.1.\n\nHealthcare professionals should consider giving post-caesarean or gynaecological surgical patients who can swallow safely, some oral intake within 24\xa0hours of surgery.\n\nHealthcare professionals should consider giving post-abdominal surgery patients who can swallow safely, and in whom there are no specific concerns about gut function or integrity, some oral intake within 24\xa0hours of surgery. The patient should be monitored carefully for any signs of nausea or vomiting.\n\n# Enteral tube feeding in hospital and the community\n\nIn this guideline, enteral tube feeding refers to the delivery of a nutritionally complete feed (as specified in section\xa01.4) via a tube into the stomach, duodenum or jejunum.\n\n## Indications\n\nHealthcare professionals should consider enteral tube feeding in people who are malnourished or at risk of malnutrition, as defined in recommendations\xa01.3.1 and 1.3.2, respectively, and have:\n\ninadequate or unsafe oral intake and\n\na functional, accessible gastrointestinal tract.\n\nEnteral tube feeding should not be given to people unless they meet the criteria in recommendation\xa01.7.1, or they are taking part in a clinical trial.\n\nEnteral tube feeding should be stopped when the patient is established on adequate oral intake.\n\n## Surgical patients\n\nSurgical patients who are malnourished, as defined in recommendation\xa01.3.1, meet the criteria in recommendation\xa01.7.1, and are due to undergo major abdominal procedures, should be considered for pre-operative enteral tube feeding.\n\nGeneral surgical patients should not have enteral tube feeding within 48\xa0hours post-surgery unless they meet the criteria in recommendation\xa01.7.1.\n\n## Route of access\n\nPeople in general medical, surgical and intensive care wards who meet the criteria in recommendation\xa01.7.1 should be fed via a tube into the stomach unless there is upper gastrointestinal dysfunction.\n\nPeople who meet the criteria in recommendation\xa01.7.1, with upper gastrointestinal dysfunction (or an inaccessible upper gastrointestinal tract) should be considered for post-pyloric (duodenal or jejunal) feeding.\n\nGastrostomy feeding should be considered in people likely to need long-term (4\xa0weeks or more) enteral tube feeding.\n\nPercutaneous endoscopic gastrostomy (PEG) tubes that have been placed without apparent complications can be used for enteral tube feeding 4\xa0hours after insertion.\n\n## People with dysphagia\n\nIn the acute setting, for example, following stroke, people unable to swallow safely or take sufficient energy and nutrients orally should have an initial 2- to 4‑week trial of nasogastric enteral tube feeding. Healthcare professionals with relevant skills and training in the diagnosis, assessment and management of swallowing disorders should assess the prognosis and options for future nutrition support.\n\n## Mode of delivery\n\nFor people being fed into the stomach, bolus or continuous methods should be considered, taking into account patient preference, convenience and drug administration.\n\nFor people in intensive care, nasogastric tube feeding should usually be delivered continuously over 16\xa0to 24\xa0hours daily. If insulin administration is needed, it is safe and more practical to administer feeding continuously over 24\xa0hours.\n\n## Motility agents\n\nFor people in intensive care with delayed gastric emptying who are not tolerating enteral tube feeding, a motility agent should be considered, unless there is a pharmacological cause that can be rectified or suspicion of gastrointestinal obstruction.\n\nPeople in other acute care settings who have delayed gastric emptying and are not tolerating enteral tube feeding should also be offered a motility agent unless there is a pharmacological cause that can be rectified or suspicion of gastrointestinal obstruction.\n\nIf delayed gastric emptying is severely limiting feeding into the stomach, despite the use of motility agents, post-pyloric enteral tube feeding and/or parenteral nutrition should be considered.\n\n## Management of tubes\n\nPeople requiring enteral tube feeding should have their tube inserted by healthcare professionals with the relevant skills and training.\n\nThe position of all nasogastric tubes should be confirmed after placement and before each use by aspiration and pH graded paper (with X‑ray if necessary) as per the advice from the National Patient Safety Agency (2011); further patient safety alerts for nasogastric tubes have also been issued in 2013 and 2016. Local protocols should address the clinical criteria that permit enteral tube feeding. These criteria include how to proceed when the ability to make repeat checks of the tube position is limited by the inability to aspirate the tube, or the checking of pH is invalid because of gastric acid suppression.\n\nThe initial placement of post-pyloric tubes should be confirmed with an abdominal X‑ray (unless placed radiologically). Agreed protocols setting out the necessary clinical checks need to be in place before this procedure is carried out.\n\n# Parenteral nutrition in hospital and the community\n\n## Indications\n\nHealthcare professionals should consider parenteral nutrition in people who are malnourished or at risk of malnutrition as defined in recommendations\xa01.3.1 and 1.3.2, respectively, and meet either of the following criteria:\n\ninadequate or unsafe oral and/or enteral nutritional intake\n\na non-functional, inaccessible or perforated (leaking) gastrointestinal tract.\n\n## Prescription\n\nParenteral nutrition should be introduced progressively and closely monitored, usually starting at no more than 50% of estimated needs for the first 24\xa0to 48\xa0hours. Parenteral nutrition can be withdrawn once adequate oral or enteral nutrition is tolerated and nutritional status is stable. Withdrawal should be planned and stepwise with a daily review of the patient's progress.\n\nPatients who need parenteral nutrition should have their nutritional requirements determined by healthcare professionals with the relevant skills and training in the prescription of nutrition support. Before using most parenteral nutrition products, micronutrients and trace elements should be added and additional electrolytes and other nutrients may also be needed. Additions should be made under appropriate pharmaceutically controlled environmental conditions before administration.\n\nParenteral nutrition should be stopped when the patient is established on adequate oral and/or enteral support. There is no minimum length of time for the duration of parenteral nutrition.\n\n## Surgical patients\n\nHealthcare professionals should consider supplementary peri‑operative parenteral nutrition in malnourished surgical patients who meet the criteria in recommendation\xa01.8.1.\n\nPeri-operative supplementary parenteral nutrition should not be given to surgical patients unless they meet the criteria set out in recommendation\xa01.8.1.\n\nIf intestinal tolerance persistently limits enteral tube feeding in surgical or critical care patients, parenteral nutrition should be used to supplement or replace enteral tube feeding.\n\n## Route of access\n\nIn hospital, parenteral nutrition can be given via a dedicated peripherally inserted central catheter as an alternative to a dedicated centrally placed central venous catheter. A free dedicated lumen in a multi-lumen centrally placed catheter may also be used.\n\nAdministration of parenteral nutrition via a peripheral venous catheter should be considered for patients who are likely to need short-term parenteral nutrition (less than 14\xa0days) who have no need for central access for other reasons. Care should be taken in catheter choice, and in attention to pH, tonicity and long-term compatibility of the parenteral nutrition formulations in order to avoid administration or stability problems.\n\nTunnelling subclavian lines is recommended for long-term use (more than 30\xa0days).\n\nCatheters do not have to be tunnelled for short-term use (less than 30\xa0days).\n\n## Mode of delivery\n\nContinuous administration of parenteral nutrition should be offered as the preferred method of infusion in severely ill people who require parenteral nutrition.\n\nCyclical delivery of parenteral nutrition should be considered when using peripheral venous cannulae with planned routine catheter change.\n\nA gradual change from continuous to cyclical delivery should be considered in patients requiring parenteral nutrition for more than 2\xa0weeks.\n\n## Management of catheters\n\nOnly healthcare professionals competent in catheter placement should be responsible for the placement of catheters and they should be aware of the importance of monitoring and managing these safely. See the NICE guideline on healthcare-associated infections: prevention and control in primary and community care.\n\n# Supporting patients in the community\n\nHealthcare professionals should ensure that patients having enteral or parenteral nutrition in the community and their carers:\n\nare kept fully informed and have access to appropriate sources of information in formats, languages and ways that are suited to an individual's requirements; consideration should be given to cognition, gender, physical needs, culture and stage of life of the individual\n\nhave the opportunity to discuss diagnosis, treatment options and relevant physical, psychological and social issues\n\nare given contact details for relevant support groups, charities and voluntary organisations.\n\n## Enteral tube feeding\n\nAll people in the community having enteral tube feeding should be supported by a coordinated multidisciplinary team, which includes dietitians, district, care home or homecare company nurses, GPs, community pharmacists and other allied healthcare professionals (for example, speech and language therapists) as appropriate. Close liaison between the multidisciplinary team and patients and carers regarding diagnoses, prescription, arrangements and potential problems is essential.\n\nPatients in the community having enteral tube feeding and their carers should receive an individualised care plan which includes overall aims and a monitoring plan.\n\nPatients in the community having enteral tube feeding and their carers, should receive training and information from members of the multidisciplinary team on:\n\nthe management of the tubes, delivery systems and the regimen, outlining all procedures related to setting up feeds, using feed pumps, the likely risks and methods for troubleshooting common problems and be provided with an instruction manual (and visual aids if appropriate)\n\nboth routine and emergency telephone numbers to contact a healthcare professional who understands the needs and potential problems of people on home enteral tube feeding\n\nthe delivery of equipment, ancillaries and feed with appropriate contact details for any homecare company involved.\n\n## Parenteral nutrition\n\nAll people in the community having parenteral nutrition should be supported by a coordinated multidisciplinary team, which includes input from specialist nutrition nurses, dietitians, GPs, pharmacists and district and/or homecare company nurses. Close liaison between the multidisciplinary team and patients and carers regarding diagnoses, prescription, arrangements and potential problems is essential.\n\nPeople in the community having parenteral nutrition and their carers should receive an individualised care plan which includes overall aims and a monitoring plan.\n\nPeople in the community having parenteral nutrition and their carers should receive training and information from members of the multidisciplinary team on:\n\nthe management of the delivery systems and the regimen, outlining all procedures related to setting up feeds, using feed pumps, the likely risks and methods for troubleshooting common problems and be provided with an instruction manual (and visual aids if appropriate)\n\nroutine and emergency telephone numbers to contact a healthcare professional with the relevant competencies (specialist nutrition nurse, pharmacist)\n\nthe arrangements for the delivery of equipment, ancillaries and feed with appropriate contact details for any homecare company involved.", 'Recommendations for research': 'The guideline committee has made the following recommendations for research.\n\n# Research question 1\n\nFurther research is needed to ascertain whether an educational intervention (for example, three 1‑week modular courses, over 6\xa0months) for all healthcare professionals, in particular medical and nursing staff including those who work with people with dementia, would have an effect on patient care (that is, effect on nutritional status, length of hospital stay, frequency of GP visits, complications and quality of life) compared with no formal education.\n\n## Why this is important\n\nIt is known that healthcare professionals in both the hospital and community setting have a poor knowledge of nutrition. This is partly due to receiving a minimal amount of education in nutrition during their undergraduate or basic training. It is therefore essential to determine whether an organised nutrition support education programme to healthcare professionals would improve the choice made about nutrition support and the consequent care of patients prescribed nutrition support.\n\n# Research question 2\n\nWhat are the benefits to patients of a nutritional screening programme (using a simple tool such as the Malnutrition Universal Screening Tool [MUST]) compared with not screening people in: a) primary care (attending GP clinics); b) care homes; c) hospital inpatients; d) hospital outpatients; e) patients with dementia in terms of determining the number of people at risk of malnutrition, complications, survival, hospital admission rates, length of stay, quality of life and cost effectiveness?\n\n## Why this is important\n\nThere is no clear evidence available as to whether screening is really beneficial or how it should be carried out. With the lack of evidence, the committee have considered in detail this problem and have instead carefully developed consensus statements to support recommendations for screening. As a priority, it is important that we determine the need for screening and intervention − in particular, primary care and the wider community.\n\n# Research question 3\n\nFurther research is needed to identify which components of nutrition monitoring are clinically and cost effective.\n\n## Why this is important\n\nThere is no clear evidence available regarding the long- and short-term benefits of clinical monitoring in terms of prevention of complications and survival. With the lack of evidence, the committee have considered in detail this problem and have instead carefully developed the guidance for monitoring by expert clinical practice and consensus opinion.\n\n# Research question 4\n\nWhat are the benefits of patients (in hospital or the community, including older people) identified as at high risk of malnutrition by a screening tool such as MUST being offered either oral nutritional supplements compared with: a) dietary modification and/or food fortification; or b) dietary modification and/or food fortification together with dietary counselling, in terms of determining complications, survival, length of hospital stay, quality of life and cost effectiveness?\n\n## Why this is important\n\nThis is an essential recommendation for research since there is insufficient evidence on the benefits of intervention used for oral nutrition support – in particular, the benefits of often first line treatment, for example food fortification and/or dietary counselling. It is essential to know this so that the indications on how to treat can be further supported.\n\n# Research question 5\n\nWhat are the benefits of enteral tube feeding to patients compared with no enteral tube feeding in people with dysphagia and early- to mid-stage dementia in terms of reduced complications associated with swallowing, improved nutritional status, delayed onset of advanced stage dementia, hospital admissions, cost effectiveness and survival?\n\n## Why this is important\n\nMuch of the research tends to focus or concentrate on tube feeding people with advanced dementia or those who may be in terminal stages of the disease. Depending on the type of dementia, swallowing disorders may occur at an earlier stage in the disease, for example vascular dementia. The benefits and complications of tube feeding may be quite different in people in the earlier stages than those who are in the advanced stage of dementia.'}
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https://www.nice.org.uk/guidance/cg32
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This guideline covers identifying and caring for adults who are malnourished or at risk of malnutrition in hospital or in their own home or a care home. It offers advice on how oral, enteral tube feeding and parenteral nutrition support should be started, administered and stopped. It aims to support healthcare professionals identify malnourished people and help them to choose the most appropriate form of support.
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d7056f657f2b1882f8998a1b8e6157055eb7baf6
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nice
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Nivolumab for treating relapsed or refractory classical Hodgkin lymphoma
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Nivolumab for treating relapsed or refractory classical Hodgkin lymphoma
Evidence-based recommendations on nivolumab (Opdivo) for treating relapsed or refractory classical Hodgkin lymphoma in adults.
# Recommendations
Nivolumab is recommended, within its marketing authorisation, as an option for treating relapsed or refractory classical Hodgkin lymphoma in adults after autologous stem cell transplant and treatment with brentuximab vedotin, when the company provides nivolumab according to the commercial arrangement.# The technology
Description of the technology
Nivolumab (Opdivo, Bristol-Myers Squibb) is a human monoclonal antibody that blocks an immune checkpoint protein receptor called programmed cell death protein 1 (PD‑1) to promote anti-tumour response.
Marketing authorisation
Nivolumab has a marketing authorisation in the UK for 'the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and treatment with brentuximab vedotin'.
Adverse reactions
The most common adverse reactions with nivolumab in clinical trials were diarrhoea, nausea, fatigue, pyrexia, rash (occurring in at least 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
mg/kg given intravenously every 2 weeks.
Price
The list price is £439 per 40-mg vial or £1,097 per 100-mg vial (excluding VAT; British national formulary June 2017).
The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Evidence
The appraisal committee (section 6) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of nivolumab, having considered evidence on the nature of classical Hodgkin lymphoma and the value placed on the benefits of nivolumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Current clinical management of Hodgkin lymphoma
The committee noted that the NICE technology appraisal guidance on brentuximab vedotin for Hodgkin lymphoma is the only NICE guidance on Hodgkin lymphoma, and that the guidance was published during the course of this appraisal. It understood that current practice is first chemotherapy with or without radiotherapy. If this fails to lead to long-term remission, people may have high-dose chemotherapy followed, when possible, by autologous stem cell transplant. Brentuximab vedotin is currently available on the Cancer Drugs Fund following at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not a treatment option, and for relapsed disease following autologous stem cell transplant in patients who have not previously had brentuximab vedotin. Up to half the people who have had autologous stem cell transplant develop progressive disease with a mean life expectancy of less than 3 years. The committee heard from the clinical experts that people whose disease has relapsed may be offered further, usually single-drug chemotherapy, including brentuximab vedotin, gemcitabine, bendamustine or cisplatin, as salvage therapy. This aims to control the disease, and if possible, elicit a disease response to enable allogeneic stem cell transplant.
The committee understood that allogeneic stem cell transplant is the treatment of choice after autologous stem cell transplant has failed, provided there is a suitable donor and a good response to systemic therapy. The committee heard that allogeneic stem cell transplant is offered to relatively fit patients whose disease achieves a partial or complete response to salvage therapy following failure of autologous stem cell transplant. The committee heard from the clinical experts that allogeneic stem cell transplant is potentially curative in around 60% of patients who have it. The committee recognised that there is an unmet clinical need for patients whose disease does not achieve a partial or complete response to salvage therapy after autologous stem cell transplant fails. It understood from the clinical experts and patient organisations that nivolumab had the potential to act as salvage therapy to enable allogeneic stem cell transplant after both autologous stem cell transplant and brentuximab vedotin.
The committee considered the experience of people with relapsed or refractory Hodgkin lymphoma following autologous stem cell transplant. It heard from the patient experts that the side effects of existing chemotherapy treatments affect their quality of life and can dissuade people from allogeneic stem cell transplant (if transplant becomes possible). It heard from the clinical experts that treatment with nivolumab was generally well tolerated because it has more manageable side effects than existing treatments, and that it can significantly improve patients' quality of life.
The committee noted that the population in the marketing authorisation could be subdivided into 3 groups, based on the position of brentuximab vedotin in the treatment pathway for Hodgkin lymphoma:
Adults with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin is used as salvage therapy to enable an autologous stem cell transplant.
Adults with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin is used as salvage therapy to enable an allogeneic stem cell transplant (after autologous stem cell transplant fails).
Adults with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin is used both as salvage therapy to enable an autologous stem cell transplant and as salvage therapy to enable an allogeneic stem cell transplant (after autologous stem cell transplant fails).The committee noted that brentuximab vedotin's UK marketing authorisation does not explicitly exclude retreatment, but retreatment was not permitted through the Cancer Drugs Fund. The committee therefore did not consider the final group because brentuximab vedotin retreatment is not currently used in clinical practice in England. The committee concluded that based on current clinical practice, nivolumab would be used in patients who have had autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin has been used as salvage therapy to either enable an autologous stem cell transplant or to enable an allogeneic stem cell transplant following failure of autologous stem cell transplant.
# Clinical effectiveness
The committee noted that the evidence for nivolumab in this population came from 2 non-comparative single-arm trials: CheckMate 205 (cohorts B and C) and CA209‑039. The trials included patients who had brentuximab vedotin after autologous stem cell transplant (CheckMate 205 cohort B and CA209‑039), patients who had brentuximab vedotin either before or after autologous stem cell transplant, or both (CheckMate 205 cohort C). The committee noted that CheckMate 205 cohort C included 8 people who had brentuximab vedotin retreatment. The primary outcome measure for CheckMate 205 and CA209‑039 was objective response rate, defined as the proportion of patients with a best overall response of complete or partial response. Progression-free and overall survival were secondary outcome measures. The objective response rates and progression-free survival reported are as assessed by the independent radiologic review committee (see table 1). The investigator-assessed objective response rates and progression-free survival are also available for both trials, but the company plan to publish the results before the end of 2017 and therefore consider these to be academic in confidence, and so they cannot be reported here.
## Table 1 Clinical data from CheckMate 205 and CA209‑039
CheckMate 205
cohort B
CheckMate 205
cohort C
CA209‑039
Number of patients
Median follow-up
months
months
months
Objective response rate (95% CI)
Progression-free survival*, median (95% CI)
months (11.33, NA)
months (8.51, NA)
months (5.91, NA)
Overall survival at 6 months (95% CI)
NA
- Assessed by independent radiologic review committee.
Median overall survival was not reached.
Abbreviations: CI, confidence interval; NA, not available.
The committee was concerned that the single-arm design of the trials, the small number of patients included and short follow-up meant that the results were potentially biased. The committee accepted that the results from the latest data cut-off for both trials (April 2016 for CheckMate 205 and August 2015 for CA209‑039) showed that nivolumab was clinically effective based on response rates but agreed that there was a large degree of uncertainty in the clinical evidence.
## Indirect treatment comparison of nivolumab with standard of care
The committee was aware that there were no data providing direct comparative evidence for the clinical effectiveness of nivolumab compared with current practice (standard of care), because nivolumab for Hodgkin lymphoma had only been studied in single-arm trials. It noted that the company had done an indirect treatment comparison of nivolumab compared with standard of care by comparing the pooled outcomes from the nivolumab trials with standard of care. The outcomes for standard of care came from Cheah et al. (2016), a retrospective real-world study done in the US. The study aimed to determine progression-free survival and overall survival in patients with Hodgkin lymphoma following disease relapse after brentuximab vedotin therapy; a secondary outcome was the efficacy of subsequent treatments.
The committee considered whether the population and composition of treatments in the Cheah study reflected clinical practice in the UK. The committee noted that the study population partially matched the population of interest because around 70% of patients had previous autologous stem cell transplant and brentuximab vedotin. The committee noted a lack of detail on the precise combinations of chemotherapies given as standard of care in the study, and the inclusion of platinum-based therapies and 'other alkylators'. It considered that the study may not reflect UK practice, particularly regarding subsequent rates of allogeneic stem cell transplant. The committee noted that in response to consultation, the company had explored UK standard-of-care data from the Haematological Malignancy Research Network and surveyed clinicians actively treating relapsed or refractory classical Hodgkin lymphoma in the UK. The committee considered that both the network data and the clinician survey somewhat supported the Cheah study as reflecting UK practice, but it recognised that the data were limited. The committee concluded that the Cheah study was the best available evidence for standard of care and considered it appropriate for its decision-making, but overall the clinical effectiveness of nivolumab compared with standard of care was highly uncertain because the comparator data may not fully represent UK clinical practice.
The committee noted that the company's indirect treatment comparison excluded results from patients who had investigational agents in the Cheah study. It heard from the company that including investigational agents could have confounded the results, because they increased survival benefit above that expected from treatments used in current practice, and that the investigational agents were likely to include PD‑1 inhibitors, one of which is nivolumab itself. It also heard from the company that use of investigational agents tended to be restricted to large centres and that they could not therefore be considered current NHS practice. The committee acknowledged that the investigational agents used in the study could have included treatments not available in the UK, but noted that there was little detail about which specific therapies were defined as 'investigational agents'. It heard from the evidence review group (ERG), who had contacted the authors of the study, that only 'a couple' of patients in the study had a PD‑1 inhibitor, and so it considered that the overall population should be used for comparator data. The committee considered that selectively excluding potentially the fittest patients from the Cheah dataset could bias the results of the indirect treatment comparison more than including some treatments that may not be used in UK current practice. The committee concluded therefore that the overall population of the Cheah study was the most appropriate dataset for standard of care to use in the indirect comparison.
The committee was aware of the results of the company's comparison of the pooled nivolumab data with the standard-of-care data from the overall population in the Cheah study for progression-free and overall survival (results are academic in confidence because the company plan to publish them before the end of 2017, and so they cannot be reported here). The committee noted that in the company's original submission, the results of the indirect treatment comparison were obtained from an unadjusted or 'naive' comparison, but that it had also presented the results of a matched-adjusted indirect comparison as a scenario analysis. The committee was aware that a matched-adjusted indirect comparison took account of different distributions of prognostic factors and effect modifiers arising from any differences in baseline characteristics of patients in the trials. It concluded that a matched-adjusted indirect comparison would produce more robust results, but considered that the unadjusted comparison used in the company's base-case analysis was similar and so was acceptable for its decision-making. Furthermore, the committee acknowledged that the company had used the results of the matched-adjusted comparison in its revised cost-effectiveness analysis submitted in response to consultation.
In conclusion, the committee acknowledged that nivolumab was clinically effective, but noted that the available evidence was highly uncertain because the data were immature and from single-arm studies. The committee noted that the company's indirect comparison with standard of care had compared pooled outcomes from the nivolumab trials with outcomes from the Cheah et al. study. The committee considered that Cheah et al. may not fully reflect UK current practice, but it acknowledged that the published evidence for comparator treatments used in the UK was limited. When considering the new evidence received from the company in response to consultation, it acknowledged that Cheah et al. was currently the best available evidence for standard of care and considered it appropriate for decision-making. The committee concluded that there was a large degree of uncertainty in the clinical evidence.
# Cost effectiveness
The committee discussed the company's economic model and modelling assumptions, which it received in response to consultation. Overall, it accepted the structure of the model as representing the treatment pathway for relapsed or refractory Hodgkin lymphoma and considered it appropriate for decision-making. The committee recognised that the company had presented a revised base-case analysis incorporating some of the committee's preferred assumptions, and a number of scenario analyses that explored alternative sources of UK standard-of-care data and rates of subsequent allogeneic stem cell transplant:
A revised base case incorporating the committee's preferred assumptions relating to the method of indirect treatment comparison, costs and utilities, including costs and outcomes of subsequent allogeneic stem cell transplant (using rates taken from the nivolumab trials and the Cheah study).
A revised base case incorporating the committee's same preferred assumptions but excluding costs and outcomes of subsequent allogeneic stem cell transplant.
A scenario analysis using the results from the clinician survey as standard-of-care data, and including costs and outcomes of subsequent allogeneic stem cell transplant (using rates taken from the survey).
A scenario analysis using the results from the clinician survey as standard-of-care data (expected overall and progression-free survival) but excluding costs and outcomes of subsequent allogeneic stem cell transplant.
A scenario analysis as per the revised base case but using rates of allogeneic stem cell transplant taken from the survey.The committee noted that in each of the new analyses that used standard-of-care data from the Cheah study, the company had presented results from both the overall population and the subpopulation excluding patients who had investigational agents. It recalled that it preferred to use the overall population in its decision-making (see section 4.8) and therefore discounted results obtained from a comparison with the Cheah dataset that excluded patients who had investigational agents. It also noted that for the analyses that included costs and outcomes of subsequent allogeneic stem cell transplant, the company had presented results for 2 different sources of cost data. The committee recalled that it preferred to use the costs of allogeneic stem cell transplant obtained from Radford et al. (2016, see section 4.16) for its decision-making and therefore discounted results that did not use allogeneic stem cell transplant costs from the Radford paper. It considered the scenario analysis that used the results of the clinician survey as standard-of-care data, but concluded that because this evidence was limited and of low quality the Cheah data were a more reasonable representation of UK standard of care and should be used for its decision-making. The committee ultimately concluded that the company's revised base case (including the costs and outcomes of subsequent allogeneic stem cell transplant) and the scenario analysis that replicated the revised base case but used rates of subsequent allogeneic stem cell transplant from the clinician survey, were the most relevant analyses for its decision-making.
## Modelling survival data
The committee noted that to model progression-free survival and overall survival, the company used the outcome data from the matched-adjusted indirect treatment comparison of nivolumab compared with the treatments in the Cheah study (see section 4.6). It was concerned that a large proportion of the survival benefit of nivolumab compared with standard of care was based on extrapolation rather than on trial data, because the trial data were very immature. It was aware that the company had extrapolated beyond the trial follow-up for nivolumab by fitting a lognormal curve to progression-free survival data (investigator-assessed) and a Weibull curve to overall survival, and that for standard of care, exponential curves had been fitted to the progression-free and overall survival data from the Cheah study. The committee heard from the ERG that the extrapolation curves used were plausible, but it also considered the plausibility of the Gompertz curve fit to the nivolumab overall survival curve, which represented a more pessimistic assumption about long-term survival. The committee concluded that the Gompertz curve may not be clinically probable, but it was not at all clear that the outcomes would be as favourable as the company's estimates. It concluded that all the parametric curves fitted to the data had a reasonable fit, but that they needed to be considered alongside survival modelling that included the long-term survival benefit of subsequent allogeneic stem cell transplant.
## Subsequent allogeneic stem cell transplant
The committee considered those patients who had a partial or complete response to nivolumab and went on to have a potentially curative allogeneic stem cell transplant, and how these patients may have affected overall survival in the model. The committee recalled that allogeneic stem cell transplant was potentially curative (see section 4.2), and that because nivolumab could be used as salvage therapy to enable allogeneic stem cell transplant, the modelling should include the projected long-term survival benefit of transplant. It was aware that the survival modelling used in the company's original base-case analysis included both patients who had allogeneic stem cell transplant and those who had not, in both treatment arms, but that the company had only modelled the effect of subsequent allogeneic stem cell transplant on long-term survival in a scenario analysis. The committee noted that in this analysis, the company had used non-UK data from the Cheah study to project long-term survival for patients who had subsequent allogeneic stem cell transplant. The committee understood that the survival data for subsequent allogeneic stem cell transplant had been extrapolated independently from the overall survival extrapolation used in the base case. It acknowledged that there would be some double counting because the overall survival extrapolation used in the base case included some patients who had allogeneic stem cell transplant, but agreed that it was an acceptable approach. The committee noted that in its revised cost-effectiveness analyses received in response to consultation, the company had censored overall survival data for patients having nivolumab who went on to have subsequent allogeneic stem cell transplant. It considered that censoring data in only 1 arm of a model introduced a more substantial bias than a small amount of double counting, and was not therefore methodologically appropriate.
The committee noted that the company had used data from a UK study to model long-term survival after allogeneic stem cell transplant in its revised cost-effectiveness analyses. The committee considered the UK study of 13 patients with classical Hodgkin lymphoma having allogeneic stem cell transplant after 3 previous therapies (Laffety et al. 2017), and noted the small number of patients included in the study. It agreed that any modelling of long-term overall survival beyond the median trial follow-up of approximately 28 months would therefore be subject to significant uncertainty. It noted that the company had fitted a Gompertz parametric curve to the data from the Laffety study to extrapolate long-term overall survival but that this projected an infinite median survival for patients having allogeneic stem cell transplant (all-cause mortality excluded), which the committee considered implausible. It therefore considered that the lognormal and Weibull parametric curves used by the ERG in its new exploratory analysis were more clinically plausible because these curves did not predict infinite median survival.
The committee considered the proportion of patients who were likely to have an allogeneic stem cell transplant in the UK, if their disease had partially or completely responded to treatment after autologous stem cell transplant failed. The committee was aware that in its original scenario analyses, the company had obtained response-specific proportions of patients having subsequent allogeneic stem cell transplant (22.2% of those with complete response, 14.1% with partial response and 5.56% with stable disease) from a study in France (Perrot et al. 2016), and applied them to the response rates seen in the nivolumab and Cheah studies to generate transition probabilities for each treatment arm for use in the model. The committee understood that the ERG had assumed the proportion of patients having subsequent allogeneic stem cell transplant would be equivalent to the proportion who had subsequent allogeneic stem cell transplant in the nivolumab and Cheah studies, which was overall slightly higher than the proportions in the Perrot study. However, it heard from the clinical experts that UK rates of allogeneic stem cell transplant were much higher than those in the US. The committee considered the results of the company's clinician survey, which it received in response to consultation. It noted that the response-specific proportions of patients expected to have subsequent allogeneic stem cell transplant, as reported by clinicians working in the UK, were significantly higher than those used in the original analyses by both the company and ERG. However, because these rates were expected rather than actual, and the results of the survey included a wide range of expected transplant rates (which were very different from the actual rates reported in the nivolumab trials and Cheah study), the committee agreed that rates of allogeneic stem cell transplant in the UK remained uncertain. The committee was also aware from supportive evidence provided by the company in response to consultation that caution may be warranted about using allogeneic stem cell transplant following treatment with nivolumab or another PD‑1 inhibitor, because of the potential for increased risk of complications from transplant linked to PD‑1 inhibitors' immunomodulatory mechanism of action. The committee also heard that recent NHS referrals for allogeneic stem cell transplant were lower than those reported in the survey. The committee concluded that UK rates of allogeneic stem cell transplant may lie somewhere between the high rates reported in the results of the survey, and the considerably lower rates of actual transplants reported in the nivolumab trials and Cheah study.
## Treatment costs
The committee recognised that some patients in the nivolumab trials and the Cheah study had subsequent allogeneic stem cell transplant, and that because the survival benefit from allogeneic stem cell transplant was captured in the survival data for both arms of the model, the costs should also be included. It recognised that the company had used 2 different sources to calculate costs of allogeneic stem cell transplant: a weighted average of NHS reference costs and the costs included in the Radford et al. (2016) paper. The committee agreed that the Radford costs were more appropriate for its decision-making because they were consistent with the costs used for allogeneic stem cell transplant in guidelines currently in development. The committee also considered the costs of comparator treatments, and agreed with the ERG that the costs of mini-BEAM (carmustine, etoposide, cytarabine and melphalan) and DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine and melphalan) should be excluded because they are not used in UK clinical practice, and their benefits would not significantly affect the progression-free or overall survival projections.
## Utility values
The committee was aware that CheckMate 205 (cohort B) collected health-related quality-of-life data for patients having nivolumab using the EQ-5D, which were then converted to utility data. It was also aware that utility data for patients having standard of care were taken from published literature (Swinburn et al. 2015). The committee recognised that response-specific utility values from CheckMate 205 and Swinburn et al. diverged, and that the ERG had instead used the response-specific utility values from CheckMate 205 to estimate utility values for standard of care. The committee agreed that this was a more consistent approach but heard from the clinical experts that pre-progression quality of life was likely to be better with nivolumab than with existing treatments because of nivolumab's potential to improve quality of life (see section 4.3). The committee recognised that the pre-progression utility values used by the ERG in its base case maintained a difference between the treatment arms and concluded that they were therefore more appropriate for its decision-making.
The committee considered the post-progression utility values and noted the large difference in values between the nivolumab and standard of care treatment arms. It heard from the clinical experts that this large difference was not clinically plausible. The committee preferred the ERG's assumption that post-progression utility values were the same across all treatments.
The committee noted the ERG's identification of an error in the company's revised analyses received in response to consultation, whereby utility values for patients who discontinued treatment and transitioned to best supportive care reflected the company's original base case and not the committee's preferred assumptions about pre- and post-progression utilities (see sections 4.17 and 4.18). The committee was aware that the ERG had corrected this in its new exploratory analysis and agreed that this was appropriate.
## Results of cost-effectiveness analyses
The committee noted that the company had presented deterministic and probabilistic incremental cost-effectiveness ratios (ICERs) in its revised base-case analysis provided in response to consultation. For nivolumab compared with standard of care, including the confidential discount agreed for nivolumab, the company's deterministic base-case ICER was £15,181 per quality-adjusted life year (QALY) gained and the probabilistic ICER was £17,826 per QALY gained.
The committee was aware that the company's revised base case included the committee's preferred assumptions about using the overall population from the Cheah study for the standard-of-care data (see section 4.8), the method of indirect treatment comparison (see section 4.9), costs (see section 4.16) and utilities (see sections 4.17 to 4.18), and incorporated subsequent allogeneic stem cell transplant overall survival data (see section 4.13). However, the committee considered that this revised base-case analysis was flawed because of errors in the utility values for best supportive care (see section 4.19) and inappropriate censoring of nivolumab overall survival data (see section 4.13). The committee noted that when the ERG corrected these errors, the company's revised base-case ICER increased to £26,664 per QALY gained. The committee also noted that the company's revised base case had extrapolated long-term survival after allogeneic stem cell transplant using a Gompertz curve, which it had considered implausible (see section 4.14). It was aware that the ERG's new exploratory analyses using the lognormal and Weibull curves increased the ICER to £30,366 and £31,031 per QALY gained respectively. However, the committee was also aware that these analyses included the high rates of allogeneic stem cell transplant from the clinician survey; because the committee considered that actual rates may be lower (see section 4.15), it concluded that the most plausible ICER was likely to be around £30,000 per QALY gained. But this ICER was associated with a large degree of uncertainty because of the immaturity of the nivolumab trial data, the lack of comparator data fully relevant to UK practice, and uncertain outcomes and rates of subsequent allogeneic stem cell transplant in the UK.
# Innovation
The committee considered whether nivolumab was an innovative treatment. It noted that nivolumab had been awarded 'promising innovative medicine' designation by the Medicines and Health products Regulatory Agency and was aware that before the marketing authorisation was granted, nivolumab was available for people in the NHS through the early access to medicines scheme. It also heard from the clinical and patient experts that nivolumab was an important new option for people with relapsed or refractory Hodgkin lymphoma. The committee agreed that nivolumab was innovative and promising, but that it had not been presented with any evidence of additional benefits that were not captured in the QALY measure.
# End-of-life considerations
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The company made the case that nivolumab met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24 months). The committee noted that the company's modelling predicted a mean overall survival in the comparator treatment arm of more than 24 months. However, the committee also considered the data from the Haematological Malignancy Research Network provided by the company in response to consultation, which showed shorter survival and suggested that the Cheah study may have been optimistic. The committee acknowledged that nivolumab did not unequivocally meet the criterion for short life expectancy but that it was plausible that the criterion could apply. It therefore agreed that on balance, nivolumab met the criterion for short life expectancy, and that it would take this into account in its decision-making.
The committee also discussed whether there was sufficient evidence to show that the treatment offers an extension to life of at least an additional 3 months compared with current NHS treatment. The committee noted that the cost-effectiveness analysis from which the survival benefit of nivolumab could be inferred did not reflect the committee's preferred analysis, and that because of the immaturity of the trial data and the lack of UK comparator data, all the estimates were uncertain. However, it concluded that based on the evidence presented, nivolumab met the criterion for extending life by at least an additional 3 months.
# Committee's conclusions
The committee was aware that an ICER of around £30,000 per QALY gained required certainty about the assumptions underpinning the ICER in order to be considered a cost-effective use of NHS resources. It considered that in this case, significant uncertainty remained because of the immaturity of the nivolumab trial data, the lack of comparator data fully relevant to UK practice, and uncertain outcomes and rates of subsequent allogeneic stem cell transplant in the UK. However, the committee also took into account the poor prognosis of people with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, and the case for nivolumab meeting the end-of-life criteria (see sections 4.23 and 4.24), and concluded that there was sufficient justification for recommending nivolumab as a cost-effective use of NHS resources.
The committee understood that there were some people with relapsed or refractory Hodgkin lymphoma who were at the last line of treatment after failure of allogeneic stem cell transplant. It agreed that, although the analysis presented did not include this group, there was no biological reason why they would not benefit from treatment with nivolumab, and so they should not be disadvantaged. The committee therefore concluded that the recommendation should also cover these people.
# Summary of appraisal committee's key conclusions
TA462
Appraisal title: Nivolumab for treating relapsed or refractory classical Hodgkin lymphoma
Section
Key conclusion
Nivolumab is recommended, within its marketing authorisation, as an option for treating relapsed or refractory classical Hodgkin lymphoma in adults after autologous stem cell transplant and treatment with brentuximab vedotin, when the company provides nivolumab according to the commercial arrangement.
Evidence for the clinical effectiveness of nivolumab was highly uncertain because the data were immature and from single-arm studies. In addition, the published evidence for comparator treatments was limited, and the committee could not be certain that the data used for standard of care fully represented UK current practice.
The evidence review group's (ERG's) deterministic incremental cost-effectiveness ratio (ICER) for nivolumab compared with standard of care was more than £30,000 per quality-adjusted life year (QALY) gained. When accounting for the high rates of subsequent allogeneic stem cell transplant included in this analysis, the committee considered that the most plausible ICER was around £30,000 per QALY gained. Although significant uncertainty remained about the assumptions underpinning the cost-effectiveness analysis, the committee took into account the poor prognosis of people with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, and the case for nivolumab meeting the end-of-life criteria, and concluded that there was sufficient justification for recommending nivolumab as a cost-effective use of NHS resources.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee recognised that there is an unmet clinical need for patients whose disease does not achieve a partial or complete response to salvage therapy such as brentuximab vedotin, after autologous stem cell transplant fails.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee heard from clinical experts that treatment with nivolumab was generally well tolerated because it has more manageable side effects than existing treatments, and can significantly improve patients' quality of life.
Nivolumab had been awarded 'promising innovative medicine' designation by the Medicines and Health products Regulatory Agency, and before the marketing authorisation was granted, it was available for people in the NHS through the early access to medicines scheme. The committee agreed that nivolumab was innovative and promising.
What is the position of the treatment in the pathway of care for the condition?
The committee concluded that based on current clinical practice, nivolumab would be used in patients who have had autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin has been used as salvage therapy to either enable an autologous stem cell transplant or to enable an allogeneic stem cell transplant following failure of autologous stem cell transplant.
The committee understood there were some people with relapsed or refractory Hodgkin lymphoma who were at the last line of treatment after failure of allogeneic stem cell transplant, and considered that the recommendation should also cover this group.
Adverse reactions
The most common adverse reactions with nivolumab in clinical trials were diarrhoea, nausea, fatigue, pyrexia and rash.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The evidence came from 2 non-comparative single-arm trials: CheckMate 205 (cohorts B and C) and CA209‑039, with a total of 193 patients.
Relevance to general clinical practice in the NHS
The committee considered that data for the comparator may not represent UK clinical practice. However, when considering the new evidence received from the company in response to consultation, it concluded that the Cheah study was the best available evidence for standard of care.
Uncertainties generated by the evidence
The single-arm design of the trials, the small number of patients included and the short follow-up meant that there was a large degree of uncertainty in the clinical evidence for nivolumab.
There was a large degree of uncertainty about the effectiveness of nivolumab compared with standard of care because the data for the comparator may not fully represent UK clinical practice.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
There are no clinically relevant subgroups for which there is evidence of differential effectiveness.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
There is substantial uncertainty about the clinical effectiveness of nivolumab because of the nature of the evidence for nivolumab (non-comparative studies, small patient numbers and short follow-up) and uncertainty about the comparator's relevance to UK practice.
Evidence for cost effectiveness
Availability and nature of evidence
The company presented an economic model that the committee accepted as representing the treatment pathway for relapsed or refractory Hodgkin lymphoma.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The cost-effectiveness estimates were uncertain because of the immaturity of the nivolumab trial data (and long-term survival modelling), the lack of comparator data fully relevant to UK practice, and uncertain outcomes and rates of subsequent allogeneic stem cell transplant in the UK.
There was substantial uncertainty around the long-term survival data because of the immaturity of the nivolumab trial data.
There was significant uncertainty around the long-term survival of people having allogeneic stem cell transplant because of the small number of patients in the relevant study, and short follow-up.
Rates of allogeneic stem cell transplant in the UK were uncertain.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee did not find the company's utility values plausible and it preferred the ERG's alternative assumptions around utility.
The committee was not presented with any evidence of additional benefits of nivolumab that were not captured in the QALY measure.
What are the key drivers of cost effectiveness?
Overall survival with nivolumab.
Post-progression utility values.
Most likely cost-effectiveness estimate (given as an ICER)
The committee noted that the company's revised base-case ICER, when corrected by the ERG, was £26,664 per QALY gained. It was aware that this incorporated an overall survival extrapolation it deemed implausible. The ERG's exploratory analysis using more plausible extrapolations increased the ICER to over £30,000 per QALY gained. However, the committee was aware that this analysis included high rates of allogeneic stem cell transplant, and because it considered that actual rates may be lower, it concluded that the most plausible ICER was likely to be around £30,000 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The company presented analyses that included the confidential patient access scheme for nivolumab.
End-of-life considerations
Nivolumab did not unequivocally meet the criterion for short life expectancy, but it was plausible that the criterion could apply, and therefore the committee agreed that on balance, nivolumab met the criterion for short life expectancy.
Nivolumab met the criterion for extending life by at least an additional 3 months.
Equalities considerations and social value judgements
No equalities issues were identified that could be addressed in the appraisal.
The committee agreed that it was important to be clear that the recommendation would include people for whom there were no more treatment options (after autologous stem cell transplant and brentuximab vedotin). It therefore included a paragraph in the guidance relating to people who were at the last line of treatment, confirming that the recommendation should also cover these people.
The equality impact assessment provides further information.
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{'Recommendations': 'Nivolumab is recommended, within its marketing authorisation, as an option for treating relapsed or refractory classical Hodgkin lymphoma in adults after autologous stem cell transplant and treatment with brentuximab vedotin, when the company provides nivolumab according to the commercial arrangement.', 'The technology': "Description of the technology\n\nNivolumab (Opdivo, Bristol-Myers Squibb) is a human monoclonal antibody that blocks an immune checkpoint protein receptor called programmed cell death protein 1 (PD‑1) to promote anti-tumour response.\n\nMarketing authorisation\n\nNivolumab has a marketing authorisation in the UK for 'the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and treatment with brentuximab vedotin'.\n\nAdverse reactions\n\nThe most common adverse reactions with nivolumab in clinical trials were diarrhoea, nausea, fatigue, pyrexia, rash (occurring in at least 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nmg/kg given intravenously every 2\xa0weeks.\n\nPrice\n\nThe list price is £439 per 40-mg vial or £1,097 per 100-mg vial (excluding VAT; British national formulary June 2017).\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Bristol-Myers Squibb and a review of this submission by the evidence review group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of nivolumab, having considered evidence on the nature of classical Hodgkin lymphoma and the value placed on the benefits of nivolumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Current clinical management of Hodgkin lymphoma\n\nThe committee noted that the NICE technology appraisal guidance on brentuximab vedotin for Hodgkin lymphoma is the only NICE guidance on Hodgkin lymphoma, and that the guidance was published during the course of this appraisal. It understood that current practice is first chemotherapy with or without radiotherapy. If this fails to lead to long-term remission, people may have high-dose chemotherapy followed, when possible, by autologous stem cell transplant. Brentuximab vedotin is currently available on the Cancer Drugs Fund following at least 2\xa0previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not a treatment option, and for relapsed disease following autologous stem cell transplant in patients who have not previously had brentuximab vedotin. Up to half the people who have had autologous stem cell transplant develop progressive disease with a mean life expectancy of less than 3\xa0years. The committee heard from the clinical experts that people whose disease has relapsed may be offered further, usually single-drug chemotherapy, including brentuximab vedotin, gemcitabine, bendamustine or cisplatin, as salvage therapy. This aims to control the disease, and if possible, elicit a disease response to enable allogeneic stem cell transplant.\n\nThe committee understood that allogeneic stem cell transplant is the treatment of choice after autologous stem cell transplant has failed, provided there is a suitable donor and a good response to systemic therapy. The committee heard that allogeneic stem cell transplant is offered to relatively fit patients whose disease achieves a partial or complete response to salvage therapy following failure of autologous stem cell transplant. The committee heard from the clinical experts that allogeneic stem cell transplant is potentially curative in around 60% of patients who have it. The committee recognised that there is an unmet clinical need for patients whose disease does not achieve a partial or complete response to salvage therapy after autologous stem cell transplant fails. It understood from the clinical experts and patient organisations that nivolumab had the potential to act as salvage therapy to enable allogeneic stem cell transplant after both autologous stem cell transplant and brentuximab vedotin.\n\nThe committee considered the experience of people with relapsed or refractory Hodgkin lymphoma following autologous stem cell transplant. It heard from the patient experts that the side effects of existing chemotherapy treatments affect their quality of life and can dissuade people from allogeneic stem cell transplant (if transplant becomes possible). It heard from the clinical experts that treatment with nivolumab was generally well tolerated because it has more manageable side effects than existing treatments, and that it can significantly improve patients' quality of life.\n\nThe committee noted that the population in the marketing authorisation could be subdivided into 3\xa0groups, based on the position of brentuximab vedotin in the treatment pathway for Hodgkin lymphoma:\n\nAdults with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin is used as salvage therapy to enable an autologous stem cell transplant.\n\nAdults with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin is used as salvage therapy to enable an allogeneic stem cell transplant (after autologous stem cell transplant fails).\n\nAdults with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin is used both as salvage therapy to enable an autologous stem cell transplant and as salvage therapy to enable an allogeneic stem cell transplant (after autologous stem cell transplant fails).The committee noted that brentuximab vedotin's UK marketing authorisation does not explicitly exclude retreatment, but retreatment was not permitted through the Cancer Drugs Fund. The committee therefore did not consider the final group because brentuximab vedotin retreatment is not currently used in clinical practice in England. The committee concluded that based on current clinical practice, nivolumab would be used in patients who have had autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin has been used as salvage therapy to either enable an autologous stem cell transplant or to enable an allogeneic stem cell transplant following failure of autologous stem cell transplant.\n\n# Clinical effectiveness\n\nThe committee noted that the evidence for nivolumab in this population came from 2\xa0non-comparative single-arm trials: CheckMate\xa0205 (cohorts B and C) and CA209‑039. The trials included patients who had brentuximab vedotin after autologous stem cell transplant (CheckMate\xa0205 cohort B and CA209‑039), patients who had brentuximab vedotin either before or after autologous stem cell transplant, or both (CheckMate\xa0205 cohort C). The committee noted that CheckMate\xa0205 cohort C included 8\xa0people who had brentuximab vedotin retreatment. The primary outcome measure for CheckMate\xa0205 and CA209‑039 was objective response rate, defined as the proportion of patients with a best overall response of complete or partial response. Progression-free and overall survival were secondary outcome measures. The objective response rates and progression-free survival reported are as assessed by the independent radiologic review committee (see table\xa01). The investigator-assessed objective response rates and progression-free survival are also available for both trials, but the company plan to publish the results before the end of 2017 and therefore consider these to be academic in confidence, and so they cannot be reported here.\n\n## Table 1 Clinical data from CheckMate\xa0205 and CA209‑039\n\n\n\nCheckMate\xa0205\n\ncohort B\n\nCheckMate\xa0205\n\ncohort C\n\nCA209‑039\n\nNumber of patients\n\n\n\n\n\n\n\nMedian follow-up\n\nmonths\n\nmonths\n\nmonths\n\nObjective response rate (95%\xa0CI)\n\n% (54)\n\n(57.2, 77.8)\n\n% (73) (64.3, 81.7)\n\n% (9)\n\nProgression-free survival*, median (95%\xa0CI)\n\nmonths (11.33, NA)\n\nmonths (8.51, NA)\n\nmonths (5.91, NA)\n\nOverall survival at 6\xa0months** (95%\xa0CI)\n\n% (92.0, 100)\n\n% (89.1, 98.8)\n\nNA\n\n* Assessed by independent radiologic review committee.\n\n** Median overall survival was not reached.\n\nAbbreviations: CI, confidence interval; NA, not available.\n\nThe committee was concerned that the single-arm design of the trials, the small number of patients included and short follow-up meant that the results were potentially biased. The committee accepted that the results from the latest data cut-off for both trials (April 2016 for CheckMate\xa0205 and August 2015 for CA209‑039) showed that nivolumab was clinically effective based on response rates but agreed that there was a large degree of uncertainty in the clinical evidence.\n\n## Indirect treatment comparison of nivolumab with standard of care\n\nThe committee was aware that there were no data providing direct comparative evidence for the clinical effectiveness of nivolumab compared with current practice (standard of care), because nivolumab for Hodgkin lymphoma had only been studied in single-arm trials. It noted that the company had done an indirect treatment comparison of nivolumab compared with standard of care by comparing the pooled outcomes from the nivolumab trials with standard of care. The outcomes for standard of care came from Cheah\xa0et\xa0al.\xa0(2016), a retrospective real-world study done in the US. The study aimed to determine progression-free survival and overall survival in patients with Hodgkin lymphoma following disease relapse after brentuximab vedotin therapy; a secondary outcome was the efficacy of subsequent treatments.\n\nThe committee considered whether the population and composition of treatments in the Cheah study reflected clinical practice in the UK. The committee noted that the study population partially matched the population of interest because around 70% of patients had previous autologous stem cell transplant and brentuximab vedotin. The committee noted a lack of detail on the precise combinations of chemotherapies given as standard of care in the study, and the inclusion of platinum-based therapies and 'other alkylators'. It considered that the study may not reflect UK practice, particularly regarding subsequent rates of allogeneic stem cell transplant. The committee noted that in response to consultation, the company had explored UK standard-of-care data from the Haematological Malignancy Research Network and surveyed clinicians actively treating relapsed or refractory classical Hodgkin lymphoma in the UK. The committee considered that both the network data and the clinician survey somewhat supported the Cheah study as reflecting UK practice, but it recognised that the data were limited. The committee concluded that the Cheah study was the best available evidence for standard of care and considered it appropriate for its decision-making, but overall the clinical effectiveness of nivolumab compared with standard of care was highly uncertain because the comparator data may not fully represent UK clinical practice.\n\nThe committee noted that the company's indirect treatment comparison excluded results from patients who had investigational agents in the Cheah study. It heard from the company that including investigational agents could have confounded the results, because they increased survival benefit above that expected from treatments used in current practice, and that the investigational agents were likely to include PD‑1 inhibitors, one of which is nivolumab itself. It also heard from the company that use of investigational agents tended to be restricted to large centres and that they could not therefore be considered current NHS practice. The committee acknowledged that the investigational agents used in the study could have included treatments not available in the UK, but noted that there was little detail about which specific therapies were defined as 'investigational agents'. It heard from the evidence review group (ERG), who had contacted the authors of the study, that only 'a couple' of patients in the study had a PD‑1 inhibitor, and so it considered that the overall population should be used for comparator data. The committee considered that selectively excluding potentially the fittest patients from the Cheah dataset could bias the results of the indirect treatment comparison more than including some treatments that may not be used in UK current practice. The committee concluded therefore that the overall population of the Cheah study was the most appropriate dataset for standard of care to use in the indirect comparison.\n\nThe committee was aware of the results of the company's comparison of the pooled nivolumab data with the standard-of-care data from the overall population in the Cheah study for progression-free and overall survival (results are academic in confidence because the company plan to publish them before the end of 2017, and so they cannot be reported here). The committee noted that in the company's original submission, the results of the indirect treatment comparison were obtained from an unadjusted or 'naive' comparison, but that it had also presented the results of a matched-adjusted indirect comparison as a scenario analysis. The committee was aware that a matched-adjusted indirect comparison took account of different distributions of prognostic factors and effect modifiers arising from any differences in baseline characteristics of patients in the trials. It concluded that a matched-adjusted indirect comparison would produce more robust results, but considered that the unadjusted comparison used in the company's base-case analysis was similar and so was acceptable for its decision-making. Furthermore, the committee acknowledged that the company had used the results of the matched-adjusted comparison in its revised cost-effectiveness analysis submitted in response to consultation.\n\nIn conclusion, the committee acknowledged that nivolumab was clinically effective, but noted that the available evidence was highly uncertain because the data were immature and from single-arm studies. The committee noted that the company's indirect comparison with standard of care had compared pooled outcomes from the nivolumab trials with outcomes from the Cheah\xa0et\xa0al.\xa0study. The committee considered that Cheah\xa0et\xa0al.\xa0may not fully reflect UK current practice, but it acknowledged that the published evidence for comparator treatments used in the UK was limited. When considering the new evidence received from the company in response to consultation, it acknowledged that Cheah\xa0et\xa0al.\xa0was currently the best available evidence for standard of care and considered it appropriate for decision-making. The committee concluded that there was a large degree of uncertainty in the clinical evidence.\n\n# Cost effectiveness\n\nThe committee discussed the company's economic model and modelling assumptions, which it received in response to consultation. Overall, it accepted the structure of the model as representing the treatment pathway for relapsed or refractory Hodgkin lymphoma and considered it appropriate for decision-making. The committee recognised that the company had presented a revised base-case analysis incorporating some of the committee's preferred assumptions, and a number of scenario analyses that explored alternative sources of UK standard-of-care data and rates of subsequent allogeneic stem cell transplant:\n\nA revised base case incorporating the committee's preferred assumptions relating to the method of indirect treatment comparison, costs and utilities, including costs and outcomes of subsequent allogeneic stem cell transplant (using rates taken from the nivolumab trials and the Cheah study).\n\nA revised base case incorporating the committee's same preferred assumptions but excluding costs and outcomes of subsequent allogeneic stem cell transplant.\n\nA scenario analysis using the results from the clinician survey as standard-of-care data, and including costs and outcomes of subsequent allogeneic stem cell transplant (using rates taken from the survey).\n\nA scenario analysis using the results from the clinician survey as standard-of-care data (expected overall and progression-free survival) but excluding costs and outcomes of subsequent allogeneic stem cell transplant.\n\nA scenario analysis as per the revised base case but using rates of allogeneic stem cell transplant taken from the survey.The committee noted that in each of the new analyses that used standard-of-care data from the Cheah study, the company had presented results from both the overall population and the subpopulation excluding patients who had investigational agents. It recalled that it preferred to use the overall population in its decision-making (see section\xa04.8) and therefore discounted results obtained from a comparison with the Cheah dataset that excluded patients who had investigational agents. It also noted that for the analyses that included costs and outcomes of subsequent allogeneic stem cell transplant, the company had presented results for 2\xa0different sources of cost data. The committee recalled that it preferred to use the costs of allogeneic stem cell transplant obtained from Radford\xa0et\xa0al.\xa0(2016, see section\xa04.16) for its decision-making and therefore discounted results that did not use allogeneic stem cell transplant costs from the Radford paper. It considered the scenario analysis that used the results of the clinician survey as standard-of-care data, but concluded that because this evidence was limited and of low quality the Cheah data were a more reasonable representation of UK standard of care and should be used for its decision-making. The committee ultimately concluded that the company's revised base case (including the costs and outcomes of subsequent allogeneic stem cell transplant) and the scenario analysis that replicated the revised base case but used rates of subsequent allogeneic stem cell transplant from the clinician survey, were the most relevant analyses for its decision-making.\n\n## Modelling survival data\n\nThe committee noted that to model progression-free survival and overall survival, the company used the outcome data from the matched-adjusted indirect treatment comparison of nivolumab compared with the treatments in the Cheah study (see section\xa04.6). It was concerned that a large proportion of the survival benefit of nivolumab compared with standard of care was based on extrapolation rather than on trial data, because the trial data were very immature. It was aware that the company had extrapolated beyond the trial follow-up for nivolumab by fitting a lognormal curve to progression-free survival data (investigator-assessed) and a Weibull curve to overall survival, and that for standard of care, exponential curves had been fitted to the progression-free and overall survival data from the Cheah study. The committee heard from the ERG that the extrapolation curves used were plausible, but it also considered the plausibility of the Gompertz curve fit to the nivolumab overall survival curve, which represented a more pessimistic assumption about long-term survival. The committee concluded that the Gompertz curve may not be clinically probable, but it was not at all clear that the outcomes would be as favourable as the company's estimates. It concluded that all the parametric curves fitted to the data had a reasonable fit, but that they needed to be considered alongside survival modelling that included the long-term survival benefit of subsequent allogeneic stem cell transplant.\n\n## Subsequent allogeneic stem cell transplant\n\nThe committee considered those patients who had a partial or complete response to nivolumab and went on to have a potentially curative allogeneic stem cell transplant, and how these patients may have affected overall survival in the model. The committee recalled that allogeneic stem cell transplant was potentially curative (see section\xa04.2), and that because nivolumab could be used as salvage therapy to enable allogeneic stem cell transplant, the modelling should include the projected long-term survival benefit of transplant. It was aware that the survival modelling used in the company's original base-case analysis included both patients who had allogeneic stem cell transplant and those who had not, in both treatment arms, but that the company had only modelled the effect of subsequent allogeneic stem cell transplant on long-term survival in a scenario analysis. The committee noted that in this analysis, the company had used non-UK data from the Cheah study to project long-term survival for patients who had subsequent allogeneic stem cell transplant. The committee understood that the survival data for subsequent allogeneic stem cell transplant had been extrapolated independently from the overall survival extrapolation used in the base case. It acknowledged that there would be some double counting because the overall survival extrapolation used in the base case included some patients who had allogeneic stem cell transplant, but agreed that it was an acceptable approach. The committee noted that in its revised cost-effectiveness analyses received in response to consultation, the company had censored overall survival data for patients having nivolumab who went on to have subsequent allogeneic stem cell transplant. It considered that censoring data in only 1\xa0arm of a model introduced a more substantial bias than a small amount of double counting, and was not therefore methodologically appropriate.\n\nThe committee noted that the company had used data from a UK study to model long-term survival after allogeneic stem cell transplant in its revised cost-effectiveness analyses. The committee considered the UK study of 13\xa0patients with classical Hodgkin lymphoma having allogeneic stem cell transplant after 3\xa0previous therapies (Laffety\xa0et\xa0al.\xa02017), and noted the small number of patients included in the study. It agreed that any modelling of long-term overall survival beyond the median trial follow-up of approximately 28\xa0months would therefore be subject to significant uncertainty. It noted that the company had fitted a Gompertz parametric curve to the data from the Laffety study to extrapolate long-term overall survival but that this projected an infinite median survival for patients having allogeneic stem cell transplant (all-cause mortality excluded), which the committee considered implausible. It therefore considered that the lognormal and Weibull parametric curves used by the ERG in its new exploratory analysis were more clinically plausible because these curves did not predict infinite median survival.\n\nThe committee considered the proportion of patients who were likely to have an allogeneic stem cell transplant in the UK, if their disease had partially or completely responded to treatment after autologous stem cell transplant failed. The committee was aware that in its original scenario analyses, the company had obtained response-specific proportions of patients having subsequent allogeneic stem cell transplant (22.2% of those with complete response, 14.1% with partial response and 5.56% with stable disease) from a study in France (Perrot\xa0et\xa0al.\xa02016), and applied them to the response rates seen in the nivolumab and Cheah studies to generate transition probabilities for each treatment arm for use in the model. The committee understood that the ERG had assumed the proportion of patients having subsequent allogeneic stem cell transplant would be equivalent to the proportion who had subsequent allogeneic stem cell transplant in the nivolumab and Cheah studies, which was overall slightly higher than the proportions in the Perrot study. However, it heard from the clinical experts that UK rates of allogeneic stem cell transplant were much higher than those in the US. The committee considered the results of the company's clinician survey, which it received in response to consultation. It noted that the response-specific proportions of patients expected to have subsequent allogeneic stem cell transplant, as reported by clinicians working in the UK, were significantly higher than those used in the original analyses by both the company and ERG. However, because these rates were expected rather than actual, and the results of the survey included a wide range of expected transplant rates (which were very different from the actual rates reported in the nivolumab trials and Cheah study), the committee agreed that rates of allogeneic stem cell transplant in the UK remained uncertain. The committee was also aware from supportive evidence provided by the company in response to consultation that caution may be warranted about using allogeneic stem cell transplant following treatment with nivolumab or another PD‑1 inhibitor, because of the potential for increased risk of complications from transplant linked to PD‑1 inhibitors' immunomodulatory mechanism of action. The committee also heard that recent NHS referrals for allogeneic stem cell transplant were lower than those reported in the survey. The committee concluded that UK rates of allogeneic stem cell transplant may lie somewhere between the high rates reported in the results of the survey, and the considerably lower rates of actual transplants reported in the nivolumab trials and Cheah study.\n\n## Treatment costs\n\nThe committee recognised that some patients in the nivolumab trials and the Cheah study had subsequent allogeneic stem cell transplant, and that because the survival benefit from allogeneic stem cell transplant was captured in the survival data for both arms of the model, the costs should also be included. It recognised that the company had used 2\xa0different sources to calculate costs of allogeneic stem cell transplant: a weighted average of NHS reference costs and the costs included in the Radford\xa0et\xa0al.\xa0(2016) paper. The committee agreed that the Radford costs were more appropriate for its decision-making because they were consistent with the costs used for allogeneic stem cell transplant in guidelines currently in development. The committee also considered the costs of comparator treatments, and agreed with the ERG that the costs of mini-BEAM (carmustine, etoposide, cytarabine and melphalan) and DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine and melphalan) should be excluded because they are not used in UK clinical practice, and their benefits would not significantly affect the progression-free or overall survival projections.\n\n## Utility values\n\nThe committee was aware that CheckMate\xa0205 (cohort B) collected health-related quality-of-life data for patients having nivolumab using the EQ-5D, which were then converted to utility data. It was also aware that utility data for patients having standard of care were taken from published literature (Swinburn\xa0et\xa0al.\xa02015). The committee recognised that response-specific utility values from CheckMate\xa0205 and Swinburn\xa0et\xa0al.\xa0diverged, and that the ERG had instead used the response-specific utility values from CheckMate\xa0205 to estimate utility values for standard of care. The committee agreed that this was a more consistent approach but heard from the clinical experts that pre-progression quality of life was likely to be better with nivolumab than with existing treatments because of nivolumab's potential to improve quality of life (see section\xa04.3). The committee recognised that the pre-progression utility values used by the ERG in its base case maintained a difference between the treatment arms and concluded that they were therefore more appropriate for its decision-making.\n\nThe committee considered the post-progression utility values and noted the large difference in values between the nivolumab and standard of care treatment arms. It heard from the clinical experts that this large difference was not clinically plausible. The committee preferred the ERG's assumption that post-progression utility values were the same across all treatments.\n\nThe committee noted the ERG's identification of an error in the company's revised analyses received in response to consultation, whereby utility values for patients who discontinued treatment and transitioned to best supportive care reflected the company's original base case and not the committee's preferred assumptions about pre- and post-progression utilities (see sections\xa04.17 and 4.18). The committee was aware that the ERG had corrected this in its new exploratory analysis and agreed that this was appropriate.\n\n## Results of cost-effectiveness analyses\n\nThe committee noted that the company had presented deterministic and probabilistic incremental cost-effectiveness ratios (ICERs) in its revised base-case analysis provided in response to consultation. For nivolumab compared with standard of care, including the confidential discount agreed for nivolumab, the company's deterministic base-case ICER was £15,181 per quality-adjusted life year (QALY) gained and the probabilistic ICER was £17,826 per QALY gained.\n\nThe committee was aware that the company's revised base case included the committee's preferred assumptions about using the overall population from the Cheah study for the standard-of-care data (see section\xa04.8), the method of indirect treatment comparison (see section\xa04.9), costs (see section\xa04.16) and utilities (see sections\xa04.17 to 4.18), and incorporated subsequent allogeneic stem cell transplant overall survival data (see section\xa04.13). However, the committee considered that this revised base-case analysis was flawed because of errors in the utility values for best supportive care (see section\xa04.19) and inappropriate censoring of nivolumab overall survival data (see section\xa04.13). The committee noted that when the ERG corrected these errors, the company's revised base-case ICER increased to £26,664 per QALY gained. The committee also noted that the company's revised base case had extrapolated long-term survival after allogeneic stem cell transplant using a Gompertz curve, which it had considered implausible (see section\xa04.14). It was aware that the ERG's new exploratory analyses using the lognormal and Weibull curves increased the ICER to £30,366 and £31,031 per QALY gained respectively. However, the committee was also aware that these analyses included the high rates of allogeneic stem cell transplant from the clinician survey; because the committee considered that actual rates may be lower (see section\xa04.15), it concluded that the most plausible ICER was likely to be around £30,000 per QALY gained. But this ICER was associated with a large degree of uncertainty because of the immaturity of the nivolumab trial data, the lack of comparator data fully relevant to UK practice, and uncertain outcomes and rates of subsequent allogeneic stem cell transplant in the UK.\n\n# Innovation\n\nThe committee considered whether nivolumab was an innovative treatment. It noted that nivolumab had been awarded 'promising innovative medicine' designation by the Medicines and Health products Regulatory Agency and was aware that before the marketing authorisation was granted, nivolumab was available for people in the NHS through the early access to medicines scheme. It also heard from the clinical and patient experts that nivolumab was an important new option for people with relapsed or refractory Hodgkin lymphoma. The committee agreed that nivolumab was innovative and promising, but that it had not been presented with any evidence of additional benefits that were not captured in the QALY measure.\n\n# End-of-life considerations\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The company made the case that nivolumab met the criteria for life-extending treatments for people with a short life expectancy (normally less than 24\xa0months). The committee noted that the company's modelling predicted a mean overall survival in the comparator treatment arm of more than 24\xa0months. However, the committee also considered the data from the Haematological Malignancy Research Network provided by the company in response to consultation, which showed shorter survival and suggested that the Cheah study may have been optimistic. The committee acknowledged that nivolumab did not unequivocally meet the criterion for short life expectancy but that it was plausible that the criterion could apply. It therefore agreed that on balance, nivolumab met the criterion for short life expectancy, and that it would take this into account in its decision-making.\n\nThe committee also discussed whether there was sufficient evidence to show that the treatment offers an extension to life of at least an additional 3\xa0months compared with current NHS treatment. The committee noted that the cost-effectiveness analysis from which the survival benefit of nivolumab could be inferred did not reflect the committee's preferred analysis, and that because of the immaturity of the trial data and the lack of UK comparator data, all the estimates were uncertain. However, it concluded that based on the evidence presented, nivolumab met the criterion for extending life by at least an additional 3\xa0months.\n\n# Committee's conclusions\n\nThe committee was aware that an ICER of around £30,000 per QALY gained required certainty about the assumptions underpinning the ICER in order to be considered a cost-effective use of NHS resources. It considered that in this case, significant uncertainty remained because of the immaturity of the nivolumab trial data, the lack of comparator data fully relevant to UK practice, and uncertain outcomes and rates of subsequent allogeneic stem cell transplant in the UK. However, the committee also took into account the poor prognosis of people with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, and the case for nivolumab meeting the end-of-life criteria (see sections\xa04.23 and 4.24), and concluded that there was sufficient justification for recommending nivolumab as a cost-effective use of NHS resources.\n\nThe committee understood that there were some people with relapsed or refractory Hodgkin lymphoma who were at the last line of treatment after failure of allogeneic stem cell transplant. It agreed that, although the analysis presented did not include this group, there was no biological reason why they would not benefit from treatment with nivolumab, and so they should not be disadvantaged. The committee therefore concluded that the recommendation should also cover these people.\n\n# Summary of appraisal committee's key conclusions\n\nTA462\n\nAppraisal title: Nivolumab for treating relapsed or refractory classical Hodgkin lymphoma\n\nSection\n\nKey conclusion\n\nNivolumab is recommended, within its marketing authorisation, as an option for treating relapsed or refractory classical Hodgkin lymphoma in adults after autologous stem cell transplant and treatment with brentuximab vedotin, when the company provides nivolumab according to the commercial arrangement.\n\nEvidence for the clinical effectiveness of nivolumab was highly uncertain because the data were immature and from single-arm studies. In addition, the published evidence for comparator treatments was limited, and the committee could not be certain that the data used for standard of care fully represented UK current practice.\n\nThe evidence review group's (ERG's) deterministic incremental cost-effectiveness ratio (ICER) for nivolumab compared with standard of care was more than £30,000 per quality-adjusted life year (QALY) gained. When accounting for the high rates of subsequent allogeneic stem cell transplant included in this analysis, the committee considered that the most plausible ICER was around £30,000 per QALY gained. Although significant uncertainty remained about the assumptions underpinning the cost-effectiveness analysis, the committee took into account the poor prognosis of people with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplant and brentuximab vedotin, and the case for nivolumab meeting the end-of-life criteria, and concluded that there was sufficient justification for recommending nivolumab as a cost-effective use of NHS resources.\n\n, 4.10, 4.21, 4.25\n\n\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee recognised that there is an unmet clinical need for patients whose disease does not achieve a partial or complete response to salvage therapy such as brentuximab vedotin, after autologous stem cell transplant fails.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee heard from clinical experts that treatment with nivolumab was generally well tolerated because it has more manageable side effects than existing treatments, and can significantly improve patients' quality of life.\n\nNivolumab had been awarded 'promising innovative medicine' designation by the Medicines and Health products Regulatory Agency, and before the marketing authorisation was granted, it was available for people in the NHS through the early access to medicines scheme. The committee agreed that nivolumab was innovative and promising.\n\n, 4.22\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that based on current clinical practice, nivolumab would be used in patients who have had autologous stem cell transplant and brentuximab vedotin, when brentuximab vedotin has been used as salvage therapy to either enable an autologous stem cell transplant or to enable an allogeneic stem cell transplant following failure of autologous stem cell transplant.\n\nThe committee understood there were some people with relapsed or refractory Hodgkin lymphoma who were at the last line of treatment after failure of allogeneic stem cell transplant, and considered that the recommendation should also cover this group.\n\n, 4.26\n\nAdverse reactions\n\nThe most common adverse reactions with nivolumab in clinical trials were diarrhoea, nausea, fatigue, pyrexia and rash.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe evidence came from 2\xa0non-comparative single-arm trials: CheckMate\xa0205 (cohorts B and C) and CA209‑039, with a total of 193\xa0patients.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee considered that data for the comparator may not represent UK clinical practice. However, when considering the new evidence received from the company in response to consultation, it concluded that the Cheah study was the best available evidence for standard of care.\n\n\n\nUncertainties generated by the evidence\n\nThe single-arm design of the trials, the small number of patients included and the short follow-up meant that there was a large degree of uncertainty in the clinical evidence for nivolumab.\n\nThere was a large degree of uncertainty about the effectiveness of nivolumab compared with standard of care because the data for the comparator may not fully represent UK clinical practice.\n\n, 4.7\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThere are no clinically relevant subgroups for which there is evidence of differential effectiveness.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThere is substantial uncertainty about the clinical effectiveness of nivolumab because of the nature of the evidence for nivolumab (non-comparative studies, small patient numbers and short follow-up) and uncertainty about the comparator's relevance to UK practice.\n\n, 4.10\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented an economic model that the committee accepted as representing the treatment pathway for relapsed or refractory Hodgkin lymphoma.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe cost-effectiveness estimates were uncertain because of the immaturity of the nivolumab trial data (and long-term survival modelling), the lack of comparator data fully relevant to UK practice, and uncertain outcomes and rates of subsequent allogeneic stem cell transplant in the UK.\n\nThere was substantial uncertainty around the long-term survival data because of the immaturity of the nivolumab trial data.\n\nThere was significant uncertainty around the long-term survival of people having allogeneic stem cell transplant because of the small number of patients in the relevant study, and short follow-up.\n\nRates of allogeneic stem cell transplant in the UK were uncertain.\n\n, 4.12, 4.14, 4.15\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee did not find the company's utility values plausible and it preferred the ERG's alternative assumptions around utility.\n\nThe committee was not presented with any evidence of additional benefits of nivolumab that were not captured in the QALY measure.\n\n, 4.18, 4.22\n\nWhat are the key drivers of cost effectiveness?\n\nOverall survival with nivolumab.\n\nPost-progression utility values.\n\n, 4.13, 4.18\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee noted that the company's revised base-case ICER, when corrected by the ERG, was £26,664 per QALY gained. It was aware that this incorporated an overall survival extrapolation it deemed implausible. The ERG's exploratory analysis using more plausible extrapolations increased the ICER to over £30,000 per QALY gained. However, the committee was aware that this analysis included high rates of allogeneic stem cell transplant, and because it considered that actual rates may be lower, it concluded that the most plausible ICER was likely to be around £30,000 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company presented analyses that included the confidential patient access scheme for nivolumab.\n\n–\n\nEnd-of-life considerations\n\nNivolumab did not unequivocally meet the criterion for short life expectancy, but it was plausible that the criterion could apply, and therefore the committee agreed that on balance, nivolumab met the criterion for short life expectancy.\n\nNivolumab met the criterion for extending life by at least an additional 3\xa0months.\n\n, 4.24\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified that could be addressed in the appraisal.\n\nThe committee agreed that it was important to be clear that the recommendation would include people for whom there were no more treatment options (after autologous stem cell transplant and brentuximab vedotin). It therefore included a paragraph in the guidance relating to people who were at the last line of treatment, confirming that the recommendation should also cover these people.\n\nThe equality impact assessment provides further information.\n\n"}
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https://www.nice.org.uk/guidance/ta462
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Evidence-based recommendations on nivolumab (Opdivo) for treating relapsed or refractory classical Hodgkin lymphoma in adults.
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8f5320a982cda9128dfda7ddfb68745006a37d8f
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nice
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Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care
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Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care
Evidence-based recommendations on faecal immunochemical tests (OC Sensor, HM-JACKarc, FOB Gold and RIDASCREEN) to guide GP referral for colorectal cancer.
# Recommendations
The OC Sensor, HM‑JACKarc and FOB Gold quantitative faecal immunochemical tests are recommended for adoption in primary care to guide referral for suspected colorectal cancer in people without rectal bleeding who have unexplained symptoms but do not meet the criteria for a suspected cancer pathway referral outlined in NICE's guideline on suspected cancer (recommendation 1.3.4).
Results should be reported using a threshold of 10 micrograms of haemoglobin per gram of faeces. Companies should provide advice about the performance characteristics of the assays to laboratories, and ensure standardisation of results.
Commissioning groups adopting the OC Sensor, HM‑JACKarc and FOB Gold should audit their outcomes and monitor the associated resource use (see section 6.1).
There is currently not enough evidence to recommend the routine adoption of the RIDASCREEN haemoglobin or the RIDASCREEN haemoglobin/haptoglobin assay in primary care to guide referral for suspected colorectal cancer in people without rectal bleeding who have unexplained symptoms but do not meet the criteria for a suspected cancer pathway referral outlined in NICE's guideline on suspected cancer (recommendation 1.3.4).# Clinical need and practice
# The problem addressed
The purpose of this assessment was to evaluate the clinical and cost effectiveness of using quantitative faecal immunochemical tests in primary care to triage low-risk symptomatic populations (that is, identify those at greatest risk) for suspected colorectal cancer referrals.
Several lower gastrointestinal symptoms can suggest colorectal cancer, including rectal bleeding, a change in bowel habits, weight loss, anaemia, abdominal pain, and blood in stools (faeces). Sometimes, blood in stools is not visible (faecal occult blood) so tests are used to detect its presence. These faecal occult blood tests can be used in primary care to assess people who are at a low risk of colorectal cancer and help determine whether they should be referred for further investigations where they do not meet the criteria for a suspected cancer pathway referral outlined in NICE's guideline on suspected cancer.
Faecal immunochemical tests, a type of faecal occult blood test, are designed to detect small amounts of blood in stool samples using antibodies specific to human haemoglobin. They have been developed as an alternative to guaiac-based faecal occult blood tests, which involve using chemicals that react with the haem component of haemoglobin in the blood and produce a blue colour change if blood is detected. Sometimes, this colour change can happen because the chemicals react with food in a person's diet or with medicine that a person is taking; this can lead to false test results. Because the faecal immunochemical tests are designed to specifically detect human haemoglobin, they may give more accurate test results than guaiac-based tests. The faecal immunochemical tests target the globin component of haemoglobin, which degrades as it travels through the gastrointestinal tract, so these tests are less likely to detect globin from upper gastrointestinal bleeding.
# The condition
Colorectal cancer is one of the most common cancers. In 2013 in the UK, 41,112 people were diagnosed with colorectal cancer and 15,903 people died from it (Cancer Research UK, 2016). Risk factors include older age, a family history of the disease, and having familial adenomatous polyposis or Lynch syndrome, colorectal polyps, or ulcerative colitis or Crohn's disease. Also, Jewish people of central and eastern European family origin are thought to be at increased risk.
# The diagnostics and care pathways
## Diagnosis
NICE's guideline on suspected cancer includes advice on assessing people presenting to primary care with certain clinical signs and symptoms that may suggest colorectal cancer. It makes the following recommendations:Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer if:
they are aged 40 or over with unexplained weight loss and abdominal pain or
they are aged 50 or over with unexplained rectal bleeding or
they are aged 60 or over with:
iron-deficiency anaemia or
changes in their bowel habit, or
tests show occult blood in their faeces.A suspected cancer referral (for an appointment within 2 weeks) should also be considered for:
people with a rectal or abdominal mass
adults aged under 50 with rectal bleeding and any of the following unexplained symptoms or findings:
abdominal pain
change in bowel habit
weight loss
iron-deficiency anaemia.
NICE's guideline on suspected cancer also previously recommended that guaiac-based faecal occult blood tests should be offered to adults without rectal bleeding who:
are aged 50 or over with unexplained:
abdominal pain or
weight loss or
are aged under 60 with:
changes in their bowel habit or
iron-deficiency anaemia or
are aged 60 or over and have anaemia without iron deficiency.
The guaiac-based faecal occult blood tests were recommended in NICE's guideline on suspected cancer to triage referral to secondary care. The tests were intended to be used in selected groups of people who have symptoms that could suggest colorectal cancer, but in whom a definitive diagnosis of cancer was unlikely. That is, they had a low probability of having colorectal cancer (their age and symptoms have a positive predictive value of between 0.1% and 3% for colorectal cancer).
If a guaiac-based faecal occult blood test was positive, NICE's guideline on suspected cancer recommended that people in England should be referred using a suspected cancer referral to establish a diagnosis. Faecal occult blood can be caused by conditions other than colorectal cancer, such as colorectal polyps and inflammatory bowel disease, so further assessment with a colonoscopy is needed to diagnose colorectal cancer; a positive faecal occult blood test was not intended be used alone.
Colonoscopy is considered to be the gold standard for diagnosing colorectal cancer because the entire colon can usually be seen and biopsies can be taken to assess the tissue in a laboratory to determine whether the sample contains benign or malignant cells. CT colonography can be offered as an alternative for people with comorbidities that make colonoscopy unsuitable. Colonoscopy is usually done as an outpatient procedure, with people having the procedure being offered sedation or painkillers.
The most common finding during a colonoscopy is colorectal polyps, which can be removed using cauterisation or a snare. If colorectal cancer is confirmed, NICE's guideline on colorectal cancer recommends further imaging tests, such as CT or MRI, to stage the cancer and determine what treatment is needed. Colonoscopy may also find other bowel diseases such as Crohn's disease, ulcerative colitis and diverticulosis, which may need further treatment and follow-up. People with a positive faecal occult blood test but no abnormalities detected during colonoscopy may be referred for further testing if a clinician thinks this is needed.
## Treatment
After diagnosis and staging, colorectal cancer may be treated with surgery, chemotherapy and radiotherapy, or sometimes with biological agents such as cetuximab. Treatment depends on the stage of the cancer and is described in more detail in NICE's guideline on colorectal cancer.# The diagnostic tests
The assessment compared 4 intervention tests with 2 comparators.
# The interventions
## OC Sensor test
The OC Sensor (Eiken Chemical/MAST Diagnostics) is a quantitative faecal immunochemical test. It comprises faecal sample collection tubes, latex reagent and buffer. The OC Sensor faecal sample collection tubes can hold 10 mg of faeces (Carroll et al. 2014) in 2 ml of buffer. The OC Sensor latex reagent contains latex particles coated with polyclonal antibodies for human haemoglobin. The antibodies bind with haemoglobin present in the faecal sample creating complexes that are detected using turbidimetry.
The test can be run on either the OC Sensor PLEDIA or the OC Sensor iO analyser. The OC Sensor PLEDIA can process up to 320 samples per hour, with a capacity of 200 samples per run. The OC Sensor iO can process up to 88 samples per hour with a maximum capacity of 20 samples per run. The performance of the assay varies according to the analyser used. The company states that a cut-off of 10 micrograms of haemoglobin (Hb)/g faeces (50 nanograms/ml) should be used for a symptomatic population.
## HM‑JACKarc system
The HM‑JACKarc system (Kyowa Medex/Alpha Laboratories) is a fully automated quantitative faecal immunochemical test system. It comprises faecal sample tubes, which incorporate a sample collection device (the Extel Hemo‑auto MC A device) and can hold 2 mg of faeces (Carroll et al. 2014) in 2 ml of buffer, and latex agglutination reagent (Extel Hemo‑Auto HS) and buffer (Extel Hemo‑auto). The reagent contains latex particles that are coated in antibodies specific to human haemoglobin. The antibodies bind to haemoglobin present in the faecal sample creating complexes that are detected using turbidimetry. The assay is compatible with the HM‑JACKarc analyser, which reports results as nanograms/ml. The user needs to convert the results to micrograms of Hb/g. However, because the test uses 2 mg of sample and 2 ml of buffer, results reported as nanograms/ml convert directly to micrograms of Hb/g faeces, that is 10 nanograms/ml equals 10 micrograms Hb/g faeces. The company suggests a cut-off of 10 micrograms Hb/g faeces for symptomatic populations. The HM‑JACKarc analyser can process up to 200 samples per hour, with a maximum capacity of 80 samples per run.
## FOB Gold system
The FOB Gold system (Sentinel/Sysmex) is an automated quantitative faecal immunochemical test system. It comprises faecal sample collection tubes (the Sentifit pierce tube faecal collection device), which collect 10 mg of faeces (Carroll et al. 2014) in 1.7 ml of buffer, and latex agglutination reagent. The FOB Gold latex agglutination reagent contains polyclonal antibodies specific to human haemoglobin, which bind to haemoglobin present in the sample creating complexes that are detected using turbidimetry. The FOB Gold kit has CE‑marked applications for a range of clinical chemistry analysers, including the BioMajesty JCA‑6010/C, the SENTiFIT270 and those supplied by Siemens, Beckman Coulter and Abbott. The performance characteristics of the assay vary depending on which analyser is used. The company suggests that each laboratory should establish their own test cut-off according to the population the laboratory serves. The throughput of the test depends on the clinical chemistry analyser used to process the samples.
## RIDASCREEN haemoglobin and haemoglobin/haptoglobin assay
The RIDASCREEN haemoglobin test (R‑Biopharm Rhone) is an enzyme immunoassay (ELISA) for the quantitative determination of human haemoglobin in stool samples. The test is run on a microtitre plate using wells coated with polyclonal antibodies for human haemoglobin. The contents of each kit are enough for 96 tests. The instructions for the test suggest that it can be used with laboratory equipment other than the DSX automated ELISA system.
The test process incorporates 3 incubations and 2 wash steps. During the first incubation, any human haemoglobin present in the sample is captured by the polyclonal antibodies in the sample well. Unbound antigens are removed in the first wash step. Then peroxidase labelled monoclonal antibodies for human haemoglobin (conjugate) are added, which bind to the captured haemoglobin during the second incubation. In the final incubation, hydrogen peroxide and TMB (substrate) is added, which react with the peroxidase creating a colour change that is detected by a plate reader. The values from the plate reader are interpreted by the RIDA-SOFT Win.net software, which reports results as the concentration of haemoglobin per gram of stool (micrograms Hb/g faeces). The company states that 91 tests can be processed manually in 150 minutes, or 546 tests in 7 hours using an automated system. The company recommends a cut-off value of more than 2 micrograms Hb/g faeces to determine a positive sample.
The company also produces the RIDASCREEN haemoglobin/haptoglobin enzyme immunoassay that can be run in combination with the haemoglobin assay, using the same sample and processing on the same microtitre plate but with the addition of a well coated with polyclonal antibodies for human haptoglobin. Haptoglobin is a protein produced by the liver that binds to haemoglobin, making it less likely to break down as it moves through the gastrointestinal tract. The detection of haptoglobin is claimed to increase the likelihood of detecting lesions in the ascending and transverse colon. The company recommends a cut-off value of 2 micrograms Hb/g faeces to determine a positive test using the haemoglobin/haptoglobin assay.
# The comparators
The first comparator used in this assessment is guaiac-based faecal occult blood testing, as previously recommended in NICE's guideline on suspected cancer (see section 2.6). Guaiac-based tests detect the pseudoperoxidase activity of the haem component of haemoglobin in stool samples using guaiac-test paper and hydrogen peroxide developer. Unlike faecal immunochemical tests, they are not specific to human haemoglobin.
The second comparator is clinical assessment and referral for colonoscopy based on lower gastrointestinal symptoms alone.# Evidence
The diagnostics advisory committee (section 8) considered evidence on quantitative faecal immunochemical tests to assess people presenting to primary care who have symptoms but are at a low risk of colorectal cancer, from several sources. Full details of all the evidence are in the committee papers.
# Clinical effectiveness
In total, 10 studies met the inclusion criteria for the systematic review. The studies were reported in 25 published papers and 2 unpublished manuscripts. Additional unpublished data were obtained for 2 of the published studies. Two of the included studies (Krivec et al. 2011; Thomas et al. 2016) were reported as conference abstracts only. Studies were included if they reported data for 1 of the intervention technologies in the scope and recruited people with lower abdominal symptoms who were being investigated for possible colorectal cancer. All included studies were appraised using the QUADAS‑2 tool if they reported diagnostic accuracy data and the PROBAST checklist if they also reported data for risk-prediction scores.
All of the included studies were diagnostic cohort studies; no randomised controlled trials or controlled clinical trials were identified. All 10 included studies were done in Europe, 1 of which was based in England (Thomas et al. 2016) and 3 in Scotland (Godber et al. 2016; McDonald et al. 2013; Mowat et al. 2015). Five of the studies had a high risk of bias. There were concerns about applicability for all of the included studies because none of them reported data that were specific to the population included in the scope of the assessment, that is, people with symptoms who are judged to be at low risk of colorectal cancer. Only 1 study (Mowat et al. 2015) was done in primary care.
The included studies reported data for the HM‑JACKarc, FOB Gold and OC Sensor assays only. No relevant data were found for the RIDASCREEN haemoglobin or the RIDASCREEN haemoglobin/haptoglobin assay. None of the included studies provided comparative accuracy data for the included technologies or made comparisons with guaiac-based faecal occult blood tests.
## Diagnostic accuracy
The bivariate/hierarchical summary receiver operating characteristic (HSROC) model was used to calculate summary sensitivity and specificity estimates and to create HSROC curves for meta-analyses, which included 4 or more studies. For meta-analyses that included fewer than 4 studies, separate pooled estimates of sensitivity and specificity were calculated using random-effects logistic regression. Data were grouped by assay, target condition and the threshold used to determine a positive test.
Five studies reported data for the OC Sensor assay. One used the iO analyser (Mowat et al. 2015), 1 used the OC Sensor Diana analyser (McDonald et al. 2013), 2 used the MICRO desktop analyser (Rodriguez-Alonso et al. 2015; Terhaar sive Droste et al. 2011) and the fifth study did not report which analyser was used (Cubiella et al. 2014). All 5 studies reported diagnostic accuracy for colorectal cancer, although the prevalence of colorectal cancer ranged from 2.1% to 12.3%. Mowat et al. (2015) was the only study done in primary care. All studies reported the accuracy of a single faecal sample only and used varying thresholds to determine a positive test. A summary of the results is shown in table 1. Additional data from Terhaar sive Droste et al. (2011) were unpublished when this guidance was written and cannot be reported here.
Study
Threshold
(micrograms Hb/g faeces)
Sensitivity %(95% CI)
Specificity %(95% CI)
Mowat et al. 2015
Rodriguez-Alonso et al. 2015
Summary estimate
McDonald et al. 2012
Mowat et al. 2015
Rodriguez-Alonso et al. 2015
Summary estimate
Rodriguez-Alonso et al. 2015
Summary estimate
Cubiella et al. 2014
Rodriguez-Alonso et al 2015
Summary estimate
Abbreviations: CI, confidence interval; Hb, haemoglobin.
The external assessment group (EAG) considered that the optimal diagnostic threshold for colorectal cancer was either 10 or 15 micrograms of haemoglobin (Hb)/g faeces, but noted that most data were available for 10 micrograms Hb/g faeces. Test accuracy data from Mowat et al. (2015) and Rodriguez-Alonso et al. (2015) were used to illustrate diagnostic outcomes for a hypothetical cohort of 1,000 people, assuming a prevalence of colorectal cancer of 3.3%, and using thresholds of both 10 micrograms Hb/g faeces and any detectable haemoglobin (4 micrograms Hb/g faeces). The results are shown in table 2.
Threshold
micrograms Hb/g faeces
micrograms Hb/g faeces
Correct referrals for colonoscopy (true positives)
Incorrect referrals for colonoscopy (false positives)
Missed colorectal cancers (false negatives)
Colonoscopies correctly avoided (true negatives)
Abbreviation: Hb, haemoglobin.
Four studies (Cubiella et al. 2014; McDonald et al. 2012; Mowat et al. 2015; Rodriguez-Alonso et al. 2015) reported diagnostic accuracy for advanced neoplasia, which includes both colorectal cancer and high-risk adenoma. The definition of high-risk adenoma and the thresholds used varied between studies. Expanding the target condition reduced the sensitivity of the test, with summary sensitivity estimates of 62.9% (95% confidence interval 55.9% to 69.4%) at a threshold of 10 micrograms Hb/g, 63.9% (95% CI 58.2% to 69.2%) at a threshold of 20 micrograms Hb/g and 84.1% (95% CI 78.3% to 88.8%) at a threshold of any detectable haemoglobin. The sensitivity of the test was lower when the target condition was expanded to include other bowel pathologies. But data from studies that reported results for both colorectal cancer and high-risk adenoma suggested that many false-positive results for colorectal cancer could be from other bowel pathologies that may benefit from treatment.
Three studies reported diagnostic accuracy data for various non‑malignant or composite target conditions. McDonald et al. (2012) reported a sensitivity of 57.0% (95% CI 45.8% to 67.6%) and a specificity of 99% (95% CI 96.3% to 99.9%) for all colorectal cancers, high-risk adenomas and inflammatory bowel disease using a threshold of 10 micrograms Hb/g faeces. Mowat et al. (2015) used the same threshold and reported a sensitivity of 68.6% (95% CI 58.7% to 77.5%) and a specificity of 83.6% (95% CI 80.6% to 86.4%) for the same composite target condition. Additional data from Terhaar sive Droste et al. (2011) were unpublished at the time of writing so cannot be reported here.
Three studies reported accuracy data for the HM‑JACKarc automated system (Auge et al. 2016; Godber et al. 2016; Thomas et al. 2016). All 3 studies were done in outpatient clinics and used single faecal samples.
Two studies (Godber et al. 2016; Thomas et al. 2016) reported accuracy data for colorectal cancer. The prevalence of colorectal cancer was 2.2% in Godber et al. and 4.9% in Thomas et al. Godber et al. reported a sensitivity of 100% (95% CI 71.5% to 100%) and a specificity of 76.6% (95% CI 72.6% to 80.3%) at a threshold of 10 micrograms Hb/g faeces. Thomas et al. reported a sensitivity of 91.3% (95% CI 72.0% to 98.9%) and a specificity of 79.2% (95% CI 75.3% to 83.0%) at a threshold of 7 micrograms Hb/g faeces. Test accuracy data from Godber et al. were used to model outcomes for a hypothetical cohort of 1,000 people, assuming a prevalence of colorectal cancer of 2.2%. The results of this analysis are shown in table 3.
Outcome
Number
Correct referrals for colonoscopy (true positives)
Incorrect referrals for colonoscopy (false positives)
Missed colorectal cancers (false negatives)
Colonoscopies correctly avoided (true negatives)
Two studies (Auge et al. 2016; Godber et al. 2016) reported data for a target condition of colorectal cancer and high-risk adenoma. Each study used a different definition of high-risk adenoma and reported different thresholds. The sensitivity estimates varied widely because of differences in the included populations. Godber et al. reported a sensitivity of 70.0% (95% CI 50.6% to 85.3%) and a specificity of 77.8% (95% CI 73.8% to 81.4%) at a threshold of 10 micrograms Hb/g faeces. Auge et al. reported a range of accuracy estimates with sensitivity ranging from 27.6% (95% CI 14.7% to 45.7%) at a threshold of 40 micrograms Hb/g faeces to 96.6% (95% CI 82.8% to 93.4%) at a threshold of any detectable haemoglobin. Specificity ranged from 10.6% (95% CI 6.9% to 15.9%) at a threshold of any detectable haemoglobin to 93.9% (95% CI 89.4% to 96.6%) at a threshold of 40 micrograms Hb/g faeces.
One study (Auge et al. 2016) also investigated the effect of multiple samples and sex on the accuracy of the HM‑JACKarc assay for detecting colorectal cancer and high-risk adenoma. The study had a prevalence of colorectal cancer of less than 1%. The authors reported that 100% sensitivity could be achieved by using a threshold of any detectable haemoglobin and using the highest value reported in 2 consecutive samples, but this reduced the specificity to 3.3%. Data were reported for single or multiple samples using a range of thresholds from any detectable haemoglobin to 40 micrograms Hb/g faeces. At thresholds above any detectable haemoglobin, using consecutive samples increased the test's sensitivity but this was still low at under 50% for all estimates.
Auge et al. (2016) also reported that sensitivity estimates at all thresholds were lower when the test was used in women than when used in men. Sensitivity estimates ranged from 8.3% at a threshold of 40 micrograms Hb/g faeces to 91.7% with any detectable haemoglobin for women, compared with a range of 41.2% at all thresholds above 20 micrograms Hb/g faeces to 100% with any detectable haemoglobin for men. Conversely, specificity estimates tended to be higher in women than in men.
Two studies (Godber et al. 2016; Thomas et al. 2016) reported accuracy data for various non‑malignant and composite target conditions. Godber et al. defined significant bowel disease as colorectal cancer, higher-risk adenoma, inflammatory bowel disease or colitis. They reported sensitivity and specificity estimates of 68.9% and 80.2% respectively at a threshold of 10 micrograms Hb/g faeces. Thomas et al. defined significant bowel disease as colorectal cancer, high-risk adenoma or inflammatory bowel disease. They reported sensitivity and specificity estimates of 72.1% and 80.6% respectively at a threshold of 7 micrograms Hb/g faeces.
Two studies reported data for the FOB Gold assay. One was reported in a conference abstract only and used the Roche Modular P/917 analyser (Krivec et al. 2011). The other was unpublished at the time of writing and used the SENTiFIT270 analyser (Hospital Clinic de Barcelona 2015). Further data from Hospital Clinic de Barcelona are unpublished and cannot be reported here. Krivec et al. (2011) reported a sensitivity of 45.2% and a specificity of 92.3% for significant bowel disease (cancer, polyps or bleeding) using a threshold of 9.35 micrograms Hb/g faeces.
## Test failures
Mowat et al. (2015) reported that fewer than 1% of samples were considered unsuitable for analysis using the OC Sensor test.
## Test uptake
Four of the included studies reporting data for the OC Sensor reported test uptake (Cubiella et al. 2014; McDonald et al. 2013; Mowat et al. 2015; Rodriguez-Alonso et al. 2015), which ranged from 41% to 98%. Methods of inviting patients to take a test varied between studies.
Two of the included studies reporting data for the HM‑JACKarc reported test uptake. Godber et al. (2016) reported an uptake of 56% when collection devices and information were sent by post, whereas Thomas et al. (2016) reported an uptake of 66% when collection devices and information were provided at an outpatient appointment.
## Management decisions
Mowat et al. (2015) reported that 11% of patients for whom a faecal immunochemical test sample was analysed were not referred to secondary care, 69% were referred for an endoscopy and 20% were referred to an outpatient clinic. However, decisions about the urgency of the referral were made before the test.
## Prediction modelling studies
Two studies (Cubiella et al. 2016; Rodriguez-Alonso et al. 2015) reported data on using prediction models, which included results of faecal immunochemical tests. These studies were also appraised with the PROBAST tool. The studies were classified as having high concerns about the applicability of the included populations, and overall were rated as being at a high risk of bias.
Rodriguez-Alonso et al. (2015) did a multivariate analysis to identify independent predictors of colorectal cancer and advanced neoplasia. Faecal haemoglobin was measured using the OC Sensor assay. The model included age as a categorical variable. The following variables were identified as independent predictors of colorectal cancer:
male sex (odds ratio 2.39; 95% CI 1.039 to 5.519; p=0.041)
iron-deficiency anaemia (OR 2.99; 95% CI 1.27 to 7.03; p=0.012)
faecal haemoglobin (OR 86.60; 95% CI 11.70 to 64.16; p<0.001).
A pre-publication copy of a manuscript by Cubiella et al. (2016) reported the development and validation of a risk score known as the FAST score (faecal haemoglobin, age and sex test). Faecal haemoglobin was measured using the OC Sensor, OC‑Auto (an earlier version of the OC Sensor) and FOB Gold assays. The logistic regression model included age as a continuous variable, and sex and faecal haemoglobin as categorical variables. The results of the model suggested that a FAST score of 4.5 had a sensitivity of 89.3% (95% CI 84.1% to 93.0%) and a specificity of 82.3% (95% CI 81.1% to 83.5%) for colorectal cancer. To avoid missing any colorectal cancers, a lower FAST score threshold of 2.12 was needed. This gave a sensitivity of 100% (95% CI 97.7% to 100%) and a specificity of 19.8% (95% CI 18.6% to 21.1%).
# Cost effectiveness
## Review of economic evidence
Only 1 study was found that reported an economic analysis of using faecal immunochemical tests in people with symptoms; the economic analysis of faecal occult blood tests in NICE's guideline on suspected cancer. Faecal immunochemical tests were included in a scenario analysis in the guideline. Faecal occult blood tests were included in the base case, which showed that guaiac-based tests and barium enema were cost effective compared with colonoscopy at a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained. In the scenario analysis, faecal immunochemical tests dominated (cost less and were more effective) barium enema and were cost effective at a maximum acceptable ICER of £20,000 per QALY gained.
## Modelling approach
The EAG developed a de novo economic model to explore the cost effectiveness of using a quantitative faecal immunochemical test to guide referral of people who present to primary care with symptoms but have a low risk of colorectal cancer. The model took the perspective of the NHS and personal social services. In the base case it compared the use of 2 quantitative faecal immunochemical tests, the OC Sensor and HM‑JACKarc assays, with both guaiac-based faecal occult blood tests and no triage (that is, referral straight to colonoscopy). A watchful waiting strategy, which may currently be used in practice, was not included as a comparator because of variability in practice and a lack of data, but was incorporated into the guaiac-based faecal occult blood and faecal immunochemical testing strategies. The FOB Gold assay was not included in the base case because no data were available for the optimal threshold (10 micrograms Hb/g faeces) determined by the EAG in the clinical-effectiveness analyses. All costs and effects included in the model were discounted by 3.5%.
The model had 3 parts. The first part was a decision tree with a 1‑year time horizon, which modelled the results of investigations for colorectal cancer (faecal immunochemical test, guaiac-based faecal occult blood test or no triage) for a cohort of patients, with symptoms, presenting to primary care. A positive faecal immunochemical test or guaiac-based faecal occult blood test resulted in referral for colonoscopy and a negative test resulted in watchful waiting, in which further investigations were done if a person's symptoms persisted. The decision tree was followed by 2 Markov state-transition models. One Markov model had a lifetime time horizon and a 1‑year cycle length and was used to estimate costs, life years and QALYs associated with the treatment and progression of colorectal cancer. The initial distribution of patients across the stages of disease at diagnosis was determined using data from the UK's National Cancer Intelligence Network. The other Markov model had a simple alive or dead structure and estimated life years and QALYs for people who did not have colorectal cancer, using UK life tables to model survival.
The model was populated with data from the clinical-effectiveness review, published literature and expert opinion. Diagnostic accuracy data were taken from the clinical-effectiveness review. The EAG concluded that a threshold of 10 micrograms Hb/g faeces with a single sample provided the optimal rule-out performance. That is, the threshold gave the maximum sensitivity and specificity, and had the lowest number of colorectal cancers missed. Data at this threshold were available for the HM‑JACKarc and OC Sensor assays. Data on the accuracy of guaiac-based faecal occult blood tests were taken from Gillberg et al. (2012), which was used in the economic model for NICE's guideline on suspected cancer. The accuracy estimates used in the base-case analysis are shown in table 4. The predictive values were calculated by the EAG assuming a prevalence of colorectal cancer of 1.5% to correspond with the prevalence assumed in NICE's guideline on suspected cancer.
Accuracy measure
OC Sensor assay
HM‑JACKarc assay
Guaiac-based faecal occult blood test
Sensitivity(95% CI)
%(86.9% to 95.3%)
%(71.5% to 100%)
%(15.0% to 85.0%)
Specificity(95% CI)
%(78.3% to 91.0%)
%(72.6% to 80.3%)
%(85.0% to 89.0%)
Positive predictive value
Negative predictive value
Abbreviation: CI, confidence interval.
Direct costs included in the model were test costs, cost of colonoscopy or CT colonography, adverse-event costs, CT scan costs, costs of first and follow-up investigations, cancer staging and treatment, drug costs, and GP and hospital visits. No costs were included in the Markov model used for outcomes for people without colorectal cancer. Costs were obtained from companies, published literature and routine sources of NHS costs. Test costs were calculated as average costs per test. The following test costs were used in the model:
OC Sensor: £4.53
HM‑JACKarc: £6.04
FOB Gold: £1.96
guaiac-based faecal occult blood test: £0.78 (rounded to 2 significant figures)
colonoscopy: £372
CT colonography: £136
CT scan: £116.
No disutilities for bleeding and perforation during colonoscopy were included in the model, because no evidence was found on quality-of-life effects in the literature and the events are often of short duration. The rates of adverse events from colonoscopy were assumed to be 0.26% for bleeding, 0.05% for perforation, and 0.0029% for death. Utilities associated with the different stages of colorectal cancer were taken from Ness et al. (1999) and sex- and age-related utilities for healthy patients were taken from Kind et al. (1999).
## Base-case results
The following key assumptions were applied in the base-case analysis:
People who had a false-negative faecal immunochemical test or guaiac-based faecal occult blood test and whose symptoms persisted were diagnosed within 1 year if they survived.
The optimal threshold for the interventions was 10 micrograms Hb/g faeces.
People who had a delayed diagnosis had an increased probability of progressing to a more advanced cancer state.
Costs of laboratory staff were the same for both faecal immunochemical tests and guaiac-based faecal occult blood tests.
Testing had no long-term (after 1 year) effect on costs or QALYs in people without colorectal cancer.
Any differences in costs between the tests in patients without colorectal cancer occurred in year 1 only.
The prevalence of colorectal cancer was 1.5%.
The probabilities of adverse events during or after colonoscopy were as follows:
bleeding: 0.26%
bowel perforation: 0.05%
death: 0.0029%.
Only patients with negative test results whose symptoms did not persist did not have a colonoscopy.
The cost of a colonoscopy or CT colonography included a follow-up appointment with a gastroenterologist.
The adverse-event rates associated with CT colonography were the same as for colonoscopy.
A CT scan was done for all patients with colorectal cancer to stage the disease.
After year 15 in the colorectal cancer Markov model, colorectal-cancer-related mortality remains constant, but overall mortality increases because age-specific mortality is included from UK life tables.
The results of the base case are shown with the fully incremental probabilistic analysis in table 5 and the probabilistic pairwise comparisons in table 6. The ICERs for the deterministic analysis were slightly higher than those in the probabilistic analysis.
Test
QALYs
Cost
Incremental QALYs
Incremental cost
ICER
gFOBT
OC Sensor assay
No triage
Dominated by HM‑JACKarc
Dominated by HM JACKarc
Dominated by HM JACKarc
HM‑JACKarc assay
Abbreviations: gFOBT, guaiac-based faecal occult blood test; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.
Intervention
Comparator
Incremental QALYs
Incremental costs
ICER
HM‑JACKarc assay
gFOBT
OC Sensor assay
gFOBT
HM‑JACKarc assay
No triage
Dominates
OC Sensor assay
No triage
£2,578,543 (savings per QALY lost)
Abbreviations: gFOBT, guaiac-based faecal occult blood test; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.
The pairwise results suggest that both the OC Sensor and the HM‑JACKarc assays are cost effective compared with both guaiac-based faecal occult blood testing and no triage. The fully incremental probabilistic analysis suggests that the OC Sensor assay is cost effective. Despite dominating no triage, the HM‑JACKarc assay has a high ICER compared with the OC sensor because of the very small difference in QALYs and higher cost, which is accounted for by the test having more positive results and so a higher number of colonoscopies.
A breakdown of the costs and outcomes in the base case showed that the number of positive tests was highest for the HMJACK‑arc assay (245.36) and lowest for guaiac-based faecal occult blood testing (130.28). The OC Sensor assay had 153.50 positive tests. The increased number of positive tests increases the costs for faecal immunochemical tests because of the associated increase in colonoscopies. No colorectal cancer patients were missed with the HM‑JACKarc assay and so no delayed diagnosis occurred with this test. By comparison, 92% of colorectal cancers were detected by the OC Sensor assay and 50% with guaiac-based faecal occult blood tests.
The cost-effectiveness acceptability curves for all strategies show that at lower maximum acceptable ICERs, the tests associated with the lowest costs have the greatest probability of being cost effective, that is guaiac-based faecal occult blood testing and the OC Sensor assay. As the maximum acceptable ICER increases, the HM‑JACKarc assay and guaiac-based faecal occult blood testing have the greatest probability of being cost effective. Pairwise comparisons showed that, when compared with faecal immunochemical testing, no triage would be cost effective only when the maximum acceptable ICER is very high. There was more uncertainty about which strategy was the most cost effective when the faecal immunochemical tests were compared with guaiac-based faecal occult blood testing.
## Analysis of alternative results
The effect of changing assumptions about the accuracy of the tests was explored in several scenario analyses. Using alternative sources of accuracy data for guaiac-based faecal occult blood tests did not substantially alter the conclusions. The faecal immunochemical tests remained cost effective compared with guaiac-based faecal occult blood tests.
When a threshold of any detectable haemoglobin was considered for the OC Sensor test it resulted in an increased number of colonoscopy referrals and an ICER of £65,192 compared with guaiac-based faecal occult blood tests.
When a threshold of 20 micrograms Hb/g faeces was considered, and the FOB Gold assay was included in the analysis using a threshold of 20.5 micrograms Hb/g faeces, this resulted in an ICER of £4,725 per QALY gained for the FOB Gold assay compared with guaiac-based faecal occult blood tests. When compared with no triage, £950,152 was saved per QALY lost.
The FOB Gold assay was included in a scenario analysis with the base-case settings, but with a threshold of 6.8 micrograms Hb/g faeces, compared with 10 micrograms Hb/g faeces for the HM‑JACKarc and OC Sensor assays. The ICER for the FOB Gold compared with guaiac-based faecal occult blood testing was £15,720 per QALY gained, and compared with no triage was £2,273,829 saved per QALY lost.
Scenario analyses were done in which the prevalence of colorectal cancer was increased from 1.5% in the base case to 3% and 5.4%. Increasing the prevalence reduced the ICERs for the interventions compared with guaiac-based faecal occult blood testing. However, at 5.4% prevalence the ICER for the OC Sensor test compared with no triage became less cost effective, from £4,133,559 saved per QALY lost to £238,380 saved per QALY lost.
A threshold analysis showed that for the ICER to remain below £30,000 per QALY gained the cost of the HM‑JACKarc test could be up to £32 more expensive than guaiac-based faecal occult blood tests. The OC Sensor assay could be up to £51 more expensive than guaiac-based faecal occult blood tests.
In the base case, the following distribution of patients across the Dukes' stages was assumed in the colorectal cancer Markov model:
stage A: 13%
stage B: 37%
stage C: 36%
stage D: 14%.
When it was assumed that there were more patients in stages A and C (16% and 44% respectively) and fewer patients in stage B (25%) there was a slight loss of QALYs and reduction in costs for all strategies.
When it was assumed that there were more patients in stages A and D (19% and 15% respectively) and fewer in stages B and C (35% and 32% respectively) there was a slight gain in QALYs and an increase in costs for all strategies.
When colorectal cancer progression was not considered in the model, the ICERs reduced from the base-case results for the HM‑JACKarc and the OC Sensor tests compared with guaiac-based faecal occult blood testing. The ICER for the OC Sensor compared with no triage became less cost effective at £163,305 saved per QALY lost.
When the probability of symptoms persisting after a negative test was doubled from the base case (65%), the interventions remained cost effective despite increased costs from increased colonoscopies and a slight reduction in QALYs. When the probability of symptoms persisting was halved from the base case (16.25%), the interventions remained cost effective with a slight QALY increase and reduction in costs.
When a mortality rate of 0.0970% was considered for colonoscopy in a worst case scenario, strategies associated with a higher rate of referrals to colonoscopy (no triage and HM‑JACKarc assay) were dominated by guaiac-based faecal occult blood testing and the OC Sensor test respectively. When it was assumed that there are no adverse events associated with colonoscopy, no triage was dominated by the HM‑JACKarc assay because it provided an equivalent number of QALYs, but cost £227.30 less.
When it was assumed that all referrals were to colonoscopy (compared with 88.3% in the base case), with no CT colonography, the cost of each of the testing strategies increased compared with the base case because of the increased cost of colonoscopy.
When it was assumed that 20% of patients, who remained symptomatic after a negative faecal immunochemical test or guaiac-based faecal occult blood test, had a second test, the cost of the faecal testing strategies increased, but not enough to affect the overall results.# Committee discussion
The committee discussed the current standard of care for people who present to their GP with symptoms, but who are at a low risk of having colorectal cancer. It noted that recommendations had previously been made for using faecal occult blood tests to triage referral for this group of people in NICE's guideline on suspected cancer, but heard from clinical specialists that this had not been widely adopted in primary care. It heard that people are typically assessed by taking into account their clinical history, their current symptoms and the results of any available tests to establish whether there is a clinical suspicion of colorectal cancer. If clinical suspicion is sufficiently raised, referral using a suspected cancer pathway for an appointment within 2 weeks is appropriate. The committee noted that in practice clinical history and current symptoms of people in this low-risk group were likely to be heterogeneous, and so management was likely to vary between individual patients and GPs. The committee concluded that current clinical practice is likely to vary because of the complexity of managing and investigating non‑specific symptoms in practice.
The committee discussed the potential benefits that may be associated with using faecal immunochemical tests in primary care. It heard from clinical specialists that faecal immunochemical tests are thought to be more accurate than guaiac-based faecal occult blood tests because they use immunochemical detection methods that are specific to human haemoglobin. They are also suitable for use with automated analysers, which allow high-throughput batch testing. It also heard from a patient specialist that faecal immunochemical tests often had sample collection devices that are easier to use than guaiac-based faecal occult blood tests and they need fewer samples, which makes them more acceptable to people and so may increase test uptake. The committee concluded that faecal immunochemical tests may have substantial analytical and practical advantages over guaiac-based faecal occult blood tests.
# Clinical effectiveness
The committee discussed the evidence base for the clinical effectiveness of the quantitative faecal immunochemical tests for triaging people with symptoms who are at a low risk of colorectal cancer. It noted that there were 10 included studies that reported data for the OC sensor, HM‑JACKarc and FOB Gold assays. It also noted that none of the included studies reported data for the RIDASCREEN haemoglobin or the RIDASCREEN haemoglobin/haptoglobin assays. It therefore concluded that, in the absence of any data, the RIDASCREEN assays could not be considered further.
The committee questioned whether the data from the studies included in the clinical-effectiveness review were generalisable to the population in the decision problem for this assessment. It noted that many of the studies were done in secondary care and included people with higher-risk symptoms than those previously outlined in NICE's guideline on suspected cancer (see section 2.6). The committee heard from clinical specialists that although the populations in the studies were likely to have a higher prevalence of colorectal cancer, the data provide evidence that faecal immunochemical tests are likely to be highly sensitive for detecting haemoglobin in faecal samples. The committee concluded that although the differences in the populations introduced some uncertainty into the analysis it was reasonable to include the data in the review.
The committee discussed the diagnostic accuracy data in the included studies. Many reported diagnostic accuracy estimates at multiple thresholds and showed that there was a clear threshold effect; when lower thresholds were used the sensitivity of the test increased, but the specificity decreased. The committee noted that the external assessment group (EAG) had used the diagnostic accuracy data to establish the threshold for the best diagnostic performance. The committee heard from clinical specialists that they supported the EAG's conclusion that a threshold of 10 micrograms of haemoglobin (Hb)/g faeces seemed to give the best diagnostic performance for ruling out colorectal cancer. It also heard that using a threshold lower than 10 micrograms Hb/g faeces would create more variability in test performance because the assays are known to be more imprecise in their lower measuring range, and the availability of quality control materials to validate the detection of low levels of haemoglobin may also be limited. The committee concluded that using a threshold of 10 micrograms Hb/g faeces gave the test enough sensitivity to reliably rule out colorectal cancer in primary care.
The committee considered the consequences of false-positive faecal immunochemical test results in practice. It heard from clinical specialists that using faecal immunochemical tests in primary care to triage suspected colorectal cancer referrals could result in unnecessary colonoscopy referrals. Data in the clinical-effectiveness review suggested that around 200 of every 1,000 people tested do not have colorectal cancer but are referred for colonoscopy. The committee noted that the tests detect a marker of colorectal cancer (haemoglobin), which could also be associated with a range of other conditions. Data from studies reporting diagnostic accuracy for multiple target conditions in the same population suggested that up to 28.9% of people with a false-positive faecal immunochemical test result for colorectal cancer had bowel pathology, such as inflammatory bowel disease or high-risk adenoma. The committee concluded that it was plausible that the number of false-positive results that occur when using the tests to rule out colorectal cancer could be partially offset by detecting other treatable bowel pathology.
The committee noted that the review did not find any data that directly compared the OC Sensor, HM‑JACKarc or FOB Gold assays. Further, it noted that the review had found substantially less data for the FOB Gold assay so the EAG could not establish the optimal threshold for this test. The committee therefore examined whether the conclusions reached based on data from the OC Sensor and HM‑JACKarc assays could be extended to the FOB Gold assay. It heard from clinical specialists that the 3 assays were likely to perform similarly in detecting haemoglobin in faecal samples. It also heard that the FOB Gold assay was compatible with a range of clinical chemistry analysers, which may be an advantage for some laboratories. The committee concluded that there was more uncertainty in the clinical effectiveness of the FOB Gold assay but that the available data suggested that it was likely to perform similarly to the OC Sensor and HM‑JACKarc assays in practice.
The committee discussed the possibility of faecal immunochemical tests performing differently in the population subgroups outlined in the decision problem. It heard from clinical specialists that it is plausible that the diagnostic accuracy of faecal immunochemical tests will differ according to age and sex because it is thought that women have lower levels of faecal haemoglobin than men and that levels are higher in older people. The committee noted that only 1 study reported data for men and women separately; this study showed that faecal immunochemical testing was more sensitive in men, but more specific in women. No studies were found that showed data by age. It also heard that both faecal immunochemical tests and guaiac-based faecal occult blood tests may have high false-positive rates in people who are taking medicines that increase their risk of gastrointestinal bleeding, such as oral anticoagulants, antiplatelets or aspirin, but no data were available for this group. The committee concluded that there were insufficient data at present to determine whether different thresholds are needed for women and older people, or whether faecal immunochemical tests help with clinical decision-making when people are taking medicines known to cause gastrointestinal bleeding.
# Cost effectiveness
The committee considered the cost-effectiveness analyses for the OC Sensor, HM‑JACKarc and FOB Gold assays. It noted that 2 comparators had been included; guaiac-based faecal occult blood testing and no triage (that is, direct referral to colonoscopy). The committee discussed which comparator was the most appropriate. It heard from clinical specialists that guaiac-based faecal occult blood testing is no longer done by most clinical chemistry laboratories so primary care clinicians are not able to request the test. It also heard that people in the population outlined in the decision problem were unlikely to be directly referred for colonoscopy, and that a watch-and-wait strategy is most often used by primary care clinicians to monitor their condition. The committee heard from the EAG that a watch-and-wait strategy had not been included in the model because there were not enough data available to characterise the variations in clinical decision-making in this group. The committee concluded that, although the model did not fully capture current practice, the comparisons it made reflected the best available data for the population included in the assessment.
The committee discussed the likely consequences of false-negative results and whether they could affect a person's prognosis by delaying their diagnosis of colorectal cancer. It noted that the economic model assumed that all people with a false-negative result were subsequently diagnosed within 12 months. It heard from clinical and patient specialists that delayed diagnosis could lead to worse outcomes, but clinical specialists advised that if symptoms persisted a referral to secondary care would be made regardless of a previous negative test result. The committee concluded that the analysis had sufficiently captured the likely prognostic implications of false-negative test results.
The committee considered the assumptions made in the model when comparing faecal immunochemical tests with guaiac-based faecal occult blood tests. It noted that none of the studies in the clinical-effectiveness review compared faecal immunochemical tests and guaiac-based faecal occult blood tests, so indirect comparisons had to be modelled. The committee discussed the diagnostic accuracy estimates used in the model (see table 4) and noted that they suggested that the faecal immunochemical tests were more sensitive than guaiac-based faecal occult blood tests. It heard from clinical specialists that the conclusions drawn from the indirect comparisons were supported by direct comparative data from bowel cancer screening programmes, which have shown that faecal immunochemical tests are more sensitive than guaiac-based faecal occult blood tests. The committee concluded that the assumptions made about the accuracy of guaiac-based faecal occult blood tests were reasonable.
The committee considered the base-case analysis. It noted that the EAG had not included the FOB Gold assay in this analysis because no data were available for the accuracy of the assay at a threshold of 10 micrograms Hb/g faeces. In the comparison with the guaiac-based faecal occult blood test both the OC Sensor and the HM‑JACKarc assays were cost effective, with probabilistic ICERs of £5,040 and £14,600 per QALY respectively. Both assays were also cost effective when compared with no triage, with the HM‑JACKarc dominating (that is, it was more effective and less expensive) and the OC Sensor having an ICER of £2,580,000 saved per QALY lost. The fully incremental base-case analysis suggested that the OC Sensor was more cost effective than the HM‑JACKarc, but the committee noted that this comparison was driven by small differences in both costs and QALYs. The committee considered the scenario analyses that included the FOB Gold assay and noted that although there was more uncertainty in the clinical effectiveness of this technology it appeared to be cost effective, with an ICER of £15,700 per QALY gained when compared with guaiac-based faecal occult blood testing at a threshold of 6.8 micrograms Hb/g faeces. The committee concluded that the OC Sensor, HM‑JACKarc and FOB Gold assays had the potential to be cost-effective options for triaging referrals in primary care for people with symptoms but a low risk of colorectal cancer.
The committee considered the drivers behind the cost savings seen when the faecal immunochemical tests were compared with no triage and noted that a reduction in colonoscopy was a key parameter. It was aware that the comparison made between faecal immunochemical tests and no triage assumes that all people have either colonoscopy or CT colonography to investigate the cause of their symptoms. The committee discussed colonoscopy capacity and whether the cost savings seen in the analysis for this comparison would be realised in practice. It heard from clinical specialists that colonoscopy capacity is very limited in many areas, and in practice it would be unlikely that all people who are at a low risk of colorectal cancer would be referred for colonoscopy. The committee concluded that the cost savings seen in comparisons made between faecal immunochemical tests and no triage could not be considered robust.
The committee discussed the uncertainties in the cost-effectiveness analysis and noted that the cost effectiveness of faecal immunochemical tests was sensitive to the prevalence of colorectal cancer which influences the pre-test probability. This parameter drives the accuracy of the tests and so the costs and resource use. It noted the scenario analyses that used prevalence values of 3% and 5.4% compared with 1.5% in the base case. The results of these scenario analysis showed that when the prevalence was increased the faecal immunochemical tests became more cost effective when compared with guaiac-based faecal occult blood testing, and when the prevalence of colorectal cancer was decreased the faecal immunochemical tests became less cost effective. The committee therefore considered that if the faecal immunochemical tests are used in a wider population in practice, the prevalence of colorectal cancer will be reduced and the tests may no longer be cost effective. The committee concluded that the tests are likely to be cost effective when used alongside clinical judgement and the results of any other testing to guide referral for suspected colorectal cancer in people without rectal bleeding who have unexplained symptoms and are at low risk. Further, it recommended that where false-negative results are suspected, active monitoring (safety netting) should be used as recommended in NICE's guideline on suspected cancer.
# Other considerations
The committee discussed the possible advantages of using quantitative faecal immunochemical tests. It heard that the ability of the tests to report the concentration of faecal haemoglobin instead of providing a semi-quantitative positive or negative result could have additional clinical uses. It heard from a clinical specialist that, in some areas of Scotland, quantitative faecal immunochemical tests have been adopted to triage referrals from primary care and that the faecal haemoglobin concentration is being used in secondary care to decide who should have a colonoscopy most urgently. The committee also heard that the prognostic-risk scoring tools, highlighted in the clinical-effectiveness review (section 4.20) are a growing area of research that aims to produce validated tools that can identify people at increased risk of colorectal cancer using variables such as age, sex and faecal haemoglobin concentration. The committee concluded that the development of risk-prediction rules may further refine the use of faecal immunochemical tests in primary care.
The committee noted that the NHS bowel cancer screening programme is adopting faecal immunochemical tests as a replacement for guaiac-based faecal occult blood tests. It considered that there may be instances when people, who have recently had a negative screening result, may get a positive result in primary care after reporting symptoms because of the use of different thresholds in the 2 clinical scenarios. The committee concluded that practices adopting faecal immunochemical tests as a triage tool should take this into account when developing their implementation plans, and ensure that information to explain the different thresholds and their consequences is available for people who have recently participated in the bowel cancer screening programme. Information about the different test thresholds should also be made available to people taking part in the NHS bowel cancer screening programme.# Recommendations for further research
The committee considered that commissioning groups adopting the faecal immunochemical tests in primary care should audit their outcomes. Possible outcomes to audit include:
number of people referred using a suspected cancer pathway for an appointment within 2 weeks
number of people diagnosed with colorectal cancer
number of colonoscopies and CT colonographies requested.The committee noted that Cancer Research UK is planning an audit in the south west of England to collect information on how people without rectal bleeding who have unexplained symptoms and are at low risk of colorectal cancer are assessed in primary care.
The committee considered that further research is needed to determine whether faecal haemoglobin levels are influenced by age, sex and medicines that increase the risk of gastrointestinal bleeding. It noted that these data could be used to further develop risk scores that include variables such as age, sex and symptoms to help determine pre-test probability. The data could also be combined with faecal haemoglobin concentration to refine management after the use of faecal immunochemical tests in primary care.
The committee noted advice from clinical experts that there is variability between the faecal immunochemical tests. This may affect the number of positive and negative results reported by the tests when a single threshold is used. It recommended further research to investigate the variability between technologies and encouraged the companies to make sure that results can be standardised for use in a symptomatic population.
|
{'Recommendations': "The OC\xa0Sensor, HM‑JACKarc and FOB\xa0Gold quantitative faecal immunochemical tests are recommended for adoption in primary care to guide referral for suspected colorectal cancer in people without rectal bleeding who have unexplained symptoms but do not meet the criteria for a suspected cancer pathway referral outlined in NICE's guideline on suspected cancer (recommendation\xa01.3.4).\n\nResults should be reported using a threshold of 10\xa0micrograms of haemoglobin per gram of faeces. Companies should provide advice about the performance characteristics of the assays to laboratories, and ensure standardisation of results.\n\nCommissioning groups adopting the OC\xa0Sensor, HM‑JACKarc and FOB\xa0Gold should audit their outcomes and monitor the associated resource use (see section 6.1).\n\nThere is currently not enough evidence to recommend the routine adoption of the RIDASCREEN haemoglobin or the RIDASCREEN haemoglobin/haptoglobin assay in primary care to guide referral for suspected colorectal cancer in people without rectal bleeding who have unexplained symptoms but do not meet the criteria for a suspected cancer pathway referral outlined in NICE's guideline on suspected cancer (recommendation\xa01.3.4).", 'Clinical need and practice': "# The problem addressed\n\nThe purpose of this assessment was to evaluate the clinical and cost effectiveness of using quantitative faecal immunochemical tests in primary care to triage low-risk symptomatic populations (that is, identify those at greatest risk) for suspected colorectal cancer referrals.\n\nSeveral lower gastrointestinal symptoms can suggest colorectal cancer, including rectal bleeding, a change in bowel habits, weight loss, anaemia, abdominal pain, and blood in stools (faeces). Sometimes, blood in stools is not visible (faecal occult blood) so tests are used to detect its presence. These faecal occult blood tests can be used in primary care to assess people who are at a low risk of colorectal cancer and help determine whether they should be referred for further investigations where they do not meet the criteria for a suspected cancer pathway referral outlined in NICE's guideline on suspected cancer.\n\nFaecal immunochemical tests, a type of faecal occult blood test, are designed to detect small amounts of blood in stool samples using antibodies specific to human haemoglobin. They have been developed as an alternative to guaiac-based faecal occult blood tests, which involve using chemicals that react with the haem component of haemoglobin in the blood and produce a blue colour change if blood is detected. Sometimes, this colour change can happen because the chemicals react with food in a person's diet or with medicine that a person is taking; this can lead to false test results. Because the faecal immunochemical tests are designed to specifically detect human haemoglobin, they may give more accurate test results than guaiac-based tests. The faecal immunochemical tests target the globin component of haemoglobin, which degrades as it travels through the gastrointestinal tract, so these tests are less likely to detect globin from upper gastrointestinal bleeding.\n\n# The condition\n\nColorectal cancer is one of the most common cancers. In 2013 in the UK, 41,112\xa0people were diagnosed with colorectal cancer and 15,903\xa0people died from it (Cancer Research UK, 2016). Risk factors include older age, a family history of the disease, and having familial adenomatous polyposis or Lynch syndrome, colorectal polyps, or ulcerative colitis or Crohn's disease. Also, Jewish people of central and eastern European family origin are thought to be at increased risk.\n\n# The diagnostics and care pathways\n\n## Diagnosis\n\nNICE's guideline on suspected cancer includes advice on assessing people presenting to primary care with certain clinical signs and symptoms that may suggest colorectal cancer. It makes the following recommendations:Refer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for colorectal cancer if:\n\nthey are aged\xa040 or over with unexplained weight loss and abdominal pain or\n\nthey are aged\xa050 or over with unexplained rectal bleeding or\n\nthey are aged\xa060 or over with:\n\n\n\niron-deficiency anaemia or\n\nchanges in their bowel habit, or\n\n\n\ntests show occult blood in their faeces.A suspected cancer referral (for an appointment within\xa02 weeks) should also be considered for:\n\npeople with a rectal or abdominal mass\n\nadults aged under\xa050 with rectal bleeding and any of the following unexplained symptoms or findings:\n\n\n\nabdominal pain\n\nchange in bowel habit\n\nweight loss\n\niron-deficiency anaemia.\n\n\n\nNICE's guideline on suspected cancer also previously recommended that guaiac-based faecal occult blood tests should be offered to adults without rectal bleeding who:\n\nare aged 50\xa0or over with unexplained:\n\n\n\nabdominal pain or\n\nweight loss or\n\n\n\nare aged under\xa060 with:\n\n\n\nchanges in their bowel habit or\n\niron-deficiency anaemia or\n\n\n\nare aged\xa060 or over and have anaemia without iron deficiency.\n\nThe guaiac-based faecal occult blood tests were recommended in NICE's guideline on suspected cancer to triage referral to secondary care. The tests were intended to be used in selected groups of people who have symptoms that could suggest colorectal cancer, but in whom a definitive diagnosis of cancer was unlikely. That is, they had a low probability of having colorectal cancer (their age and symptoms have a positive predictive value of between 0.1% and 3% for colorectal cancer).\n\nIf a guaiac-based faecal occult blood test was positive, NICE's guideline on suspected cancer recommended that people in England should be referred using a suspected cancer referral to establish a diagnosis. Faecal occult blood can be caused by conditions other than colorectal cancer, such as colorectal polyps and inflammatory bowel disease, so further assessment with a colonoscopy is needed to diagnose colorectal cancer; a positive faecal occult blood test was not intended be used alone.\n\nColonoscopy is considered to be the gold standard for diagnosing colorectal cancer because the entire colon can usually be seen and biopsies can be taken to assess the tissue in a laboratory to determine whether the sample contains benign or malignant cells. CT colonography can be offered as an alternative for people with comorbidities that make colonoscopy unsuitable. Colonoscopy is usually done as an outpatient procedure, with people having the procedure being offered sedation or painkillers.\n\nThe most common finding during a colonoscopy is colorectal polyps, which can be removed using cauterisation or a snare. If colorectal cancer is confirmed, NICE's guideline on colorectal cancer recommends further imaging tests, such as CT or MRI, to stage the cancer and determine what treatment is needed. Colonoscopy may also find other bowel diseases such as Crohn's disease, ulcerative colitis and diverticulosis, which may need further treatment and follow-up. People with a positive faecal occult blood test but no abnormalities detected during colonoscopy may be referred for further testing if a clinician thinks this is needed.\n\n## Treatment\n\nAfter diagnosis and staging, colorectal cancer may be treated with surgery, chemotherapy and radiotherapy, or sometimes with biological agents such as cetuximab. Treatment depends on the stage of the cancer and is described in more detail in NICE's guideline on colorectal cancer.", 'The diagnostic tests': "The assessment compared 4\xa0intervention tests with 2\xa0comparators.\n\n# The interventions\n\n## OC\xa0Sensor test\n\nThe OC\xa0Sensor (Eiken Chemical/MAST Diagnostics) is a quantitative faecal immunochemical test. It comprises faecal sample collection tubes, latex reagent and buffer. The OC\xa0Sensor faecal sample collection tubes can hold 10\xa0mg of faeces (Carroll et al. 2014) in 2\xa0ml of buffer. The OC\xa0Sensor latex reagent contains latex particles coated with polyclonal antibodies for human haemoglobin. The antibodies bind with haemoglobin present in the faecal sample creating complexes that are detected using turbidimetry.\n\nThe test can be run on either the OC\xa0Sensor PLEDIA or the OC\xa0Sensor\xa0iO analyser. The OC\xa0Sensor PLEDIA can process up to 320\xa0samples per hour, with a capacity of 200\xa0samples per run. The OC\xa0Sensor\xa0iO can process up to 88\xa0samples per hour with a maximum capacity of 20\xa0samples per run. The performance of the assay varies according to the analyser used. The company states that a cut-off of 10\xa0micrograms of haemoglobin (Hb)/g faeces (50\xa0nanograms/ml) should be used for a symptomatic population.\n\n## HM‑JACKarc system\n\nThe HM‑JACKarc system (Kyowa Medex/Alpha Laboratories) is a fully automated quantitative faecal immunochemical test system. It comprises faecal sample tubes, which incorporate a sample collection device (the Extel Hemo‑auto\xa0MC\xa0A device) and can hold 2\xa0mg of faeces (Carroll et al. 2014) in 2\xa0ml of buffer, and latex agglutination reagent (Extel Hemo‑Auto\xa0HS) and buffer (Extel Hemo‑auto). The reagent contains latex particles that are coated in antibodies specific to human haemoglobin. The antibodies bind to haemoglobin present in the faecal sample creating complexes that are detected using turbidimetry. The assay is compatible with the HM‑JACKarc analyser, which reports results as nanograms/ml. The user needs to convert the results to micrograms of Hb/g. However, because the test uses 2\xa0mg of sample and 2\xa0ml of buffer, results reported as nanograms/ml convert directly to micrograms of Hb/g faeces, that is 10\xa0nanograms/ml equals 10\xa0micrograms Hb/g faeces. The company suggests a cut-off of 10\xa0micrograms Hb/g faeces for symptomatic populations. The HM‑JACKarc analyser can process up to 200\xa0samples per hour, with a maximum capacity of 80\xa0samples per run.\n\n## FOB\xa0Gold system\n\nThe FOB\xa0Gold system (Sentinel/Sysmex) is an automated quantitative faecal immunochemical test system. It comprises faecal sample collection tubes (the Sentifit pierce tube faecal collection device), which collect 10\xa0mg of faeces (Carroll et al. 2014) in 1.7\xa0ml of buffer, and latex agglutination reagent. The FOB\xa0Gold latex agglutination reagent contains polyclonal antibodies specific to human haemoglobin, which bind to haemoglobin present in the sample creating complexes that are detected using turbidimetry. The FOB\xa0Gold kit has CE‑marked applications for a range of clinical chemistry analysers, including the BioMajesty JCA‑6010/C, the SENTiFIT270 and those supplied by Siemens, Beckman Coulter and Abbott. The performance characteristics of the assay vary depending on which analyser is used. The company suggests that each laboratory should establish their own test cut-off according to the population the laboratory serves. The throughput of the test depends on the clinical chemistry analyser used to process the samples.\n\n## RIDASCREEN haemoglobin and haemoglobin/haptoglobin assay\n\nThe RIDASCREEN haemoglobin test (R‑Biopharm Rhone) is an enzyme immunoassay (ELISA) for the quantitative determination of human haemoglobin in stool samples. The test is run on a microtitre plate using wells coated with polyclonal antibodies for human haemoglobin. The contents of each kit are enough for 96\xa0tests. The instructions for the test suggest that it can be used with laboratory equipment other than the DSX automated ELISA system.\n\nThe test process incorporates 3\xa0incubations and 2\xa0wash steps. During the first incubation, any human haemoglobin present in the sample is captured by the polyclonal antibodies in the sample well. Unbound antigens are removed in the first wash step. Then peroxidase labelled monoclonal antibodies for human haemoglobin (conjugate) are added, which bind to the captured haemoglobin during the second incubation. In the final incubation, hydrogen peroxide and TMB (substrate) is added, which react with the peroxidase creating a colour change that is detected by a plate reader. The values from the plate reader are interpreted by the RIDA-SOFT Win.net software, which reports results as the concentration of haemoglobin per gram of stool (micrograms Hb/g faeces). The company states that 91\xa0tests can be processed manually in 150\xa0minutes, or 546\xa0tests in 7\xa0hours using an automated system. The company recommends a cut-off value of more than 2\xa0micrograms Hb/g faeces to determine a positive sample.\n\nThe company also produces the RIDASCREEN haemoglobin/haptoglobin enzyme immunoassay that can be run in combination with the haemoglobin assay, using the same sample and processing on the same microtitre plate but with the addition of a well coated with polyclonal antibodies for human haptoglobin. Haptoglobin is a protein produced by the liver that binds to haemoglobin, making it less likely to break down as it moves through the gastrointestinal tract. The detection of haptoglobin is claimed to increase the likelihood of detecting lesions in the ascending and transverse colon. The company recommends a cut-off value of 2\xa0micrograms Hb/g faeces to determine a positive test using the haemoglobin/haptoglobin assay.\n\n# The comparators\n\nThe first comparator used in this assessment is guaiac-based faecal occult blood testing, as previously recommended in NICE's guideline on suspected cancer (see section 2.6). Guaiac-based tests detect the pseudoperoxidase activity of the haem component of haemoglobin in stool samples using guaiac-test paper and hydrogen peroxide developer. Unlike faecal immunochemical tests, they are not specific to human haemoglobin.\n\nThe second comparator is clinical assessment and referral for colonoscopy based on lower gastrointestinal symptoms alone.", 'Evidence': "The diagnostics advisory committee (section 8) considered evidence on quantitative faecal immunochemical tests to assess people presenting to primary care who have symptoms but are at a low risk of colorectal cancer, from several sources. Full details of all the evidence are in the committee papers.\n\n# Clinical effectiveness\n\nIn total, 10\xa0studies met the inclusion criteria for the systematic review. The studies were reported in 25\xa0published papers and 2\xa0unpublished manuscripts. Additional unpublished data were obtained for 2\xa0of the published studies. Two of the included studies (Krivec et al. 2011; Thomas et al. 2016) were reported as conference abstracts only. Studies were included if they reported data for 1\xa0of the intervention technologies in the scope and recruited people with lower abdominal symptoms who were being investigated for possible colorectal cancer. All included studies were appraised using the QUADAS‑2 tool if they reported diagnostic accuracy data and the PROBAST checklist if they also reported data for risk-prediction scores.\n\nAll of the included studies were diagnostic cohort studies; no randomised controlled trials or controlled clinical trials were identified. All 10\xa0included studies were done in Europe, 1\xa0of which was based in England (Thomas et al. 2016) and 3\xa0in Scotland (Godber et al. 2016; McDonald et al. 2013; Mowat et al. 2015). Five of the studies had a high risk of bias. There were concerns about applicability for all of the included studies because none of them reported data that were specific to the population included in the scope of the assessment, that is, people with symptoms who are judged to be at low risk of colorectal cancer. Only 1\xa0study (Mowat et al. 2015) was done in primary care.\n\nThe included studies reported data for the HM‑JACKarc, FOB\xa0Gold and OC\xa0Sensor assays only. No relevant data were found for the RIDASCREEN haemoglobin or the RIDASCREEN haemoglobin/haptoglobin assay. None of the included studies provided comparative accuracy data for the included technologies or made comparisons with guaiac-based faecal occult blood tests.\n\n## Diagnostic accuracy\n\nThe bivariate/hierarchical summary receiver operating characteristic (HSROC) model was used to calculate summary sensitivity and specificity estimates and to create HSROC curves for meta-analyses, which included 4\xa0or more studies. For meta-analyses that included fewer than 4\xa0studies, separate pooled estimates of sensitivity and specificity were calculated using random-effects logistic regression. Data were grouped by assay, target condition and the threshold used to determine a positive test.\n\nFive studies reported data for the OC\xa0Sensor assay. One used the iO\xa0analyser (Mowat et al. 2015), 1\xa0used the OC\xa0Sensor Diana analyser (McDonald et al. 2013), 2\xa0used the MICRO desktop analyser (Rodriguez-Alonso et al. 2015; Terhaar sive Droste et al. 2011) and the fifth study did not report which analyser was used (Cubiella et al. 2014). All 5\xa0studies reported diagnostic accuracy for colorectal cancer, although the prevalence of colorectal cancer ranged from 2.1% to 12.3%. Mowat et al. (2015) was the only study done in primary care. All studies reported the accuracy of a single faecal sample only and used varying thresholds to determine a positive test. A summary of the results is shown in table\xa01. Additional data from Terhaar sive Droste et al. (2011) were unpublished when this guidance was written and cannot be reported here.\n\nStudy\n\nThreshold\n\n(micrograms Hb/g faeces)\n\nSensitivity %(95% CI)\n\nSpecificity %(95% CI)\n\nMowat et al. 2015\n\n\n\n(87.7, 100)\n\n(39.7, 47.1)\n\nRodriguez-Alonso et al. 2015\n\n\n\n(88.4, 100)\n\n(40.1, 46.4)\n\nSummary estimate\n\n–\n\n(93.8, 100)\n\n(40.9, 45.7)\n\nMcDonald et al. 2012\n\n≥10\n\n(54.1, 100)\n\n(90.3, 96.3)\n\nMowat et al. 2015\n\n≥10\n\n(71.8, 97.7)\n\n(75.9, 82)\n\nRodriguez-Alonso et al. 2015\n\n≥10\n\n(82.8, 99.9)\n\n(77.2, 82.3)\n\nSummary estimate\n\n–\n\n(86.9, 95.3)\n\n(78.3, 91.0)\n\nRodriguez-Alonso et al. 2015\n\n≥15\n\n(82.8, 99.9)\n\n(80.6, 85.4)\n\nSummary estimate\n\n–\n\n(86.6, 96.1)\n\n(85.6, 88.1)\n\nCubiella et al. 2014\n\n≥20\n\n(79.0, 93.2)\n\n(74.0, 80.4)\n\nRodriguez-Alonso et al 2015\n\n≥20\n\n(77.9, 99.2)\n\n(83.8, 88.2)\n\nSummary estimate\n\n–\n\n(84.9, 93.1)\n\n(85.4, 87.7)\n\nAbbreviations: CI, confidence interval; Hb, haemoglobin.\n\nThe external assessment group (EAG) considered that the optimal diagnostic threshold for colorectal cancer was either 10\xa0or 15\xa0micrograms of haemoglobin (Hb)/g faeces, but noted that most data were available for 10\xa0micrograms Hb/g faeces. Test accuracy data from Mowat et al. (2015) and Rodriguez-Alonso et al. (2015) were used to illustrate diagnostic outcomes for a hypothetical cohort of 1,000 people, assuming a prevalence of colorectal cancer of 3.3%, and using thresholds of both 10\xa0micrograms Hb/g faeces and any detectable haemoglobin (4\xa0micrograms Hb/g faeces). The results are shown in table\xa02.\n\nThreshold\n\nmicrograms Hb/g faeces\n\nmicrograms Hb/g faeces\n\nCorrect referrals for colonoscopy (true positives)\n\n\n\n\n\nIncorrect referrals for colonoscopy (false positives)\n\n\n\n\n\nMissed colorectal cancers (false negatives)\n\n\n\n\n\nColonoscopies correctly avoided (true negatives)\n\n\n\n\n\nAbbreviation: Hb, haemoglobin.\n\nFour studies (Cubiella et al. 2014; McDonald et al. 2012; Mowat et al. 2015; Rodriguez-Alonso et al. 2015) reported diagnostic accuracy for advanced neoplasia, which includes both colorectal cancer and high-risk adenoma. The definition of high-risk adenoma and the thresholds used varied between studies. Expanding the target condition reduced the sensitivity of the test, with summary sensitivity estimates of 62.9% (95% confidence interval [CI] 55.9% to\xa069.4%) at a threshold of 10\xa0micrograms Hb/g, 63.9% (95% CI\xa058.2% to\xa069.2%) at a threshold of 20\xa0micrograms Hb/g and 84.1% (95% CI\xa078.3% to\xa088.8%) at a threshold of any detectable haemoglobin. The sensitivity of the test was lower when the target condition was expanded to include other bowel pathologies. But data from studies that reported results for both colorectal cancer and high-risk adenoma suggested that many false-positive results for colorectal cancer could be from other bowel pathologies that may benefit from treatment.\n\nThree studies reported diagnostic accuracy data for various non‑malignant or composite target conditions. McDonald et al. (2012) reported a sensitivity of 57.0% (95% CI\xa045.8% to\xa067.6%) and a specificity of 99% (95% CI\xa096.3% to\xa099.9%) for all colorectal cancers, high-risk adenomas and inflammatory bowel disease using a threshold of 10\xa0micrograms Hb/g faeces. Mowat et al. (2015) used the same threshold and reported a sensitivity of 68.6% (95% CI\xa058.7% to\xa077.5%) and a specificity of 83.6% (95% CI\xa080.6% to\xa086.4%) for the same composite target condition. Additional data from Terhaar sive Droste et al. (2011) were unpublished at the time of writing so cannot be reported here.\n\nThree studies reported accuracy data for the HM‑JACKarc automated system (Auge et al. 2016; Godber et al. 2016; Thomas et al. 2016). All 3\xa0studies were done in outpatient clinics and used single faecal samples.\n\nTwo studies (Godber et al. 2016; Thomas et al. 2016) reported accuracy data for colorectal cancer. The prevalence of colorectal cancer was 2.2% in Godber et al. and 4.9% in Thomas et al. Godber et al. reported a sensitivity of 100% (95% CI\xa071.5% to\xa0100%) and a specificity of 76.6% (95% CI\xa072.6% to\xa080.3%) at a threshold of 10\xa0micrograms Hb/g faeces. Thomas et al. reported a sensitivity of 91.3% (95% CI\xa072.0% to\xa098.9%) and a specificity of 79.2% (95% CI\xa075.3% to\xa083.0%) at a threshold of 7\xa0micrograms Hb/g faeces. Test accuracy data from Godber et al. were used to model outcomes for a hypothetical cohort of 1,000 people, assuming a prevalence of colorectal cancer of 2.2%. The results of this analysis are shown in table\xa03.\n\nOutcome\n\nNumber\n\nCorrect referrals for colonoscopy (true positives)\n\n\n\nIncorrect referrals for colonoscopy (false positives)\n\n\n\nMissed colorectal cancers (false negatives)\n\n\n\nColonoscopies correctly avoided (true negatives)\n\n\n\nTwo studies (Auge et al. 2016; Godber et al. 2016) reported data for a target condition of colorectal cancer and high-risk adenoma. Each study used a different definition of high-risk adenoma and reported different thresholds. The sensitivity estimates varied widely because of differences in the included populations. Godber et al. reported a sensitivity of 70.0% (95% CI\xa050.6% to\xa085.3%) and a specificity of 77.8% (95% CI\xa073.8% to\xa081.4%) at a threshold of 10\xa0micrograms Hb/g faeces. Auge et al. reported a range of accuracy estimates with sensitivity ranging from 27.6% (95% CI\xa014.7% to\xa045.7%) at a threshold of 40\xa0micrograms Hb/g faeces to 96.6% (95% CI\xa082.8% to\xa093.4%) at a threshold of any detectable haemoglobin. Specificity ranged from 10.6% (95% CI\xa06.9% to\xa015.9%) at a threshold of any detectable haemoglobin to 93.9% (95% CI\xa089.4% to\xa096.6%) at a threshold of 40\xa0micrograms Hb/g faeces.\n\nOne study (Auge et al. 2016) also investigated the effect of multiple samples and sex on the accuracy of the HM‑JACKarc assay for detecting colorectal cancer and high-risk adenoma. The study had a prevalence of colorectal cancer of less than 1%. The authors reported that 100% sensitivity could be achieved by using a threshold of any detectable haemoglobin and using the highest value reported in 2\xa0consecutive samples, but this reduced the specificity to 3.3%. Data were reported for single or multiple samples using a range of thresholds from any detectable haemoglobin to 40\xa0micrograms Hb/g faeces. At thresholds above any detectable haemoglobin, using consecutive samples increased the test's sensitivity but this was still low at under 50% for all estimates.\n\nAuge et al. (2016) also reported that sensitivity estimates at all thresholds were lower when the test was used in women than when used in men. Sensitivity estimates ranged from 8.3% at a threshold of 40\xa0micrograms Hb/g faeces to 91.7% with any detectable haemoglobin for women, compared with a range of 41.2% at all thresholds above 20\xa0micrograms Hb/g faeces to 100% with any detectable haemoglobin for men. Conversely, specificity estimates tended to be higher in women than in men.\n\nTwo studies (Godber et al. 2016; Thomas et al. 2016) reported accuracy data for various non‑malignant and composite target conditions. Godber et al. defined significant bowel disease as colorectal cancer, higher-risk adenoma, inflammatory bowel disease or colitis. They reported sensitivity and specificity estimates of 68.9% and 80.2% respectively at a threshold of 10\xa0micrograms Hb/g faeces. Thomas et al. defined significant bowel disease as colorectal cancer, high-risk adenoma or inflammatory bowel disease. They reported sensitivity and specificity estimates of 72.1% and 80.6% respectively at a threshold of 7\xa0micrograms Hb/g faeces.\n\nTwo studies reported data for the FOB\xa0Gold assay. One was reported in a conference abstract only and used the Roche Modular P/917 analyser (Krivec et al. 2011). The other was unpublished at the time of writing and used the SENTiFIT270 analyser (Hospital Clinic de Barcelona 2015). Further data from Hospital Clinic de Barcelona are unpublished and cannot be reported here. Krivec et al. (2011) reported a sensitivity of 45.2% and a specificity of 92.3% for significant bowel disease (cancer, polyps or bleeding) using a threshold of 9.35\xa0micrograms Hb/g faeces.\n\n## Test failures\n\nMowat et al. (2015) reported that fewer than 1% of samples were considered unsuitable for analysis using the OC\xa0Sensor test.\n\n## Test uptake\n\nFour of the included studies reporting data for the OC\xa0Sensor reported test uptake (Cubiella et al. 2014; McDonald et al. 2013; Mowat et al. 2015; Rodriguez-Alonso et al. 2015), which ranged from 41% to 98%. Methods of inviting patients to take a test varied between studies.\n\nTwo of the included studies reporting data for the HM‑JACKarc reported test uptake. Godber et al. (2016) reported an uptake of 56% when collection devices and information were sent by post, whereas Thomas et al. (2016) reported an uptake of 66% when collection devices and information were provided at an outpatient appointment.\n\n## Management decisions\n\nMowat et al. (2015) reported that 11% of patients for whom a faecal immunochemical test sample was analysed were not referred to secondary care, 69% were referred for an endoscopy and 20% were referred to an outpatient clinic. However, decisions about the urgency of the referral were made before the test.\n\n## Prediction modelling studies\n\nTwo studies (Cubiella et al. 2016; Rodriguez-Alonso et al. 2015) reported data on using prediction models, which included results of faecal immunochemical tests. These studies were also appraised with the PROBAST tool. The studies were classified as having high concerns about the applicability of the included populations, and overall were rated as being at a high risk of bias.\n\nRodriguez-Alonso et al. (2015) did a multivariate analysis to identify independent predictors of colorectal cancer and advanced neoplasia. Faecal haemoglobin was measured using the OC\xa0Sensor assay. The model included age as a categorical variable. The following variables were identified as independent predictors of colorectal cancer:\n\nmale sex (odds ratio [OR] 2.39; 95% CI\xa01.039 to\xa05.519; p=0.041)\n\niron-deficiency anaemia (OR\xa02.99; 95% CI\xa01.27 to\xa07.03; p=0.012)\n\nfaecal haemoglobin (OR\xa086.60; 95% CI\xa011.70 to\xa064.16; p<0.001).\n\nA pre-publication copy of a manuscript by Cubiella et al. (2016) reported the development and validation of a risk score known as the FAST score (faecal haemoglobin, age and sex test). Faecal haemoglobin was measured using the OC\xa0Sensor, OC‑Auto (an earlier version of the OC\xa0Sensor) and FOB\xa0Gold assays. The logistic regression model included age as a continuous variable, and sex and faecal haemoglobin as categorical variables. The results of the model suggested that a FAST score of 4.5\xa0had a sensitivity of 89.3% (95% CI\xa084.1% to\xa093.0%) and a specificity of 82.3% (95% CI\xa081.1% to\xa083.5%) for colorectal cancer. To avoid missing any colorectal cancers, a lower FAST score threshold of 2.12\xa0was needed. This gave a sensitivity of 100% (95% CI\xa097.7% to 100%) and a specificity of 19.8% (95% CI\xa018.6% to\xa021.1%).\n\n# Cost effectiveness\n\n## Review of economic evidence\n\nOnly 1\xa0study was found that reported an economic analysis of using faecal immunochemical tests in people with symptoms; the economic analysis of faecal occult blood tests in NICE's guideline on suspected cancer. Faecal immunochemical tests were included in a scenario analysis in the guideline. Faecal occult blood tests were included in the base case, which showed that guaiac-based tests and barium enema were cost effective compared with colonoscopy at a maximum acceptable incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained. In the scenario analysis, faecal immunochemical tests dominated (cost less and were more effective) barium enema and were cost effective at a maximum acceptable ICER of £20,000 per QALY gained.\n\n## Modelling approach\n\nThe EAG developed a de novo economic model to explore the cost effectiveness of using a quantitative faecal immunochemical test to guide referral of people who present to primary care with symptoms but have a low risk of colorectal cancer. The model took the perspective of the NHS and personal social services. In the base case it compared the use of 2\xa0quantitative faecal immunochemical tests, the OC\xa0Sensor and HM‑JACKarc assays, with both guaiac-based faecal occult blood tests and no triage (that is, referral straight to colonoscopy). A watchful waiting strategy, which may currently be used in practice, was not included as a comparator because of variability in practice and a lack of data, but was incorporated into the guaiac-based faecal occult blood and faecal immunochemical testing strategies. The FOB\xa0Gold assay was not included in the base case because no data were available for the optimal threshold (10\xa0micrograms Hb/g faeces) determined by the EAG in the clinical-effectiveness analyses. All costs and effects included in the model were discounted by 3.5%.\n\nThe model had 3\xa0parts. The first part was a decision tree with a 1‑year time horizon, which modelled the results of investigations for colorectal cancer (faecal immunochemical test, guaiac-based faecal occult blood test or no triage) for a cohort of patients, with symptoms, presenting to primary care. A positive faecal immunochemical test or guaiac-based faecal occult blood test resulted in referral for colonoscopy and a negative test resulted in watchful waiting, in which further investigations were done if a person's symptoms persisted. The decision tree was followed by 2\xa0Markov state-transition models. One Markov model had a lifetime time horizon and a 1‑year cycle length and was used to estimate costs, life years and QALYs associated with the treatment and progression of colorectal cancer. The initial distribution of patients across the stages of disease at diagnosis was determined using data from the UK's National Cancer Intelligence Network. The other Markov model had a simple alive or dead structure and estimated life years and QALYs for people who did not have colorectal cancer, using UK life tables to model survival.\n\nThe model was populated with data from the clinical-effectiveness review, published literature and expert opinion. Diagnostic accuracy data were taken from the clinical-effectiveness review. The EAG concluded that a threshold of 10\xa0micrograms Hb/g faeces with a single sample provided the optimal rule-out performance. That is, the threshold gave the maximum sensitivity and specificity, and had the lowest number of colorectal cancers missed. Data at this threshold were available for the HM‑JACKarc and OC\xa0Sensor assays. Data on the accuracy of guaiac-based faecal occult blood tests were taken from Gillberg et al. (2012), which was used in the economic model for NICE's guideline on suspected cancer. The accuracy estimates used in the base-case analysis are shown in table\xa04. The predictive values were calculated by the EAG assuming a prevalence of colorectal cancer of 1.5% to correspond with the prevalence assumed in NICE's guideline on suspected cancer.\n\nAccuracy measure\n\nOC\xa0Sensor assay\n\nHM‑JACKarc assay\n\nGuaiac-based faecal occult blood test\n\nSensitivity(95% CI)\n\n%(86.9% to 95.3%)\n\n%(71.5% to 100%)\n\n%(15.0% to 85.0%)\n\nSpecificity(95% CI)\n\n%(78.3% to 91.0%)\n\n%(72.6% to 80.3%)\n\n%(85.0% to 89.0%)\n\nPositive predictive value\n\n%\n\n%\n\n%\n\nNegative predictive value\n\n%\n\n%\n\n%\n\nAbbreviation: CI, confidence interval.\n\nDirect costs included in the model were test costs, cost of colonoscopy or CT colonography, adverse-event costs, CT scan costs, costs of first and follow-up investigations, cancer staging and treatment, drug costs, and GP and hospital visits. No costs were included in the Markov model used for outcomes for people without colorectal cancer. Costs were obtained from companies, published literature and routine sources of NHS costs. Test costs were calculated as average costs per test. The following test costs were used in the model:\n\nOC\xa0Sensor: £4.53\n\nHM‑JACKarc: £6.04\n\nFOB\xa0Gold: £1.96\n\nguaiac-based faecal occult blood test: £0.78 (rounded to 2 significant figures)\n\ncolonoscopy: £372\n\nCT colonography: £136\n\nCT scan: £116.\n\nNo disutilities for bleeding and perforation during colonoscopy were included in the model, because no evidence was found on quality-of-life effects in the literature and the events are often of short duration. The rates of adverse events from colonoscopy were assumed to be 0.26% for bleeding, 0.05% for perforation, and 0.0029% for death. Utilities associated with the different stages of colorectal cancer were taken from Ness et al. (1999) and sex- and age-related utilities for healthy patients were taken from Kind et al. (1999).\n\n## Base-case results\n\nThe following key assumptions were applied in the base-case analysis:\n\nPeople who had a false-negative faecal immunochemical test or guaiac-based faecal occult blood test and whose symptoms persisted were diagnosed within 1\xa0year if they survived.\n\nThe optimal threshold for the interventions was 10\xa0micrograms Hb/g faeces.\n\nPeople who had a delayed diagnosis had an increased probability of progressing to a more advanced cancer state.\n\nCosts of laboratory staff were the same for both faecal immunochemical tests and guaiac-based faecal occult blood tests.\n\nTesting had no long-term (after 1\xa0year) effect on costs or QALYs in people without colorectal cancer.\n\nAny differences in costs between the tests in patients without colorectal cancer occurred in year\xa01 only.\n\nThe prevalence of colorectal cancer was 1.5%.\n\nThe probabilities of adverse events during or after colonoscopy were as follows:\n\n\n\nbleeding: 0.26%\n\nbowel perforation: 0.05%\n\ndeath: 0.0029%.\n\n\n\nOnly patients with negative test results whose symptoms did not persist did not have a colonoscopy.\n\nThe cost of a colonoscopy or CT colonography included a follow-up appointment with a gastroenterologist.\n\nThe adverse-event rates associated with CT colonography were the same as for colonoscopy.\n\nA CT scan was done for all patients with colorectal cancer to stage the disease.\n\nAfter year\xa015 in the colorectal cancer Markov model, colorectal-cancer-related mortality remains constant, but overall mortality increases because age-specific mortality is included from UK life tables.\n\nThe results of the base case are shown with the fully incremental probabilistic analysis in table\xa05 and the probabilistic pairwise comparisons in table\xa06. The ICERs for the deterministic analysis were slightly higher than those in the probabilistic analysis.\n\nTest\n\nQALYs\n\nCost\n\nIncremental QALYs\n\nIncremental cost\n\nICER\n\ngFOBT\n\n\n\n£230.49\n\n–\n\n–\n\n–\n\nOC\xa0Sensor assay\n\n\n\n£242.51\n\n\n\n£12.02\n\n£5,039\n\nNo triage\n\n\n\n£500.60\n\nDominated by HM‑JACKarc\n\nDominated by HM JACKarc\n\nDominated by HM JACKarc\n\nHM‑JACKarc assay\n\n\n\n£272.50\n\n\n\n£29.99\n\n£61,619\n\nAbbreviations: gFOBT, guaiac-based faecal occult blood test; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.\n\nIntervention\n\nComparator\n\nIncremental QALYs\n\nIncremental costs\n\nICER\n\nHM‑JACKarc assay\n\ngFOBT\n\n\n\n£42.01\n\n£14,626\n\nOC\xa0Sensor assay\n\ngFOBT\n\n\n\n£12.02\n\n£5,039\n\nHM‑JACKarc assay\n\nNo triage\n\n\n\n-£228.10\n\nDominates\n\nOC\xa0Sensor assay\n\nNo triage\n\n-0.0001\n\n-£258.09\n\n£2,578,543 (savings per QALY lost)\n\nAbbreviations: gFOBT, guaiac-based faecal occult blood test; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.\n\nThe pairwise results suggest that both the OC\xa0Sensor and the HM‑JACKarc assays are cost effective compared with both guaiac-based faecal occult blood testing and no triage. The fully incremental probabilistic analysis suggests that the OC\xa0Sensor assay is cost effective. Despite dominating no triage, the HM‑JACKarc assay has a high ICER compared with the OC\xa0sensor because of the very small difference in QALYs and higher cost, which is accounted for by the test having more positive results and so a higher number of colonoscopies.\n\nA breakdown of the costs and outcomes in the base case showed that the number of positive tests was highest for the HMJACK‑arc assay (245.36) and lowest for guaiac-based faecal occult blood testing (130.28). The OC\xa0Sensor assay had 153.50\xa0positive tests. The increased number of positive tests increases the costs for faecal immunochemical tests because of the associated increase in colonoscopies. No colorectal cancer patients were missed with the HM‑JACKarc assay and so no delayed diagnosis occurred with this test. By comparison, 92% of colorectal cancers were detected by the OC\xa0Sensor assay and 50% with guaiac-based faecal occult blood tests.\n\nThe cost-effectiveness acceptability curves for all strategies show that at lower maximum acceptable ICERs, the tests associated with the lowest costs have the greatest probability of being cost effective, that is guaiac-based faecal occult blood testing and the OC\xa0Sensor assay. As the maximum acceptable ICER increases, the HM‑JACKarc assay and guaiac-based faecal occult blood testing have the greatest probability of being cost effective. Pairwise comparisons showed that, when compared with faecal immunochemical testing, no triage would be cost effective only when the maximum acceptable ICER is very high. There was more uncertainty about which strategy was the most cost effective when the faecal immunochemical tests were compared with guaiac-based faecal occult blood testing.\n\n## Analysis of alternative results\n\nThe effect of changing assumptions about the accuracy of the tests was explored in several scenario analyses. Using alternative sources of accuracy data for guaiac-based faecal occult blood tests did not substantially alter the conclusions. The faecal immunochemical tests remained cost effective compared with guaiac-based faecal occult blood tests.\n\nWhen a threshold of any detectable haemoglobin was considered for the OC\xa0Sensor test it resulted in an increased number of colonoscopy referrals and an ICER of £65,192 compared with guaiac-based faecal occult blood tests.\n\nWhen a threshold of 20\xa0micrograms Hb/g faeces was considered, and the FOB\xa0Gold assay was included in the analysis using a threshold of 20.5\xa0micrograms Hb/g faeces, this resulted in an ICER of £4,725 per QALY gained for the FOB\xa0Gold assay compared with guaiac-based faecal occult blood tests. When compared with no triage, £950,152 was saved per QALY lost.\n\nThe FOB\xa0Gold assay was included in a scenario analysis with the base-case settings, but with a threshold of 6.8\xa0micrograms Hb/g faeces, compared with 10\xa0micrograms Hb/g faeces for the HM‑JACKarc and OC\xa0Sensor assays. The ICER for the FOB\xa0Gold compared with guaiac-based faecal occult blood testing was £15,720 per QALY gained, and compared with no triage was £2,273,829 saved per QALY lost.\n\nScenario analyses were done in which the prevalence of colorectal cancer was increased from 1.5% in the base case to 3% and 5.4%. Increasing the prevalence reduced the ICERs for the interventions compared with guaiac-based faecal occult blood testing. However, at 5.4% prevalence the ICER for the OC\xa0Sensor test compared with no triage became less cost effective, from £4,133,559 saved per QALY lost to £238,380 saved per QALY lost.\n\nA threshold analysis showed that for the ICER to remain below £30,000 per QALY gained the cost of the HM‑JACKarc test could be up to £32 more expensive than guaiac-based faecal occult blood tests. The OC\xa0Sensor assay could be up to £51 more expensive than guaiac-based faecal occult blood tests.\n\nIn the base case, the following distribution of patients across the Dukes' stages was assumed in the colorectal cancer Markov model:\n\nstage\xa0A: 13%\n\nstage\xa0B: 37%\n\nstage\xa0C: 36%\n\nstage\xa0D: 14%.\n\nWhen it was assumed that there were more patients in stages\xa0A and\xa0C (16% and 44% respectively) and fewer patients in stage\xa0B (25%) there was a slight loss of QALYs and reduction in costs for all strategies.\n\nWhen it was assumed that there were more patients in stages\xa0A and\xa0D (19% and 15% respectively) and fewer in stages\xa0B and\xa0C (35% and 32% respectively) there was a slight gain in QALYs and an increase in costs for all strategies.\n\nWhen colorectal cancer progression was not considered in the model, the ICERs reduced from the base-case results for the HM‑JACKarc and the OC\xa0Sensor tests compared with guaiac-based faecal occult blood testing. The ICER for the OC\xa0Sensor compared with no triage became less cost effective at £163,305 saved per QALY lost.\n\nWhen the probability of symptoms persisting after a negative test was doubled from the base case (65%), the interventions remained cost effective despite increased costs from increased colonoscopies and a slight reduction in QALYs. When the probability of symptoms persisting was halved from the base case (16.25%), the interventions remained cost effective with a slight QALY increase and reduction in costs.\n\nWhen a mortality rate of 0.0970% was considered for colonoscopy in a worst case scenario, strategies associated with a higher rate of referrals to colonoscopy (no triage and HM‑JACKarc assay) were dominated by guaiac-based faecal occult blood testing and the OC\xa0Sensor test respectively. When it was assumed that there are no adverse events associated with colonoscopy, no triage was dominated by the HM‑JACKarc assay because it provided an equivalent number of QALYs, but cost £227.30 less.\n\nWhen it was assumed that all referrals were to colonoscopy (compared with 88.3% in the base case), with no CT colonography, the cost of each of the testing strategies increased compared with the base case because of the increased cost of colonoscopy.\n\nWhen it was assumed that 20% of patients, who remained symptomatic after a negative faecal immunochemical test or guaiac-based faecal occult blood test, had a second test, the cost of the faecal testing strategies increased, but not enough to affect the overall results.", 'Committee discussion': "The committee discussed the current standard of care for people who present to their GP with symptoms, but who are at a low risk of having colorectal cancer. It noted that recommendations had previously been made for using faecal occult blood tests to triage referral for this group of people in NICE's guideline on suspected cancer, but heard from clinical specialists that this had not been widely adopted in primary care. It heard that people are typically assessed by taking into account their clinical history, their current symptoms and the results of any available tests to establish whether there is a clinical suspicion of colorectal cancer. If clinical suspicion is sufficiently raised, referral using a suspected cancer pathway for an appointment within 2\xa0weeks is appropriate. The committee noted that in practice clinical history and current symptoms of people in this low-risk group were likely to be heterogeneous, and so management was likely to vary between individual patients and GPs. The committee concluded that current clinical practice is likely to vary because of the complexity of managing and investigating non‑specific symptoms in practice.\n\nThe committee discussed the potential benefits that may be associated with using faecal immunochemical tests in primary care. It heard from clinical specialists that faecal immunochemical tests are thought to be more accurate than guaiac-based faecal occult blood tests because they use immunochemical detection methods that are specific to human haemoglobin. They are also suitable for use with automated analysers, which allow high-throughput batch testing. It also heard from a patient specialist that faecal immunochemical tests often had sample collection devices that are easier to use than guaiac-based faecal occult blood tests and they need fewer samples, which makes them more acceptable to people and so may increase test uptake. The committee concluded that faecal immunochemical tests may have substantial analytical and practical advantages over guaiac-based faecal occult blood tests.\n\n# Clinical effectiveness\n\nThe committee discussed the evidence base for the clinical effectiveness of the quantitative faecal immunochemical tests for triaging people with symptoms who are at a low risk of colorectal cancer. It noted that there were 10\xa0included studies that reported data for the OC\xa0sensor, HM‑JACKarc and FOB\xa0Gold assays. It also noted that none of the included studies reported data for the RIDASCREEN haemoglobin or the RIDASCREEN haemoglobin/haptoglobin assays. It therefore concluded that, in the absence of any data, the RIDASCREEN assays could not be considered further.\n\nThe committee questioned whether the data from the studies included in the clinical-effectiveness review were generalisable to the population in the decision problem for this assessment. It noted that many of the studies were done in secondary care and included people with higher-risk symptoms than those previously outlined in NICE's guideline on suspected cancer (see section 2.6). The committee heard from clinical specialists that although the populations in the studies were likely to have a higher prevalence of colorectal cancer, the data provide evidence that faecal immunochemical tests are likely to be highly sensitive for detecting haemoglobin in faecal samples. The committee concluded that although the differences in the populations introduced some uncertainty into the analysis it was reasonable to include the data in the review.\n\nThe committee discussed the diagnostic accuracy data in the included studies. Many reported diagnostic accuracy estimates at multiple thresholds and showed that there was a clear threshold effect; when lower thresholds were used the sensitivity of the test increased, but the specificity decreased. The committee noted that the external assessment group (EAG) had used the diagnostic accuracy data to establish the threshold for the best diagnostic performance. The committee heard from clinical specialists that they supported the EAG's conclusion that a threshold of 10\xa0micrograms of haemoglobin (Hb)/g faeces seemed to give the best diagnostic performance for ruling out colorectal cancer. It also heard that using a threshold lower than 10\xa0micrograms Hb/g faeces would create more variability in test performance because the assays are known to be more imprecise in their lower measuring range, and the availability of quality control materials to validate the detection of low levels of haemoglobin may also be limited. The committee concluded that using a threshold of 10\xa0micrograms Hb/g faeces gave the test enough sensitivity to reliably rule out colorectal cancer in primary care.\n\nThe committee considered the consequences of false-positive faecal immunochemical test results in practice. It heard from clinical specialists that using faecal immunochemical tests in primary care to triage suspected colorectal cancer referrals could result in unnecessary colonoscopy referrals. Data in the clinical-effectiveness review suggested that around 200\xa0of every 1,000\xa0people tested do not have colorectal cancer but are referred for colonoscopy. The committee noted that the tests detect a marker of colorectal cancer (haemoglobin), which could also be associated with a range of other conditions. Data from studies reporting diagnostic accuracy for multiple target conditions in the same population suggested that up to 28.9% of people with a false-positive faecal immunochemical test result for colorectal cancer had bowel pathology, such as inflammatory bowel disease or high-risk adenoma. The committee concluded that it was plausible that the number of false-positive results that occur when using the tests to rule out colorectal cancer could be partially offset by detecting other treatable bowel pathology.\n\nThe committee noted that the review did not find any data that directly compared the OC\xa0Sensor, HM‑JACKarc or FOB\xa0Gold assays. Further, it noted that the review had found substantially less data for the FOB\xa0Gold assay so the EAG could not establish the optimal threshold for this test. The committee therefore examined whether the conclusions reached based on data from the OC\xa0Sensor and HM‑JACKarc assays could be extended to the FOB\xa0Gold assay. It heard from clinical specialists that the 3\xa0assays were likely to perform similarly in detecting haemoglobin in faecal samples. It also heard that the FOB\xa0Gold assay was compatible with a range of clinical chemistry analysers, which may be an advantage for some laboratories. The committee concluded that there was more uncertainty in the clinical effectiveness of the FOB\xa0Gold assay but that the available data suggested that it was likely to perform similarly to the OC\xa0Sensor and HM‑JACKarc assays in practice.\n\nThe committee discussed the possibility of faecal immunochemical tests performing differently in the population subgroups outlined in the decision problem. It heard from clinical specialists that it is plausible that the diagnostic accuracy of faecal immunochemical tests will differ according to age and sex because it is thought that women have lower levels of faecal haemoglobin than men and that levels are higher in older people. The committee noted that only 1\xa0study reported data for men and women separately; this study showed that faecal immunochemical testing was more sensitive in men, but more specific in women. No studies were found that showed data by age. It also heard that both faecal immunochemical tests and guaiac-based faecal occult blood tests may have high false-positive rates in people who are taking medicines that increase their risk of gastrointestinal bleeding, such as oral anticoagulants, antiplatelets or aspirin, but no data were available for this group. The committee concluded that there were insufficient data at present to determine whether different thresholds are needed for women and older people, or whether faecal immunochemical tests help with clinical decision-making when people are taking medicines known to cause gastrointestinal bleeding.\n\n# Cost effectiveness\n\nThe committee considered the cost-effectiveness analyses for the OC\xa0Sensor, HM‑JACKarc and FOB\xa0Gold assays. It noted that 2\xa0comparators had been included; guaiac-based faecal occult blood testing and no triage (that is, direct referral to colonoscopy). The committee discussed which comparator was the most appropriate. It heard from clinical specialists that guaiac-based faecal occult blood testing is no longer done by most clinical chemistry laboratories so primary care clinicians are not able to request the test. It also heard that people in the population outlined in the decision problem were unlikely to be directly referred for colonoscopy, and that a watch-and-wait strategy is most often used by primary care clinicians to monitor their condition. The committee heard from the EAG that a watch-and-wait strategy had not been included in the model because there were not enough data available to characterise the variations in clinical decision-making in this group. The committee concluded that, although the model did not fully capture current practice, the comparisons it made reflected the best available data for the population included in the assessment.\n\nThe committee discussed the likely consequences of false-negative results and whether they could affect a person's prognosis by delaying their diagnosis of colorectal cancer. It noted that the economic model assumed that all people with a false-negative result were subsequently diagnosed within 12\xa0months. It heard from clinical and patient specialists that delayed diagnosis could lead to worse outcomes, but clinical specialists advised that if symptoms persisted a referral to secondary care would be made regardless of a previous negative test result. The committee concluded that the analysis had sufficiently captured the likely prognostic implications of false-negative test results.\n\nThe committee considered the assumptions made in the model when comparing faecal immunochemical tests with guaiac-based faecal occult blood tests. It noted that none of the studies in the clinical-effectiveness review compared faecal immunochemical tests and guaiac-based faecal occult blood tests, so indirect comparisons had to be modelled. The committee discussed the diagnostic accuracy estimates used in the model (see table\xa04) and noted that they suggested that the faecal immunochemical tests were more sensitive than guaiac-based faecal occult blood tests. It heard from clinical specialists that the conclusions drawn from the indirect comparisons were supported by direct comparative data from bowel cancer screening programmes, which have shown that faecal immunochemical tests are more sensitive than guaiac-based faecal occult blood tests. The committee concluded that the assumptions made about the accuracy of guaiac-based faecal occult blood tests were reasonable.\n\nThe committee considered the base-case analysis. It noted that the EAG had not included the FOB\xa0Gold assay in this analysis because no data were available for the accuracy of the assay at a threshold of 10\xa0micrograms Hb/g faeces. In the comparison with the guaiac-based faecal occult blood test both the OC\xa0Sensor and the HM‑JACKarc assays were cost effective, with probabilistic ICERs of £5,040 and £14,600 per QALY respectively. Both assays were also cost effective when compared with no triage, with the HM‑JACKarc dominating (that is, it was more effective and less expensive) and the OC\xa0Sensor having an ICER of £2,580,000 saved per QALY lost. The fully incremental base-case analysis suggested that the OC\xa0Sensor was more cost effective than the HM‑JACKarc, but the committee noted that this comparison was driven by small differences in both costs and QALYs. The committee considered the scenario analyses that included the FOB\xa0Gold assay and noted that although there was more uncertainty in the clinical effectiveness of this technology it appeared to be cost effective, with an ICER of £15,700 per QALY gained when compared with guaiac-based faecal occult blood testing at a threshold of 6.8\xa0micrograms Hb/g faeces. The committee concluded that the OC\xa0Sensor, HM‑JACKarc and FOB\xa0Gold assays had the potential to be cost-effective options for triaging referrals in primary care for people with symptoms but a low risk of colorectal cancer.\n\nThe committee considered the drivers behind the cost savings seen when the faecal immunochemical tests were compared with no triage and noted that a reduction in colonoscopy was a key parameter. It was aware that the comparison made between faecal immunochemical tests and no triage assumes that all people have either colonoscopy or CT colonography to investigate the cause of their symptoms. The committee discussed colonoscopy capacity and whether the cost savings seen in the analysis for this comparison would be realised in practice. It heard from clinical specialists that colonoscopy capacity is very limited in many areas, and in practice it would be unlikely that all people who are at a low risk of colorectal cancer would be referred for colonoscopy. The committee concluded that the cost savings seen in comparisons made between faecal immunochemical tests and no triage could not be considered robust.\n\nThe committee discussed the uncertainties in the cost-effectiveness analysis and noted that the cost effectiveness of faecal immunochemical tests was sensitive to the prevalence of colorectal cancer which influences the pre-test probability. This parameter drives the accuracy of the tests and so the costs and resource use. It noted the scenario analyses that used prevalence values of 3% and 5.4% compared with 1.5% in the base case. The results of these scenario analysis showed that when the prevalence was increased the faecal immunochemical tests became more cost effective when compared with guaiac-based faecal occult blood testing, and when the prevalence of colorectal cancer was decreased the faecal immunochemical tests became less cost effective. The committee therefore considered that if the faecal immunochemical tests are used in a wider population in practice, the prevalence of colorectal cancer will be reduced and the tests may no longer be cost effective. The committee concluded that the tests are likely to be cost effective when used alongside clinical judgement and the results of any other testing to guide referral for suspected colorectal cancer in people without rectal bleeding who have unexplained symptoms and are at low risk. Further, it recommended that where false-negative results are suspected, active monitoring (safety netting) should be used as recommended in NICE's guideline on suspected cancer.\n\n# Other considerations\n\nThe committee discussed the possible advantages of using quantitative faecal immunochemical tests. It heard that the ability of the tests to report the concentration of faecal haemoglobin instead of providing a semi-quantitative positive or negative result could have additional clinical uses. It heard from a clinical specialist that, in some areas of Scotland, quantitative faecal immunochemical tests have been adopted to triage referrals from primary care and that the faecal haemoglobin concentration is being used in secondary care to decide who should have a colonoscopy most urgently. The committee also heard that the prognostic-risk scoring tools, highlighted in the clinical-effectiveness review (section\xa04.20) are a growing area of research that aims to produce validated tools that can identify people at increased risk of colorectal cancer using variables such as age, sex and faecal haemoglobin concentration. The committee concluded that the development of risk-prediction rules may further refine the use of faecal immunochemical tests in primary care.\n\nThe committee noted that the NHS bowel cancer screening programme is adopting faecal immunochemical tests as a replacement for guaiac-based faecal occult blood tests. It considered that there may be instances when people, who have recently had a negative screening result, may get a positive result in primary care after reporting symptoms because of the use of different thresholds in the 2\xa0clinical scenarios. The committee concluded that practices adopting faecal immunochemical tests as a triage tool should take this into account when developing their implementation plans, and ensure that information to explain the different thresholds and their consequences is available for people who have recently participated in the bowel cancer screening programme. Information about the different test thresholds should also be made available to people taking part in the NHS bowel cancer screening programme.", 'Recommendations for further research': 'The committee considered that commissioning groups adopting the faecal immunochemical tests in primary care should audit their outcomes. Possible outcomes to audit include:\n\nnumber of people referred using a suspected cancer pathway for an appointment within 2\xa0weeks\n\nnumber of people diagnosed with colorectal cancer\n\nnumber of colonoscopies and CT colonographies requested.The committee noted that Cancer Research UK is planning an audit in the south west of England to collect information on how people without rectal bleeding who have unexplained symptoms and are at low risk of colorectal cancer are assessed in primary care.\n\nThe committee considered that further research is needed to determine whether faecal haemoglobin levels are influenced by age, sex and medicines that increase the risk of gastrointestinal bleeding. It noted that these data could be used to further develop risk scores that include variables such as age, sex and symptoms to help determine pre-test probability. The data could also be combined with faecal haemoglobin concentration to refine management after the use of faecal immunochemical tests in primary care.\n\nThe committee noted advice from clinical experts that there is variability between the faecal immunochemical tests. This may affect the number of positive and negative results reported by the tests when a single threshold is used. It recommended further research to investigate the variability between technologies and encouraged the companies to make sure that results can be standardised for use in a symptomatic population.'}
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https://www.nice.org.uk/guidance/dg30
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Evidence-based recommendations on faecal immunochemical tests (OC Sensor, HM-JACKarc, FOB Gold and RIDASCREEN) to guide GP referral for colorectal cancer.
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226cb1f709b8f51b3f7939a8bd0583028a6860c6
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nice
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Transcatheter aortic valve implantation for aortic stenosis
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Transcatheter aortic valve implantation for aortic stenosis
Evidence-based recommendations on transcatheter aortic valve implantation (TAVI) for aortic stenosis. This involves inserting a new valve through a catheter, usually by way of a large blood vessel at the top of the leg, into the heart and inside the existing faulty valve.
# Recommendations
Current evidence on the safety and efficacy of transcatheter aortic valve implantation (TAVI) for aortic stenosis is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.
Details of all patients should be entered into the UK TAVI registry managed by the National Institute for Cardiovascular Outcomes Research. Contact bartshealth.nicor-generalenquiries@nhs.net for details. Adverse events should be reported to the Medicines and Healthcare products Regulatory Agency.
Patient selection should be carried out by an experienced multidisciplinary team, which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging and, when appropriate, a cardiac anaesthetist and a specialist in elderly medicine. The multidisciplinary team should determine the risk level for each patient and the TAVI device most suitable for them.
During the consent process patients should be told about all treatment options and their advantages and disadvantages.
TAVI is a technically challenging procedure that should only be done in specialised centres and only by clinicians and teams with special training and experience in complex endovascular interventions. Units doing this procedure should have both cardiac and vascular surgical support for the emergency treatment of complications and subsequent patient care.# Indications and current treatments
Aortic stenosis causes impaired outflow of blood from the heart and is usually progressive. The increased cardiac workload leads to left ventricular hypertrophy and heart failure. Symptoms of aortic stenosis typically include shortness of breath and chest pain on exertion. Mortality rates are high in symptomatic patients.
Surgical aortic valve replacement (SAVR) with an artificial (biological or mechanical) prosthesis is the conventional treatment for patients with severe symptomatic aortic stenosis who are well enough for surgery. Optimal medical care has traditionally been the only option for those whose condition is unsuitable for surgery. Aortic balloon valvuloplasty is occasionally used as bridging or palliative treatment. Transcatheter aortic valve implantation (TAVI) is another less invasive alternative treatment.
Patients for whom SAVR is suitable range from those considered to be high risk (for example, as defined in the PARTNER 1A trial) to those for whom the benefits of surgery clearly outweigh the risks of surgery. SAVR may not be suitable for patients because of medical comorbidities or technical considerations (for example, if the patient has a calcified aorta or scarring from previous cardiac surgery), which mean that the risks of SAVR outweigh the potential benefits.# The procedure
Transcatheter aortic valve implantation (TAVI) aims to provide a less invasive alternative to open cardiac surgery for treating aortic stenosis, avoiding the need for sternotomy and cardiopulmonary bypass.
TAVI may be done with the patient under general anaesthesia or using local anaesthesia with or without sedation. Access to the aortic valve is most commonly transluminal, through a large artery (usually the femoral or subclavian artery; percutaneous or endovascular approach), or occasionally surgical, by a minithoracotomy with apical puncture of the left ventricle (transapical approach). The choice of access route (transluminal or transapical) depends on various patient-related factors including atherosclerotic disease in the arteries, which would make the transluminal approach impossible.
Initially the aortic valve ring may be dilated using a balloon catheter, which is advanced over a guidewire. The new prosthetic valve is manipulated into position and inserted inside the existing aortic valve.
Different devices are available for this procedure and contain material derived from animal sources.# Efficacy
This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Evidence is based only on studies that reported outcomes by the risk level of the patients.
# Survival beyond 30 days
A randomised controlled trial (RCT) of 358 patients (PARTNER 1B) for whom surgical aortic valve replacement (SAVR) was unsuitable compared transcatheter aortic valve implantation (TAVI; n=179) with medical management (n=179). Patients who had TAVI had significantly lower all-cause mortality and cardiovascular mortality compared with medical management at a follow-up of 1, 2 and 5 years (31% compared with 51% at 1 year, 43% compared with 68% at 2 years and 72% compared with 94% at 5 years for all-cause mortality and 21% compared with 45% at 1 year, 31% compared with 62% at 2 years and 58% compared with 86% at 5 years for cardiovascular mortality).
In an RCT of 795 patients for whom SAVR was suitable but high risk (the CoreValve trial), a Kaplan–Meier cumulative probability analysis for all-cause mortality at 3‑year follow-up was 33% for TAVI compared with 39% for SAVR (p=0.068). In another RCT of 699 patients for whom SAVR was suitable but high risk (the PARTNER 1A trial), a Kaplan–Meier probability analysis for all-cause mortality at up to 5 years of follow-up was 68% for TAVI compared with 62% for SAVR (p=0.76). When data were pooled for both RCTs (based on an intention-to-treat analysis), the hazard ratios did not show statistically significant differences between TAVI and SAVR for hazard of death (pooled estimates were risk ratio 0.89; 95% confidence interval 0.73 to 1.09, p=0.26 at 1 year and RR 0.95; 95% CI 0.79 to 1.13, p=0.55 at 2 years). There were no significant differences for cardiovascular mortality at 1 year (RR 1.05; 95% CI 0.79 to 1.39, p=0.73) and 2 years (RR 0.92; 95% CI 0.67 to 1.28, p=0.79).
In an RCT of 2,032 patients for whom SAVR was suitable but intermediate risk (the PARTNER 2A trial) there were no significant differences between TAVI and SAVR at 1- and 2‑year follow-up for all-cause mortality and cardiovascular mortality (all-cause mortality: 12% compared with 13%, p=0.69, at 1 year and 17% compared with 18%, p=0.45, at 2 years; cardiovascular mortality: 7% compared with 8%, p=0.4, at 1 year and 10% compared with 11%, p=0.38, at 2 years). In an RCT of 276 patients for whom SAVR was suitable but low to intermediate risk (the NOTION study) there were no significant differences between TAVI and SAVR at 1- and 2‑year follow-up for all-cause mortality and cardiovascular mortality (all-cause mortality: 5% compared with 8%, p=0.38, at 1 year and 8% compared with 10%, p=0.54, at 2 years; cardiovascular mortality: 4% compared with 8%, p=0.25, at 1 year and 7% compared with 9%, p=0.40, at 2 years). A systematic review including 2 RCTs and 6 observational studies of 16,638 patients for whom SAVR was suitable and not high risk (comprising 6,875 patients in an analysis) showed a non-significant difference in all-cause mortality for TAVI compared with SAVR (odds ratio 0.67; 95% CI 0.42 to 1.07, p=0.08, at 30 days; OR 0.91; 95% CI 0.67 to 1.23 at 1 year; OR 1.06; 95% CI 0.59 to 1.91 at long-term follow-up ). In a systematic review of patients at low and intermediate risk from surgery including 4 RCTs (n=3,179 patients, including the CoreValve trial), in which patients had a mean Society of Thoracic Surgeons' (STS) risk score of 7%, TAVI was associated with a lower hazard of death at 2 years than SAVR when done by the transfemoral but not by the transapical route (transfemoral route: hazard ratio 0.79; 95% CI 0.66 to 0.94, ; transapical route: HR 1.34; 95% CI 0.91 to 1.97).
# Symptomatic improvement
The RCT of 358 patients (PARTNER 1B) for whom SAVR was unsuitable compared TAVI (n=179) with medical management (n=179). More patients were asymptomatic or had mild symptoms (New York Heart Association class I or II) in the TAVI group than those in the medical management group (at 2 years: 83% compared with 42% , p<0.0001; at 3 years: 70% compared with 50% , p=0.245; and at 5 years: 86% compared with 60% , p=0.531; NYHA class was not significantly different at baseline among these groups).
In the RCT of 795 patients for whom SAVR was suitable but high risk (the CoreValve trial), a greater proportion of patients were in NYHA class I or II in the TAVI group than in the SAVR group at 1 month (83% compared with 73%, p<0.001) and at 6 months (84% compared with 79%, p=0.04). At 12 months, there were no statistically significant differences between the TAVI and SAVR groups (79% compared with 72%, p=0.10). In the other RCT of 699 patients for whom SAVR was suitable but high risk (PARTNER 1A), the proportion of patients in NYHA class I or II was the same (64%) for TAVI and SAVR at 12 months.
In the RCT of 2,032 patients for whom SAVR was suitable but intermediate risk (PARTNER 2A) there were no significant differences between TAVI and SAVR in the proportion of patients in NYHA class I or II at 1- and 2‑year follow-up. In the RCT of 276 patients for whom SAVR was suitable but low to intermediate risk (NOTION) there were no significant differences between TAVI and SAVR in NYHA class at 3‑month and 2‑year follow-up. The systematic review (4 studies; n=2,146) of patients for whom SAVR was suitable but low to intermediate risk found that TAVI was associated with an increased risk of heart failure symptoms (NYHA class II or more: OR 1.29; 95% CI 1.08 to 1.55) at 2‑year follow-up compared with SAVR.
# Haemodynamic improvement
The RCT of 358 patients (PARTNER 1B) for whom SAVR was unsuitable compared TAVI (n=179) with medical management (n=179). There was a significantly higher mean aortic valve area in the TAVI group than in the medical management group at 1‑year follow-up (1.6 cm2 compared with 0.7 cm2 , significance level not given). Mean pressure gradient improved from 44.7 mmHg (SD 15.4) at baseline to 13.2 mmHg (SD 11.2) for TAVI and changed from 43.2 mmHg (SD 15.4) to 44.3 mmHg (SD 16.1) at 1 year for medical management (p values not reported). Left ventricular ejection fraction (LVEF) improved from 53.9% (SD 13.1) at baseline to 57.2% (SD 10.6) for TAVI and from 51.2% (SD 14.3) to 56.9% (SD 10.3) at 1 year for medical management.
In the RCT of 699 patients for whom SAVR was suitable but high risk (PARTNER 1A, TAVI compared with SAVR ), there was a significantly higher mean aortic valve area in the TAVI group than in the SAVR group at 30‑day, 6‑month and 1‑year follow-up respectively (1.7 cm2 compared with 1.5 cm2 , p=0.001, at 30 days; 1.7 cm2 compared with 1.5 cm2 , p=0.01, at 6 months; and 1.6 cm2 compared with 1.4 cm2 , p=0.002, at 1 year). Mean pressure gradients improved but were not statistically significant (9.9 mmHg compared with 10.8 mmHg , p=0.04, at 30 days; 10.2 mmHg compared with 10.8 mmHg , p=0.16, at 6 months; and 10.2 mmHg compared with 11.5 mmHg , p=0.008, at 1 year). LVEFs improved but not statistically significantly (55.5 compared with 56.0 , p=0.63, at 30 days; 56.2 compared with 56.8 , p=0.56, at 6 months; and 56.6 compared with 57.1 , p=0.64, at 1 year). Baseline values were not significantly different for all the outcomes. In the other RCT of 795 patients for whom SAVR was suitable but high risk (CoreValve trial, TAVI compared with SAVR ), there was a significantly higher mean aortic valve area in the TAVI group compared with the SAVR group (1.70 cm2 compared with 1.55 cm2 , p<0.001, at 1 year; and 1.79 cm2 compared with 1.53 cm2 , p<0.0001, at 3 years). Mean pressure gradients also improved significantly (8.90 mmHg compared with 12.17 mmHg , p<0.0001, at 1 year; and 7.62 mmHg compared with 11.40 mmHg , p<0.0001, at 3 years). Baseline values were not significantly different for all the outcomes.
In the RCT of 2,032 patients for whom SAVR was suitable but intermediate risk (PARTNER 2A) the mean aortic valve area was significantly higher in the TAVI group than in the SAVR group at 30 days (1.7 cm2 compared with 1.5 cm2 , p<0.001), and this persisted at 1 year (1.6 cm2 compared with 1.4 cm2 , p<0.001) and at 2 years (1.5 cm2 compared with 1.4 cm2 , p<0.001). Mean pressure gradients also improved significantly (9.7 mmHg compared with 10.9 mmHg , p<0.001) at 30 days and this persisted at 1 year (10.7 mmHg compared with 11.5 mmHg , p=0.001) and 2 years (10.8 mmHg compared with 11.7 mmHg , p<0.001). LVEF was higher for the TAVI group than for the SAVR group (56.9% compared with 55.0% , p=0.04) at 30 days but this was reversed at 1 year (55.9% compared with 57.2% , p=0.04) and at 2 years (54.9% compared with 57.2% , p=0.005). In the RCT of 276 patients for whom SAVR was suitable but low to intermediate risk (NOTION) there were significantly greater improvements in mean valve area in the TAVI group than in the SAVR group (1.7 cm2 compared with 1.3 cm2, p<0.001, at 3 months; 1.7 cm2 compared with 1.3 cm2, p<0.001, at 1 year; 1.6 cm2 compared with 1.3 cm2, p<0.001, at 2 years). There were no significant differences from baseline for mean pressure gradient.
# Quality of life
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) there were significant improvements in self-reported quality of life in patients in the TAVI group compared with those in the medical management group (Kansas City Cardiomyopathy Questionnaire quality-of-life summary score for heart failure: mean difference 14.8; 95% CI 8.6 to 21.0, p<0.001, at 1 month and greater benefits at 6 months and at 12 months ). At 12 months, the TAVI group also had higher SF‑12 physical and mental health scores (MD 5.7 and 6.4 respectively, p<0.001).
In both the PARTNER 1A and CoreValve trials (patients for whom SAVR was suitable but high risk), patients having TAVI using the transfemoral route reported a greater improvement in quality of life (measured using EQ-5D, where 0 equals dead and 1 perfect health-related quality of life) than those having SAVR (PARTNER 1A: average change of 0.08 compared with 0.02 at 1 month, 0.1 compared with 0.09 at 6 months and 0.09 compared with 0.08 at 1 year; CoreValve study: average change of 0.055 compared with −0.073 at 1 month; 0.053 compared with 0.04 at 6 months and 0.043 compared with 0.0003 at 1 year). When data from these 2 trials were pooled for the transfemoral route, the overall estimates for EQ‑5D showed statistically significant differences between the TAVI and SAVR groups at 1 month in favour of TAVI (RR 0.09; 95% CI 0.03 to 0.16; p=0.006). However, the differences were not significant at 6 months (RR 0.01; 95% CI −0.02 to 0.05, p=0.47) and at 1 year (RR 0.03; 95% CI 0.00 to 0.06, p=0.09). When data were pooled for transapical TAVI compared with SAVR (from PARTNER 1A) and non-transfemoral TAVI compared with SAVR (from the CoreValve trial), the overall estimates for EQ‑5D showed no statistically significant differences between the TAVI and SAVR groups (RR −0.03; 95% CI −0.09 to 0.04, p=0.44 at 1 month, RR −0.02; 95% CI −0.10 to 0.07, p=0.66 at 6 months and RR −0.02; 95% CI −0.09 to 0.05, p=0.58 at 1 year). There was a greater improvement in SF‑12 scores (both physical and mental) in the TAVI group than in the SAVR group at 1‑month follow-up (MD for physical summary scores 2.0; 95% CI 0.1 to 3.9, p=0.4 in PARTNER 1A and MD 4.9; 95% CI 3.1 to 6.7, p<0.001 in the CoreValve trial; MD for mental summary scores 5.4; 95% CI 3.1 to 7.7, p<0.001 in PARTNER 1A and 6.1; 95% CI 3.8 to 8.5, p<0.001 in the CoreValve trial). There were no statistically significant differences between TAVI using either the transfemoral or non-transfemoral route and SAVR at 12 months for both physical and mental scores. Statistically significant differences in favour of TAVI were reported for KCCQ quality-of-life summary score at 1‑month follow-up in both PARTNER 1A (MD 9.8; 95% CI 4.0 to 15.6, p=0.001) and in the CoreValve study (19.0; 95% CI 13.7 to 24.3, p<0.001) but did not persist at 6- and 12‑month follow-up. There were no statistically significant differences in KCCQ quality-of-life scores using either the transapical route in PARTNER 1A or the non-transfemoral routes in the CoreValve study.
In the systematic review of patients for whom SAVR was suitable but low to intermediate risk (n=2,146, including data from 795 patients in 1 study with a follow-up of 2 years), there was a non-significant difference in KCCQ quality-of-life summary score (22.2 for TAVI compared with 18.7 for SAVR, MD 3.5; 95% CI 1.9 to 8.9).
# Repeat hospitalisation
The RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B) compared TAVI (n=179) with medical management (n=179). TAVI had a statistically significantly lower hazard ratio for repeat hospitalisation because of aortic stenosis (including complications because of TAVI) than medical management at 2 year- (HR 0.41; 95% CI 0.30 to 0.58, p<0.001), 3 year- (p<0.0001) and 5‑year follow-up (p<0.001).
In the RCT of 699 patients for whom SAVR was suitable but high risk (PARTNER 1A, TAVI compared with SAVR) there was a non-significant difference in re-hospitalisation rates (59 compared with 45 , p=0.38, at 1 year; 74 compared with 60 , p=0.41, at 2 years; and 108 compared with 81 , p=0.17, at 5 years). In the RCT of 795 patients (CoreValve trial; TAVI, n=394 compared with SAVR, n=401) for whom SAVR was suitable but high risk, there was no significant difference in re-hospitalisation rates (95 for TAVI compared with 64 for SAVR, p=0.087) at 3 years. In the RCT of 2,032 patients for whom SAVR was suitable but intermediate risk (PARTNER 2A) there were no significant differences in re-hospitalisation rates between TAVI and SAVR.
The specialist advisers listed key efficacy outcomes as procedural success, satisfactory device positioning, shorter length of hospital stay, haemodynamic improvement, improvement in left ventricular function, improved quality of life, improved exercise capacity, symptom relief, prolonged survival, reduced mortality and morbidity and reduced re-hospitalisation.# Safety
This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.
Evidence is based only on studies that reported outcomes by the risk level of the patients.
# All-cause mortality and cardiovascular mortality within 30 days
A randomised controlled trial (RCT) of 358 patients for whom surgical aortic valve replacement (SAVR) was unsuitable (PARTNER 1B) compared transcatheter aortic valve implantation (TAVI; n=179) with medical management (n=179). There were no statistically significant differences in all-cause mortality (5% compared with 3% , p=0.41) and cardiovascular mortality (5% compared with 2% , p=0.22) between TAVI and medical management at 30‑day follow-up.
In an RCT of 699 patients for whom SAVR was suitable but high risk (PARTNER 1A; TAVI, n=348 compared with SAVR, n=351) there were no statistically significant differences in all-cause mortality (3% compared with 7% , p=0.07) and cardiovascular mortality (3% compared with 13% , p=0.90) between the TAVI group and SAVR group at 30‑day follow-up. In another RCT of 795 patients (the US CoreValve trial; TAVI, n=394 compared with SAVR, n=401) there were also no statistically significant differences in all-cause mortality (3% compared with 5% , p=0.43) and cardiovascular mortality (3% compared with 5% , p=0.32) between the TAVI group and SAVR group at 30‑day follow-up. When data were pooled for both studies, the risk ratio (less than 1 favours TAVI) for all-cause mortality was 0.64 (95% confidence interval 0.38 to 1.39, p=0.06) and for cardiovascular mortality was 0.90 (95% CI 0.52 to 1.56, p=0.70).
In an RCT of 2,032 patients for whom SAVR was suitable but intermediate or low risk (TAVI, n=1,011 compared with SAVR, n=1,021) there was a non-significant lower all-cause mortality (3% compared with 4%, p=0.24) and cardiovascular mortality (2% compared with 3%, p=0.72) for TAVI using the femoral route compared with SAVR at 30-day follow-up. For the transthoracic route all-cause mortality (6% compared with 4%, p=0.21) and cardiovascular mortality (5% compared with 3%, p=0.47) were not significantly different. In another RCT of 280 low- and intermediate-risk patients (TAVI, n=145 compared with SAVR, n=135), all-cause mortality (2% compared with 3% , p=0.43) and cardiovascular mortality (2% compared with 4% , p=0.43) were not significantly different. A systematic review of 3,179 patients (with risk scores of 8% or less in 4 RCTs) also reported a non-significant lower all-cause mortality for TAVI compared with SAVR (OR 0.67; 95% CI 0.42 to 1.07).
# Cerebral complications
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) the hazard ratio for stroke or transient ischaemic attack (TIA) was significantly higher in the TAVI group (hazard ratio 2.81; 95% CI 1.26 to 6.26, p=0.004) at 3-year follow-up, whereas at 5-year follow-up there were no significant differences between the TAVI and medical management groups (HR 1.39; 95% CI 0.62 to 3.11, p=0.555).
In 2 RCTs (PARTNER 1A and the CoreValve trial ) in patients for whom SAVR was suitable but high risk, the incidence of stroke and TIA was reported. Both pooled and individual risk ratios from PARTNER 1A and the CoreValve trial showed no statistically significant differences in the incidence of all stroke in patients for whom SAVR was suitable but high risk at 30 days (risk ratio 1.26; 95% CI 0.56 to 2.86, p=0.57), 1 year (RR 1.21; 95% CI 0.49 to 2.98, p=0.68), 2 years (RR 1.11; 95% CI 0.51 to 2.41, p=0.78), 3 years (CoreValve, ITT RR 1.14; 95% CI 0.53 to 2.46, p=0.75) and 5 years (PARTNER 1A, ITT RR 1.13; 95% CI 0.68 to 1.87, p=0.65). Both pooled and individual risk ratios for TIA from PARTNER 1A and the CoreValve trial also showed no statistically significant differences at 30 days (RR 3.04; 95% CI 0.62 to 15.01, p=0.17), 1 year (RR 1.46; 95% 0.63 to 3.41, p=0.38), 2 years (RR 1.92; 95% CI 0.90 to 4.11, p=0.09), 3 years (CoreValve, ITT RR 1.53; 95% CI 0.55 to 4.25, p=0.42) and 5 years (PARTNER 1A, ITT RR 1.77; 95% CI 0.75 to 4.15, p=0.19).
In the RCT of 2,032 patients for whom SAVR was suitable but intermediate risk (PARTNER 2A, TAVI compared with SAVR) there were no significant differences between groups in all strokes at 30 days (55 compared with 61 , p=0.57), 1 year (78 compared with 79 , p=0.88) and at 2 years (91 compared with 85 , p=0.67). An RCT of 276 patients for whom SAVR was suitable but low to intermediate risk (the NOTION study, TAVI compared with SAVR) reported incidence of stroke and TIA at 30 days (4 compared with 4 , p=0.94), 1 year (7 compared with 8 , p=0.68) and at 2 years (13 compared with 10 , p=0.67). The systematic review of 3,179 patients (based on data from 2,576 patients in 3 studies) reported a non-significant reduction in stroke rates (RR 0.80; 95% CI 0.63 to 1.01) for transfemoral TAVI compared with SAVR at 2-year follow-up. Comparing transapical TAVI with SAVR (based on data from 552 patients in 2 studies), the risk ratio was 1.67 (95% CI 0.97 to 2.87) at 2-year follow-up.
# Aortic regurgitation
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) there were similar rates of moderate or severe aortic regurgitation in both groups at 30‑day and 1‑year follow-up (15% compared with 17%).
In 2 RCTs (PARTNER 1A and the CoreValve trial) the incidence of aortic regurgitation (paravalvular and transvalvular) in patients for whom SAVR was suitable but high risk was reported. Pooled data (RR 4.02; 95% CI 1.99 to 8.11, p=0.0001) at 1 year and individual study data favoured SAVR over TAVI at all follow-up points up to 3 years (PARTNER 1A: at 30 days RR 16.29; 95% CI 3.98 to 66.6, p=0.0001; at 6 months RR 30.26; 95% CI 4.16 to 220.01, p=0.0008; at 2 years p=0.008; CoreValve trial: at 3 years p=0.04).
In the RCT of 276 patients for whom SAVR was suitable but low to intermediate risk (NOTION, TAVI compared with SAVR) significant differences in moderate to severe aortic regurgitation at 3 months (15% compared with 22%, p<0.001) and at 1 year (16% compared with 1%, p=0.001) were reported. In the systematic review of 3,179 patients (based on data from 3 trials) moderate or severe aortic regurgitation occurred more often after TAVI than after SAVR at 2‑year follow-up (RR 12.22; 95% CI 5.17 to 28.88).
# Aortic valve re-intervention
In the systematic review of 3,179 patients for whom SAVR was suitable but low to intermediate risk (based on data from 3,058 patients in 4 studies) the risk of aortic valve re-intervention was significantly higher after TAVI than after SAVR (RR 3.25; 95% CI 1.29 to 8.14).
# Prosthesis-patient mismatch
In the RCT of 699 patients (PARTNER 1A) for whom SAVR was suitable but high risk, the overall incidence and severity of prosthesis-patient mismatch was significantly better in the TAVI group than in the SAVR group (assessed at first postoperative echocardiogram: 46% compared with 60% ; p<0.001 and 42% compared with 57%, p<0.001, at 30 days).
# Myocardial infarction
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, comparing TAVI with medical management) there were no significant differences in the occurrence of myocardial infarction (MI) at 2‑year (p=0.69) and 3‑year (p=0.59) follow-up.
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) the incidence of MI for patients for whom SAVR was suitable but high risk was reported. Pooled data (at 30 days RR 0.72; 95% CI 0.17 to 2.94, p=0.64; at 1 year RR 1.18; 95% CI 0.42 to 3.29, p=0.76; at 2 years RR 0.51; 95% CI 0.06 to 4.05, p=0.52) and individual study data (3-year CoreValve ITT, RR 1.45; 95% CI 0.45 to 2.94, p=0.52 or 5-year PARTNER 1A ITT, RR 0.46; 95% CI 0.16 to 1.31, p=0.14) showed no statistically significant differences between the treatment groups.
In 2 RCTs (PARTNER 2A and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients for whom SAVR was suitable but intermediate risk there were no significant differences in incidence of MI between TAVI and SAVR. The systematic review of 3,179 patients for whom SAVR was suitable but intermediate to low risk (based on data from 3,128 patients in 4 studies) found no difference between the treatment groups for MI (RR 0.87; 95% CI 0.59 to 1.29) at 2‑year follow-up.
# Endocarditis
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, comparing TAVI with medical management) there were no significant differences between the groups in endocarditis at 2‑year (3% compared with 1%, p=0.32) and 3‑year (2% compared with 1%, p=0.32) follow-up.
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were no significant differences between groups in endocarditis (PARTNER 1A: 0% compared with less than 1%, p=0.32, at 1 month; 2 compared with 3 , p=0.63, at 1 year; 4 compared with 3 , p=0.61, at 2 years; and 5 compared with 6 , p=0.65, at 5 years; CoreValve study: 3 compared with 5 , p=0.346, at 3 years).
In 2 RCTs (PARTNER 2A study and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients, for whom SAVR was suitable but intermediate risk, there were no significant differences in endocarditis between TAVI and SAVR (RCT of 276 patients: 1 compared with 0, p=0.33, at 30 days; 4 compared with 2 , p=0.47, at 1 year; RCT of 2,032 patients: transfemoral route 6 compared with 6 , p=0.92, at 1 year; 10 compared with 6 , p=0.33, at 2 years; transthoracic route 1 compared with 0, p=0.32).
# Atrial fibrillation
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) there were no significant differences in the incidence of new atrial fibrillation between the treatment groups (at 30 days less than 1% compared with 1%, p=1.00; at 1 year less than 1% compared with 2%, p=0.62).
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were significant differences in the incidence of atrial fibrillation (PARTNER 1A: 12% compared with 17%, p=0.07, at 1 year; CoreValve study: 12% compared with 31% , p<0.001, at 30 days; 16% compared with 33% , p<0.001, at 1 year).
In 2 RCTs (PARTNER 2A and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients, for whom SAVR was suitable but intermediate risk, there were significant differences in the incidence of new atrial fibrillation between the treatment groups. In the RCT of 2,032 patients, for transfemoral TAVI compared with SAVR the incidence was 38 (5%) compared with 204 (27%), p<0.001, at 30 days; 45 (6%) compared with 210 (28%), p<0.001, at 1 year and 55 (7%) compared with 211 (28%) p<0.001, at 2 years. In the same RCT, for transthoracic TAVI compared with SAVR the incidence was 53 (23%) compared with 61 (26%), p=0.50, at 30 days; 55 (24%) compared with 62 (26%), p=0.60, at 1 year; and 55 (24%) compared with 62 , p=0.60, at 2 years. In the RCT of 276 patients the incidence was: 24 compared with 77 , p<0.001, at 30 days; 51 compared with 79 p<0.001, at 1 year; 32 compared with 80 , p<0.001, at 2 years). The systematic review of 3,179 patients (based on data from 3,058 patients in 3 studies) found that the risk ratio for new onset atrial fibrillation at 2‑year follow-up was 0.43 (0.35 to 0.52) for TAVI compared with SAVR.
# Need for permanent pacemaker
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) the proportion of patients with permanent pacemaker implantation (PPI) was lower in the TAVI group at 2 years (6% compared with 9%, p=0.47) and 3 years (8% compared with 9%, p=0.75) but these differences were not significant.
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, the need for PPI was reported. Pooled data tended to favour the SAVR group. However the differences were not statistically significant at 30 days (RR 1.94; 95% CI 0.70 to 5.34, p=0.20), at 1 year (RR 1.75; 95% CI 0.94 to 3.25, p=0.08) and at 2 years (RR 1.77; 95% CI 0.95 to 3.30, p=0.07). At 3‑year follow-up (CoreValve trial: TAVI, n=394, SAVR, n=401) there were significantly fewer PPI in the SAVR group than in the TAVI group (14.5% compared with 28%, p<0.001). At 5 years (PARTNER 1A) there were no statistically significant differences between the treatment groups (9.7% compared with 9.1%, p=0.64).
In 2 RCTs (PARTNER 2A and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients, for whom SAVR was suitable but intermediate risk, the need for PPI was reported. In the RCT of 2,032 patients there were no significant differences between the groups (9% compared with 7%, p=0.17, at 30 days; 10% compared with 9%, p=0.43, at 1 year; 12% compared with 10%, p=0.29, at 2 years). But in the RCT of 276 patients the need for PPI was higher in the TAVI group than in the SAVR group (46 compared with 2 , p<0.001, at 30 days; 51 compared with 3 , p<0.001, at 1 year; and 55 compared with 5 , p<0.001, at 2 years). The systematic review of 3,179 patients (based on data from 3,128 patients in 4 studies) reported an increased risk of PPI (RR 2.46; 95% CI 1.17 to 5.15) for TAVI compared with SAVR.
# Acute kidney injury and renal failure
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) there were no significant differences in the occurrence of acute kidney injury (AKI) between the treatment groups at 2-year (3% compared with 8%, p=0.15) and 3-year follow-up (3% compared with 11%, p=0.08).
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, the occurrence of AKI was reported. Pooled data (at 30 days RR 0.51; 95% CI 0.27 to 0.98, p=0.04) and data from the CoreValve study at 3 years (RR 0.45; 95% CI 0.29 to 0.72, p=0.0007) significantly favoured the TAVI group, whereas there were no statistically significant differences in the pooled estimates at 1 year and 2 years (RR 0.76; 95% CI 0.23 to 2.59, p=0.67, at 1 year; RR 0.64; 95% CI 0.31 to 1.34, p=0.24, at 2 years) and from PARTNER 1A at 5 years (RR 1.01; 95% CI 0.58 to 1.74).
In 2 RCTs (PARTNER 2A and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients, for whom SAVR was suitable but intermediate risk, the occurrence of AKI was reported. The RCT of 2,032 patients reported a lower incidence of AKI in the TAVI group than in the SAVR group at 30 days (13 compared with 31 , p=0.0006). Incidence rates were similar for transthoracic TAVI and SAVR (4% compared with 3%). The incidence rates were significantly lower for transfemoral TAVI than for SAVR (2.2% compared with 5%, p=0.002, at 1 year; 3% compared with 7%, p<0.001, at 2 years) and higher for transthoracic TAVI (7% compared with 4.4%, p=0.18, at 1 year, 8% compared with 6%, p=0.23, at 2 years). The RCT of 276 patients reported a higher occurrence of AKI in the SAVR group than in the TAVI group (9 ) compared with 1 , p=0.01) at 30 days. The systematic review of 3,179 patients (based on data from 2,576 patients in 3 studies) reported that the risk ratio of AKI at 2‑year follow-up was 0.38 (95% CI 0.27 to 0.54) for transfemoral TAVI and 1.54 (95% CI 0.77 to 3.07) for transapical TAVI compared with SAVR.
# Vascular complications
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management) the hazard ratio for major vascular complications at 3‑year follow-up was statistically significantly higher with TAVI (17%) than with medical management (3%, HR 8.27; 95% CI 2.92 to 23.44, p<0.0001).
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were no statistically significant differences between the treatment groups in the incidence of major vascular complications in either pooled data at 30‑day (RR 3.04; 95% CI 0.63 to 3.41, p=0.17), 1‑year (RR 1.46; 95% CI 0.63 to 3.41, p=0.38) or 2‑year follow-up (RR 1.92; 95% CI 0.90 to 4.11, p=0.09), or in the individual studies at 3‑year (CoreValve study, p=0.42) or 5‑year follow-up (PARTNER 1A, p=0.19).
In 2 RCTs (PARTNER 2A and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients, for whom SAVR was suitable but intermediate risk, major vascular complications were reported. In the RCT of 2,032 patients there was a higher incidence of major complications in the TAVI group than in the SAVR group (7.9% compared with 5%, p=0.008 at 30 days; 8% compared with 5.3%, p=0.007 at 1 year and 9% compared with 6%, p=0.006 at 2 years). The incidence rate was lower for transthoracic TAVI than for SAVR. The RCT of 276 patients reported more major vascular complications in the TAVI group than in the SAVR group at 30 days (6% compared with 2%, p=0.10).
# Major bleeding
In the RCT of 358 patients for whom SAVR was unsuitable (PARTNER 1B, TAVI compared with medical management), the risk of major bleeding was statistically significantly higher for TAVI than for medical management (29% compared with 20%, p=0.04) at 2 years, but not statistically significant different (32% compared with 33%, p=0.92) at 3-year follow-up.
In 2 RCTs (PARTNER 1A and the CoreValve trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were no statistically significant differences between the treatment groups in the risk of major bleeding in either pooled data at 30 day (RR 0.67; 95% CI 0.36 to 1.25, p=0.21), 1‑year (RR 0.73; 95% CI 0.48 to 1.12, p=0.02) and 2‑year follow-up (RR 0.78; 95% CI 0.54 to1.13, p=0.19) or in the individual (CoreValve) study at 3‑year follow-up (RR 0.92; 95% CI 0.75 to 1.12, p=0.38). However, major bleeding was significantly lower in the TAVI group than in the SAVR group in the individual (PARTNER 1A) study at 5‑year follow-up (RR 0.73; 95% CI 0.57 to 0.95, p=0.02).
In 2 RCTs (PARTNER 2A and NOTION, comparing TAVI with SAVR) with 2,032 and 276 patients, for whom SAVR was suitable but intermediate risk, the risk of major bleeding was reported. In the RCT of 2,032 patients there was significantly lower life-threatening or disabling bleeding in patients who had TAVI than in those who had SAVR at 30‑day (10% compared with 43% , p<0.001), 1‑year (15% compared with 46% , p<0.001) and 2‑year follow-up (17% compared with 47% , p<0.001). The rates were also significantly lower in patients who had transthoracic TAVI than in those who had SAVR (23% compared with 50%, p<0.001, at 30‑day, 29% compared with 52%, p<0.001, at 1-year and 30% compared with 54%, p<0.001, at 2‑year follow-up). The RCT of 276 patients reported significantly lower bleeding in the TAVI group than in the SAVR group at 30 days (11% compared with 21% , p=0.03). The systematic review of 3,179 patients (data from 2,576 patients in 3 studies) reported that transfemoral TAVI was associated with a significant reduction in major bleeding compared with SAVR (RR 0.39; 95% CI 0.29 to 0.54). Transapical TAVI (based on data from 552 patients in 2 studies) also had a reduced risk of bleeding, RR 0.53; 95% CI 0.42 to 0.67.
# Rare safety events
A number of observational studies reported rare safety events with TAVI for severe aortic stenosis including: acute MI, acute myocardial injury from damage to apical epicardial collateral circulation, acute occlusion of right coronary artery, acute severe occlusion of the left main coronary artery, aortic arch rupture, aortic dissection, aortic perforation, aortic rupture (abdominal), aorto-right ventricular defect (lethal), apical left ventricular thrombus, apical tear, balloon rupture, catheter-induced ventricular septum defect, circumflex artery occlusion, cutaneo-pericardial fistula, delayed ventricular apical bleed, distal coronary embolisation, early valve degeneration, elliptic distortion of the aortic prosthesis, false left ventricular apical aneurysm, guide wire thrombus formation, iatrogenic chordal rupture, iliac artery rupture, intercostal artery pseudoaneurysm, interventricular septum rupture, late prosthesis migration and rotation, left ventricular pseudoaneurysm, major bleeding from the apex, mitral valve destruction by wire entrapment, multivessel coronary artery spasm, papillary muscle rupture, perforation of the medial circumflex branch of the common femoral artery, pseudoaneurysm at the left ventricular apical access site, pseudoaneurysm of the apex, ruptured pseudoaneurysm of a renal artery, Takotsubo syndrome and valve embolisation.
In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: valve migration, embolisation, thrombosis, valve or annular trauma during TAVI implants leading to late 'fistulous' connections to adjacent cardiac structures. They considered that the following were theoretical adverse events: haemolytic anaemia, infective endocarditis, structural valve failure, reduced leaflet movement and longer-term problems with device durability needing re-intervention by either SAVR or 'valve-in-valve' TAVI.# Further information
For related NICE guidance, see the NICE website.
Patient commentary was sought but none was received.
# Information for patients
NICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.
ISBN: 978-1-4731-2584-1
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{'Recommendations': 'Current evidence on the safety and efficacy of transcatheter aortic valve implantation (TAVI) for aortic stenosis is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.\n\nDetails of all patients should be entered into the UK TAVI registry managed by the National Institute for Cardiovascular Outcomes Research. Contact bartshealth.nicor-generalenquiries@nhs.net for details. Adverse events should be reported to the Medicines and Healthcare products Regulatory Agency.\n\nPatient selection should be carried out by an experienced multidisciplinary team, which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging and, when appropriate, a cardiac anaesthetist and a specialist in elderly medicine. The multidisciplinary team should determine the risk level for each patient and the TAVI device most suitable for them.\n\nDuring the consent process patients should be told about all treatment options and their advantages and disadvantages.\n\nTAVI is a technically challenging procedure that should only be done in specialised centres and only by clinicians and teams with special training and experience in complex endovascular interventions. Units doing this procedure should have both cardiac and vascular surgical support for the emergency treatment of complications and subsequent patient care.', 'Indications and current treatments': 'Aortic stenosis causes impaired outflow of blood from the heart and is usually progressive. The increased cardiac workload leads to left ventricular hypertrophy and heart failure. Symptoms of aortic stenosis typically include shortness of breath and chest pain on exertion. Mortality rates are high in symptomatic patients.\n\nSurgical aortic valve replacement (SAVR) with an artificial (biological or mechanical) prosthesis is the conventional treatment for patients with severe symptomatic aortic stenosis who are well enough for surgery. Optimal medical care has traditionally been the only option for those whose condition is unsuitable for surgery. Aortic balloon valvuloplasty is occasionally used as bridging or palliative treatment. Transcatheter aortic valve implantation (TAVI) is another less invasive alternative treatment.\n\nPatients for whom SAVR is suitable range from those considered to be high risk (for example, as defined in the PARTNER\xa01A trial) to those for whom the benefits of surgery clearly outweigh the risks of surgery. SAVR may not be suitable for patients because of medical comorbidities or technical considerations (for example, if the patient has a calcified aorta or scarring from previous cardiac surgery), which mean that the risks of SAVR outweigh the potential benefits.', 'The procedure': 'Transcatheter aortic valve implantation (TAVI) aims to provide a less invasive alternative to open cardiac surgery for treating aortic stenosis, avoiding the need for sternotomy and cardiopulmonary bypass.\n\nTAVI may be done with the patient under general anaesthesia or using local anaesthesia with or without sedation. Access to the aortic valve is most commonly transluminal, through a large artery (usually the femoral or subclavian artery; percutaneous or endovascular approach), or occasionally surgical, by a minithoracotomy with apical puncture of the left ventricle (transapical approach). The choice of access route (transluminal or transapical) depends on various patient-related factors including atherosclerotic disease in the arteries, which would make the transluminal approach impossible.\n\nInitially the aortic valve ring may be dilated using a balloon catheter, which is advanced over a guidewire. The new prosthetic valve is manipulated into position and inserted inside the existing aortic valve.\n\nDifferent devices are available for this procedure and contain material derived from animal sources.', 'Efficacy': "This section describes efficacy outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nEvidence is based only on studies that reported outcomes by the risk level of the patients.\n\n# Survival beyond 30\xa0days\n\nA randomised controlled trial (RCT) of 358\xa0patients (PARTNER\xa01B) for whom surgical aortic valve replacement (SAVR) was unsuitable compared transcatheter aortic valve implantation (TAVI; n=179) with medical management (n=179). Patients who had TAVI had significantly lower all-cause mortality and cardiovascular mortality compared with medical management at a follow-up of 1, 2 and 5\xa0years (31% compared with 51% at 1\xa0year, 43% compared with 68% at 2\xa0years and 72% compared with 94% at 5\xa0years for all-cause mortality and 21% compared with 45% at 1\xa0year, 31% compared with 62% at 2\xa0years and 58% compared with 86% at 5\xa0years for cardiovascular mortality).\n\nIn an RCT of 795\xa0patients for whom SAVR was suitable but high risk (the CoreValve trial), a Kaplan–Meier cumulative probability analysis for all-cause mortality at 3‑year follow-up was 33% for TAVI compared with 39% for SAVR (p=0.068). In another RCT of 699\xa0patients for whom SAVR was suitable but high risk (the PARTNER\xa01A trial), a Kaplan–Meier probability analysis for all-cause mortality at up to 5\xa0years of follow-up was 68% for TAVI compared with 62% for SAVR (p=0.76). When data were pooled for both RCTs (based on an intention-to-treat [ITT] analysis), the hazard ratios did not show statistically significant differences between TAVI and SAVR for hazard of death (pooled estimates were risk ratio [RR] 0.89; 95% confidence interval [CI] 0.73 to 1.09, p=0.26 at 1\xa0year and RR 0.95; 95% CI 0.79 to 1.13, p=0.55 at 2\xa0years). There were no significant differences for cardiovascular mortality at 1\xa0year (RR 1.05; 95% CI 0.79 to 1.39, p=0.73) and 2\xa0years (RR 0.92; 95% CI 0.67 to 1.28, p=0.79).\n\nIn an RCT of 2,032\xa0patients for whom SAVR was suitable but intermediate risk (the PARTNER\xa02A trial) there were no significant differences between TAVI and SAVR at 1- and 2‑year follow-up for all-cause mortality and cardiovascular mortality (all-cause mortality: 12% compared with 13%, p=0.69, at 1\xa0year and 17% compared with 18%, p=0.45, at 2\xa0years; cardiovascular mortality: 7% compared with 8%, p=0.4, at 1\xa0year and 10% compared with 11%, p=0.38, at 2\xa0years). In an RCT of 276\xa0patients for whom SAVR was suitable but low to intermediate risk (the NOTION study) there were no significant differences between TAVI and SAVR at 1- and 2‑year follow-up for all-cause mortality and cardiovascular mortality (all-cause mortality: 5% compared with 8%, p=0.38, at 1\xa0year and 8% compared with 10%, p=0.54, at 2\xa0years; cardiovascular mortality: 4% compared with 8%, p=0.25, at 1\xa0year and 7% compared with 9%, p=0.40, at 2\xa0years). A systematic review including 2\xa0RCTs and 6\xa0observational studies of 16,638\xa0patients for whom SAVR was suitable and not high risk (comprising 6,875\xa0patients in an analysis) showed a non-significant difference in all-cause mortality for TAVI compared with SAVR (odds ratio [OR] 0.67; 95% CI 0.42 to 1.07, p=0.08, at 30\xa0days; OR 0.91; 95% CI 0.67 to 1.23 at 1\xa0year; OR 1.06; 95% CI 0.59 to 1.91 at long-term follow-up [more than 1\xa0year]). In a systematic review of patients at low and intermediate risk from surgery including 4\xa0RCTs (n=3,179\xa0patients, including the CoreValve trial), in which patients had a mean Society of Thoracic Surgeons' (STS) risk score of 7%, TAVI was associated with a lower hazard of death at 2\xa0years than SAVR when done by the transfemoral but not by the transapical route (transfemoral route: hazard ratio [HR] 0.79; 95% CI 0.66 to 0.94, [risk difference −3.0, 95% CI −0.8 to −4.9]; transapical route: HR 1.34; 95% CI 0.91 to 1.97).\n\n# Symptomatic improvement\n\nThe RCT of 358\xa0patients (PARTNER\xa01B) for whom SAVR was unsuitable compared TAVI (n=179) with medical management (n=179). More patients were asymptomatic or had mild symptoms (New York Heart Association [NYHA] class\xa0I or\xa0II) in the TAVI group than those in the medical management group (at 2\xa0years: 83% [79/95] compared with 42% [17/40], p<0.0001; at 3\xa0years: 70% [49/70] compared with 50% [7/14], p=0.245; and at 5\xa0years: 86% [42/49] compared with 60% [3/5], p=0.531; NYHA class was not significantly different at baseline among these groups).\n\nIn the RCT of 795\xa0patients for whom SAVR was suitable but high risk (the CoreValve trial), a greater proportion of patients were in NYHA class\xa0I or\xa0II in the TAVI group than in the SAVR group at 1\xa0month (83% compared with 73%, p<0.001) and at 6\xa0months (84% compared with 79%, p=0.04). At 12\xa0months, there were no statistically significant differences between the TAVI and SAVR groups (79% compared with 72%, p=0.10). In the other RCT of 699\xa0patients for whom SAVR was suitable but high risk (PARTNER\xa01A), the proportion of patients in NYHA class\xa0I or\xa0II was the same (64%) for TAVI and SAVR at 12\xa0months.\n\nIn the RCT of 2,032\xa0patients for whom SAVR was suitable but intermediate risk (PARTNER\xa02A) there were no significant differences between TAVI and SAVR in the proportion of patients in NYHA class\xa0I or\xa0II at 1- and 2‑year follow-up. In the RCT of 276\xa0patients for whom SAVR was suitable but low to intermediate risk (NOTION) there were no significant differences between TAVI and SAVR in NYHA class at 3‑month and 2‑year follow-up. The systematic review (4\xa0studies; n=2,146) of patients for whom SAVR was suitable but low to intermediate risk found that TAVI was associated with an increased risk of heart failure symptoms (NYHA class\xa0II or more: OR 1.29; 95% CI 1.08 to 1.55) at 2‑year follow-up compared with SAVR.\n\n# Haemodynamic improvement\n\nThe RCT of 358\xa0patients (PARTNER\xa01B) for whom SAVR was unsuitable compared TAVI (n=179) with medical management (n=179). There was a significantly higher mean aortic valve area in the TAVI group than in the medical management group at 1‑year follow-up (1.6\xa0cm2 [standard deviation; SD 0.5] compared with 0.7\xa0cm2 [SD 0.3], significance level not given). Mean pressure gradient improved from 44.7\xa0mmHg (SD 15.4) at baseline to 13.2\xa0mmHg (SD 11.2) for TAVI and changed from 43.2\xa0mmHg (SD 15.4) to 44.3\xa0mmHg (SD 16.1) at 1\xa0year for medical management (p\xa0values not reported). Left ventricular ejection fraction (LVEF) improved from 53.9% (SD 13.1) at baseline to 57.2% (SD 10.6) for TAVI and from 51.2% (SD 14.3) to 56.9% (SD 10.3) at 1\xa0year for medical management.\n\nIn the RCT of 699\xa0patients for whom SAVR was suitable but high risk (PARTNER\xa01A, TAVI [n=348] compared with SAVR [n=351]), there was a significantly higher mean aortic valve area in the TAVI group than in the SAVR group at 30‑day, 6‑month and 1‑year follow-up respectively (1.7\xa0cm2 [SD 0.5] compared with 1.5\xa0cm2 [SD 0.4], p=0.001, at 30\xa0days; 1.7\xa0cm2 [SD 0.5] compared with 1.5\xa0cm2 [SD 0.5], p=0.01, at 6\xa0months; and 1.6\xa0cm2 [SD 0.5] compared with 1.4\xa0cm2 [SD 0.5], p=0.002, at 1\xa0year). Mean pressure gradients improved but were not statistically significant (9.9\xa0mmHg [SD 4.8] compared with 10.8\xa0mmHg [SD 5.0], p=0.04, at 30\xa0days; 10.2\xa0mmHg [SD 4.3] compared with 10.8\xa0mmHg [SD 4.8], p=0.16, at 6\xa0months; and 10.2\xa0mmHg [SD 4.3] compared with 11.5\xa0mmHg [SD 5.4], p=0.008, at 1\xa0year). LVEFs improved but not statistically significantly (55.5 [SD 11.4] compared with 56.0 [SD 11.4], p=0.63, at 30 days; 56.2 [SD 10.8] compared with 56.8 [SD 9.9], p=0.56, at 6\xa0months; and 56.6 [SD 10.5] compared with 57.1 [SD 10.3], p=0.64, at 1\xa0year). Baseline values were not significantly different for all the outcomes. In the other RCT of 795\xa0patients for whom SAVR was suitable but high risk (CoreValve trial, TAVI [n=394] compared with SAVR [n=401]), there was a significantly higher mean aortic valve area in the TAVI group compared with the SAVR group (1.70\xa0cm2 [SD 0.49] compared with 1.55\xa0cm2 [SD 0.51], p<0.001, at 1\xa0year; and 1.79\xa0cm2 [SD 0.48] compared with 1.53\xa0cm2 [SD 0.52], p<0.0001, at 3\xa0years). Mean pressure gradients also improved significantly (8.90\xa0mmHg [SD 3.73] compared with 12.17\xa0mmHg [SD 7.10], p<0.0001, at 1\xa0year; and 7.62\xa0mmHg [SD 3.57] compared with 11.40\xa0mmHg [SD 6.8], p<0.0001, at 3\xa0years). Baseline values were not significantly different for all the outcomes.\n\nIn the RCT of 2,032\xa0patients for whom SAVR was suitable but intermediate risk (PARTNER\xa02A) the mean aortic valve area was significantly higher in the TAVI group than in the SAVR group at 30\xa0days (1.7\xa0cm2 [SD 0.5] compared with 1.5\xa0cm2 [SD 0.4], p<0.001), and this persisted at 1\xa0year (1.6\xa0cm2 [SD 0.4] compared with 1.4\xa0cm2 [SD 0.4], p<0.001) and at 2\xa0years (1.5\xa0cm2 [SD 0.4] compared with 1.4\xa0cm2 [SD 0.4], p<0.001). Mean pressure gradients also improved significantly (9.7\xa0mmHg [SD 3.5] compared with 10.9\xa0mmHg [SD 4.3], p<0.001) at 30\xa0days and this persisted at 1\xa0year (10.7\xa0mmHg [SD 4.5] compared with 11.5\xa0mmHg [SD 4.4], p=0.001) and 2\xa0years (10.8\xa0mmHg [SD 4.6] compared with 11.7\xa0mmHg [SD 4.8], p<0.001). LVEF was higher for the TAVI group than for the SAVR group (56.9% [SD 10.2] compared with 55.0% [SD 11.0], p=0.04) at 30\xa0days but this was reversed at 1\xa0year (55.9% [SD 11.2] compared with 57.2% [SD 9.9], p=0.04) and at 2\xa0years (54.9% [SD 11.2] compared with 57.2% [SD 9.7], p=0.005). In the RCT of 276\xa0patients for whom SAVR was suitable but low to intermediate risk (NOTION) there were significantly greater improvements in mean valve area in the TAVI group than in the SAVR group (1.7\xa0cm2 compared with 1.3\xa0cm2, p<0.001, at 3\xa0months; 1.7\xa0cm2 compared with 1.3\xa0cm2, p<0.001, at 1\xa0year; 1.6\xa0cm2 compared with 1.3\xa0cm2, p<0.001, at 2\xa0years). There were no significant differences from baseline for mean pressure gradient.\n\n# Quality of life\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) there were significant improvements in self-reported quality of life in patients in the TAVI group compared with those in the medical management group (Kansas City Cardiomyopathy Questionnaire [KCCQ] quality-of-life summary score for heart failure: mean difference [MD] 14.8; 95% CI 8.6 to 21.0, p<0.001, at 1\xa0month and greater benefits at 6\xa0months [MD 24.2; 95% CI 17.4 to 31.0, p<0.001] and at 12\xa0months [MD 30.5; 95% CI 22.3 to 38.7, p<0.001]). At 12\xa0months, the TAVI group also had higher SF‑12 physical and mental health scores (MD 5.7 and 6.4 respectively, p<0.001).\n\nIn both the PARTNER\xa01A and CoreValve trials (patients for whom SAVR was suitable but high risk), patients having TAVI using the transfemoral route reported a greater improvement in quality of life (measured using EQ-5D, where 0\xa0equals dead and 1\xa0perfect health-related quality of life) than those having SAVR (PARTNER\xa01A: average change of 0.08 [SD 0.25] compared with 0.02 [SD 0.25] at 1\xa0month, 0.1 [SD 0.3] compared with 0.09 [SD 0.27] at 6\xa0months and 0.09 [SD 0.23] compared with 0.08 [SD 0.08] at 1\xa0year; CoreValve study: average change of 0.055 [SD 0.23] compared with −0.073 [SD 0.26] at 1\xa0month; 0.053 [SD 0.22] compared with 0.04 [SD 0.17] at 6\xa0months and 0.043 [SD 0.2] compared with 0.0003 [SD 0.02] at 1\xa0year). When data from these 2\xa0trials were pooled for the transfemoral route, the overall estimates for EQ‑5D showed statistically significant differences between the TAVI and SAVR groups at 1\xa0month in favour of TAVI (RR 0.09; 95% CI 0.03 to 0.16; p=0.006). However, the differences were not significant at 6\xa0months (RR 0.01; 95% CI −0.02 to 0.05, p=0.47) and at 1\xa0year (RR 0.03; 95% CI 0.00 to 0.06, p=0.09). When data were pooled for transapical TAVI compared with SAVR (from PARTNER\xa01A) and non-transfemoral TAVI compared with SAVR (from the CoreValve trial), the overall estimates for EQ‑5D showed no statistically significant differences between the TAVI and SAVR groups (RR −0.03; 95% CI −0.09 to 0.04, p=0.44 at 1\xa0month, RR −0.02; 95% CI −0.10 to 0.07, p=0.66 at 6\xa0months and RR −0.02; 95% CI −0.09 to 0.05, p=0.58 at 1\xa0year). There was a greater improvement in SF‑12 scores (both physical and mental) in the TAVI group than in the SAVR group at 1‑month follow-up (MD for physical summary scores 2.0; 95% CI 0.1 to 3.9, p=0.4 in PARTNER\xa01A and MD 4.9; 95% CI 3.1 to 6.7, p<0.001 in the CoreValve trial; MD for mental summary scores 5.4; 95% CI 3.1 to 7.7, p<0.001 in PARTNER\xa01A and 6.1; 95% CI 3.8 to 8.5, p<0.001 in the CoreValve trial). There were no statistically significant differences between TAVI using either the transfemoral or non-transfemoral route and SAVR at 12\xa0months for both physical and mental scores. Statistically significant differences in favour of TAVI were reported for KCCQ quality-of-life summary score at 1‑month follow-up in both PARTNER\xa01A (MD 9.8; 95% CI 4.0 to 15.6, p=0.001) and in the CoreValve study (19.0; 95% CI 13.7 to 24.3, p<0.001) but did not persist at 6- and 12‑month follow-up. There were no statistically significant differences in KCCQ quality-of-life scores using either the transapical route in PARTNER\xa01A or the non-transfemoral routes in the CoreValve study.\n\nIn the systematic review of patients for whom SAVR was suitable but low to intermediate risk (n=2,146, including data from 795\xa0patients in 1\xa0study [CoreValve study] with a follow-up of 2\xa0years), there was a non-significant difference in KCCQ quality-of-life summary score (22.2 for TAVI compared with 18.7 for SAVR, MD 3.5; 95% CI 1.9 to 8.9).\n\n# Repeat hospitalisation\n\nThe RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B) compared TAVI (n=179) with medical management (n=179). TAVI had a statistically significantly lower hazard ratio for repeat hospitalisation because of aortic stenosis (including complications because of TAVI) than medical management at 2\xa0year- (HR 0.41; 95% CI 0.30 to 0.58, p<0.001), 3\xa0year- (p<0.0001) and 5‑year follow-up (p<0.001).\n\nIn the RCT of 699\xa0patients for whom SAVR was suitable but high risk (PARTNER\xa01A, TAVI compared with SAVR) there was a non-significant difference in re-hospitalisation rates (59 [19%] compared with 45 [16%], p=0.38, at 1\xa0year; 74 [25%] compared with 60 [22%], p=0.41, at 2\xa0years; and 108 [42%] compared with 81 [34%], p=0.17, at 5\xa0years). In the RCT of 795\xa0patients (CoreValve trial; TAVI, n=394 compared with SAVR, n=401) for whom SAVR was suitable but high risk, there was no significant difference in re-hospitalisation rates (95 [27%] for TAVI compared with 64 [21.9%] for SAVR, p=0.087) at 3\xa0years. In the RCT of 2,032\xa0patients for whom SAVR was suitable but intermediate risk (PARTNER\xa02A) there were no significant differences in re-hospitalisation rates between TAVI and SAVR.\n\nThe specialist advisers listed key efficacy outcomes as procedural success, satisfactory device positioning, shorter length of hospital stay, haemodynamic improvement, improvement in left ventricular function, improved quality of life, improved exercise capacity, symptom relief, prolonged survival, reduced mortality and morbidity and reduced re-hospitalisation.", 'Safety': "This section describes safety outcomes from the published literature that the committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview.\n\nEvidence is based only on studies that reported outcomes by the risk level of the patients.\n\n# All-cause mortality and cardiovascular mortality within 30\xa0days\n\nA randomised controlled trial (RCT) of 358\xa0patients for whom surgical aortic valve replacement (SAVR) was unsuitable (PARTNER\xa01B) compared transcatheter aortic valve implantation (TAVI; n=179) with medical management (n=179). There were no statistically significant differences in all-cause mortality (5% [9/179] compared with 3% [5/179], p=0.41) and cardiovascular mortality (5% [8/179] compared with 2% [3/179], p=0.22) between TAVI and medical management at 30‑day follow-up.\n\nIn an RCT of 699\xa0patients for whom SAVR was suitable but high risk (PARTNER\xa01A; TAVI, n=348 compared with SAVR, n=351) there were no statistically significant differences in all-cause mortality (3% [12/348] compared with 7% [22/351], p=0.07) and cardiovascular mortality (3% [11/348] compared with 13% [10/251], p=0.90) between the TAVI group and SAVR group at 30‑day follow-up. In another RCT of 795\xa0patients (the US CoreValve trial; TAVI, n=394 compared with SAVR, n=401) there were also no statistically significant differences in all-cause mortality (3% [13/390] compared with 5% [16/357], p=0.43) and cardiovascular mortality (3% [12/390] compared with 5% [16/357], p=0.32) between the TAVI group and SAVR group at 30‑day follow-up. When data were pooled for both studies, the risk ratio (less than\xa01 favours TAVI) for all-cause mortality was 0.64 (95% confidence interval [CI] 0.38 to 1.39, p=0.06) and for cardiovascular mortality was 0.90 (95% CI 0.52 to 1.56, p=0.70).\n\nIn an RCT of 2,032\xa0patients for whom SAVR was suitable but intermediate or low risk (TAVI, n=1,011 compared with SAVR, n=1,021) there was a non-significant lower all-cause mortality (3% compared with 4%, p=0.24) and cardiovascular mortality (2% compared with 3%, p=0.72) for TAVI using the femoral route compared with SAVR at 30-day follow-up. For the transthoracic route all-cause mortality (6% compared with 4%, p=0.21) and cardiovascular mortality (5% compared with 3%, p=0.47) were not significantly different. In another RCT of 280\xa0low- and intermediate-risk patients (TAVI, n=145 compared with SAVR, n=135), all-cause mortality (2% [3/142] compared with 3% [5/134], p=0.43) and cardiovascular mortality (2% [3/142] compared with 4% [5/134], p=0.43) were not significantly different. A systematic review of 3,179\xa0patients (with risk scores of 8% or less in 4\xa0RCTs) also reported a non-significant lower all-cause mortality for TAVI compared with SAVR (OR 0.67; 95% CI 0.42 to 1.07).\n\n# Cerebral complications\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) the hazard ratio for stroke or transient ischaemic attack (TIA) was significantly higher in the TAVI group (hazard ratio [HR] 2.81; 95% CI 1.26 to 6.26, p=0.004) at 3-year follow-up, whereas at 5-year follow-up there were no significant differences between the TAVI and medical management groups (HR 1.39; 95% CI 0.62 to 3.11, p=0.555).\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve trial [n=795]) in patients for whom SAVR was suitable but high risk, the incidence of stroke and TIA was reported. Both pooled and individual risk ratios from PARTNER\xa01A and the CoreValve trial showed no statistically significant differences in the incidence of all stroke in patients for whom SAVR was suitable but high risk at 30\xa0days (risk ratio [RR] 1.26; 95% CI 0.56 to 2.86, p=0.57), 1\xa0year (RR 1.21; 95% CI 0.49 to 2.98, p=0.68), 2\xa0years (RR 1.11; 95% CI 0.51 to 2.41, p=0.78), 3\xa0years (CoreValve, ITT RR 1.14; 95% CI 0.53 to 2.46, p=0.75) and 5\xa0years (PARTNER\xa01A, ITT RR 1.13; 95% CI 0.68 to 1.87, p=0.65). Both pooled and individual risk ratios for TIA from PARTNER\xa01A and the CoreValve trial also showed no statistically significant differences at 30\xa0days (RR 3.04; 95% CI 0.62 to 15.01, p=0.17), 1\xa0year (RR 1.46; 95% 0.63 to 3.41, p=0.38), 2\xa0years (RR 1.92; 95% CI 0.90 to 4.11, p=0.09), 3\xa0years (CoreValve, ITT RR 1.53; 95% CI 0.55 to 4.25, p=0.42) and 5\xa0years (PARTNER\xa01A, ITT RR 1.77; 95% CI 0.75 to 4.15, p=0.19).\n\nIn the RCT of 2,032\xa0patients for whom SAVR was suitable but intermediate risk (PARTNER\xa02A, TAVI compared with SAVR) there were no significant differences between groups in all strokes at 30\xa0days (55 [6%] compared with 61 [6%], p=0.57), 1\xa0year (78 [8%] compared with 79 [8%], p=0.88) and at 2\xa0years (91 [10%] compared with 85 [9%], p=0.67). An RCT of 276\xa0patients for whom SAVR was suitable but low to intermediate risk (the NOTION study, TAVI compared with SAVR) reported incidence of stroke and TIA at 30\xa0days (4 [3%] compared with 4 [3%], p=0.94), 1\xa0year (7 [5%] compared with 8 [6%], p=0.68) and at 2\xa0years (13 [10%] compared with 10 [8%], p=0.67). The systematic review of 3,179\xa0patients (based on data from 2,576\xa0patients in 3\xa0studies) reported a non-significant reduction in stroke rates (RR 0.80; 95% CI 0.63 to 1.01) for transfemoral TAVI compared with SAVR at 2-year follow-up. Comparing transapical TAVI with SAVR (based on data from 552\xa0patients in 2\xa0studies), the risk ratio was 1.67 (95% CI 0.97 to 2.87) at 2-year follow-up.\n\n# Aortic regurgitation\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) there were similar rates of moderate or severe aortic regurgitation in both groups at 30‑day and 1‑year follow-up (15% compared with 17%).\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial) the incidence of aortic regurgitation (paravalvular and transvalvular) in patients for whom SAVR was suitable but high risk was reported. Pooled data (RR 4.02; 95% CI 1.99 to 8.11, p=0.0001) at 1\xa0year and individual study data favoured SAVR over TAVI at all follow-up points up to 3\xa0years (PARTNER\xa01A: at 30\xa0days RR 16.29; 95% CI 3.98 to 66.6, p=0.0001; at 6\xa0months RR 30.26; 95% CI 4.16 to 220.01, p=0.0008; at 2\xa0years p=0.008; CoreValve trial: at 3\xa0years p=0.04).\n\nIn the RCT of 276\xa0patients for whom SAVR was suitable but low to intermediate risk (NOTION, TAVI compared with SAVR) significant differences in moderate to severe aortic regurgitation at 3\xa0months (15% compared with 22%, p<0.001) and at 1\xa0year (16% compared with 1%, p=0.001) were reported. In the systematic review of 3,179\xa0patients (based on data from 3\xa0trials) moderate or severe aortic regurgitation occurred more often after TAVI than after SAVR at 2‑year follow-up (RR 12.22; 95% CI 5.17 to 28.88).\n\n# Aortic valve re-intervention\n\nIn the systematic review of 3,179\xa0patients for whom SAVR was suitable but low to intermediate risk (based on data from 3,058\xa0patients in 4\xa0studies) the risk of aortic valve re-intervention was significantly higher after TAVI than after SAVR (RR 3.25; 95% CI 1.29 to 8.14).\n\n# Prosthesis-patient mismatch\n\nIn the RCT of 699\xa0patients (PARTNER\xa01A) for whom SAVR was suitable but high risk, the overall incidence and severity of prosthesis-patient mismatch was significantly better in the TAVI group than in the SAVR group (assessed at first postoperative echocardiogram: 46% [severe 20%] compared with 60% [severe 28%]; p<0.001 and 42% compared with 57%, p<0.001, at 30\xa0days).\n\n# Myocardial infarction\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, comparing TAVI with medical management) there were no significant differences in the occurrence of myocardial infarction (MI) at 2‑year (p=0.69) and 3‑year (p=0.59) follow-up.\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) the incidence of MI for patients for whom SAVR was suitable but high risk was reported. Pooled data (at 30\xa0days RR 0.72; 95% CI 0.17 to 2.94, p=0.64; at 1\xa0year RR 1.18; 95% CI 0.42 to 3.29, p=0.76; at 2\xa0years RR 0.51; 95% CI 0.06 to 4.05, p=0.52) and individual study data (3-year CoreValve ITT, RR 1.45; 95% CI 0.45 to 2.94, p=0.52 or 5-year PARTNER\xa01A ITT, RR 0.46; 95% CI 0.16 to 1.31, p=0.14) showed no statistically significant differences between the treatment groups.\n\nIn 2\xa0RCTs (PARTNER\xa02A and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients for whom SAVR was suitable but intermediate risk there were no significant differences in incidence of MI between TAVI and SAVR. The systematic review of 3,179\xa0patients for whom SAVR was suitable but intermediate to low risk (based on data from 3,128\xa0patients in 4\xa0studies) found no difference between the treatment groups for MI (RR 0.87; 95% CI 0.59 to 1.29) at 2‑year follow-up.\n\n# Endocarditis\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, comparing TAVI with medical management) there were no significant differences between the groups in endocarditis at 2‑year (3% compared with 1%, p=0.32) and 3‑year (2% compared with 1%, p=0.32) follow-up.\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were no significant differences between groups in endocarditis (PARTNER\xa01A: 0% compared with less than\xa01%, p=0.32, at 1\xa0month; 2 [less than 1%] compared with 3\xa0[1%], p=0.63, at 1\xa0year; 4 [2%] compared with 3 [1%], p=0.61, at 2\xa0years; and 5 [2%] compared with 6 [3%], p=0.65, at 5\xa0years; CoreValve study: 3 [1%] compared with 5 [2%], p=0.346, at 3\xa0years).\n\nIn 2\xa0RCTs (PARTNER\xa02A study and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients, for whom SAVR was suitable but intermediate risk, there were no significant differences in endocarditis between TAVI and SAVR (RCT of 276\xa0patients: 1\xa0[1%] compared with 0, p=0.33, at 30\xa0days; 4 [3%] compared with 2 [2%], p=0.47, at 1\xa0year; RCT of 2,032\xa0patients: transfemoral route 6 [1%] compared with 6 [1%], p=0.92, at 1\xa0year; 10 [2%] compared with 6 [1%], p=0.33, at 2\xa0years; transthoracic route 1 compared with 0, p=0.32).\n\n# Atrial fibrillation\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) there were no significant differences in the incidence of new atrial fibrillation between the treatment groups (at 30\xa0days less than 1% compared with 1%, p=1.00; at 1\xa0year less than 1% compared with 2%, p=0.62).\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were significant differences in the incidence of atrial fibrillation (PARTNER\xa01A: 12% compared with 17%, p=0.07, at 1\xa0year; CoreValve study: 12% compared with 31% , p<0.001, at 30\xa0days; 16% compared with 33% , p<0.001, at 1\xa0year).\n\nIn 2\xa0RCTs (PARTNER\xa02A and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients, for whom SAVR was suitable but intermediate risk, there were significant differences in the incidence of new atrial fibrillation between the treatment groups. In the RCT of 2,032\xa0patients, for transfemoral TAVI compared with SAVR the incidence was 38 (5%) compared with 204 (27%), p<0.001, at 30\xa0days; 45 (6%) compared with 210 (28%), p<0.001, at 1\xa0year and 55 (7%) compared with 211 (28%) p<0.001, at 2\xa0years. In the same RCT, for transthoracic TAVI compared with SAVR the incidence was 53 (23%) compared with 61 (26%), p=0.50, at 30\xa0days; 55 (24%) compared with 62 (26%), p=0.60, at 1\xa0year; and 55 (24%) compared with 62 [26%], p=0.60, at 2\xa0years. In the RCT of 276\xa0patients the incidence was: 24 [17%] compared with 77 [58%], p<0.001, at 30\xa0days; 51 [38%] compared with 79 [60%] p<0.001, at 1\xa0year; 32 [23%] compared with 80 [60%], p<0.001, at 2\xa0years). The systematic review of 3,179\xa0patients (based on data from 3,058\xa0patients in 3\xa0studies) found that the risk ratio for new onset atrial fibrillation at 2‑year follow-up was 0.43 (0.35 to 0.52) for TAVI compared with SAVR.\n\n# Need for permanent pacemaker\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) the proportion of patients with permanent pacemaker implantation (PPI) was lower in the TAVI group at 2\xa0years (6% compared with 9%, p=0.47) and 3\xa0years (8% compared with 9%, p=0.75) but these differences were not significant.\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, the need for PPI was reported. Pooled data tended to favour the SAVR group. However the differences were not statistically significant at 30\xa0days (RR 1.94; 95% CI 0.70 to 5.34, p=0.20), at 1\xa0year (RR 1.75; 95% CI 0.94 to 3.25, p=0.08) and at 2\xa0years (RR 1.77; 95% CI 0.95 to 3.30, p=0.07). At 3‑year follow-up (CoreValve trial: TAVI, n=394, SAVR, n=401) there were significantly fewer PPI in the SAVR group than in the TAVI group (14.5% compared with 28%, p<0.001). At 5\xa0years (PARTNER\xa01A) there were no statistically significant differences between the treatment groups (9.7% compared with 9.1%, p=0.64).\n\nIn 2\xa0RCTs (PARTNER\xa02A and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients, for whom SAVR was suitable but intermediate risk, the need for PPI was reported. In the RCT of 2,032\xa0patients there were no significant differences between the groups (9% compared with 7%, p=0.17, at 30\xa0days; 10% compared with 9%, p=0.43, at 1\xa0year; 12% compared with 10%, p=0.29, at 2\xa0years). But in the RCT of 276\xa0patients the need for PPI was higher in the TAVI group than in the SAVR group (46 [34%] compared with 2 [2%], p<0.001, at 30\xa0days; 51 [38%] compared with 3 [2%], p<0.001, at 1\xa0year; and 55 [41%] compared with 5\xa0[4%], p<0.001, at 2\xa0years). The systematic review of 3,179\xa0patients (based on data from 3,128\xa0patients in 4\xa0studies) reported an increased risk of PPI (RR 2.46; 95% CI 1.17 to 5.15) for TAVI compared with SAVR.\n\n# Acute kidney injury and renal failure\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) there were no significant differences in the occurrence of acute kidney injury (AKI) between the treatment groups at 2-year (3% compared with 8%, p=0.15) and 3-year follow-up (3% compared with 11%, p=0.08).\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, the occurrence of AKI was reported. Pooled data (at 30\xa0days RR 0.51; 95% CI 0.27 to 0.98, p=0.04) and data from the CoreValve study at 3\xa0years (RR 0.45; 95% CI 0.29 to 0.72, p=0.0007) significantly favoured the TAVI group, whereas there were no statistically significant differences in the pooled estimates at 1\xa0year and 2\xa0years (RR 0.76; 95% CI 0.23 to 2.59, p=0.67, at 1\xa0year; RR 0.64; 95% CI 0.31 to 1.34, p=0.24, at 2\xa0years) and from PARTNER\xa01A at 5\xa0years (RR 1.01; 95% CI 0.58 to 1.74).\n\nIn 2\xa0RCTs (PARTNER\xa02A and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients, for whom SAVR was suitable but intermediate risk, the occurrence of AKI was reported. The RCT of 2,032\xa0patients reported a lower incidence of AKI in the TAVI group than in the SAVR group at 30\xa0days (13 [1.3%] compared with 31 [3%], p=0.0006). Incidence rates were similar for transthoracic TAVI and SAVR (4% compared with 3%). The incidence rates were significantly lower for transfemoral TAVI than for SAVR (2.2% compared with 5%, p=0.002, at 1\xa0year; 3% compared with 7%, p<0.001, at 2\xa0years) and higher for transthoracic TAVI (7% compared with 4.4%, p=0.18, at 1\xa0year, 8% compared with 6%, p=0.23, at 2\xa0years). The RCT of 276\xa0patients reported a higher occurrence of AKI in the SAVR group than in the TAVI group (9\xa0[7%]) compared with 1 [0.7%], p=0.01) at 30\xa0days. The systematic review of 3,179\xa0patients (based on data from 2,576\xa0patients in 3\xa0studies) reported that the risk ratio of AKI at 2‑year follow-up was 0.38 (95% CI 0.27 to 0.54) for transfemoral TAVI and 1.54 (95% CI 0.77 to 3.07) for transapical TAVI compared with SAVR.\n\n# Vascular complications\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management) the hazard ratio for major vascular complications at 3‑year follow-up was statistically significantly higher with TAVI (17%) than with medical management (3%, HR 8.27; 95% CI 2.92 to 23.44, p<0.0001).\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were no statistically significant differences between the treatment groups in the incidence of major vascular complications in either pooled data at 30‑day (RR 3.04; 95% CI 0.63 to 3.41, p=0.17), 1‑year (RR 1.46; 95% CI 0.63 to 3.41, p=0.38) or 2‑year follow-up (RR 1.92; 95% CI 0.90 to 4.11, p=0.09), or in the individual studies at 3‑year (CoreValve study, p=0.42) or 5‑year follow-up (PARTNER\xa01A, p=0.19).\n\nIn 2\xa0RCTs (PARTNER\xa02A and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients, for whom SAVR was suitable but intermediate risk, major vascular complications were reported. In the RCT of 2,032\xa0patients there was a higher incidence of major complications in the TAVI group than in the SAVR group (7.9% compared with 5%, p=0.008 at 30\xa0days; 8% compared with 5.3%, p=0.007 at 1\xa0year and 9% compared with 6%, p=0.006 at 2\xa0years). The incidence rate was lower for transthoracic TAVI than for SAVR. The RCT of 276\xa0patients reported more major vascular complications in the TAVI group than in the SAVR group at 30\xa0days (6% compared with 2%, p=0.10).\n\n# Major bleeding\n\nIn the RCT of 358\xa0patients for whom SAVR was unsuitable (PARTNER\xa01B, TAVI compared with medical management), the risk of major bleeding was statistically significantly higher for TAVI than for medical management (29% compared with 20%, p=0.04) at 2\xa0years, but not statistically significant different (32% compared with 33%, p=0.92) at 3-year follow-up.\n\nIn 2\xa0RCTs (PARTNER\xa01A [n=699] and the CoreValve [n=795] trial, comparing TAVI with SAVR) in patients for whom SAVR was suitable but high risk, there were no statistically significant differences between the treatment groups in the risk of major bleeding in either pooled data at 30\xa0day (RR 0.67; 95% CI 0.36 to 1.25, p=0.21), 1‑year (RR 0.73; 95% CI 0.48 to 1.12, p=0.02) and 2‑year follow-up (RR 0.78; 95% CI 0.54 to1.13, p=0.19) or in the individual (CoreValve) study at 3‑year follow-up (RR 0.92; 95% CI 0.75 to 1.12, p=0.38). However, major bleeding was significantly lower in the TAVI group than in the SAVR group in the individual (PARTNER\xa01A) study at 5‑year follow-up (RR 0.73; 95% CI 0.57 to 0.95, p=0.02).\n\nIn 2\xa0RCTs (PARTNER\xa02A and NOTION, comparing TAVI with SAVR) with 2,032 and 276\xa0patients, for whom SAVR was suitable but intermediate risk, the risk of major bleeding was reported. In the RCT of 2,032\xa0patients there was significantly lower life-threatening or disabling bleeding in patients who had TAVI than in those who had SAVR at 30‑day (10% [105/1,011] compared with 43% [442/1,021], p<0.001), 1‑year (15% compared with 46% , p<0.001) and 2‑year follow-up (17% compared with 47% , p<0.001). The rates were also significantly lower in patients who had transthoracic TAVI than in those who had SAVR (23% compared with 50%, p<0.001, at 30‑day, 29% compared with 52%, p<0.001, at 1-year and 30% compared with 54%, p<0.001, at 2‑year follow-up). The RCT of 276\xa0patients reported significantly lower bleeding in the TAVI group than in the SAVR group at 30\xa0days (11% compared with 21% , p=0.03). The systematic review of 3,179\xa0patients (data from 2,576\xa0patients in 3\xa0studies) reported that transfemoral TAVI was associated with a significant reduction in major bleeding compared with SAVR (RR 0.39; 95% CI 0.29 to 0.54). Transapical TAVI (based on data from 552\xa0patients in 2\xa0studies) also had a reduced risk of bleeding, RR 0.53; 95% CI 0.42 to 0.67.\n\n# Rare safety events\n\nA number of observational studies reported rare safety events with TAVI for severe aortic stenosis including: acute MI, acute myocardial injury from damage to apical epicardial collateral circulation, acute occlusion of right coronary artery, acute severe occlusion of the left main coronary artery, aortic arch rupture, aortic dissection, aortic perforation, aortic rupture (abdominal), aorto-right ventricular defect (lethal), apical left ventricular thrombus, apical tear, balloon rupture, catheter-induced ventricular septum defect, circumflex artery occlusion, cutaneo-pericardial fistula, delayed ventricular apical bleed, distal coronary embolisation, early valve degeneration, elliptic distortion of the aortic prosthesis, false left ventricular apical aneurysm, guide wire thrombus formation, iatrogenic chordal rupture, iliac artery rupture, intercostal artery pseudoaneurysm, interventricular septum rupture, late prosthesis migration and rotation, left ventricular pseudoaneurysm, major bleeding from the apex, mitral valve destruction by wire entrapment, multivessel coronary artery spasm, papillary muscle rupture, perforation of the medial circumflex branch of the common femoral artery, pseudoaneurysm at the left ventricular apical access site, pseudoaneurysm of the apex, ruptured pseudoaneurysm of a renal artery, Takotsubo syndrome and valve embolisation.\n\nIn addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse events: valve migration, embolisation, thrombosis, valve or annular trauma during TAVI implants leading to late 'fistulous' connections to adjacent cardiac structures. They considered that the following were theoretical adverse events: haemolytic anaemia, infective endocarditis, structural valve failure, reduced leaflet movement and longer-term problems with device durability needing re-intervention by either SAVR or 'valve-in-valve' TAVI.", 'Further information': 'For related NICE guidance, see the NICE website.\n\nPatient commentary was sought but none was received.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers (information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nISBN: 978-1-4731-2584-1'}
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https://www.nice.org.uk/guidance/ipg586
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Evidence-based recommendations on transcatheter aortic valve implantation (TAVI) for aortic stenosis. This involves inserting a new valve through a catheter, usually by way of a large blood vessel at the top of the leg, into the heart and inside the existing faulty valve.
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b0c43b75678ca743c035dcb5d68bf57f9b35e00f
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nice
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Roflumilast for treating chronic obstructive pulmonary disease
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Roflumilast for treating chronic obstructive pulmonary disease
Evidence-based recommendations on roflumilast (Daxas) for treating chronic obstructive pulmonary disease in adults with chronic bronchitis.
# Recommendations
Roflumilast, as an add-on to bronchodilator therapy, is recommended as an option for treating severe chronic obstructive pulmonary disease in adults with chronic bronchitis, only if:
the disease is severe, defined as a forced expiratory volume in 1 second (FEV1) after a bronchodilator of less than 50% of predicted normal, and
the person has had 2 or more exacerbations in the previous 12 months despite triple inhaled therapy with a long-acting muscarinic antagonist, a long-acting beta-2 agonist and an inhaled corticosteroid.
Treatment with roflumilast should be started by a specialist in respiratory medicine.
These recommendations are not intended to affect treatment with roflumilast that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Roflumilast (Daxas, AstraZeneca) is an orally administered long-acting selective phosphodiesterase-4 enzyme inhibitor. It targets cells and mediators believed to be important in chronic obstructive pulmonary disease (COPD).
Marketing authorisation
Roflumilast has a marketing authorisation in the UK for maintenance treatment of severe COPD (forced expiratory volume in the first second post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment.
Adverse reactions
The most common adverse reactions associated with roflumilast include diarrhoea, weight loss, nausea, abdominal pain and headache. Roflumilast is subject to additional monitoring for weight loss. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
The recommended dose is 500 micrograms (1 tablet) of roflumilast once daily.
Price
£37.71 for 30 tablets and £113.14 for 90 tablets (excluding VAT; 'British national formulary' edition 72). Costs may vary in different settings because of negotiated procurement discounts.# Evidence
The appraisal committee (section 6) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of roflumilast, having considered evidence on the nature of chronic obstructive pulmonary disease (COPD) and the value placed on the benefits of roflumilast by clinical experts. No evidence was submitted by patient groups and no patient experts attended the committee meetings. The committee also took into account the effective use of NHS resources.
# Clinical need of people with COPD
The committee heard that COPD is a chronic and progressive disease characterised by obstruction of the airways, breathlessness and cough. Airflow limitation becomes worse over time, with periodic acute exacerbations. The clinical expert advised that despite treatment with optimal inhaled therapy many people with severe COPD have several exacerbations each year, which is a huge burden on patients and the NHS. Exacerbations worsen a patient's health status, reduce their quality of life, accelerate decline in lung function, lead to hospitalisation and increase mortality. The committee was disappointed that no evidence was submitted by patient groups and that no patient experts attended the committee meeting. However, it recognised that a new treatment that reduced exacerbations in people with severe COPD would be highly valued by patients and their carers, and addresses an unmet need.
# Clinical management of COPD
The committee heard from the clinical expert that COPD is treated according to NICE's clinical guideline on chronic obstructive pulmonary disease in over 16s: diagnosis and management. For severe COPD (defined as forced expiratory volume in the first second less than 50% predicted) the guideline recommends using either an inhaled long-acting muscarinic antagonist alone, a fixed combination of an inhaled corticosteroid and a long-acting beta‑2 agonist (dual inhaled therapy), or a combination of all these treatments (triple inhaled therapy). The committee understood that triple inhaled therapy is the standard treatment for people who continue to have exacerbations despite treatment with monotherapy or dual therapy. It noted that the company was seeking a recommendation for the use of roflumilast as an add-on treatment to triple inhaled therapy but not for monotherapy or dual therapy, which were included in the NICE scope. The committee considered whether this was appropriate. It heard from the clinical expert that the 2017 update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommended roflumilast as an add-on therapy for people with severe COPD who continue to have exacerbations despite treatment with triple therapy, particularly if they had at least 1 hospitalisation for an exacerbation in the previous year. The committee also heard from the clinical expert that the company's proposed placement of roflumilast in the treatment pathway is consistent with clinical practice, and that around 90% of people having roflumilast will be on triple therapy. The committee concluded that the company's proposed positioning of roflumilast as an add-on to triple inhaled therapy is appropriate.
# Comparators
The committee understood that the comparators in the appraisal scope included monotherapy (a long-acting muscarinic or beta‑2 agonist), dual therapy (the above treatments combined with each other or with inhaled corticosteroids), triple therapy (all of the above treatments) and theophylline in combination with inhaled maintenance bronchodilator treatment. The committee noted that the company did not consider monotherapy and dual therapy to be appropriate comparators because it intended to position roflumilast as an add-on treatment to triple inhaled therapy (see section 4.2). The committee accepted that this approach is appropriate. It also noted that the company does not consider theophylline to be an appropriate comparator. The committee heard from the clinical expert that theophylline is not generally used in clinical practice because of the high risk of toxicity, lack of evidence for clinical effectiveness, and associated side effects (such as seizures and cardiac arrhythmias). The committee accepted the company's rationale for excluding theophylline and concluded that triple inhaled therapy is the appropriate comparator for this appraisal.
# Clinical effectiveness
## Source of clinical evidence
The evidence for roflumilast submitted by the company came from REACT, a multicentre double-blind randomised controlled trial that included 1,935 patients with severe COPD, chronic bronchitis and 2 or more exacerbations in the previous year. It compared roflumilast plus inhaled combination therapy (a long-acting beta‑2 agonist plus inhaled corticosteroids, with or without a long-acting muscarinic antagonist) with placebo plus inhaled combination therapy. The committee noted that the evidence review group (ERG) presented a pooled analysis of REACT plus another multicentre double-blind trial of roflumilast that included 2,352 patients with severe COPD, chronic bronchitis and 2 or more exacerbations and/or hospitalisations in the previous year (RE2SPOND). It understood that the company did not include detailed information on RE2SPOND in its submission because it believed that the people in the trial do not accurately reflect the target population. The company stated that fewer than half of patients in RE2SPOND were on triple therapy (47% compared with 70% in REACT), 0.5% were from Western Europe (compared with 29.5% in REACT) and pre-treatment with inhaled therapies was for a minimum of 3 months rather than 12 months as in REACT. The committee heard from the clinical expert that the duration of background inhaled therapies is an important difference between the 2 trials. Patients in REACT were more likely to have well controlled COPD because they had optimal inhaled therapy for 12 months, whereas patients in RE2SPOND were not appropriately pre-treated with inhaled therapies. The clinical expert suggested that the population in RE2SPOND had a higher risk of exacerbations compared with the population in REACT. The committee also heard from the company that RE2SPOND did not reflect current clinical practice in the UK because it used lower doses of long-acting beta‑2 agonists and inhaled corticosteroids and an alternative formulation of roflumilast. The committee discussed the characteristics of the people included in both trials and considered that there were many similarities between the trial populations. The committee also decided that any heterogeneity between the studies, including the difference in the duration of background inhaled therapy, is unlikely to have systematically biased the relative treatment estimates for roflumilast. The committee concluded that it had not heard adequate justification for not including RE2SPOND and therefore that both REACT and RE2SPOND are relevant for this appraisal.
## Clinical-effectiveness results
The committee noted that the company had presented clinical-effectiveness results for the subgroup of patients in REACT who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy (1,346 patients). It also noted that the ERG presented results for the same subgroup from RE2SPOND (1,094 patients) and had pooled the relative effect of roflumilast from the 2 studies. The committee considered that it was reasonable to consider the results for this subgroup given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy (see section 3). It noted that the company's response to consultation presented pooled analyses from REACT and RE2SPOND based on individual patient-level data. The committee considered that these pooled analyses are appropriate and showed that roflumilast reduced the rate of moderate or severe exacerbations (the primary outcome in both trials) compared with placebo. The committee concluded that the company's pooled analyses provided sufficient evidence of the clinical efficacy of roflumilast compared with placebo in the subgroup of patients with severe COPD having exacerbations despite triple inhaled therapy.
## Adverse effects
The committee heard from the clinical expert that roflumilast is generally well tolerated but that weight loss and gastrointestinal adverse effects can lead to discontinuation of treatment in some people. It acknowledged that in its response to consultation, the company highlighted that there were more occurrences of weight loss, nausea and abdominal pain in patients taking roflumilast than patients taking placebo in the pooled individual patient-level data from REACT and RE2SPOND. The committee also heard from the clinical expert that there is virtually no clinical experience of using roflumilast in the UK. In addition, it was aware that roflumilast is subject to additional monitoring for weight loss and that patients are issued with a patient card for reporting side effects. The committee concluded that roflumilast appears to be generally well tolerated but that there is limited experience of using it in clinical practice in the UK.
# Cost effectiveness
The committee noted that the company had developed a Markov model with 3 health states (severe COPD, very severe COPD and death) and monthly cycles. The model was based on the rate of moderate and severe exacerbations for patients having roflumilast plus triple inhaled therapy, compared with triple therapy alone. The committee understood that exacerbations led to additional costs, a temporary decrease in quality of life and, in the case of a severe exacerbation, an increased risk of death. The committee agreed with the ERG that the model structure excluded some important aspects of COPD progression. For example, health states were defined by FEV1 values alone rather than incorporating other prognostic information. The model also assumed that exacerbations did not affect FEV1, previous exacerbations did not affect future risk of exacerbations and baseline characteristics such as smoking status did not affect disease progression and risk of exacerbation. The committee noted the limitations of the model but concluded that it is adequate for decision-making.
## Modelling rates of exacerbation
The committee noted that in each cycle of the model, patients were at risk of moderate or severe exacerbations and that these rates were incorporated separately in the model. It noted that in response to consultation the company presented a revised base-case model, using exacerbation rate ratios derived from individual patient-level data from the pooled intention-to-treat populations of REACT and RE2SPOND (see section 4.5). The committee considered that the company's approach was appropriate.
## Incorporation of health-related quality-of-life data in the model
The committee noted that in its original base case, the company derived the utility values in the model from 2 studies: Rutten van Molken (2006) for COPD severity and Rutten van Molken (2009) for disutilities for exacerbation. Rutten van Molken (2006) estimated utilities in 1,235 patients, including patients with COPD from the UK, using the UK tariff of the EQ-5D. Utility values from Rutten van Molken (2009) were from valuations of COPD health profiles (presented as vignettes) by the Dutch general public rather than EQ-5D. The committee noted that the ERG's analysis used disutilities for exacerbation from Hoogendoorn et al. (2011), because these were based on patient-reported EQ-5D values and used the UK tariff. The committee acknowledged that in its revised base case, the company incorporated disutilities for exacerbation from Hoogendoorn et al. (2011), which it considered appropriate. The committee recognised, however, that using a different data source for disutilities did not have a large impact on the incremental cost-effectiveness ratio (ICER).
## Incorporation of annual FEV1 decline in the model
The committee noted that the company's revised base case incorporated an annual FEV1 decline of 52 ml based on a review by Tantucci and Modena (2012). The committee heard from the clinical expert that 52 ml is a reasonable estimate of FEV1 decline, noting that the 2012 review identified studies reporting mean annual FEV1 declines of 56 ml and 59 ml for people with severe COPD. The committee noted that changing the FEV1 decline in the model did not have a large effect on the ICER and concluded that 52 ml was a reasonable estimate of annual FEV1 decline in people with severe COPD.
## Incorporation of post-hospitalisation excess mortality in the model
The committee noted that the company's revised base case incorporated an increased post-discharge mortality risk associated with hospitalisation for a COPD exacerbation of 15.3% from Connolly et al. (2006). The committee was aware that the ERG considered a 12% increased risk to be more plausible, based on the UK National COPD Audit 2014. It heard from the clinical expert that it is difficult to be precise about the mortality rate because of variation each year. The committee concluded that the company's estimate was reasonable but also recognised that post-hospitalisation mortality was a key driver of the results.
The committee noted the ERG's comment that the company's method of incorporating post-hospitalisation mortality into the revised model causes double counting of deaths already accounted for while calculating standardised mortality ratios in the original model. The committee accepted that correcting this would slightly decrease the revised base-case ICER estimated by the company.
## Most plausible incremental cost-effectiveness ratio
Taking into account the amendments described in section 4.8, and sections 4.10–4.11, the company's revised base-case ICER was £24,976 per quality-adjusted life year (QALY) gained. The committee acknowledged that this incorporated the adjustments made by the ERG to the company's original model, which the committee agreed was appropriate. The committee noted that the company had done scenario analyses that varied the estimate for post-hospitalisation mortality, resulting in ICERs between £16,293 and £30,349 per QALY gained. It appreciated that the true ICER may be slightly lower because of the double counting of deaths highlighted by the ERG (see section 4.12). The committee concluded that the company's revised base-case ICER was a plausible estimate of the cost effectiveness of roflumilast as an add-on treatment to triple inhaled therapy, and that the company's ICERs are within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained).
The committee recalled that roflumilast is generally well tolerated but that there are potential adverse effects such as weight loss, for which people taking roflumilast should be monitored. It also recalled that there is a lack of clinical experience in using roflumilast in the UK. The committee concluded that roflumilast could be recommended for use in the NHS for adults with severe COPD, chronic bronchitis and frequent exacerbations (2 or more exacerbations in the previous 12 months) despite triple inhaled therapy, but that treatment should only be started by a specialist in respiratory medicine.
# Pharmaceutical Price Regulation Scheme 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Summary of appraisal committee's key conclusions
TA461
Appraisal title: Roflumilast for treating chronic obstructive pulmonary disease
Section
Key conclusion
Roflumilast, as an add-on to bronchodilator therapy, is recommended as an option for treating severe chronic obstructive pulmonary disease in adults with chronic bronchitis, only if:
the disease is severe, defined as a forced expiratory volume in 1 second (FEV1) after a bronchodilator of less than 50% of predicted normal, and
the person has had 2 or more exacerbations in the previous 12 months despite triple inhaled therapy with a long-acting muscarinic antagonist, a long-acting beta-2 agonist and an inhaled corticosteroid.
The committee concluded that there is sufficient evidence of the clinical efficacy of roflumilast compared with placebo in the subgroup of patients with severe COPD having exacerbations despite triple inhaled therapy.
The committee concluded that the company's revised base-case incremental cost-effectiveness ratio (ICER) of £24,976 per quality-adjusted life year (QALY) gained is a plausible estimate of the cost effectiveness of roflumilast as an add-on treatment to triple inhaled therapy, and is within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained).
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee heard from the clinical expert that despite treatment with optimal inhaled therapy many people with severe COPD have several exacerbations each year, which is a huge burden on patients and the NHS. The committee was disappointed that no evidence had been submitted by patient groups and that no patient experts attended the committee meeting.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee recognised that a new treatment that reduces exacerbations in people with severe COPD would be highly valued by patients and their carers and address an unmet need.
What is the position of the treatment in the pathway of care for the condition?
The committee understood that triple inhaled therapy is the standard treatment for people who continue to have exacerbations despite treatment with monotherapy or dual therapy. It concluded that the company's proposed positioning of roflumilast as an add-on to triple inhaled therapy is appropriate.
Adverse reactions
The committee concluded that roflumilast appears to be generally well tolerated but that there is limited experience of using it in clinical practice in the UK.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that the evidence for roflumilast submitted by the company came from REACT (a multicentre double-blind randomised controlled trial with 1,935 patients, comparing roflumilast plus inhaled combination therapy with placebo plus inhaled combination therapy) and RE2SPOND, another multicentre double-blind trial of roflumilast that included 2,352 patients.
Relevance to general clinical practice in the NHS
The committee concluded that both REACT and RE2SPOND are relevant for this appraisal.
Uncertainties generated by the evidence
The committee considered uncertainties in the clinical evidence and acknowledged the difference in duration of background inhaled therapies in REACT and RE2SPOND, but concluded that both trials are relevant for this appraisal.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee considered that it was reasonable to consider the results for the subgroup of patients who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy, given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
In the subgroup of patients who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy, the committee concluded that there was sufficient evidence of the clinical efficacy of roflumilast compared with placebo.
How has the new clinical evidence that has emerged since the original appraisal (TA244) influenced the current recommendations?
TA244 recommended that roflumilast should only be used as part of a clinical trial for adults with severe COPD. Since TA244 was published, 2 multicentre double-blind randomised controlled trials have been published and the results of both trials have informed the recommendations in this appraisal.
Evidence for cost effectiveness
Availability and nature of evidence
The committee noted that the company had developed a Markov model that was based on the rate of moderate and severe exacerbations for patients having roflumilast plus triple inhaled therapy, compared with triple therapy alone. The committee noted some limitations in the model but concluded that it is adequate for decision-making.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee noted that there is uncertainty in the estimates used for annual decline in forced expiratory volume in the first second and post-hospitalisation mortality, but concluded that the estimates used by the company were reasonable.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee recognised that the data source for disutilities did not have a large impact on the ICER.
Are there specific groups of people for whom the technology is particularly cost effective?
The company presented cost-effectiveness results for the subgroup of people taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy. The committee considered this was appropriate given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy.
What are the key drivers of cost effectiveness?
The committee recognised that post-hospitalisation mortality was a key driver of the cost-effectiveness results.
Most likely cost-effectiveness estimate (given as an ICER)
The committee concluded that the company's revised base-case estimate of £24,976 per QALY gained was a plausible estimate of the cost effectiveness of roflumilast.
How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA244) influenced the current recommendations?
The current appraisal used clinical evidence from 2 randomised controlled trials (REACT and RE2SPOND) to re-model the cost effectiveness of roflumilast and this has led to a change in the recommendations.
Additional factors taken into account
Patient access schemes (PPRS)
The company did not submit a patient access scheme.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee did not note any specific equalities considerations.
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{'Recommendations': 'Roflumilast, as an add-on to bronchodilator therapy, is recommended as an option for treating severe chronic obstructive pulmonary disease in adults with chronic bronchitis, only if:\n\nthe disease is severe, defined as a forced expiratory volume in 1\xa0second (FEV1) after a bronchodilator of less than 50% of predicted normal, and\n\nthe person has had 2\xa0or more exacerbations in the previous 12\xa0months despite triple inhaled therapy with a long-acting muscarinic antagonist, a long-acting beta-2 agonist and an inhaled corticosteroid.\n\nTreatment with roflumilast should be started by a specialist in respiratory medicine.\n\nThese recommendations are not intended to affect treatment with roflumilast that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'The technology': "Description of the technology\n\nRoflumilast (Daxas, AstraZeneca) is an orally administered long-acting selective phosphodiesterase-4 enzyme inhibitor. It targets cells and mediators believed to be important in chronic obstructive pulmonary disease (COPD).\n\nMarketing authorisation\n\nRoflumilast has a marketing authorisation in the UK for maintenance treatment of severe COPD (forced expiratory volume in the first\xa0second [FEV1] post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment.\n\nAdverse reactions\n\nThe most common adverse reactions associated with roflumilast include diarrhoea, weight loss, nausea, abdominal pain and headache. Roflumilast is subject to additional monitoring for weight loss. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nThe recommended dose is 500\xa0micrograms (1\xa0tablet) of roflumilast once daily.\n\nPrice\n\n£37.71 for 30\xa0tablets and £113.14 for 90\xa0tablets (excluding VAT; 'British national formulary' [BNF] edition\xa072). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence': 'The appraisal committee (section 6) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of roflumilast, having considered evidence on the nature of chronic obstructive pulmonary disease (COPD) and the value placed on the benefits of roflumilast by clinical experts. No evidence was submitted by patient groups and no patient experts attended the committee meetings. The committee also took into account the effective use of NHS resources.\n\n# Clinical need of people with COPD\n\nThe committee heard that COPD is a chronic and progressive disease characterised by obstruction of the airways, breathlessness and cough. Airflow limitation becomes worse over time, with periodic acute exacerbations. The clinical expert advised that despite treatment with optimal inhaled therapy many people with severe COPD have several exacerbations each year, which is a huge burden on patients and the NHS. Exacerbations worsen a patient's health status, reduce their quality of life, accelerate decline in lung function, lead to hospitalisation and increase mortality. The committee was disappointed that no evidence was submitted by patient groups and that no patient experts attended the committee meeting. However, it recognised that a new treatment that reduced exacerbations in people with severe COPD would be highly valued by patients and their carers, and addresses an unmet need.\n\n# Clinical management of COPD\n\nThe committee heard from the clinical expert that COPD is treated according to NICE's clinical guideline on chronic obstructive pulmonary disease in over 16s: diagnosis and management. For severe COPD (defined as forced expiratory volume in the first second [FEV1] less than 50% predicted) the guideline recommends using either an inhaled long-acting muscarinic antagonist alone, a fixed combination of an inhaled corticosteroid and a long-acting beta‑2 agonist (dual inhaled therapy), or a combination of all these treatments (triple inhaled therapy). The committee understood that triple inhaled therapy is the standard treatment for people who continue to have exacerbations despite treatment with monotherapy or dual therapy. It noted that the company was seeking a recommendation for the use of roflumilast as an add-on treatment to triple inhaled therapy but not for monotherapy or dual therapy, which were included in the NICE scope. The committee considered whether this was appropriate. It heard from the clinical expert that the 2017 update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommended roflumilast as an add-on therapy for people with severe COPD who continue to have exacerbations despite treatment with triple therapy, particularly if they had at least\xa01 hospitalisation for an exacerbation in the previous year. The committee also heard from the clinical expert that the company's proposed placement of roflumilast in the treatment pathway is consistent with clinical practice, and that around 90% of people having roflumilast will be on triple therapy. The committee concluded that the company's proposed positioning of roflumilast as an add-on to triple inhaled therapy is appropriate.\n\n# Comparators\n\nThe committee understood that the comparators in the appraisal scope included monotherapy (a long-acting muscarinic or beta‑2 agonist), dual therapy (the above treatments combined with each other or with inhaled corticosteroids), triple therapy (all of the above treatments) and theophylline in combination with inhaled maintenance bronchodilator treatment. The committee noted that the company did not consider monotherapy and dual therapy to be appropriate comparators because it intended to position roflumilast as an add-on treatment to triple inhaled therapy (see section\xa04.2). The committee accepted that this approach is appropriate. It also noted that the company does not consider theophylline to be an appropriate comparator. The committee heard from the clinical expert that theophylline is not generally used in clinical practice because of the high risk of toxicity, lack of evidence for clinical effectiveness, and associated side effects (such as seizures and cardiac arrhythmias). The committee accepted the company's rationale for excluding theophylline and concluded that triple inhaled therapy is the appropriate comparator for this appraisal.\n\n# Clinical effectiveness\n\n## Source of clinical evidence\n\nThe evidence for roflumilast submitted by the company came from REACT, a multicentre double-blind randomised controlled trial that included 1,935\xa0patients with severe COPD, chronic bronchitis and 2\xa0or more exacerbations in the previous year. It compared roflumilast plus inhaled combination therapy (a long-acting beta‑2 agonist plus inhaled corticosteroids, with or without a long-acting muscarinic antagonist) with placebo plus inhaled combination therapy. The committee noted that the evidence review group (ERG) presented a pooled analysis of REACT plus another multicentre double-blind trial of roflumilast that included 2,352\xa0patients with severe COPD, chronic bronchitis and 2\xa0or more exacerbations and/or hospitalisations in the previous year (RE2SPOND). It understood that the company did not include detailed information on RE2SPOND in its submission because it believed that the people in the trial do not accurately reflect the target population. The company stated that fewer than half of patients in RE2SPOND were on triple therapy (47% compared with 70% in REACT), 0.5% were from Western Europe (compared with 29.5% in REACT) and pre-treatment with inhaled therapies was for a minimum of 3\xa0months rather than 12\xa0months as in REACT. The committee heard from the clinical expert that the duration of background inhaled therapies is an important difference between the 2\xa0trials. Patients in REACT were more likely to have well controlled COPD because they had optimal inhaled therapy for 12 months, whereas patients in RE2SPOND were not appropriately pre-treated with inhaled therapies. The clinical expert suggested that the population in RE2SPOND had a higher risk of exacerbations compared with the population in REACT. The committee also heard from the company that RE2SPOND did not reflect current clinical practice in the UK because it used lower doses of long-acting beta‑2 agonists and inhaled corticosteroids and an alternative formulation of roflumilast. The committee discussed the characteristics of the people included in both trials and considered that there were many similarities between the trial populations. The committee also decided that any heterogeneity between the studies, including the difference in the duration of background inhaled therapy, is unlikely to have systematically biased the relative treatment estimates for roflumilast. The committee concluded that it had not heard adequate justification for not including RE2SPOND and therefore that both REACT and RE2SPOND are relevant for this appraisal.\n\n## Clinical-effectiveness results\n\nThe committee noted that the company had presented clinical-effectiveness results for the subgroup of patients in REACT who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy (1,346 [70%] patients). It also noted that the ERG presented results for the same subgroup from RE2SPOND (1,094\xa0[47%] patients) and had pooled the relative effect of roflumilast from the 2\xa0studies. The committee considered that it was reasonable to consider the results for this subgroup given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy (see section\xa03). It noted that the company's response to consultation presented pooled analyses from REACT and RE2SPOND based on individual patient-level data. The committee considered that these pooled analyses are appropriate and showed that roflumilast reduced the rate of moderate or severe exacerbations (the primary outcome in both trials) compared with placebo. The committee concluded that the company's pooled analyses provided sufficient evidence of the clinical efficacy of roflumilast compared with placebo in the subgroup of patients with severe COPD having exacerbations despite triple inhaled therapy.\n\n## Adverse effects\n\nThe committee heard from the clinical expert that roflumilast is generally well tolerated but that weight loss and gastrointestinal adverse effects can lead to discontinuation of treatment in some people. It acknowledged that in its response to consultation, the company highlighted that there were more occurrences of weight loss, nausea and abdominal pain in patients taking roflumilast than patients taking placebo in the pooled individual patient-level data from REACT and RE2SPOND. The committee also heard from the clinical expert that there is virtually no clinical experience of using roflumilast in the UK. In addition, it was aware that roflumilast is subject to additional monitoring for weight loss and that patients are issued with a patient card for reporting side effects. The committee concluded that roflumilast appears to be generally well tolerated but that there is limited experience of using it in clinical practice in the UK.\n\n# Cost effectiveness\n\nThe committee noted that the company had developed a Markov model with 3\xa0health states (severe COPD, very severe COPD and death) and monthly cycles. The model was based on the rate of moderate and severe exacerbations for patients having roflumilast plus triple inhaled therapy, compared with triple therapy alone. The committee understood that exacerbations led to additional costs, a temporary decrease in quality of life and, in the case of a severe exacerbation, an increased risk of death. The committee agreed with the ERG that the model structure excluded some important aspects of COPD progression. For example, health states were defined by FEV1 values alone rather than incorporating other prognostic information. The model also assumed that exacerbations did not affect FEV1, previous exacerbations did not affect future risk of exacerbations and baseline characteristics such as smoking status did not affect disease progression and risk of exacerbation. The committee noted the limitations of the model but concluded that it is adequate for decision-making.\n\n## Modelling rates of exacerbation\n\nThe committee noted that in each cycle of the model, patients were at risk of moderate or severe exacerbations and that these rates were incorporated separately in the model. It noted that in response to consultation the company presented a revised base-case model, using exacerbation rate ratios derived from individual patient-level data from the pooled intention-to-treat populations of REACT and RE2SPOND (see section\xa04.5). The committee considered that the company's approach was appropriate.\n\n## Incorporation of health-related quality-of-life data in the model\n\nThe committee noted that in its original base case, the company derived the utility values in the model from 2\xa0studies: Rutten van Molken (2006) for COPD severity and Rutten van Molken (2009) for disutilities for exacerbation. Rutten van Molken (2006) estimated utilities in 1,235\xa0patients, including patients with COPD from the UK, using the UK tariff of the EQ-5D. Utility values from Rutten van Molken (2009) were from valuations of COPD health profiles (presented as vignettes) by the Dutch general public rather than EQ-5D. The committee noted that the ERG's analysis used disutilities for exacerbation from Hoogendoorn et al. (2011), because these were based on patient-reported EQ-5D values and used the UK tariff. The committee acknowledged that in its revised base case, the company incorporated disutilities for exacerbation from Hoogendoorn et al. (2011), which it considered appropriate. The committee recognised, however, that using a different data source for disutilities did not have a large impact on the incremental cost-effectiveness ratio (ICER).\n\n## Incorporation of annual FEV1 decline in the model\n\nThe committee noted that the company's revised base case incorporated an annual FEV1 decline of 52\xa0ml based on a review by Tantucci and Modena (2012). The committee heard from the clinical expert that 52\xa0ml is a reasonable estimate of FEV1 decline, noting that the 2012\xa0review identified studies reporting mean annual FEV1 declines of 56\xa0ml and 59\xa0ml for people with severe COPD. The committee noted that changing the FEV1 decline in the model did not have a large effect on the ICER and concluded that 52\xa0ml was a reasonable estimate of annual FEV1 decline in people with severe COPD.\n\n## Incorporation of post-hospitalisation excess mortality in the model\n\nThe committee noted that the company's revised base case incorporated an increased post-discharge mortality risk associated with hospitalisation for a COPD exacerbation of 15.3% from Connolly et al. (2006). The committee was aware that the ERG considered a 12% increased risk to be more plausible, based on the UK National COPD Audit 2014. It heard from the clinical expert that it is difficult to be precise about the mortality rate because of variation each year. The committee concluded that the company's estimate was reasonable but also recognised that post-hospitalisation mortality was a key driver of the results.\n\nThe committee noted the ERG's comment that the company's method of incorporating post-hospitalisation mortality into the revised model causes double counting of deaths already accounted for while calculating standardised mortality ratios in the original model. The committee accepted that correcting this would slightly decrease the revised base-case ICER estimated by the company.\n\n## Most plausible incremental cost-effectiveness ratio\n\nTaking into account the amendments described in section 4.8, and sections 4.10–4.11, the company's revised base-case ICER was £24,976 per quality-adjusted life year (QALY) gained. The committee acknowledged that this incorporated the adjustments made by the ERG to the company's original model, which the committee agreed was appropriate. The committee noted that the company had done scenario analyses that varied the estimate for post-hospitalisation mortality, resulting in ICERs between £16,293 and £30,349 per QALY gained. It appreciated that the true ICER may be slightly lower because of the double counting of deaths highlighted by the ERG (see section\xa04.12). The committee concluded that the company's revised base-case ICER was a plausible estimate of the cost effectiveness of roflumilast as an add-on treatment to triple inhaled therapy, and that the company's ICERs are within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained).\n\nThe committee recalled that roflumilast is generally well tolerated but that there are potential adverse effects such as weight loss, for which people taking roflumilast should be monitored. It also recalled that there is a lack of clinical experience in using roflumilast in the UK. The committee concluded that roflumilast could be recommended for use in the NHS for adults with severe COPD, chronic bronchitis and frequent exacerbations (2\xa0or more exacerbations in the previous 12\xa0months) despite triple inhaled therapy, but that treatment should only be started by a specialist in respiratory medicine.\n\n# Pharmaceutical Price Regulation Scheme 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA461\n\nAppraisal title: Roflumilast for treating chronic obstructive pulmonary disease\n\nSection\n\nKey conclusion\n\nRoflumilast, as an add-on to bronchodilator therapy, is recommended as an option for treating severe chronic obstructive pulmonary disease in adults with chronic bronchitis, only if:\n\nthe disease is severe, defined as a forced expiratory volume in 1\xa0second (FEV1) after a bronchodilator of less than 50% of predicted normal, and\n\nthe person has had 2\xa0or more exacerbations in the previous 12\xa0months despite triple inhaled therapy with a long-acting muscarinic antagonist, a long-acting beta-2 agonist and an inhaled corticosteroid.\n\nThe committee concluded that there is sufficient evidence of the clinical efficacy of roflumilast compared with placebo in the subgroup of patients with severe COPD having exacerbations despite triple inhaled therapy.\n\nThe committee concluded that the company's revised base-case incremental cost-effectiveness ratio (ICER) of £24,976 per quality-adjusted life year (QALY) gained is a plausible estimate of the cost effectiveness of roflumilast as an add-on treatment to triple inhaled therapy, and is within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained).\n\n, 4.5, 4.13\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from the clinical expert that despite treatment with optimal inhaled therapy many people with severe COPD have several exacerbations each year, which is a huge burden on patients and the NHS. The committee was disappointed that no evidence had been submitted by patient groups and that no patient experts attended the committee meeting.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee recognised that a new treatment that reduces exacerbations in people with severe COPD would be highly valued by patients and their carers and address an unmet need.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee understood that triple inhaled therapy is the standard treatment for people who continue to have exacerbations despite treatment with monotherapy or dual therapy. It concluded that the company's proposed positioning of roflumilast as an add-on to triple inhaled therapy is appropriate.\n\n\n\nAdverse reactions\n\nThe committee concluded that roflumilast appears to be generally well tolerated but that there is limited experience of using it in clinical practice in the UK.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee noted that the evidence for roflumilast submitted by the company came from REACT (a multicentre double-blind randomised controlled trial with 1,935\xa0patients, comparing roflumilast plus inhaled combination therapy with placebo plus inhaled combination therapy) and RE2SPOND, another multicentre double-blind trial of roflumilast that included 2,352\xa0patients.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that both REACT and RE2SPOND are relevant for this appraisal.\n\n\n\nUncertainties generated by the evidence\n\nThe committee considered uncertainties in the clinical evidence and acknowledged the difference in duration of background inhaled therapies in REACT and RE2SPOND, but concluded that both trials are relevant for this appraisal.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee considered that it was reasonable to consider the results for the subgroup of patients who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy, given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nIn the subgroup of patients who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy, the committee concluded that there was sufficient evidence of the clinical efficacy of roflumilast compared with placebo.\n\n\n\nHow has the new clinical evidence that has emerged since the original appraisal (TA244) influenced the current recommendations?\n\nTA244 recommended that roflumilast should only be used as part of a clinical trial for adults with severe COPD. Since TA244 was published, 2 multicentre double-blind randomised controlled trials have been published and the results of both trials have informed the recommendations in this appraisal.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee noted that the company had developed a Markov model that was based on the rate of moderate and severe exacerbations for patients having roflumilast plus triple inhaled therapy, compared with triple therapy alone. The committee noted some limitations in the model but concluded that it is adequate for decision-making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee noted that there is uncertainty in the estimates used for annual decline in forced expiratory volume in the first\xa0second [FEV1] and post-hospitalisation mortality, but concluded that the estimates used by the company were reasonable.\n\n, 4.11\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee recognised that the data source for disutilities did not have a large impact on the ICER.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe company presented cost-effectiveness results for the subgroup of people taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy. The committee considered this was appropriate given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy.\n\n, 4.7, 4.13\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee recognised that post-hospitalisation mortality was a key driver of the cost-effectiveness results.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee concluded that the company's revised base-case estimate of £24,976 per QALY gained was a plausible estimate of the cost effectiveness of roflumilast.\n\n\n\nHow has the new cost-effectiveness evidence that has emerged since the original appraisal (TA244) influenced the current recommendations?\n\nThe current appraisal used clinical evidence from 2\xa0randomised controlled trials (REACT and RE2SPOND) to re-model the cost effectiveness of roflumilast and this has led to a change in the recommendations.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe company did not submit a patient access scheme.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee did not note any specific equalities considerations.\n\n–"}
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https://www.nice.org.uk/guidance/ta461
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Evidence-based recommendations on roflumilast (Daxas) for treating chronic obstructive pulmonary disease in adults with chronic bronchitis.
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667b8d37554332bfa8fa32aef46fa1b51b57710e
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nice
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Adalimumab and dexamethasone for treating non-infectious uveitis
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Adalimumab and dexamethasone for treating non-infectious uveitis
Evidence-based recommendations on adalimumab (Humira) and dexamethasone (Ozurdex) for treating non-infectious uveitis in adults.
# Recommendations
Adalimumab is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids, only if there is:
active disease (that is, current inflammation in the eye) and
inadequate response or intolerance to immunosuppressants and
systemic disease or both eyes are affected (or 1 eye is affected if the second eye has poor visual acuity) and
worsening vision with a high risk of blindness (for example, risk of blindness that is similar to that seen in people with macular oedema).
Stop adalimumab for non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids if there is 1 of the following:
new active inflammatory chorioretinal or inflammatory retinal vascular lesions, or both or
a 2‑step increase in vitreous haze or anterior chamber cell grade or
worsening of best corrected visual acuity by 3 or more lines or 15 letters.
Dexamethasone intravitreal implant is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults, only if there is:
active disease (that is, current inflammation in the eye) and
worsening vision with a risk of blindness.
These recommendations are not intended to affect treatment with adalimumab and dexamethasone that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# Technologies
Description of the technologies
Adalimumab (Humira, AbbVie) is a monoclonal antibody that reduces inflammation by inhibiting pro-inflammatory cytokine tumour necrosis factor-alpha.
Dexamethasone intravitreal implant (Ozurdex, Allergan) is a biodegradable corticosteroid implant that suppresses inflammation by inhibiting the expression of pro-inflammatory mediators.
Marketing authorisations
Adalimumab is indicated 'for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid sparing, or in whom corticosteroid treatment is inappropriate.'
Dexamethasone intravitreal implant is indicated 'for the treatment of adult patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis.'
Adverse reactions
The most commonly reported adverse reactions with adalimumab are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.
The most commonly reported adverse events after treatment with dexamethasone intravitreal implant are those often seen with ophthalmic steroid treatment or intravitreal injections (elevated intraocular pressure, cataract formation and conjunctival, or vitreal haemorrhage respectively).
For full details of adverse reactions and contraindications for adalimumab and dexamethasone, see the summaries of product characteristics.
Recommended doses and schedules
The recommended dose of adalimumab for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg every other week starting 1 week after the initial dose. Adalimumab is given by subcutaneous injection. There is limited experience in starting treatment with adalimumab alone. Treatment with adalimumab can be started in combination with corticosteroids or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered off according to clinical practice from 2 weeks after starting treatment.
The recommended dose of dexamethasone intravitreal implant is 1 implant, containing 700 micrograms of dexamethasone, to be administered intravitreally to the affected eye. Administration to both eyes concurrently is not recommended. Repeat doses should be considered when a patient experiences a response to treatment followed subsequently by a loss in visual acuity and in the clinician's opinion may benefit from retreatment without being exposed to significant risk.
Prices
Adalimumab costs £704.28 for 2 pre-filled injections and each dexamethasone intravitreal implant costs £870.00 (excluding VAT; 'British National Formulary' edition 72). Costs may vary in different settings because of negotiated procurement discounts.# Evidence
The appraisal committee (section 6) considered evidence submitted by AbbVie and Allergan and a review of these submissions by the assessment group. See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of adalimumab and dexamethasone intravitreal implant. It considered evidence on the nature of non-infectious uveitis and the value placed on the benefits of adalimumab and dexamethasone by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical need and management of non-infectious uveitis
The committee heard from the clinical experts that uveitis describes a group of conditions characterised by inflammation inside the eye. It understood that this appraisal covers most sight-threatening forms of non-infectious uveitis (that is, those affecting the posterior structure of eye). This includes panuveitis, as well as intermediate and posterior uveitis. The committee heard from the patient experts that symptoms include blurred vision and floaters in the eye, and sometimes pain and redness. It also heard that the condition may lead to complications such as cystoid macular oedema, vitreous haze, cataracts, glaucoma and irreversible retinal damage. People may also have sudden and temporary or progressive and permanent visual impairment. The patient experts explained that losing visual function can affect a person's ability to do daily activities, work or study. One patient expert described the psychological effect of visual impairment after going blind in 1 eye within 3 months of the condition starting, stating that knowing how quickly sight could be completely lost was very distressing. The patient experts also explained that it is common for people with uveitis to suffer depression and anxiety and to feel isolated. The clinical and patient experts advised that current treatment options are associated with significant side effects. The committee concluded that uveitis has a substantial effect on quality of life.
The committee heard from the clinical experts that there are 3 main reasons for treating non-infectious uveitis in clinical practice: vitreous haze, macular oedema and worsening vision. The committee also heard from the clinical experts and the assessment group that there is no nationally agreed pathway for treating non-infectious uveitis. The assessment group advised that in clinical practice, systemic steroids are usually used as a first-line treatment and 1 or 2 immunosuppressants, such as mycophenolate mofetil, are either used alone or with steroids as second-line treatment. This general treatment pathway was agreed by the clinical experts, although it was noted that treatment in clinical practice depends on whether disease is:
active (that is, current inflammation in the eye) or inactive (that is, limited inflammation, usually because of treatment with corticosteroids or immunosuppressants)
systemic (when disease is not only in the eye) or non-systemic (when disease is limited to the eye)
unilateral (when 1 eye is affected) or bilateral (when both eyes are affected).It heard from clinical experts that adalimumab would generally be used as a third-line treatment option in people with bilateral or systemic disease or both, but dexamethasone is generally used in people with unilateral disease. The committee concluded that the treatment pathway reflected current practice.
The clinical and patient experts stated that treatment options are currently restricted and there was a significant unmet need for both adalimumab and dexamethasone intravitreal implant. The committee heard from the clinical and patient experts that adalimumab and dexamethasone allow corticosteroid sparing, which is important not just for patients' short-term quality of life but also to avoid glaucoma, diabetes, stroke and heart attack. The committee recognised that patients and their carers would greatly value a new treatment which prevented or delayed sight loss, particularly if it reduced the significant side effects associated with current treatments.
# Clinical effectiveness
## Clinical evidence
The committee was aware that the comparators in the appraisal scope included corticosteroid injections and implants, systemic immunosuppressive therapies, tumour necrosis factor-alpha inhibitors (such as infliximab), intravitreal methotrexate and best supportive care. The scope also stated that the interventions should be compared with each other. However, direct clinical evidence was only available for the interventions compared with either placebo or a sham procedure. The evidence for adalimumab came from the VISUAL I and VISUAL II trials and the evidence for dexamethasone intravitreal implant came from the HURON trial. The VISUAL trials compared adalimumab plus background therapy (that is, initial steroids tapered to zero with or without 1 immunosuppressant) with placebo plus background therapy. The HURON trial compared dexamethasone plus background therapy with a sham procedure plus background therapy. The committee noted that there was no clinical evidence which directly compared adalimumab with dexamethasone and the assessment group did not do an indirect comparison using HURON and the VISUAL trials. The assessment group advised that an indirect comparison was not appropriate because patient characteristics in VISUAL I, VISUAL II and HURON differed and there was a lack of common comparators and outcomes. Furthermore, adalimumab and dexamethasone could be used at different points in the treatment pathway. The committee agreed that there was a lack of relevant evidence on therapy for non-infectious uveitis, with varied and often limited current treatments available. However, the available clinical evidence was adequate for decision-making.
## Patients included in the trials
Although the marketing authorisations for adalimumab and dexamethasone did not distinguish between active and inactive disease, the committee understood that VISUAL I and HURON included patients with active disease but VISUAL II included patients with inactive disease. The committee heard from the clinical experts that the distinction between active and inactive disease was clinically relevant because they were different populations, which would have different treatments. It heard that because maintenance treatment with immunosuppressants and corticosteroids may control inactive disease, the next line of treatment, such as adalimumab or dexamethasone intravitreal implant may not be needed. The committee was aware of an ongoing trial, ASTUTE, that examines the effectiveness of adalimumab compared with placebo as an add-on to standard care. It understood there were no data from this study at the time of this appraisal. The committee concluded that it would take these different populations into account when making its final recommendations.
The committee noted that the inclusion criteria for the VISUAL trials did not specify patients with macular oedema. It heard from clinical experts that people with macular oedema have a high risk of blindness. Because patients with macular oedema were not specifically included in the VISUAL trials, the clinical effectiveness of adalimumab may be underestimated in this group. It also heard from clinical experts that people with bilateral disease or systemic disease are likely to have a higher risk of blindness compared with people with unilateral or localised disease. The committee noted that most patients (over 90%) in the VISUAL trials had bilateral or systemic non-infectious uveitis. It also noted that the proportion of people with bilateral uveitis in HURON was unclear but patients had only 1 dexamethasone implant, and current clinical practice preferred dexamethasone for unilateral disease. The committee concluded that it would be useful to distinguish unilateral from systemic and bilateral disease and that people with a higher risk of blindness formed a clinically important subgroup.
## Clinical-effectiveness results
The committee noted that the primary outcome in the VISUAL trials was a composite measure of time to treatment failure. The committee understood that the VISUAL trials showed that adalimumab had improved outcomes, such as time to treatment failure and visual acuity, compared with placebo. The committee noted that the primary outcome in the HURON trial was the proportion of people with a vitreous haze score of 0. It understood that HURON showed that dexamethasone had improved outcomes, such as vitreous haze score and visual acuity (in the affected eye), compared with the sham procedure. The committee concluded that there is evidence to show that both adalimumab and dexamethasone are clinically effective treatments for improving visual acuity, anterior chamber cell grade and vitreous haze.
## Table 1 Summary of clinical-effectiveness results
Adalimumab versus placebo
Dexamethasone versus sham
VISUAL I
VISUAL II
HURON
Time to treatment failure (worsening of AC, VH, BCVA or new lesions)
HR 0.50 (95% CI 0.36 to 0.70)
HR 0.57 (95% CI 0.39 to 0.84)
Not reported
Visual acuity (BCVA, logMAR, change)
MD −0.07 (95% CI −0.11 to −0.02)*
MD −0.04 (95% CI −0.08 to 0.01)
MD not reported (p=0.002) at 26 weeks
Vitreous haze grade = 0
Not reported
Not reported
RR 4.0 (95% CI 2.0 to 7.6) at 8 weeks
Not reported
Not reported
RR 2.2 (95% CI 1.1 to 4.1) at 26 weeks
- Change from best state reached before week 6 to final or early termination.
From baseline to final or early termination.
Abbreviations: AC, anterior chamber; BCVA, best corrected visual acuity; CI, confidence interval; HR, hazard ratio; logMAR, logarithm of the Minimum Angle of Resolution; MD, mean difference; RR, relative risk; VH, vitreous haze.
# Cost effectiveness
## Model structure
The committee noted the assessment group had developed a Markov model with 4 health states in the base case (on treatment, treatment failure, permanent blindness and death). The assessment group gave 3 separate base cases, based on the underpinning trial evidence: adalimumab for active disease, adalimumab for inactive disease, and dexamethasone intravitreal implant for active disease. The assessment group noted it had not been possible to distinguish between unilateral and bilateral disease in the model; however, over 90% of patients in the VISUAL trials on adalimumab had bilateral disease. The committee concluded that the assessment group's decision to separate its analyses into 3 separate base cases was appropriate and supported by clinical evidence and that it would need to consider all 3 base-case analyses when making its recommendations.
The committee was aware that the assessment group did an exploratory analysis with a 'remission' health state for the adalimumab model only. This was based on clinical advice that some people who have treatment with adalimumab will have disease which is in remission (the assessment group excluded this health state from its base case because of a lack of evidence). The committee understood that the exploratory analysis assumed that after around 2 years of stable disease, treatment is no longer needed. This is because the disease is in remission but patients will have the same health-related quality of life as when they were having treatment. The committee heard from the clinical experts that the disease could be expected to go into remission in at least some of the people who have adalimumab. The committee concluded that although there is no evidence for remission, it was reasonable to assume that at least some people's disease could be in remission after treatment with adalimumab.
## Modelling the rate of blindness
The committee noted that the follow-up time in the HURON trial was 26 weeks, but a maximum follow-up of 80 weeks was included in the VISUAL trials. None of the trials reported patients with permanent legal blindness. The assessment group advised that the rate of blindness and the relative risk of blindness associated with adalimumab and dexamethasone had a large effect on the incremental cost-effectiveness ratio (ICER) and did scenario analyses to model this potential effect. The committee acknowledged there was a lack of robust, long-term studies for the rate of blindness but concluded that the scenario analyses including blindness were appropriate for decision-making because it is likely that both adalimumab and dexamethasone had an effect on the rate of blindness, although the extent of this effect was uncertain.
The committee understood that in its base case, the assessment group preferred to use a constant annual rate of blindness of 0.0066 from Dick et al. (2016), a retrospective analysis of 1,769 insurance claims of adults with non-infectious intermediate uveitis, posterior uveitis or panuveitis in the US. In contrast, the company for adalimumab preferred the higher rate of blindness (0.0374) that was used in a scenario analysis by the assessment group. This rate was reported in a retrospective review of 315 medical records in the UK (Durrani et al. 2004). However, the assessment group advised that this study included a wider population compared with the scope of this appraisal (only 61% of patients had posterior, intermediate or panuveitis and age ranged from 7 to 86 years) and was done in a tertiary centre in which patients are more likely to have severe, and often bilateral uveitis. The committee was aware that a higher rate of blindness would lead to more favourable cost-effectiveness results for the interventions. The committee agreed that for people at higher risk of blindness (for example, people with macular oedema and bilateral disease) the background rate of blindness is likely to be higher than in the base case. However, it noted that macular oedema was not the only precursor to blindness. The committee also agreed that the risk of permanent legal blindness in people having dexamethasone was probably lower compared with the risk of blindness in people having adalimumab. This is because dexamethasone is often used to treat unilateral disease, whereas adalimumab is more often used to treat bilateral disease later in the treatment pathway. The committee concluded that the rate of blindness in people at high risk was uncertain but likely to be higher than in the base case (0.0066). The committee also concluded the base-case rate of 0.0066 was acceptable for unilateral disease, because although this group might include people with macular oedema and at a higher risk of unilateral blindness, this was not the same as permanent legal blindness.
The committee noted that the assessment group's base case used a relative risk of blindness of 0.5 for dexamethasone (that is, a 50% lower rate of blindness in the dexamethasone group compared with the comparator group). For adalimumab, the base case did not allow blindness in either the adalimumab or comparator arms while on treatment, and used the same overall rate of blindness after treatment failure, which was strictly defined in the VISUAL trials. However, there was a lack of evidence to support a relative risk of 0.5 for dexamethasone. The clinical experts agreed that there was a lack of evidence to support this assumption, but considered a value of 0.5 to be clinically plausible for the affected eye. For adalimumab, the committee accepted the base-case assumptions. The committee concluded that the assessment group's approach to modelling was appropriate for decision-making provided that the dexamethasone rate is only applied to the affected eye, unless both eyes were affected and treated.
The committee noted that the assessment group did additional scenario analyses for adalimumab for active non-infectious uveitis using the committee's preferred utility for blindness of 0.57. The scenarios combined varying the relative risk of blindness with treatment and the rate at which treatment is stopped because of remission. The committee recalled its earlier conclusion that at least some people having adalimumab are likely to go into remission. The committee concluded that these scenarios were appropriate for decision-making because they accounted for both the possible effect on blindness and the additional benefit of remission.
## Health-related quality of life
The committee was aware that the quality-of-life data from the clinical trials were assumed to include the effects of adverse events during the treatment period. Utility values for blindness were also taken from the literature. The committee heard from the patient and clinical experts that they were unsure whether this approach to modelling utility included the effect of uveitis on the whole person. This was because uveitis substantially affected quality of life, with visual disability having significant consequences for people (including depression and stress, for example, because of a loss of ability to support self and family), and their families and carers. However, the assessment group stated that the trial included holistic treatment benefit, as well as the main costs of adverse events and blindness. The committee agreed that uveitis had a significant effect on quality of life, and that there were limited data to inform the utility assumptions. However, it was aware that the utility values are designed to represent whole person health. The committee concluded that the utility values used were appropriate for decision-making.
The committee considered the approach to modelling the utility of the blindness health state. The committee noted that the quality-of-life value used in the base case (0.38 from Czoski-Murray et al. 2009) was low, and agreed that scenario analyses using the higher utility of 0.57 (from Brown et al. 1999) were more plausible. It was aware that in the model people were either permanently legally blind or not blind. The committee was aware this omitted the effect of worsening visual acuity and that level of vision was likely to be a continuous variable. The committee further discussed the effect of blindness depending on whether disease was unilateral or bilateral, which was not captured in the model. In its experience of previous appraisals for eye diseases, the utility loss of blindness in both eyes was likely to be much higher than in unilateral blindness.
The committee noted that EQ‑5D data were reported at baseline and follow-up in the VISUAL trials, but only at baseline in HURON. It was aware that all 3 trials also assessed health-related quality of life using the Visual-Functioning Questionnaire (VFQ‑25) and that this measure is more specific to visual function. The committee understood that to model utilities for adalimumab over time, the assessment group used EQ‑5D data directly from the VISUAL trials. To estimate utility over time for dexamethasone, the assessment group used individual patient-level VFQ‑25 data and mapped these to EQ‑5D using a regression analysis. Individual patient-level data for adalimumab were not made available in time for the assessment group to use them. The committee heard from the assessment group that using VFQ‑25 data instead of EQ‑5D data had only a small effect on the ICERs. The committee concluded that the methodology used to derive this utility was acceptable for decision-making.
## Resource use
The committee noted that to calculate the cost of blindness, the assessment group assumed that 30% of patients would have residential care. It understood that this cost was based on a health technology assessment (Colquitt et al. 2008) on treating age-related macular degeneration, which is likely to affect people who are older than those with uveitis. It recalled that people with non-infectious uveitis are between 20 to 50 years and only a small proportion would need residential care. The committee concluded that the proportion of people needing residential care is likely to be overestimated in the assessment group's model and, if this proportion were smaller, the ICERs would increase (that is, the treatments would become less cost effective) for the scenario analyses involving blindness.
The committee heard from the clinical experts that using multiple dexamethasone implants consecutively was associated with adverse events, including increased intraocular pressure and cataracts. It heard that for this reason, the clinical experts would use at most 3 implants consecutively although this may vary in clinical practice. It also heard from the assessment group that using multiple implants consecutively was likely to produce similar cost-effectiveness results because the model assumed that dexamethasone would only provide a treatment benefit for around 6 months. The committee concluded that consecutive use of dexamethasone was unlikely to have a large effect on the cost-effectiveness analyses.
## Most plausible incremental cost-effectiveness ratios
The committee recalled its earlier concern that the cost of blindness had been overestimated in the model. This meant that the base-case and scenario analyses for both interventions favoured the interventions that were more effective in reducing blindness. However, it also noted that there was uncertainty around the background rate of blindness, which it considered had been underestimated for the high-risk groups for whom treatment with adalimumab or dexamethasone is possible. This was likely to make the cost-effectiveness results more conservative. The committee concluded that, although there was uncertainty, the reduction (that is, improvement) in ICERs resulting from overestimated costs of blindness were likely to be offset by the low rate of background blindness in this high-risk group.
The committee noted that the assessment group's base-case ICER for adalimumab in patients with inactive non-infectious uveitis was £321,405 per quality-adjusted life year (QALY) gained. It noted that all the ICERs in all the scenario analyses were above £80,000 per QALY gained. The committee agreed that these ICERs were substantially above the range normally considered a cost-effective use of NHS resources. The committee also noted that people with inactive disease would be unlikely to have treatment with adalimumab in clinical practice (see section 4.5). Therefore the committee did not recommend adalimumab for treating inactive non-infectious uveitis.
The committee noted that the assessment group's base-case ICER for adalimumab in patients with active non-infectious uveitis was £95,506 per QALY gained. However, this base case did not take account of its reasoning that there would be a relatively severely affected subgroup of patients (see section 4.6). The committee noted that disease was likely to be more severe in people with bilateral disease later in the treatment pathway. It agreed that the treatment would be more cost effective in those at higher risk of permanent legal blindness, and bilateral disease with macular oedema was a useful proxy for this. However, the committee also recognised that people with unilateral disease in the better seeing eye were also at a high risk of permanent blindness if they have poor visual acuity in the other eye. Using its preferred assumptions for severe disease (see section 4.6), high rates of blindness (see sections 4.11 and 4.12), utility values (see section 4.15) and occasional remission (see section 4.9), adalimumab resulted in ICERs that ranged from £23,688 to £37,279 per QALY gained, and these were probably lower because the rate of blindness was likely to have been underestimated for patients with progressive loss of visual acuity (see section 4.11). The committee noted that the VISUAL trials included some patients taking only 1 immunosuppressant but understood that in clinical practice, 2 immunosuppressants may be taken as second-line treatment (see section 4.2). Therefore it agreed that either 1 or 2 immunosuppressants may be used as part of second-line treatment before adalimumab is started. The committee also took into account the lack of available treatment options for this subgroup, the evidence from the patient and clinical experts about the adverse effects associated with current treatment options and comments from consultation. Taking all of this into account, it recommended adalimumab as a cost-effective use of NHS resources for treating non-infectious uveitis in the posterior segment of the eye in adults, if there is:
active disease and
an inadequate response or intolerance to immunosuppressants and
systemic disease or both eyes are affected (or 1 eye is affected if the second eye has poor visual acuity) and
worsening vision with a high risk of blindness (for example, risk of blindness that is similar to that seen in people with macular oedema).The committee also agreed that a stopping rule should be included, which reflected the strict criteria for defining treatment failure in the VISUAL I trial. Based on these criteria, it concluded that treatment should be stopped if there is evidence of 1 of the following:
new active inflammatory chorioretinal or inflammatory retinal vascular lesions or both or
a 2‑step increase in vitreous haze or anterior chamber cell grade or
worsening of best corrected visual acuity by 3 or more lines or 15 letters.The committee's recommendations are therefore in line with the clinical trial evidence that has underpinned the marketing authorisation granted by the regulator.
The committee noted that the assessment group's base-case ICER for dexamethasone in patients with active uveitis was £20,058 per QALY gained. The committee recalled that the clinical experts stated that people who have dexamethasone in current clinical practice are likely to have disease affecting only 1 eye (see section 4.2), but the proportion of unilateral uveitis in the HURON trial was unclear (see section 4.6). Using the committee's preferred assumptions for unilateral disease (see section 4.6), low rates of blindness (see section 4.11 and section 4.12) and utility values (see section 4.15) resulted in ICERs that ranged between £25,000 and £49,000 per QALY gained. The committee considered that the lower ICER would apply to patients whose better seeing eye needed treatment, because this reflected a risk of bilateral blindness; the higher ICER applied to patients at no risk of bilateral blindness, and was likely to be a significant overestimate because the disutility of monocular blindness was not modelled. The committee decided that dexamethasone for monocular disease with worsening vision and a risk of blindness was an acceptable use of NHS resources and that patient need is high. The committee concluded that the ICER for unilateral disease with a risk of blindness was likely to be in the range normally considered cost effective, and recommended dexamethasone for treating active non-infectious uveitis with worsening vision and a risk of blindness.
# Summary of appraisal committee's key conclusions
TA460
Appraisal title: Adalimumab and dexamethasone for treating non-infectious uveitis
Section
Key conclusion
Adalimumab is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids, only if there is:
active disease (that is, current inflammation in the eye) and
inadequate response or intolerance to immunosuppressants and
systemic disease or both eyes are affected (or 1 eye is affected if the second eye has poor visual acuity) and
worsening vision with a high risk of blindness (for example, risk of blindness that is similar to that seen in people with macular oedema).
Stop adalimumab for non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids if there is 1 of the following:
new active inflammatory chorioretinal, inflammatory retinal vascular lesions or both or
a 2‑step increase in vitreous haze or anterior chamber cell grade or
worsening of best corrected visual acuity by 3 or more lines or 15 letters.
Dexamethasone intravitreal implant is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults, only if there is:
active disease (that is, current inflammation in the eye) and
worsening vision with a risk of blindness.
The committee concluded that there is evidence to show that both adalimumab and dexamethasone are clinically effective treatments because there were significant improvements in the primary outcomes for the VISUAL trials (time to treatment failure: hazard ratio 0.50, 95% confidence interval 0.36 to 0.70 in VISUAL I; and HR 0.57, 95% CI 0.39 to 0.84 in VISUAL II), and HURON (vitreous haze score relative risk 4.0, 95% CI 2.0 to 7.6 at 8 weeks; and RR 2.2, 95% CI 1.1 to 4.1 at 26 weeks).
For adalimumab in patients with active non-infectious uveitis, the committee considered incremental cost-effectiveness ratios (ICERs) ranged from £23,688 to £37,279 per quality-adjusted life year (QALY) gained as most plausible and noted that they were probably lower because the rate of blindness was likely to have been underestimated for patients with progressive loss of visual acuity.
For adalimumab in patients with inactive non-infectious uveitis, the committee noted that all the ICERs in all the scenario analyses were above £80,000 per QALY gained, which is above the range normally considered a cost-effective use of NHS resources.
The committee considered that the most plausible ICER for dexamethasone was between £25,000 and £49,000 per QALY gained. It noted that the lower ICER would apply to patients whose better seeing eye needed treatment, because this reflected a risk of bilateral blindness; the higher ICER applied to patients at no risk of bilateral blindness, and was likely to be a significant overestimate because the disutility of monocular blindness was not modelled. The committee concluded that the ICER was likely to be in the range normally considered cost effective.
to 1.3, 4.19 to 4.22
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee heard from patient experts that symptoms include blurred vision and floaters in the eye, and sometimes pain and redness. It also heard that the condition may lead to complications such as cystoid macular oedema, vitreous haze, cataracts, glaucoma and irreversible retinal damage. The committee concluded that uveitis had a large effect on quality of life.
The technologies
Proposed benefits of the technologies
How innovative is the technology/are the technologies in its/their potential to make a significant and substantial impact on health-related benefits?
The committee recognised that patients and their carers would greatly value a new treatment which prevented or delayed sight loss, particularly if it reduced the significant adverse events associated with current treatments.
What is the position of the treatment(s) in the pathway of care for the condition?
The committee heard from clinical experts that adalimumab would generally be used in people with bilateral or systemic disease or both, but dexamethasone is generally used in people with unilateral disease.
Adverse reactions
The most commonly reported adverse reactions with adalimumab are infections, injection site reactions, headache and musculoskeletal pain. The most commonly reported adverse events after treatment with dexamethasone intravitreal implant are those often seen with ophthalmic steroid treatment or intravitreal injections.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee was aware that the clinical evidence came from 3 trials: VISUAL I and VISUAL II (adalimumab) and HURON (dexamethasone intravitreal implant). The VISUAL trials compared adalimumab plus background therapy (that is, initial steroids tapered to zero with or without 1 immunosuppressant) with placebo plus background therapy. The HURON trial compared dexamethasone plus background therapy with a sham procedure plus background therapy. The committee noted that there was no clinical evidence which directly compared adalimumab with dexamethasone and the assessment group did not do an indirect comparison using HURON and the VISUAL trials.
Relevance to general clinical practice in the NHS
The committee concluded the 3 trials were relevant for this appraisal.
Uncertainties generated by the evidence
The committee concluded that there was a lack of relevant evidence on therapy for non-infectious uveitis, with varied and often limited current treatments available. However, the available clinical evidence was adequate for decision-making.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee concluded that it would be useful to distinguish unilateral from systemic and bilateral disease and that people with a higher risk of blindness formed a clinically important subgroup.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee understood that the VISUAL trials showed that adalimumab had improved outcomes, such as time to treatment failure (HR 0.50, 95% CI 0.36 to 0.70 in VISUAL I and HR 0.57, 95% CI 0.39 to 0.84 in VISUAL II) and visual acuity, compared with placebo. It also understood that HURON showed that dexamethasone had improved outcomes, such as vitreous haze score (RR 4.0, 95% CI 2.0 to 7.6 at 8 weeks and RR 2.2, 95% CI 1.1 to 4.1 at 26 weeks) and visual acuity (in the affected eye), compared with the sham procedure.
Evidence for cost effectiveness
Availability and nature of evidence
The committee noted the assessment group had developed a Markov model with 4 health states in the base case (on treatment, treatment failure, permanent blindness, and death). The assessment group gave 3 separate base cases, based on the underpinning trial evidence: adalimumab for active disease, adalimumab for inactive disease, and dexamethasone intravitreal implant for active disease.
Uncertainties around and plausibility of assumptions and inputs in the economic model
For both adalimumab and dexamethasone, the committee acknowledged a lack of evidence but concluded that:
treatment is likely to have an effect on the future rate of blindness, although the extent of this effect was uncertain
the utility loss of blindness in both eyes was likely to be much higher than in unilateral blindness.
For adalimumab, the committee concluded that scenarios accounting for both the potential effect of blindness and the additional benefit of remission were most appropriate for decision-making and it was reasonable to assume that at least some people's disease would be in remission after treatment.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee noted that the disutility of monocular blindness was not modelled. The committee further discussed the effect of blindness depending on whether disease was unilateral or bilateral, which was not captured in the model. In its experience of previous appraisals for eye diseases, the utility loss of blindness in both eyes was likely to be much higher than in unilateral blindness.
Are there specific groups of people for whom the technologies are particularly cost effective?
The committee agreed that treatment with adalimumab and dexamethasone vitreal implant would be more cost effective in those at higher risk of permanent legal blindness, and it agreed that the presence of bilateral disease with macular oedema was a useful proxy for this. However, it noted that macular oedema was not the only precursor to blindness. The committee also recognised that people with unilateral disease in the better seeing eye were also at a high risk of permanent blindness if they had poor visual acuity in the other eye.
, 4.19 to 4.22
What are the key drivers of cost effectiveness?
The committee understood that the rate and relative risk of blindness were key drivers of the cost effectiveness.
Most likely cost-effectiveness estimate (given as an ICER)
For adalimumab in patients with active disease, the committee considered ICERs that ranged from £23,688 to £37,279 per QALY gained as most plausible and noted they were probably lower because the rate of blindness was likely to have been underestimated for patients with progressive loss of visual acuity.
For adalimumab in patients with inactive uveitis, the committee noted that all the ICERs in all the scenario analyses were above £80,000 per QALY gained.
The committee considered that the most plausible ICER for dexamethasone was between £25,000 and £49,000 per QALY gained. It noted that the lower ICER would apply to patients whose better seeing eye needed treatment, because this reflected a risk of bilateral blindness.
to 4.22
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee did not identify any specific equalities' considerations.
|
{'Recommendations': 'Adalimumab is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids, only if there is:\n\nactive disease (that is, current inflammation in the eye) and\n\ninadequate response or intolerance to immunosuppressants and\n\nsystemic disease or both eyes are affected (or 1\xa0eye is affected if the second eye has poor visual acuity) and\n\nworsening vision with a high risk of blindness (for example, risk of blindness that is similar to that seen in people with macular oedema).\n\nStop adalimumab for non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids if there is 1\xa0of the following:\n\nnew active inflammatory chorioretinal or inflammatory retinal vascular lesions, or both or\n\na 2‑step increase in vitreous haze or anterior chamber cell grade or\n\nworsening of best corrected visual acuity by 3\xa0or more lines or 15\xa0letters.\n\nDexamethasone intravitreal implant is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults, only if there is:\n\nactive disease (that is, current inflammation in the eye) and\n\nworsening vision with a risk of blindness.\n\nThese recommendations are not intended to affect treatment with adalimumab and dexamethasone that was started in the NHS before this guidance was published. Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.', 'Technologies': "Description of the technologies\n\nAdalimumab (Humira, AbbVie) is a monoclonal antibody that reduces inflammation by inhibiting pro-inflammatory cytokine tumour necrosis factor-alpha.\n\nDexamethasone intravitreal implant (Ozurdex, Allergan) is a biodegradable corticosteroid implant that suppresses inflammation by inhibiting the expression of pro-inflammatory mediators.\n\nMarketing authorisations\n\nAdalimumab is indicated 'for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid sparing, or in whom corticosteroid treatment is inappropriate.'\n\nDexamethasone intravitreal implant is indicated 'for the treatment of adult patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis.'\n\nAdverse reactions\n\nThe most commonly reported adverse reactions with adalimumab are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.\n\nThe most commonly reported adverse events after treatment with dexamethasone intravitreal implant are those often seen with ophthalmic steroid treatment or intravitreal injections (elevated intraocular pressure, cataract formation and conjunctival, or vitreal haemorrhage respectively).\n\nFor full details of adverse reactions and contraindications for adalimumab and dexamethasone, see the summaries of product characteristics.\n\nRecommended doses and schedules\n\nThe recommended dose of adalimumab for adults with non-infectious uveitis is an initial dose of 80\xa0mg, followed by 40\xa0mg every other week starting 1\xa0week after the initial dose. Adalimumab is given by subcutaneous injection. There is limited experience in starting treatment with adalimumab alone. Treatment with adalimumab can be started in combination with corticosteroids or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered off according to clinical practice from 2\xa0weeks after starting treatment.\n\nThe recommended dose of dexamethasone intravitreal implant is 1\xa0implant, containing 700\xa0micrograms of dexamethasone, to be administered intravitreally to the affected eye. Administration to both eyes concurrently is not recommended. Repeat doses should be considered when a patient experiences a response to treatment followed subsequently by a loss in visual acuity and in the clinician's opinion may benefit from retreatment without being exposed to significant risk.\n\nPrices\n\nAdalimumab costs £704.28 for 2\xa0pre-filled injections and each dexamethasone intravitreal implant costs £870.00 (excluding VAT; 'British National Formulary' [BNF] edition\xa072). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by AbbVie and Allergan and a review of these submissions by the assessment group. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of adalimumab and dexamethasone intravitreal implant. It considered evidence on the nature of non-infectious uveitis and the value placed on the benefits of adalimumab and dexamethasone by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical need and management of non-infectious uveitis\n\nThe committee heard from the clinical experts that uveitis describes a group of conditions characterised by inflammation inside the eye. It understood that this appraisal covers most sight-threatening forms of non-infectious uveitis (that is, those affecting the posterior structure of eye). This includes panuveitis, as well as intermediate and posterior uveitis. The committee heard from the patient experts that symptoms include blurred vision and floaters in the eye, and sometimes pain and redness. It also heard that the condition may lead to complications such as cystoid macular oedema, vitreous haze, cataracts, glaucoma and irreversible retinal damage. People may also have sudden and temporary or progressive and permanent visual impairment. The patient experts explained that losing visual function can affect a person's ability to do daily activities, work or study. One patient expert described the psychological effect of visual impairment after going blind in 1\xa0eye within 3\xa0months of the condition starting, stating that knowing how quickly sight could be completely lost was very distressing. The patient experts also explained that it is common for people with uveitis to suffer depression and anxiety and to feel isolated. The clinical and patient experts advised that current treatment options are associated with significant side effects. The committee concluded that uveitis has a substantial effect on quality of life.\n\nThe committee heard from the clinical experts that there are 3\xa0main reasons for treating non-infectious uveitis in clinical practice: vitreous haze, macular oedema and worsening vision. The committee also heard from the clinical experts and the assessment group that there is no nationally agreed pathway for treating non-infectious uveitis. The assessment group advised that in clinical practice, systemic steroids are usually used as a first-line treatment and 1 or 2 immunosuppressants, such as mycophenolate mofetil, are either used alone or with steroids as second-line treatment. This general treatment pathway was agreed by the clinical experts, although it was noted that treatment in clinical practice depends on whether disease is:\n\nactive (that is, current inflammation in the eye) or inactive (that is, limited inflammation, usually because of treatment with corticosteroids or immunosuppressants)\n\nsystemic (when disease is not only in the eye) or non-systemic (when disease is limited to the eye)\n\nunilateral (when 1\xa0eye is affected) or bilateral (when both eyes are affected).It heard from clinical experts that adalimumab would generally be used as a third-line treatment option in people with bilateral or systemic disease or both, but dexamethasone is generally used in people with unilateral disease. The committee concluded that the treatment pathway reflected current practice.\n\nThe clinical and patient experts stated that treatment options are currently restricted and there was a significant unmet need for both adalimumab and dexamethasone intravitreal implant. The committee heard from the clinical and patient experts that adalimumab and dexamethasone allow corticosteroid sparing, which is important not just for patients' short-term quality of life but also to avoid glaucoma, diabetes, stroke and heart attack. The committee recognised that patients and their carers would greatly value a new treatment which prevented or delayed sight loss, particularly if it reduced the significant side effects associated with current treatments.\n\n# Clinical effectiveness\n\n## Clinical evidence\n\nThe committee was aware that the comparators in the appraisal scope included corticosteroid injections and implants, systemic immunosuppressive therapies, tumour necrosis factor-alpha inhibitors (such as infliximab), intravitreal methotrexate and best supportive care. The scope also stated that the interventions should be compared with each other. However, direct clinical evidence was only available for the interventions compared with either placebo or a sham procedure. The evidence for adalimumab came from the VISUAL\xa0I and VISUAL\xa0II trials and the evidence for dexamethasone intravitreal implant came from the HURON trial. The VISUAL trials compared adalimumab plus background therapy (that is, initial steroids tapered to zero with or without 1 immunosuppressant) with placebo plus background therapy. The HURON trial compared dexamethasone plus background therapy with a sham procedure plus background therapy. The committee noted that there was no clinical evidence which directly compared adalimumab with dexamethasone and the assessment group did not do an indirect comparison using HURON and the VISUAL trials. The assessment group advised that an indirect comparison was not appropriate because patient characteristics in VISUAL\xa0I, VISUAL\xa0II and HURON differed and there was a lack of common comparators and outcomes. Furthermore, adalimumab and dexamethasone could be used at different points in the treatment pathway. The committee agreed that there was a lack of relevant evidence on therapy for non-infectious uveitis, with varied and often limited current treatments available. However, the available clinical evidence was adequate for decision-making.\n\n## Patients included in the trials\n\nAlthough the marketing authorisations for adalimumab and dexamethasone did not distinguish between active and inactive disease, the committee understood that VISUAL\xa0I and HURON included patients with active disease but VISUAL\xa0II included patients with inactive disease. The committee heard from the clinical experts that the distinction between active and inactive disease was clinically relevant because they were different populations, which would have different treatments. It heard that because maintenance treatment with immunosuppressants and corticosteroids may control inactive disease, the next line of treatment, such as adalimumab or dexamethasone intravitreal implant may not be needed. The committee was aware of an ongoing trial, ASTUTE, that examines the effectiveness of adalimumab compared with placebo as an add-on to standard care. It understood there were no data from this study at the time of this appraisal. The committee concluded that it would take these different populations into account when making its final recommendations.\n\nThe committee noted that the inclusion criteria for the VISUAL trials did not specify patients with macular oedema. It heard from clinical experts that people with macular oedema have a high risk of blindness. Because patients with macular oedema were not specifically included in the VISUAL trials, the clinical effectiveness of adalimumab may be underestimated in this group. It also heard from clinical experts that people with bilateral disease or systemic disease are likely to have a higher risk of blindness compared with people with unilateral or localised disease. The committee noted that most patients (over 90%) in the VISUAL trials had bilateral or systemic non-infectious uveitis. It also noted that the proportion of people with bilateral uveitis in HURON was unclear but patients had only 1\xa0dexamethasone implant, and current clinical practice preferred dexamethasone for unilateral disease. The committee concluded that it would be useful to distinguish unilateral from systemic and bilateral disease and that people with a higher risk of blindness formed a clinically important subgroup.\n\n## Clinical-effectiveness results\n\nThe committee noted that the primary outcome in the VISUAL trials was a composite measure of time to treatment failure. The committee understood that the VISUAL trials showed that adalimumab had improved outcomes, such as time to treatment failure and visual acuity, compared with placebo. The committee noted that the primary outcome in the HURON trial was the proportion of people with a vitreous haze score of\xa00. It understood that HURON showed that dexamethasone had improved outcomes, such as vitreous haze score and visual acuity (in the affected eye), compared with the sham procedure. The committee concluded that there is evidence to show that both adalimumab and dexamethasone are clinically effective treatments for improving visual acuity, anterior chamber cell grade and vitreous haze.\n\n## Table 1 Summary of clinical-effectiveness results\n\nAdalimumab versus placebo\n\nDexamethasone versus sham\n\nVISUAL I\n\nVISUAL II\n\nHURON\n\nTime to treatment failure (worsening of AC, VH, BCVA or new lesions)\n\nHR 0.50 (95%\xa0CI 0.36 to 0.70)\n\nHR 0.57 (95%\xa0CI 0.39 to 0.84)\n\nNot reported\n\nVisual acuity (BCVA, logMAR, change)\n\nMD −0.07 (95%\xa0CI −0.11 to\xa0−0.02)*\n\nMD −0.04 (95%\xa0CI −0.08 to 0.01)**\n\nMD not reported (p=0.002) at 26\xa0weeks\n\nVitreous haze grade = 0\n\nNot reported\n\nNot reported\n\nRR 4.0 (95%\xa0CI 2.0 to 7.6) at 8\xa0weeks\n\nNot reported\n\nNot reported\n\nRR 2.2 (95%\xa0CI 1.1 to 4.1) at 26\xa0weeks\n\n* Change from best state reached before\xa0week\xa06 to final or early termination.\n\n** From baseline to final or early termination.\n\nAbbreviations: AC, anterior chamber; BCVA, best corrected visual acuity; CI, confidence interval; HR, hazard ratio; logMAR, logarithm of the Minimum Angle of Resolution; MD, mean difference; RR, relative risk; VH, vitreous haze.\n\n# Cost effectiveness\n\n## Model structure\n\nThe committee noted the assessment group had developed a Markov model with 4\xa0health states in the base case (on treatment, treatment failure, permanent blindness and death). The assessment group gave 3\xa0separate base cases, based on the underpinning trial evidence: adalimumab for active disease, adalimumab for inactive disease, and dexamethasone intravitreal implant for active disease. The assessment group noted it had not been possible to distinguish between unilateral and bilateral disease in the model; however, over 90% of patients in the VISUAL trials on adalimumab had bilateral disease. The committee concluded that the assessment group's decision to separate its analyses into 3\xa0separate base cases was appropriate and supported by clinical evidence and that it would need to consider all 3\xa0base-case analyses when making its recommendations.\n\nThe committee was aware that the assessment group did an exploratory analysis with a 'remission' health state for the adalimumab model only. This was based on clinical advice that some people who have treatment with adalimumab will have disease which is in remission (the assessment group excluded this health state from its base case because of a lack of evidence). The committee understood that the exploratory analysis assumed that after around 2\xa0years of stable disease, treatment is no longer needed. This is because the disease is in remission but patients will have the same health-related quality of life as when they were having treatment. The committee heard from the clinical experts that the disease could be expected to go into remission in at least some of the people who have adalimumab. The committee concluded that although there is no evidence for remission, it was reasonable to assume that at least some people's disease could be in remission after treatment with adalimumab.\n\n## Modelling the rate of blindness\n\nThe committee noted that the follow-up time in the HURON trial was 26\xa0weeks, but a maximum follow-up of 80\xa0weeks was included in the VISUAL trials. None of the trials reported patients with permanent legal blindness. The assessment group advised that the rate of blindness and the relative risk of blindness associated with adalimumab and dexamethasone had a large effect on the incremental cost-effectiveness ratio (ICER) and did scenario analyses to model this potential effect. The committee acknowledged there was a lack of robust, long-term studies for the rate of blindness but concluded that the scenario analyses including blindness were appropriate for decision-making because it is likely that both adalimumab and dexamethasone had an effect on the rate of blindness, although the extent of this effect was uncertain.\n\nThe committee understood that in its base case, the assessment group preferred to use a constant annual rate of blindness of 0.0066 from Dick\xa0et\xa0al.\xa0(2016), a retrospective analysis of 1,769 insurance claims of adults with non-infectious intermediate uveitis, posterior uveitis or panuveitis in the US. In contrast, the company for adalimumab preferred the higher rate of blindness (0.0374) that was used in a scenario analysis by the assessment group. This rate was reported in a retrospective review of 315\xa0medical records in the UK (Durrani\xa0et\xa0al.\xa02004). However, the assessment group advised that this study included a wider population compared with the scope of this appraisal (only 61% of patients had posterior, intermediate or panuveitis and age ranged from 7\xa0to\xa086\xa0years) and was done in a tertiary centre in which patients are more likely to have severe, and often bilateral uveitis. The committee was aware that a higher rate of blindness would lead to more favourable cost-effectiveness results for the interventions. The committee agreed that for people at higher risk of blindness (for example, people with macular oedema and bilateral disease) the background rate of blindness is likely to be higher than in the base case. However, it noted that macular oedema was not the only precursor to blindness. The committee also agreed that the risk of permanent legal blindness in people having dexamethasone was probably lower compared with the risk of blindness in people having adalimumab. This is because dexamethasone is often used to treat unilateral disease, whereas adalimumab is more often used to treat bilateral disease later in the treatment pathway. The committee concluded that the rate of blindness in people at high risk was uncertain but likely to be higher than in the base case (0.0066). The committee also concluded the base-case rate of 0.0066 was acceptable for unilateral disease, because although this group might include people with macular oedema and at a higher risk of unilateral blindness, this was not the same as permanent legal blindness.\n\nThe committee noted that the assessment group's base case used a relative risk of blindness of\xa00.5 for dexamethasone (that is, a 50% lower rate of blindness in the dexamethasone group compared with the comparator group). For adalimumab, the base case did not allow blindness in either the adalimumab or comparator arms while on treatment, and used the same overall rate of blindness after treatment failure, which was strictly defined in the VISUAL trials. However, there was a lack of evidence to support a relative risk of\xa00.5 for dexamethasone. The clinical experts agreed that there was a lack of evidence to support this assumption, but considered a value of\xa00.5 to be clinically plausible for the affected eye. For adalimumab, the committee accepted the base-case assumptions. The committee concluded that the assessment group's approach to modelling was appropriate for decision-making provided that the dexamethasone rate is only applied to the affected eye, unless both eyes were affected and treated.\n\nThe committee noted that the assessment group did additional scenario analyses for adalimumab for active non-infectious uveitis using the committee's preferred utility for blindness of 0.57. The scenarios combined varying the relative risk of blindness with treatment and the rate at which treatment is stopped because of remission. The committee recalled its earlier conclusion that at least some people having adalimumab are likely to go into remission. The committee concluded that these scenarios were appropriate for decision-making because they accounted for both the possible effect on blindness and the additional benefit of remission.\n\n## Health-related quality of life\n\nThe committee was aware that the quality-of-life data from the clinical trials were assumed to include the effects of adverse events during the treatment period. Utility values for blindness were also taken from the literature. The committee heard from the patient and clinical experts that they were unsure whether this approach to modelling utility included the effect of uveitis on the whole person. This was because uveitis substantially affected quality of life, with visual disability having significant consequences for people (including depression and stress, for example, because of a loss of ability to support self and family), and their families and carers. However, the assessment group stated that the trial included holistic treatment benefit, as well as the main costs of adverse events and blindness. The committee agreed that uveitis had a significant effect on quality of life, and that there were limited data to inform the utility assumptions. However, it was aware that the utility values are designed to represent whole person health. The committee concluded that the utility values used were appropriate for decision-making.\n\nThe committee considered the approach to modelling the utility of the blindness health state. The committee noted that the quality-of-life value used in the base case (0.38 from Czoski-Murray\xa0et\xa0al.\xa02009) was low, and agreed that scenario analyses using the higher utility of\xa00.57 (from Brown\xa0et\xa0al.\xa01999) were more plausible. It was aware that in the model people were either permanently legally blind or not blind. The committee was aware this omitted the effect of worsening visual acuity and that level of vision was likely to be a continuous variable. The committee further discussed the effect of blindness depending on whether disease was unilateral or bilateral, which was not captured in the model. In its experience of previous appraisals for eye diseases, the utility loss of blindness in both eyes was likely to be much higher than in unilateral blindness.\n\nThe committee noted that EQ‑5D data were reported at baseline and follow-up in the VISUAL trials, but only at baseline in HURON. It was aware that all 3\xa0trials also assessed health-related quality of life using the Visual-Functioning Questionnaire (VFQ‑25) and that this measure is more specific to visual function. The committee understood that to model utilities for adalimumab over time, the assessment group used EQ‑5D data directly from the VISUAL trials. To estimate utility over time for dexamethasone, the assessment group used individual patient-level VFQ‑25 data and mapped these to EQ‑5D using a regression analysis. Individual patient-level data for adalimumab were not made available in time for the assessment group to use them. The committee heard from the assessment group that using VFQ‑25 data instead of EQ‑5D data had only a small effect on the ICERs. The committee concluded that the methodology used to derive this utility was acceptable for decision-making.\n\n## Resource use\n\nThe committee noted that to calculate the cost of blindness, the assessment group assumed that 30% of patients would have residential care. It understood that this cost was based on a health technology assessment (Colquitt\xa0et\xa0al.\xa02008) on treating age-related macular degeneration, which is likely to affect people who are older than those with uveitis. It recalled that people with non-infectious uveitis are between 20\xa0to 50\xa0years and only a small proportion would need residential care. The committee concluded that the proportion of people needing residential care is likely to be overestimated in the assessment group's model and, if this proportion were smaller, the ICERs would increase (that is, the treatments would become less cost effective) for the scenario analyses involving blindness.\n\nThe committee heard from the clinical experts that using multiple dexamethasone implants consecutively was associated with adverse events, including increased intraocular pressure and cataracts. It heard that for this reason, the clinical experts would use at most 3\xa0implants consecutively although this may vary in clinical practice. It also heard from the assessment group that using multiple implants consecutively was likely to produce similar cost-effectiveness results because the model assumed that dexamethasone would only provide a treatment benefit for around 6\xa0months. The committee concluded that consecutive use of dexamethasone was unlikely to have a large effect on the cost-effectiveness analyses.\n\n## Most plausible incremental cost-effectiveness ratios\n\nThe committee recalled its earlier concern that the cost of blindness had been overestimated in the model. This meant that the base-case and scenario analyses for both interventions favoured the interventions that were more effective in reducing blindness. However, it also noted that there was uncertainty around the background rate of blindness, which it considered had been underestimated for the high-risk groups for whom treatment with adalimumab or dexamethasone is possible. This was likely to make the cost-effectiveness results more conservative. The committee concluded that, although there was uncertainty, the reduction (that is, improvement) in ICERs resulting from overestimated costs of blindness were likely to be offset by the low rate of background blindness in this high-risk group.\n\nThe committee noted that the assessment group's base-case ICER for adalimumab in patients with inactive non-infectious uveitis was £321,405 per quality-adjusted life\xa0year (QALY) gained. It noted that all the ICERs in all the scenario analyses were above £80,000 per QALY gained. The committee agreed that these ICERs were substantially above the range normally considered a cost-effective use of NHS resources. The committee also noted that people with inactive disease would be unlikely to have treatment with adalimumab in clinical practice (see section\xa04.5). Therefore the committee did not recommend adalimumab for treating inactive non-infectious uveitis.\n\nThe committee noted that the assessment group's base-case ICER for adalimumab in patients with active non-infectious uveitis was £95,506 per QALY gained. However, this base case did not take account of its reasoning that there would be a relatively severely affected subgroup of patients (see section\xa04.6). The committee noted that disease was likely to be more severe in people with bilateral disease later in the treatment pathway. It agreed that the treatment would be more cost effective in those at higher risk of permanent legal blindness, and bilateral disease with macular oedema was a useful proxy for this. However, the committee also recognised that people with unilateral disease in the better seeing eye were also at a high risk of permanent blindness if they have poor visual acuity in the other eye. Using its preferred assumptions for severe disease (see section\xa04.6), high rates of blindness (see sections\xa04.11 and\xa04.12), utility values (see section\xa04.15) and occasional remission (see section\xa04.9), adalimumab resulted in ICERs that ranged from £23,688 to £37,279 per QALY gained, and these were probably lower because the rate of blindness was likely to have been underestimated for patients with progressive loss of visual acuity (see section\xa04.11). The committee noted that the VISUAL trials included some patients taking only 1 immunosuppressant but understood that in clinical practice, 2 immunosuppressants may be taken as second-line treatment (see section 4.2). Therefore it agreed that either 1 or 2 immunosuppressants may be used as part of second-line treatment before adalimumab is started. The committee also took into account the lack of available treatment options for this subgroup, the evidence from the patient and clinical experts about the adverse effects associated with current treatment options and comments from consultation. Taking all of this into account, it recommended adalimumab as a cost-effective use of NHS resources for treating non-infectious uveitis in the posterior segment of the eye in adults, if there is:\n\nactive disease and\n\nan inadequate response or intolerance to immunosuppressants and\n\nsystemic disease or both eyes are affected (or 1\xa0eye is affected if the second eye has poor visual acuity) and\n\nworsening vision with a high risk of blindness (for example, risk of blindness that is similar to that seen in people with macular oedema).The committee also agreed that a stopping rule should be included, which reflected the strict criteria for defining treatment failure in the VISUAL\xa0I trial. Based on these criteria, it concluded that treatment should be stopped if there is evidence of 1\xa0of the following:\n\nnew active inflammatory chorioretinal or inflammatory retinal vascular lesions or both or\n\na 2‑step increase in vitreous haze or anterior chamber cell grade or\n\nworsening of best corrected visual acuity by 3\xa0or more lines or 15\xa0letters.The committee's recommendations are therefore in line with the clinical trial evidence that has underpinned the marketing authorisation granted by the regulator.\n\nThe committee noted that the assessment group's base-case ICER for dexamethasone in patients with active uveitis was £20,058 per QALY gained. The committee recalled that the clinical experts stated that people who have dexamethasone in current clinical practice are likely to have disease affecting only 1\xa0eye (see section\xa04.2), but the proportion of unilateral uveitis in the HURON trial was unclear (see section\xa04.6). Using the committee's preferred assumptions for unilateral disease (see section\xa04.6), low rates of blindness (see section\xa04.11 and section\xa04.12) and utility values (see section\xa04.15) resulted in ICERs that ranged between £25,000 and £49,000 per QALY gained. The committee considered that the lower ICER would apply to patients whose better seeing eye needed treatment, because this reflected a risk of bilateral blindness; the higher ICER applied to patients at no risk of bilateral blindness, and was likely to be a significant overestimate because the disutility of monocular blindness was not modelled. The committee decided that dexamethasone for monocular disease with worsening vision and a risk of blindness was an acceptable use of NHS resources and that patient need is high. The committee concluded that the ICER for unilateral disease with a risk of blindness was likely to be in the range normally considered cost effective, and recommended dexamethasone for treating active non-infectious uveitis with worsening vision and a risk of blindness.\n\n# Summary of appraisal committee's key conclusions\n\nTA460\n\nAppraisal title: Adalimumab and dexamethasone for treating non-infectious uveitis\n\nSection\n\nKey conclusion\n\nAdalimumab is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids, only if there is:\n\nactive disease (that is, current inflammation in the eye) and\n\ninadequate response or intolerance to immunosuppressants and\n\nsystemic disease or both eyes are affected (or 1\xa0eye is affected if the second eye has poor visual acuity) and\n\nworsening vision with a high risk of blindness (for example, risk of blindness that is similar to that seen in people with macular oedema).\n\nStop adalimumab for non-infectious uveitis in the posterior segment of the eye in adults with inadequate response to corticosteroids if there is 1\xa0of the following:\n\nnew active inflammatory chorioretinal, inflammatory retinal vascular lesions or both or\n\na 2‑step increase in vitreous haze or anterior chamber cell grade or\n\nworsening of best corrected visual acuity by 3\xa0or more lines or 15\xa0letters.\n\nDexamethasone intravitreal implant is recommended as an option for treating non-infectious uveitis in the posterior segment of the eye in adults, only if there is:\n\nactive disease (that is, current inflammation in the eye) and\n\nworsening vision with a risk of blindness.\n\nThe committee concluded that there is evidence to show that both adalimumab and dexamethasone are clinically effective treatments because there were significant improvements in the primary outcomes for the VISUAL trials (time to treatment failure: hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.36 to 0.70 in VISUAL\xa0I; and HR\xa00.57, 95%\xa0CI 0.39 to 0.84 in VISUAL\xa0II), and HURON (vitreous haze score relative risk [RR] 4.0, 95%\xa0CI 2.0 to 7.6 at 8\xa0weeks; and RR\xa02.2, 95%\xa0CI 1.1 to 4.1 at 26\xa0weeks).\n\nFor adalimumab in patients with active non-infectious uveitis, the committee considered incremental cost-effectiveness ratios (ICERs) ranged from £23,688 to £37,279 per quality-adjusted life\xa0year (QALY) gained as most plausible and noted that they were probably lower because the rate of blindness was likely to have been underestimated for patients with progressive loss of visual acuity.\n\nFor adalimumab in patients with inactive non-infectious uveitis, the committee noted that all the ICERs in all the scenario analyses were above £80,000 per QALY gained, which is above the range normally considered a cost-effective use of NHS resources.\n\nThe committee considered that the most plausible ICER for dexamethasone was between £25,000 and £49,000 per QALY gained. It noted that the lower ICER would apply to patients whose better seeing eye needed treatment, because this reflected a risk of bilateral blindness; the higher ICER applied to patients at no risk of bilateral blindness, and was likely to be a significant overestimate because the disutility of monocular blindness was not modelled. The committee concluded that the ICER was likely to be in the range normally considered cost effective.\n\nto 1.3, 4.19 to 4.22\n\n\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee heard from patient experts that symptoms include blurred vision and floaters in the eye, and sometimes pain and redness. It also heard that the condition may lead to complications such as cystoid macular oedema, vitreous haze, cataracts, glaucoma and irreversible retinal damage. The committee concluded that uveitis had a large effect on quality of life.\n\n\n\nThe technologies\n\nProposed benefits of the technologies\n\nHow innovative is the technology/are the technologies in its/their potential to make a significant and substantial impact on health-related benefits?\n\nThe committee recognised that patients and their carers would greatly value a new treatment which prevented or delayed sight loss, particularly if it reduced the significant adverse events associated with current treatments.\n\n\n\nWhat is the position of the treatment(s) in the pathway of care for the condition?\n\nThe committee heard from clinical experts that adalimumab would generally be used in people with bilateral or systemic disease or both, but dexamethasone is generally used in people with unilateral disease.\n\n\n\nAdverse reactions\n\nThe most commonly reported adverse reactions with adalimumab are infections, injection site reactions, headache and musculoskeletal pain. The most commonly reported adverse events after treatment with dexamethasone intravitreal implant are those often seen with ophthalmic steroid treatment or intravitreal injections.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee was aware that the clinical evidence came from 3\xa0trials: VISUAL\xa0I and VISUAL\xa0II (adalimumab) and HURON (dexamethasone intravitreal implant). The VISUAL trials compared adalimumab plus background therapy (that is, initial steroids tapered to zero with or without 1\xa0immunosuppressant) with placebo plus background therapy. The HURON trial compared dexamethasone plus background therapy with a sham procedure plus background therapy. The committee noted that there was no clinical evidence which directly compared adalimumab with dexamethasone and the assessment group did not do an indirect comparison using HURON and the VISUAL trials.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded the 3\xa0trials were relevant for this appraisal.\n\n\n\nUncertainties generated by the evidence\n\nThe committee concluded that there was a lack of relevant evidence on therapy for non-infectious uveitis, with varied and often limited current treatments available. However, the available clinical evidence was adequate for decision-making.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee concluded that it would be useful to distinguish unilateral from systemic and bilateral disease and that people with a higher risk of blindness formed a clinically important subgroup.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee understood that the VISUAL trials showed that adalimumab had improved outcomes, such as time to treatment failure (HR\xa00.50, 95%\xa0CI 0.36 to 0.70 in VISUAL\xa0I and HR\xa00.57, 95%\xa0CI 0.39 to 0.84 in VISUAL\xa0II) and visual acuity, compared with placebo. It also understood that HURON showed that dexamethasone had improved outcomes, such as vitreous haze score (RR\xa04.0, 95%\xa0CI 2.0 to 7.6 at 8\xa0weeks and RR\xa02.2, 95%\xa0CI 1.1 to 4.1 at 26\xa0weeks) and visual acuity (in the affected eye), compared with the sham procedure.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee noted the assessment group had developed a Markov model with 4\xa0health states in the base case (on treatment, treatment failure, permanent blindness, and death). The assessment group gave 3\xa0separate base cases, based on the underpinning trial evidence: adalimumab for active disease, adalimumab for inactive disease, and dexamethasone intravitreal implant for active disease.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nFor both adalimumab and dexamethasone, the committee acknowledged a lack of evidence but concluded that:\n\ntreatment is likely to have an effect on the future rate of blindness, although the extent of this effect was uncertain\n\nthe utility loss of blindness in both eyes was likely to be much higher than in unilateral blindness.\n\nFor adalimumab, the committee concluded that scenarios accounting for both the potential effect of blindness and the additional benefit of remission were most appropriate for decision-making and it was reasonable to assume that at least some people's disease would be in remission after treatment.\n\n, 4.10, 4.15, 4.19\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee noted that the disutility of monocular blindness was not modelled. The committee further discussed the effect of blindness depending on whether disease was unilateral or bilateral, which was not captured in the model. In its experience of previous appraisals for eye diseases, the utility loss of blindness in both eyes was likely to be much higher than in unilateral blindness.\n\n\n\nAre there specific groups of people for whom the technologies are particularly cost effective?\n\nThe committee agreed that treatment with adalimumab and dexamethasone vitreal implant would be more cost effective in those at higher risk of permanent legal blindness, and it agreed that the presence of bilateral disease with macular oedema was a useful proxy for this. However, it noted that macular oedema was not the only precursor to blindness. The committee also recognised that people with unilateral disease in the better seeing eye were also at a high risk of permanent blindness if they had poor visual acuity in the other eye.\n\n, 4.19 to 4.22\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee understood that the rate and relative risk of blindness were key drivers of the cost effectiveness.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nFor adalimumab in patients with active disease, the committee considered ICERs that ranged from £23,688 to £37,279 per QALY gained as most plausible and noted they were probably lower because the rate of blindness was likely to have been underestimated for patients with progressive loss of visual acuity.\n\nFor adalimumab in patients with inactive uveitis, the committee noted that all the ICERs in all the scenario analyses were above £80,000 per QALY gained.\n\nThe committee considered that the most plausible ICER for dexamethasone was between £25,000 and £49,000 per QALY gained. It noted that the lower ICER would apply to patients whose better seeing eye needed treatment, because this reflected a risk of bilateral blindness.\n\nto 4.22\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable.\n\n–\n\nEnd-of-life considerations\n\nNot applicable.\n\n–\n\nEqualities considerations and social value judgements\n\nThe committee did not identify any specific equalities' considerations.\n\n–"}
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https://www.nice.org.uk/guidance/ta460
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Evidence-based recommendations on adalimumab (Humira) and dexamethasone (Ozurdex) for treating non-infectious uveitis in adults.
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d0eca53ca6e52502ca377e4bf8f75affd6703eef
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nice
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Parkinson's disease in adults
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Parkinson's disease in adults
This guideline covers diagnosing and managing Parkinson's disease in people aged 18 and over. It aims to improve care from the time of diagnosis, including monitoring and managing symptoms, providing information and support, and palliative care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Communication with people with Parkinson's disease and their carers
Communication with people with Parkinson's disease should aim towards empowering them to participate in judgements and choices about their own care.
In discussions, aim to achieve a balance between providing honest, realistic information about the condition and promoting a feeling of optimism.
Because people with Parkinson's disease may develop impaired cognitive ability, communication problems and/or depression, provide them with:
both oral and written communication throughout the course of the disease, which should be individually tailored and reinforced as necessary
consistent communication from the professionals involved.
Advise family members and carers about their right to carer assessment, and assessment for respite care and other support.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.
People with Parkinson's disease should have a comprehensive care plan agreed between the person, their family members and carers (as appropriate), and specialist and secondary healthcare providers.
Offer people with Parkinson's disease an accessible point of contact with specialist services. This could be provided by a Parkinson's disease nurse specialist.
Advise people with Parkinson's disease who drive that they should inform the Driver and Vehicle Licensing Agency (DVLA) and their car insurer of their condition when Parkinson's disease is diagnosed.
# Diagnosing Parkinson's disease
## Definition and differential diagnosis
Suspect Parkinson's disease in people presenting with tremor, stiffness, slowness, balance problems and/or gait disorders.
If Parkinson's disease is suspected, refer people quickly and untreated to a specialist with expertise in the differential diagnosis of this condition.
## Clinical and post-mortem diagnosis
Diagnose Parkinson's disease clinically, based on the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria.
Encourage healthcare professionals to discuss with people with Parkinson's disease the possibility of donating tissue to a brain bank for diagnostic confirmation and research.
## Review of diagnosis
Review the diagnosis of Parkinson's disease regularly, and reconsider it if atypical clinical features develop. (People diagnosed with Parkinson's disease should be seen at regular intervals of 6 to 12 months to review their diagnosis.)
## Single photon emission computed tomography
Consider 123I‑FP‑CIT single photon emission computed tomography (SPECT) for people with tremor if essential tremor cannot be clinically differentiated from parkinsonism.
123I‑FP‑CIT SPECT should be available to specialists with expertise in its use and interpretation.
## Positron emission tomography
Do not use positron emission tomography (PET) in the differential diagnosis of parkinsonian syndromes, except in the context of clinical trials.
## Structural MRI
Do not use structural MRI to diagnose Parkinson's disease.
Structural MRI may be considered in the differential diagnosis of other parkinsonian syndromes.
## Magnetic resonance volumetry
Do not use magnetic resonance volumetry in the differential diagnosis of parkinsonian syndromes, except in the context of clinical trials.
## Magnetic resonance spectroscopy
Do not use magnetic resonance spectroscopy in the differential diagnosis of parkinsonian syndromes.
## Acute levodopa and apomorphine challenge tests
Do not use acute levodopa and apomorphine challenge tests in the differential diagnosis of parkinsonian syndromes.
## Objective smell testing
Do not use objective smell testing in the differential diagnosis of parkinsonian syndromes, except in the context of clinical trials.
# Pharmacological management of motor symptoms
Before starting treatment for people with Parkinson's disease, discuss:
the person's individual clinical circumstances, for example, their symptoms, comorbidities and risks from polypharmacy
the person's individual lifestyle circumstances, preferences, needs and goals
the potential benefits and harms of the different drug classes (see table 1).
Levodopa
Dopamine agonists
Monoamine oxidase‑B (MAO‑B) inhibitors
Motor symptoms
More improvement in motor symptoms
Less improvement in motor symptoms
Less improvement in motor symptoms
Activities of daily living
More improvement in activities of daily living
Less improvement in activities of daily living
Less improvement in activities of daily living
Motor complications
More motor complications
Fewer motor complications
Fewer motor complications
Adverse events
(Excessive sleepiness, hallucinations and impulse control disorders; see the summary of product characteristics for full information on individual medicines)
Fewer specified adverse events
More specified adverse events
Fewer specified adverse events
Antiparkinsonian medicines should not be withdrawn abruptly or allowed to fail suddenly due to poor absorption (for example, gastroenteritis, abdominal surgery) to avoid the potential for acute akinesia or neuroleptic malignant syndrome.
The practice of withdrawing people from their antiparkinsonian drugs (so called 'drug holidays') to reduce motor complications should not be undertaken because of the risk of neuroleptic malignant syndrome.
In view of the risks of sudden changes in antiparkinsonian medicines, people with Parkinson's disease who are admitted to hospital or care homes should have their medicines:
given at the appropriate times, which in some cases may mean allowing self-medication
adjusted by, or adjusted only after discussion with, a specialist in the management of Parkinson's disease.
## First-line treatment
Offer levodopa to people in the early stages of Parkinson's disease whose motor symptoms impact on their quality of life.
Consider a choice of dopamine agonists, levodopa or monoamine oxidase B (MAO‑B) inhibitors for people in the early stages of Parkinson's disease whose motor symptoms do not impact on their quality of life.
Do not offer ergot-derived dopamine agonists as first-line treatment for Parkinson's disease. Follow the Medicines and Healthcare products Regulatory Agency guidance on the warnings and contraindications for ergot-derived dopamine agonists.
## Information and support
When starting treatment for people with Parkinson's disease, give people and their family members and carers (as appropriate) oral and written information about the following risks, and record that the discussion has taken place:
Impulse control disorders with all dopaminergic therapy (and the increased risk with dopamine agonists). Also see recommendations in the section on managing and monitoring impulse control disorders as an adverse effect of dopaminergic therapy
Excessive sleepiness and sudden onset of sleep with dopamine agonists. Also see recommendations on daytime sleepiness in the section on pharmacological management of non-motor symptoms
Psychotic symptoms (hallucinations and delusions) with all Parkinson's disease treatments (and the higher risk with dopamine agonists). Also see the recommendations on psychotic symptoms (hallucinations and delusions) in the section on pharmacological management of non-motor symptoms.
## Adjuvant treatment of motor symptoms
If a person with Parkinson's disease has developed dyskinesia and/or motor fluctuations, including medicines 'wearing off', seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying therapy.
Offer a choice of dopamine agonists, MAO‑B inhibitors or catechol‑O‑methyl transferase (COMT) inhibitors as an adjunct to levodopa for people with Parkinson's disease who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy, after discussing:
the person's individual clinical circumstances, for example, their Parkinson's disease symptoms, comorbidities and risks from polypharmacy
the person's individual lifestyle circumstances, preferences, needs and goals
the potential benefits and harms of the different drug classes (see table 2).
Dopamine agonists
Monoamine oxidase-B (MAO‑B) inhibitors
Catechol-O-methyl transferase (COMT) inhibitors
Amantadine
Motor symptoms
Improvement in motor symptoms
Improvement in motor symptoms
Improvement in motor symptoms
No evidence of improvement in motor symptoms
Activities of daily living
Improvement in activities of daily living
Improvement in activities of daily living
Improvement in activities of daily living
No evidence of improvement in activities of daily living
Off time
More off‑time reduction
Off‑time reduction
Off‑time reduction
No studies reporting this outcome
Adverse events
Intermediate risk of adverse events
Fewer adverse events
More adverse events
No studies reporting this outcome
Hallucinations
More risk of hallucinations
Lower risk of hallucinations
Lower risk of hallucinations
No studies reporting this outcome
Choose a non-ergot-derived dopamine agonist in most cases, because of the monitoring that is needed with ergot-derived dopamine agonists. Follow the Medicines and Healthcare products Regulatory Agency guidance on the warnings and contraindications for ergot-derived dopamine agonists.
Only consider an ergot-derived dopamine agonist as an adjunct to levodopa for people with Parkinson's disease:
who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy and
whose symptoms are not adequately controlled with a non-ergot-derived dopamine agonist. Follow the Medicines and Healthcare products Regulatory Agency guidance on the warnings and contraindications for ergot-derived dopamine agonists.
If dyskinesia is not adequately managed by modifying existing therapy, consider amantadine.
Do not offer anticholinergics to people with Parkinson's disease who have developed dyskinesia and/or motor fluctuations.
# Managing and monitoring impulse control disorders as an adverse effect of dopaminergic therapy
## Predictors for the development of impulse control disorders
Recognise that impulse control disorders can develop in a person with Parkinson's disease who is on any dopaminergic therapy at any stage in the disease course.
Recognise that the following are associated with an increased risk of developing impulse control disorders:
Dopamine agonist therapy.
A history of previous impulsive behaviours.
A history of alcohol consumption and/or smoking.
## Information and support
When starting dopamine agonist therapy, give people and their family members and carers (as appropriate) oral and written information about the following, and record that the discussion has taken place:
The increased risk of developing impulse control disorders when taking dopamine agonist therapy, and that these may be concealed by the person affected.
The different types of impulse control disorders (for example, compulsive gambling, hypersexuality, binge eating and obsessive shopping).
Who to contact if impulse control disorders develop.
The possibility that if problematic impulse control disorders develop, dopamine agonist therapy will be reviewed and may be reduced or stopped.
Discuss potential impulse control disorders at review appointments, particularly when modifying therapy, and record that the discussion has taken place.
Be aware that impulse control disorders can also develop while taking dopaminergic therapies other than dopamine agonists.
## Managing dopaminergic therapy in people who have developed an impulse control disorder
If a person with Parkinson's disease has developed a problematic impulse control disorder, seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying dopaminergic therapy.
Discuss the following with the person and their family members and carers (as appropriate):
How the impulse control disorder is affecting their life.
Possible treatments, such as reducing or stopping dopaminergic therapy.
The benefits and disadvantages of reducing or stopping dopaminergic therapy.
When managing impulse control disorders, modify dopaminergic therapy by first gradually reducing any dopamine agonist. Monitor whether the impulse control disorder improves and whether the person has any symptoms of dopamine agonist withdrawal.
Offer specialist cognitive behavioural therapy targeted at impulse control disorders if modifying dopaminergic therapy is not effective.
# Pharmacological management of non-motor symptoms
## Daytime sleepiness
Advise people with Parkinson's disease who have daytime sleepiness and/or sudden onset of sleep not to drive (and to inform the DVLA of their symptoms) and to think about any occupation hazards. Adjust their medicines to reduce its occurrence, having first sought advice from a healthcare professional with specialist expertise in Parkinson's disease.
Consider modafinil to treat excessive daytime sleepiness in people with Parkinson's disease, only if a detailed sleep history has excluded reversible pharmacological and physical causes. Women who are pregnant or who are planning a pregnancy should not take modafinil, in line with the MHRA safety advice on modafinil.
At least every 12 months, a healthcare professional with specialist expertise in Parkinson's disease should review people with Parkinson's disease who are taking modafinil. Women who are pregnant or who are planning a pregnancy should not take modafinil, in line with the MHRA safety advice on modafinil.
## Restless leg syndrome and rapid eye movement sleep behaviour disorder
Take care to identify and manage restless leg syndrome and rapid eye movement sleep behaviour disorder in people with Parkinson's disease and sleep disturbance.
Consider clonazepam or melatonin to treat rapid eye movement sleep behaviour disorder if a medicines review has addressed possible pharmacological causes. For guidance on safe prescribing of benzodiazapines (such as clonazepam) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.In July 2017, this was an off-label use of clonazepam and melatonin. See NICE's information on prescribing medicines.
## Nocturnal akinesia
Consider levodopa or oral dopamine agonists to treat nocturnal akinesia in people with Parkinson's disease. If the selected option is not effective or not tolerated, offer the other instead.
Consider rotigotine if levodopa and/or oral dopamine agonists are not effective in treating nocturnal akinesia.
## Orthostatic hypotension
If a person with Parkinson's disease has developed orthostatic hypotension, review the person's existing medicines to address possible pharmacological causes, including:
antihypertensives (including diuretics)
dopaminergics
anticholinergics
antidepressants.
Consider midodrine for people with Parkinson's disease and orthostatic hypotension, taking into account the contraindications and monitoring requirements (including monitoring for supine hypertension).
If midodrine is contraindicated, not tolerated or not effective, consider fludrocortisone (taking into account its safety profile, in particular its cardiac risk and potential interactions with other medicines). In July 2017, this was an off-label use of fludrocortisone. See NICE's information on prescribing medicines.
## Depression
For guidance on identifying, treating and managing depression in people with Parkinson's disease, see the NICE guideline on depression in adults with a chronic physical health problem.
## Psychotic symptoms (hallucinations and delusions)
In July 2017, the use of quetiapine in recommendations 1.5.16 and 1.5.18 was off-label. See NICE's information on prescribing medicines.
At review appointments and following medicines changes, ask people with Parkinson's disease and their family members and carers (as appropriate) if the person is experiencing hallucinations (particularly visual) or delusions.
Perform a general medical evaluation for people with hallucinations or delusions, and offer treatment for any conditions that might have triggered them.
Do not treat hallucinations and delusions if they are well tolerated by the person with Parkinson's disease and their family members and carers (as appropriate).
Reduce the dosage of any Parkinson's disease medicines that might have triggered hallucinations or delusions, taking into account the severity of symptoms and possible withdrawal effects. Seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying therapy.
Consider quetiapine to treat hallucinations and delusions in people with Parkinson's disease who have no cognitive impairment.
If standard treatment is not effective, offer clozapine to treat hallucinations and delusions in people with Parkinson's disease. Be aware that registration with a patient monitoring service is needed.
Be aware that lower doses of quetiapine and clozapine are needed for people with Parkinson's disease than in other indications.
Do not offer olanzapine to treat hallucinations and delusions in people with Parkinson's disease.
Recognise that other antipsychotic medicines (such as phenothiazines and butyrophenones) can worsen the motor features of Parkinson's disease.
For guidance on hallucinations and delusions in people with dementia, see the section on managing non-cognitive symptoms in the NICE guideline on dementia.
## Parkinson's disease dementia
Offer a cholinesterase inhibitor for people with mild or moderate Parkinson's disease dementia. In July 2017, rivastigmine capsules are the only treatment with a UK marketing authorisation for this indication. Use of donepezil, galantamine and rivastigmine patches was off-label. See NICE's information on prescribing medicines.
Consider a cholinesterase inhibitor for people with severe Parkinson's disease dementia. In July 2017, this was an off-label use of cholinesterase inhibitors. See NICE's information on prescribing medicines.
Consider memantine for people with Parkinson's disease dementia, only if cholinesterase inhibitors are not tolerated or are contraindicated. In July 2017, this was an off-label use of memantine. See NICE's information on prescribing medicines.
For guidance on assessing and managing dementia, and supporting people living with dementia, see the NICE guideline on dementia.
## Drooling of saliva
In July 2017, use of glycopyrronium bromide in recommendations 1.5.27, 1.5.28 and 1.5.29 was off-label.
In September 2019, Xeomin was the only preparation of botulinum toxin A (recommendation 1.5.28) licensed in the UK for treating chronic sialorrhoea caused by neurological conditions in adults. Use of other preparation of botulinum toxin type A was off-label.
See NICE's information on prescribing medicines.
Only consider pharmacological management for drooling of saliva in people with Parkinson's disease if non-pharmacological management (for example, speech and language therapy; see recommendation 1.7.8) is not available or has not been effective.
Consider glycopyrronium bromide to manage drooling of saliva in people with Parkinson's disease.
If treatment for drooling of saliva with glycopyrronium bromide is not effective, not tolerated or contraindicated (for example, in people with cognitive impairment, hallucinations or delusions, or a history of adverse effects following anticholinergic treatment), consider referral to a specialist service for botulinum toxin A.
Only consider anticholinergic medicines other than glycopyrronium bromide to manage drooling of saliva in people with Parkinson's disease if their risk of cognitive adverse effects is thought to be minimal. Use topical preparations if possible (for example, atropine) to reduce the risk of adverse events.
# Pharmacological neuroprotective therapy
Do not use vitamin E as a neuroprotective therapy for people with Parkinson's disease.
Do not use co‑enzyme Q10 as a neuroprotective therapy for people with Parkinson's disease, except in the context of clinical trials.
Do not use dopamine agonists as neuroprotective therapies for people with Parkinson's disease, except in the context of clinical trials.
Do not use MAO‑B inhibitors as neuroprotective therapies for people with Parkinson's disease, except in the context of clinical trials.
# Non-pharmacological management of motor and non-motor symptoms
## Parkinson's disease nurse specialist interventions
People with Parkinson's disease should have regular access to:
clinical monitoring and medicines adjustment
a continuing point of contact for support, including home visits when appropriate
a reliable source of information about clinical and social matters of concern to people with Parkinson's disease and their family members and their carers (as appropriate),which may be provided by a Parkinson's disease nurse specialist.
## Physiotherapy and physical activity
Consider referring people who are in the early stages of Parkinson's disease to a physiotherapist with experience of Parkinson's disease for assessment, education and advice, including information about physical activity.
Offer Parkinson's disease-specific physiotherapy for people who are experiencing balance or motor function problems.
Consider the Alexander Technique for people with Parkinson's disease who are experiencing balance or motor function problems.
## Occupational therapy
Consider referring people who are in the early stages of Parkinson's disease to an occupational therapist with experience of Parkinson's disease for assessment, education and advice on motor and non-motor symptoms.
Offer Parkinson's disease-specific occupational therapy for people who are having difficulties with activities of daily living.
## Speech and language therapy
Consider referring people who are in the early stages of Parkinson's disease to a speech and language therapist with experience of Parkinson's disease for assessment, education and advice.
Offer speech and language therapy for people with Parkinson's disease who are experiencing problems with communication, swallowing or saliva. This should include:
strategies to improve the safety and efficiency of swallowing to minimise the risk of aspiration, such as expiratory muscle strength training (EMST)
strategies to improve speech and communication, such as attention to effort therapies.
Consider referring people for alternative and augmentative communication equipment that meets their communication needs as Parkinson's disease progresses and their needs change.
## Nutrition
Consider referring people with Parkinson's disease to a dietitian for specialist advice.
Discuss a diet in which most of the protein is eaten in the final main meal of the day (a protein redistribution diet) for people with Parkinson's disease on levodopa who experience motor fluctuations.
Advise people with Parkinson's disease to avoid a reduction in their total daily protein consumption.
Advise people with Parkinson's disease to take a vitamin D supplement. See the NICE guideline on vitamin D for recommendations on vitamin D testing, and the NICE guidelines on falls in older people and osteoporosis.
Do not offer creatine supplements to people with Parkinson's disease.
Advise people with Parkinson's disease not to take over-the-counter dietary supplements without first consulting their pharmacist or other healthcare professional.
# Deep brain stimulation and levodopa–carbidopa intestinal gel
## Deep brain stimulation
Offer people with advanced Parkinson's disease best medical therapy, which may include intermittent apomorphine injection and/or continuous subcutaneous apomorphine infusion.
Do not offer deep brain stimulation to people with Parkinson's disease whose symptoms are adequately controlled by best medical therapy.
Consider deep brain stimulation for people with advanced Parkinson's disease whose symptoms are not adequately controlled by best medical therapy.
## Levodopa–carbidopa intestinal gel
Levodopa–carbidopa intestinal gel is currently available through an NHS England clinical commissioning policy. It is recommended that this policy is reviewed in light of this guidance.
# Palliative care
## Information and support
Offer people with Parkinson's disease and their family members and carers (as appropriate) opportunities to discuss the prognosis of their condition. These discussions should promote people's priorities, shared decision-making and patient-centred care.
Offer people with Parkinson's disease and their family members and carers (as appropriate) oral and written information about the following, and record that the discussion has taken place:
Progression of Parkinson's disease.
Possible future adverse effects of Parkinson's disease medicines in advanced Parkinson's disease.
Advance care planning, including Advance Decisions to Refuse Treatment (ADRT) and Do Not Attempt Resuscitation (DNACPR) orders, and Lasting Power of Attorney for finance and/or health and social care.
Options for future management.
What could happen at the end of life.
Available support services, for example, personal care, equipment and practical support, financial support and advice, care at home and respite care.
When discussing palliative care, recognise that family members and carers may have different information needs from the person with Parkinson's disease.
## Referral
Consider referring people at any stage of Parkinson's disease to the palliative care team to give them and their family members or carers (as appropriate) the opportunity to discuss palliative care and care at the end of life. # Context
Parkinson's disease is a progressive neurodegenerative condition resulting from the death of dopamine-containing cells of the substantia nigra in the brain. There is no consistently reliable test that can distinguish Parkinson's disease from other conditions that have a similar clinical presentation. The diagnosis is primarily based on a clinical history and examination.
Parkinson's disease is one of the most common neurological conditions. It is estimated to affect up to 160 people per 100,000, with an annual incidence in the UK of 15 to 20 per 100,000.
People with Parkinson's disease classically present with the symptoms and signs described as 'parkinsonism': these include bradykinesia (slow movements), rigidity, rest tremor (shaking) and postural instability (loss of balance).
The symptoms of parkinsonism are not always a result of Parkinson's disease. Other causes include side effects of medicines, vascular disease, and less common degenerative conditions such as progressive supranuclear palsy and multiple system atrophy.
Parkinson's disease has historically been recognised as a primary movement disorder; however, other symptoms may be prominent, such as depression, cognitive impairment and dementia. In the later stages of the disease, people may develop pain and autonomic disturbances (such as dizziness and fainting, and problems with sweating, heart rate, digestion, vision and sexual function). These other symptoms are sometimes described as the 'non-motor' manifestations of Parkinson's disease. The condition may progress to cause significant impairments, adversely affecting quality of life and, indirectly, the quality of life of family and carers.# Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
# Combination treatment for Parkinson's disease dementia
What is the effectiveness of combination treatment with a cholinesterase inhibitor and memantine for people with Parkinson's disease dementia if treatment with a cholinesterase inhibitor alone is not effective or no longer effective?
## Why this is important
The guideline committee felt that cholinesterase inhibitors, memantine and combination therapy with both treatments are all reasonable clinical options, but noted that some people do not tolerate cholinesterase inhibitors well due to side effects. The evidence base for memantine was considerably weaker than for cholinesterase inhibitors, and therefore there would be value in either additional trials of memantine compared with placebo (in people for whom cholinesterase inhibitors are not an option), or non-inferiority studies compared with cholinesterase inhibitors.
In clinical practice, memantine is often added to a cholinesterase inhibitor when it is no longer proving effective, but there is no evidence base for this and randomised trials to establish whether there is additional benefit would be valuable. Both of these questions could potentially be answered in a single study with 3 arms of memantine monotherapy, cholinesterase inhibitor monotherapy and combination treatment.
# Orthostatic hypotension treatment
For people with Parkinson's disease, what is the most effective pharmacological treatment for orthostatic hypotension?
Particular interventions and comparisons of interest are:
midodrine compared with fludrocortisone (primary comparison)
pyridostigmine
ephedrine
pseudoephedrine.
## Why this is important
The guideline committee felt that orthostatic hypotension was an important practical problem, common in people with Parkinson's disease and a contributor to falls and injuries. The current best pharmacological treatment is not yet established and research in this area would help to determine this. The randomised controlled trials that have previously been undertaken have only provided low-quality evidence (because of both small sample sizes and weaknesses in the trial designs) and cover only a subset of the comparisons of interest, making future research in this area of value.
# Psychotic symptoms (hallucinations and delusions)
What is the effectiveness of rivastigmine compared with atypical antipsychotic drugs for treating psychotic symptoms (particularly hallucinations and delusions) associated with Parkinson's disease?
## Why this is important
Rivastigmine is commonly used to treat Parkinson's disease psychosis because it has shown some effectiveness in improving behavioural symptoms in people with Parkinson's disease dementia. At present, no evidence exists to support the efficacy of rivastigmine in treating people with Parkinson's disease whose symptoms are predominantly psychotic. It would be beneficial to undertake primary research in this area to determine the most effective treatment options for managing Parkinson's disease psychosis.
# Rapid eye movement sleep behaviour disorder treatment
What is the best first-line treatment for rapid eye movement sleep behaviour disorder (RBD) in people with Parkinson's disease?
## Why this is important
The guideline committee highlighted the importance of minimising RBD, for both people with Parkinson's disease and their carers, particularly because of potential safety concerns. Only 1 paper was found to address optimal management, and this involved people in whom first-line treatment had failed. With multiple possible treatment options and no current evidence on what the most effective first-line treatment is, research (in the form of randomised controlled trials) in this area would be beneficial.
# Physiotherapy
Does physiotherapy started early in the course of Parkinson's disease, as opposed to after motor symptom onset, confer benefits in terms of delaying symptom onset and/or reducing severity?
## Why this is important
The guideline committee felt that physiotherapy was beneficial for those earlier in the course of the disease as it may delay or lessen problems associated with symptoms, as well as for those who have developed symptoms and problems. At present, no substantial evidence exists to support the efficacy of physiotherapy as an early intervention to prevent the onset or reduce severity of motor symptoms, because most of the trials have been conducted in people who have already developed motor symptoms.
If physiotherapy were shown to have a beneficial effect in either delaying the onset or decreasing the severity of symptoms, this would have a substantial beneficial impact on the quality of life of people with Parkinson's disease and their family and carers. Relevant trials would not compare physiotherapy with no physiotherapy, but rather early physiotherapy (at the time of diagnosis) with physiotherapy offered at the current standard times in the UK.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Communication with people with Parkinson's disease and their carers\n\nCommunication with people with Parkinson's disease should aim towards empowering them to participate in judgements and choices about their own care. \n\nIn discussions, aim to achieve a balance between providing honest, realistic information about the condition and promoting a feeling of optimism. \n\nBecause people with Parkinson's disease may develop impaired cognitive ability, communication problems and/or depression, provide them with:\n\nboth oral and written communication throughout the course of the disease, which should be individually tailored and reinforced as necessary\n\nconsistent communication from the professionals involved. \n\nAdvise family members and carers about their right to carer assessment, and assessment for respite care and other support.See the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. \n\nPeople with Parkinson's disease should have a comprehensive care plan agreed between the person, their family members and carers (as appropriate), and specialist and secondary healthcare providers. \n\nOffer people with Parkinson's disease an accessible point of contact with specialist services. This could be provided by a Parkinson's disease nurse specialist. \n\nAdvise people with Parkinson's disease who drive that they should inform the Driver and Vehicle Licensing Agency (DVLA) and their car insurer of their condition when Parkinson's disease is diagnosed. \n\n# Diagnosing Parkinson's disease\n\n## Definition and differential diagnosis\n\nSuspect Parkinson's disease in people presenting with tremor, stiffness, slowness, balance problems and/or gait disorders. \n\nIf Parkinson's disease is suspected, refer people quickly and untreated to a specialist with expertise in the differential diagnosis of this condition. [2006, amended 2017]\n\n## Clinical and post-mortem diagnosis\n\nDiagnose Parkinson's disease clinically, based on the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria. \n\nEncourage healthcare professionals to discuss with people with Parkinson's disease the possibility of donating tissue to a brain bank for diagnostic confirmation and research. \n\n## Review of diagnosis\n\nReview the diagnosis of Parkinson's disease regularly, and reconsider it if atypical clinical features develop. (People diagnosed with Parkinson's disease should be seen at regular intervals of 6\xa0to 12\xa0months to review their diagnosis.) \n\n## Single photon emission computed tomography\n\nConsider 123I‑FP‑CIT single photon emission computed tomography (SPECT) for people with tremor if essential tremor cannot be clinically differentiated from parkinsonism. [2006, amended 2017]\n\n123I‑FP‑CIT\xa0SPECT should be available to specialists with expertise in its use and interpretation. \n\n## Positron emission tomography\n\nDo not use positron emission tomography (PET) in the differential diagnosis of parkinsonian syndromes, except in the context of clinical trials. [2006, amended 2017]\n\n## Structural MRI\n\nDo not use structural MRI to diagnose Parkinson's disease. [2006, amended 2017]\n\nStructural MRI may be considered in the differential diagnosis of other parkinsonian syndromes. \n\n## Magnetic resonance volumetry\n\nDo not use magnetic resonance volumetry in the differential diagnosis of parkinsonian syndromes, except in the context of clinical trials. [2006, amended 2017]\n\n## Magnetic resonance spectroscopy\n\nDo not use magnetic resonance spectroscopy in the differential diagnosis of parkinsonian syndromes. [2006, amended 2017]\n\n## Acute levodopa and apomorphine challenge tests\n\nDo not use acute levodopa and apomorphine challenge tests in the differential diagnosis of parkinsonian syndromes. [2006, amended 2017]\n\n## Objective smell testing\n\nDo not use objective smell testing in the differential diagnosis of parkinsonian syndromes, except in the context of clinical trials. [2006, amended 2017]\n\n# Pharmacological management of motor symptoms\n\nBefore starting treatment for people with Parkinson's disease, discuss:\n\nthe person's individual clinical circumstances, for example, their symptoms, comorbidities and risks from polypharmacy\n\nthe person's individual lifestyle circumstances, preferences, needs and goals\n\nthe potential benefits and harms of the different drug classes (see table\xa01). \n\n-\n\nLevodopa\n\nDopamine agonists\n\nMonoamine oxidase‑B (MAO‑B) inhibitors\n\nMotor symptoms\n\nMore improvement in motor symptoms\n\nLess improvement in motor symptoms\n\nLess improvement in motor symptoms\n\nActivities of daily living\n\nMore improvement in activities of daily living\n\nLess improvement in activities of daily living\n\nLess improvement in activities of daily living\n\nMotor complications\n\nMore motor complications\n\nFewer motor complications\n\nFewer motor complications\n\nAdverse events\n\n(Excessive sleepiness, hallucinations and impulse control disorders; see the summary of product characteristics for full information on individual medicines)\n\nFewer specified adverse events\n\nMore specified adverse events\n\nFewer specified adverse events\n\nAntiparkinsonian medicines should not be withdrawn abruptly or allowed to fail suddenly due to poor absorption (for example, gastroenteritis, abdominal surgery) to avoid the potential for acute akinesia or neuroleptic malignant syndrome. \n\nThe practice of withdrawing people from their antiparkinsonian drugs (so called 'drug holidays') to reduce motor complications should not be undertaken because of the risk of neuroleptic malignant syndrome. \n\nIn view of the risks of sudden changes in antiparkinsonian medicines, people with Parkinson's disease who are admitted to hospital or care homes should have their medicines:\n\ngiven at the appropriate times, which in some cases may mean allowing self-medication\n\nadjusted by, or adjusted only after discussion with, a specialist in the management of Parkinson's disease. \n\n## First-line treatment\n\nOffer levodopa to people in the early stages of Parkinson's disease whose motor symptoms impact on their quality of life. \n\nConsider a choice of dopamine agonists, levodopa or monoamine oxidase\xa0B (MAO‑B) inhibitors for people in the early stages of Parkinson's disease whose motor symptoms do not impact on their quality of life. \n\nDo not offer ergot-derived dopamine agonists as first-line treatment for Parkinson's disease. Follow the Medicines and Healthcare products Regulatory Agency guidance on the warnings and contraindications for ergot-derived dopamine agonists.\n\n## Information and support\n\nWhen starting treatment for people with Parkinson's disease, give people and their family members and carers (as appropriate) oral and written information about the following risks, and record that the discussion has taken place:\n\nImpulse control disorders with all dopaminergic therapy (and the increased risk with dopamine agonists). Also see recommendations in the section on managing and monitoring impulse control disorders as an adverse effect of dopaminergic therapy\n\nExcessive sleepiness and sudden onset of sleep with dopamine agonists. Also see recommendations on daytime sleepiness in the section on pharmacological management of non-motor symptoms\n\nPsychotic symptoms (hallucinations and delusions) with all Parkinson's disease treatments (and the higher risk with dopamine agonists). Also see the recommendations on psychotic symptoms (hallucinations and delusions) in the section on pharmacological management of non-motor symptoms. \n\n## Adjuvant treatment of motor symptoms\n\nIf a person with Parkinson's disease has developed dyskinesia and/or motor fluctuations, including medicines 'wearing off', seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying therapy. \n\nOffer a choice of dopamine agonists, MAO‑B inhibitors or catechol‑O‑methyl transferase (COMT) inhibitors as an adjunct to levodopa for people with Parkinson's disease who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy, after discussing:\n\nthe person's individual clinical circumstances, for example, their Parkinson's disease symptoms, comorbidities and risks from polypharmacy\n\nthe person's individual lifestyle circumstances, preferences, needs and goals\n\nthe potential benefits and harms of the different drug classes (see table\xa02). \n\n\n\n-\n\nDopamine agonists\n\nMonoamine oxidase-B (MAO‑B) inhibitors\n\nCatechol-O-methyl transferase (COMT) inhibitors\n\nAmantadine\n\nMotor symptoms\n\nImprovement in motor symptoms\n\nImprovement in motor symptoms\n\nImprovement in motor symptoms\n\nNo evidence of improvement in motor symptoms\n\nActivities of daily living\n\nImprovement in activities of daily living\n\nImprovement in activities of daily living\n\nImprovement in activities of daily living\n\nNo evidence of improvement in activities of daily living\n\nOff time\n\nMore off‑time reduction\n\nOff‑time reduction\n\nOff‑time reduction\n\nNo studies reporting this outcome\n\nAdverse events\n\nIntermediate risk of adverse events\n\nFewer adverse events\n\nMore adverse events\n\nNo studies reporting this outcome\n\nHallucinations\n\nMore risk of hallucinations\n\nLower risk of hallucinations\n\nLower risk of hallucinations\n\nNo studies reporting this outcome\n\nChoose a non-ergot-derived dopamine agonist in most cases, because of the monitoring that is needed with ergot-derived dopamine agonists. Follow the Medicines and Healthcare products Regulatory Agency guidance on the warnings and contraindications for ergot-derived dopamine agonists.\n\nOnly consider an ergot-derived dopamine agonist as an adjunct to levodopa for people with Parkinson's disease:\n\nwho have developed dyskinesia or motor fluctuations despite optimal levodopa therapy and\n\nwhose symptoms are not adequately controlled with a non-ergot-derived dopamine agonist. Follow the Medicines and Healthcare products Regulatory Agency guidance on the warnings and contraindications for ergot-derived dopamine agonists.\n\nIf dyskinesia is not adequately managed by modifying existing therapy, consider amantadine. \n\nDo not offer anticholinergics to people with Parkinson's disease who have developed dyskinesia and/or motor fluctuations. \n\n# Managing and monitoring impulse control disorders as an adverse effect of dopaminergic therapy\n\n## Predictors for the development of impulse control disorders\n\nRecognise that impulse control disorders can develop in a person with Parkinson's disease who is on any dopaminergic therapy at any stage in the disease course. \n\nRecognise that the following are associated with an increased risk of developing impulse control disorders:\n\nDopamine agonist therapy.\n\nA history of previous impulsive behaviours.\n\nA history of alcohol consumption and/or smoking. \n\n## Information and support\n\nWhen starting dopamine agonist therapy, give people and their family members and carers (as appropriate) oral and written information about the following, and record that the discussion has taken place:\n\nThe increased risk of developing impulse control disorders when taking dopamine agonist therapy, and that these may be concealed by the person affected.\n\nThe different types of impulse control disorders (for example, compulsive gambling, hypersexuality, binge eating and obsessive shopping).\n\nWho to contact if impulse control disorders develop.\n\nThe possibility that if problematic impulse control disorders develop, dopamine agonist therapy will be reviewed and may be reduced or stopped. \n\nDiscuss potential impulse control disorders at review appointments, particularly when modifying therapy, and record that the discussion has taken place. \n\nBe aware that impulse control disorders can also develop while taking dopaminergic therapies other than dopamine agonists. \n\n## Managing dopaminergic therapy in people who have developed an impulse control disorder\n\nIf a person with Parkinson's disease has developed a problematic impulse control disorder, seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying dopaminergic therapy. \n\nDiscuss the following with the person and their family members and carers (as appropriate):\n\nHow the impulse control disorder is affecting their life.\n\nPossible treatments, such as reducing or stopping dopaminergic therapy.\n\nThe benefits and disadvantages of reducing or stopping dopaminergic therapy. \n\nWhen managing impulse control disorders, modify dopaminergic therapy by first gradually reducing any dopamine agonist. Monitor whether the impulse control disorder improves and whether the person has any symptoms of dopamine agonist withdrawal. \n\nOffer specialist cognitive behavioural therapy targeted at impulse control disorders if modifying dopaminergic therapy is not effective. \n\n# Pharmacological management of non-motor symptoms\n\n## Daytime sleepiness\n\nAdvise people with Parkinson's disease who have daytime sleepiness and/or sudden onset of sleep not to drive (and to inform the DVLA of their symptoms) and to think about any occupation hazards. Adjust their medicines to reduce its occurrence, having first sought advice from a healthcare professional with specialist expertise in Parkinson's disease. \n\nConsider modafinil to treat excessive daytime sleepiness in people with Parkinson's disease, only if a detailed sleep history has excluded reversible pharmacological and physical causes. Women who are pregnant or who are planning a pregnancy should not take modafinil, in line with the MHRA safety advice on modafinil.\n\nAt least every 12\xa0months, a healthcare professional with specialist expertise in Parkinson's disease should review people with Parkinson's disease who are taking modafinil. Women who are pregnant or who are planning a pregnancy should not take modafinil, in line with the MHRA safety advice on modafinil.\n\n## Restless leg syndrome and rapid eye movement sleep behaviour disorder\n\nTake care to identify and manage restless leg syndrome and rapid eye movement sleep behaviour disorder in people with Parkinson's disease and sleep disturbance. \n\nConsider clonazepam or melatonin to treat rapid eye movement sleep behaviour disorder if a medicines review has addressed possible pharmacological causes. For guidance on safe prescribing of benzodiazapines (such as clonazepam) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.In July 2017, this was an off-label use of clonazepam and melatonin. See\xa0NICE's information on prescribing medicines.\n\n## Nocturnal akinesia\n\nConsider levodopa or oral dopamine agonists to treat nocturnal akinesia in people with Parkinson's disease. If the selected option is not effective or not tolerated, offer the other instead. \n\nConsider rotigotine if levodopa and/or oral dopamine agonists are not effective in treating nocturnal akinesia. \n\n## Orthostatic hypotension\n\nIf a person with Parkinson's disease has developed orthostatic hypotension, review the person's existing medicines to address possible pharmacological causes, including:\n\nantihypertensives (including diuretics)\n\ndopaminergics\n\nanticholinergics\n\nantidepressants. \n\nConsider midodrine for people with Parkinson's disease and orthostatic hypotension, taking into account the contraindications and monitoring requirements (including monitoring for supine hypertension). \n\nIf midodrine is contraindicated, not tolerated or not effective, consider fludrocortisone (taking into account its safety profile, in particular its cardiac risk and potential interactions with other medicines). In July 2017, this was an off-label use of fludrocortisone. See\xa0NICE's information on prescribing medicines.\n\n## Depression\n\nFor guidance on identifying, treating and managing depression in people with Parkinson's disease, see the NICE guideline on depression in adults with a chronic physical health problem. \n\n## Psychotic symptoms (hallucinations and delusions)\n\nIn July 2017, the use of quetiapine in recommendations 1.5.16 and 1.5.18 was off-label. See\xa0NICE's information on prescribing medicines.\n\nAt review appointments and following medicines changes, ask people with Parkinson's disease and their family members and carers (as appropriate) if the person is experiencing hallucinations (particularly visual) or delusions. \n\nPerform a general medical evaluation for people with hallucinations or delusions, and offer treatment for any conditions that might have triggered them. \n\nDo not treat hallucinations and delusions if they are well tolerated by the person with Parkinson's disease and their family members and carers (as appropriate). \n\nReduce the dosage of any Parkinson's disease medicines that might have triggered hallucinations or delusions, taking into account the severity of symptoms and possible withdrawal effects. Seek advice from a healthcare professional with specialist expertise in Parkinson's disease before modifying therapy. \n\nConsider quetiapine to treat hallucinations and delusions in people with Parkinson's disease who have no cognitive impairment. \n\nIf standard treatment is not effective, offer clozapine to treat hallucinations and delusions in people with Parkinson's disease. Be aware that registration with a patient monitoring service is needed. \n\nBe aware that lower doses of quetiapine and clozapine are needed for people with Parkinson's disease than in other indications. \n\nDo not offer olanzapine to treat hallucinations and delusions in people with Parkinson's disease. \n\nRecognise that other antipsychotic medicines (such as phenothiazines and butyrophenones) can worsen the motor features of Parkinson's disease. \n\nFor guidance on hallucinations and delusions in people with dementia, see the section on managing non-cognitive symptoms in the NICE guideline on dementia. \n\n## Parkinson's disease dementia\n\nOffer a cholinesterase inhibitor for people with mild or moderate Parkinson's disease dementia. In July 2017, rivastigmine capsules are the only treatment with a UK marketing authorisation for this indication. Use of donepezil, galantamine and rivastigmine patches was off-label. See\xa0NICE's information on prescribing medicines.\n\nConsider a cholinesterase inhibitor for people with severe Parkinson's disease dementia. In July 2017, this was an off-label use of cholinesterase inhibitors. See\xa0NICE's information on prescribing medicines.\n\nConsider memantine for people with Parkinson's disease dementia, only if cholinesterase inhibitors are not tolerated or are contraindicated. In July 2017, this was an off-label use of memantine. See\xa0NICE's information on prescribing medicines.\n\nFor guidance on assessing and managing dementia, and supporting people living with dementia, see the NICE guideline on dementia. \n\n## Drooling of saliva\n\nIn July 2017, use of glycopyrronium bromide in recommendations 1.5.27, 1.5.28 and 1.5.29 was off-label.\n\nIn September 2019, Xeomin was the only preparation of botulinum toxin A (recommendation 1.5.28) licensed in the UK for treating chronic sialorrhoea caused by neurological conditions in adults. Use of other preparation of botulinum toxin type A was off-label.\n\nSee\xa0NICE's information on prescribing medicines.\n\nOnly consider pharmacological management for drooling of saliva in people with Parkinson's disease if non-pharmacological management (for example, speech and language therapy; see recommendation\xa01.7.8) is not available or has not been effective. \n\nConsider glycopyrronium bromide to manage drooling of saliva in people with Parkinson's disease. \n\nIf treatment for drooling of saliva with glycopyrronium bromide is not effective, not tolerated or contraindicated (for example, in people with cognitive impairment, hallucinations or delusions, or a history of adverse effects following anticholinergic treatment), consider referral to a specialist service for botulinum toxin\xa0A. \n\nOnly consider anticholinergic medicines other than glycopyrronium bromide to manage drooling of saliva in people with Parkinson's disease if their risk of cognitive adverse effects is thought to be minimal. Use topical preparations if possible (for example, atropine) to reduce the risk of adverse events. \n\n# Pharmacological neuroprotective therapy\n\nDo not use vitamin\xa0E as a neuroprotective therapy for people with Parkinson's disease. [2006, amended 2017]\n\nDo not use co‑enzyme\xa0Q10 as a neuroprotective therapy for people with Parkinson's disease, except in the context of clinical trials. [2006, amended 2017]\n\nDo not use dopamine agonists as neuroprotective therapies for people with Parkinson's disease, except in the context of clinical trials. [2006, amended 2017]\n\nDo not use MAO‑B inhibitors as neuroprotective therapies for people with Parkinson's disease, except in the context of clinical trials. [2006, amended 2017]\n\n# Non-pharmacological management of motor and non-motor symptoms\n\n## Parkinson's disease nurse specialist interventions\n\nPeople with Parkinson's disease should have regular access to:\n\nclinical monitoring and medicines adjustment\n\na continuing point of contact for support, including home visits when appropriate\n\na reliable source of information about clinical and social matters of concern to people with Parkinson's disease and their family members and their carers (as appropriate),which may be provided by a Parkinson's disease nurse specialist. \n\n## Physiotherapy and physical activity\n\nConsider referring people who are in the early stages of Parkinson's disease to a physiotherapist with experience of Parkinson's disease for assessment, education and advice, including information about physical activity. \n\nOffer Parkinson's disease-specific physiotherapy for people who are experiencing balance or motor function problems. \n\nConsider the Alexander Technique for people with Parkinson's disease who are experiencing balance or motor function problems. \n\n## Occupational therapy\n\nConsider referring people who are in the early stages of Parkinson's disease to an occupational therapist with experience of Parkinson's disease for assessment, education and advice on motor and non-motor symptoms. \n\nOffer Parkinson's disease-specific occupational therapy for people who are having difficulties with activities of daily living. \n\n## Speech and language therapy\n\nConsider referring people who are in the early stages of Parkinson's disease to a speech and language therapist with experience of Parkinson's disease for assessment, education and advice. \n\nOffer speech and language therapy for people with Parkinson's disease who are experiencing problems with communication, swallowing or saliva. This should include:\n\nstrategies to improve the safety and efficiency of swallowing to minimise the risk of aspiration, such as expiratory muscle strength training (EMST)\n\nstrategies to improve speech and communication, such as attention to effort therapies. \n\nConsider referring people for alternative and augmentative communication equipment that meets their communication needs as Parkinson's disease progresses and their needs change. \n\n## Nutrition\n\nConsider referring people with Parkinson's disease to a dietitian for specialist advice. \n\nDiscuss a diet in which most of the protein is eaten in the final main meal of the day (a protein redistribution diet) for people with Parkinson's disease on levodopa who experience motor fluctuations. \n\nAdvise people with Parkinson's disease to avoid a reduction in their total daily protein consumption. \n\nAdvise people with Parkinson's disease to take a vitamin\xa0D supplement. See the NICE guideline on vitamin\xa0D for recommendations on vitamin\xa0D testing, and the NICE guidelines on falls in older people and osteoporosis. \n\nDo not offer creatine supplements to people with Parkinson's disease. \n\nAdvise people with Parkinson's disease not to take over-the-counter dietary supplements without first consulting their pharmacist or other healthcare professional. \n\n# Deep brain stimulation and levodopa–carbidopa intestinal gel\n\n## Deep brain stimulation\n\nOffer people with advanced Parkinson's disease best medical therapy, which may include intermittent apomorphine injection and/or continuous subcutaneous apomorphine infusion. \n\nDo not offer deep brain stimulation to people with Parkinson's disease whose symptoms are adequately controlled by best medical therapy. \n\nConsider deep brain stimulation for people with advanced Parkinson's disease whose symptoms are not adequately controlled by best medical therapy. \n\n## Levodopa–carbidopa intestinal gel\n\nLevodopa–carbidopa intestinal gel is currently available through an NHS England clinical commissioning policy. It is recommended that this policy is reviewed in light of this guidance. \n\n# Palliative care\n\n## Information and support\n\nOffer people with Parkinson's disease and their family members and carers (as appropriate) opportunities to discuss the prognosis of their condition. These discussions should promote people's priorities, shared decision-making and patient-centred care. \n\nOffer people with Parkinson's disease and their family members and carers (as appropriate) oral and written information about the following, and record that the discussion has taken place:\n\nProgression of Parkinson's disease.\n\nPossible future adverse effects of Parkinson's disease medicines in advanced Parkinson's disease.\n\nAdvance care planning, including Advance Decisions to Refuse Treatment (ADRT) and Do Not Attempt Resuscitation (DNACPR) orders, and Lasting Power of Attorney for finance and/or health and social care.\n\nOptions for future management.\n\nWhat could happen at the end of life.\n\nAvailable support services, for example, personal care, equipment and practical support, financial support and advice, care at home and respite care. \n\nWhen discussing palliative care, recognise that family members and carers may have different information needs from the person with Parkinson's disease. \n\n## Referral\n\nConsider referring people at any stage of Parkinson's disease to the palliative care team to give them and their family members or carers (as appropriate) the opportunity to discuss palliative care and care at the end of life. ", 'Context': "Parkinson's disease is a progressive neurodegenerative condition resulting from the death of dopamine-containing cells of the substantia nigra in the brain. There is no consistently reliable test that can distinguish Parkinson's disease from other conditions that have a similar clinical presentation. The diagnosis is primarily based on a clinical history and examination.\n\nParkinson's disease is one of the most common neurological conditions. It is estimated to affect up to 160\xa0people per\xa0100,000, with an annual incidence in the UK of\xa015\xa0to\xa020 per\xa0100,000.\n\nPeople with Parkinson's disease classically present with the symptoms and signs described as 'parkinsonism': these include bradykinesia (slow movements), rigidity, rest tremor (shaking) and postural instability (loss of balance).\n\nThe symptoms of parkinsonism are not always a result of Parkinson's disease. Other causes include side effects of medicines, vascular disease, and less common degenerative conditions such as progressive supranuclear palsy and multiple system atrophy.\n\nParkinson's disease has historically been recognised as a primary movement disorder; however, other symptoms may be prominent, such as depression, cognitive impairment and dementia. In the later stages of the disease, people may develop pain and autonomic disturbances (such as dizziness and fainting, and problems with sweating, heart rate, digestion, vision and sexual function). These other symptoms are sometimes described as the 'non-motor' manifestations of Parkinson's disease. The condition may progress to cause significant impairments, adversely affecting quality of life and, indirectly, the quality of life of family and carers.", 'Recommendations for research': "The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.\n\n# Combination treatment for Parkinson's disease dementia\n\nWhat is the effectiveness of combination treatment with a cholinesterase inhibitor and memantine for people with Parkinson's disease dementia if treatment with a cholinesterase inhibitor alone is not effective or no longer effective?\n\n## Why this is important\n\nThe guideline committee felt that cholinesterase inhibitors, memantine and combination therapy with both treatments are all reasonable clinical options, but noted that some people do not tolerate cholinesterase inhibitors well due to side effects. The evidence base for memantine was considerably weaker than for cholinesterase inhibitors, and therefore there would be value in either additional trials of memantine compared with placebo (in people for whom cholinesterase inhibitors are not an option), or non-inferiority studies compared with cholinesterase inhibitors.\n\nIn clinical practice, memantine is often added to a cholinesterase inhibitor when it is no longer proving effective, but there is no evidence base for this and randomised trials to establish whether there is additional benefit would be valuable. Both of these questions could potentially be answered in a single study with 3\xa0arms of memantine monotherapy, cholinesterase inhibitor monotherapy and combination treatment.\n\n# Orthostatic hypotension treatment\n\nFor people with Parkinson's disease, what is the most effective pharmacological treatment for orthostatic hypotension?\n\nParticular interventions and comparisons of interest are:\n\nmidodrine compared with fludrocortisone (primary comparison)\n\npyridostigmine\n\nephedrine\n\npseudoephedrine.\n\n## Why this is important\n\nThe guideline committee felt that orthostatic hypotension was an important practical problem, common in people with Parkinson's disease and a contributor to falls and injuries. The current best pharmacological treatment is not yet established and research in this area would help to determine this. The randomised controlled trials that have previously been undertaken have only provided low-quality evidence (because of both small sample sizes and weaknesses in the trial designs) and cover only a subset of the comparisons of interest, making future research in this area of value.\n\n# Psychotic symptoms (hallucinations and delusions)\n\nWhat is the effectiveness of rivastigmine compared with atypical antipsychotic drugs for treating psychotic symptoms (particularly hallucinations and delusions) associated with Parkinson's disease?\n\n## Why this is important\n\nRivastigmine is commonly used to treat Parkinson's disease psychosis because it has shown some effectiveness in improving behavioural symptoms in people with Parkinson's disease dementia. At present, no evidence exists to support the efficacy of rivastigmine in treating people with Parkinson's disease whose symptoms are predominantly psychotic. It would be beneficial to undertake primary research in this area to determine the most effective treatment options for managing Parkinson's disease psychosis.\n\n# Rapid eye movement sleep behaviour disorder treatment\n\nWhat is the best first-line treatment for rapid eye movement sleep behaviour disorder (RBD) in people with Parkinson's disease?\n\n## Why this is important\n\nThe guideline committee highlighted the importance of minimising RBD, for both people with Parkinson's disease and their carers, particularly because of potential safety concerns. Only 1\xa0paper was found to address optimal management, and this involved people in whom first-line treatment had failed. With multiple possible treatment options and no current evidence on what the most effective first-line treatment is, research (in the form of randomised controlled trials) in this area would be beneficial.\n\n# Physiotherapy\n\nDoes physiotherapy started early in the course of Parkinson's disease, as opposed to after motor symptom onset, confer benefits in terms of delaying symptom onset and/or reducing severity?\n\n## Why this is important\n\nThe guideline committee felt that physiotherapy was beneficial for those earlier in the course of the disease as it may delay or lessen problems associated with symptoms, as well as for those who have developed symptoms and problems. At present, no substantial evidence exists to support the efficacy of physiotherapy as an early intervention to prevent the onset or reduce severity of motor symptoms, because most of the trials have been conducted in people who have already developed motor symptoms.\n\nIf physiotherapy were shown to have a beneficial effect in either delaying the onset or decreasing the severity of symptoms, this would have a substantial beneficial impact on the quality of life of people with Parkinson's disease and their family and carers. Relevant trials would not compare physiotherapy with no physiotherapy, but rather early physiotherapy (at the time of diagnosis) with physiotherapy offered at the current standard times in the UK."}
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https://www.nice.org.uk/guidance/ng71
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This guideline covers diagnosing and managing Parkinson's disease in people aged 18 and over. It aims to improve care from the time of diagnosis, including monitoring and managing symptoms, providing information and support, and palliative care.
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67f8bf935e0031918a53cb4451506cacc178a126
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nice
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Constipation in children and young people: diagnosis and management
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Constipation in children and young people: diagnosis and management
This guideline covers diagnosing and managing constipation in children and young people up to 18. It provides strategies to support the early identification and timely, effective treatment of constipation which will help improve outcomes for patients. It does not cover constipation caused by a specific condition.
# Introduction
Constipation is common in childhood. It is prevalent in around 5% to 30% of the child population, depending on the criteria used for diagnosis. Symptoms become chronic in more than one third of patients and constipation is a common reason for referral to secondary care. Morbidity may be under-reported because people may not seek advice because they are embarrassed.
The exact cause of constipation is not fully understood but factors that may contribute include pain, fever, dehydration, dietary and fluid intake, psychological issues, toilet training, medicines and familial history of constipation. Constipation is referred to as 'idiopathic' if it cannot be explained by anatomical or physiological abnormalities.
Many people don't recognise the signs and symptoms of constipation and few relate the presence of soiling to constipation. The signs and symptoms of childhood idiopathic constipation include: infrequent bowel activity, foul smelling wind and stools, excessive flatulence, irregular stool texture, passing occasional enormous stools or frequent small pellets, withholding or straining to stop passage of stools, soiling or overflow, abdominal pain, distension or discomfort, poor appetite, lack of energy, an unhappy, angry or irritable mood and general malaise.
Painful defecation is an important factor in constipation but it is not always recognised; withholding behaviours to prevent passage of painful stools are often confused with straining to pass stools. Families may delay seeking help for fear of a negative response from healthcare professionals. It has been suggested that some healthcare professionals underestimate the impact of constipation on the child or young person and their family. This may contribute to the poor clinical outcomes often seen in children and young people with constipation.
Soiling is debilitating but rarely life threatening so it might be expected to have little impact on healthcare provision. But many children and young people experience social, psychological and educational consequences that require prolonged support.
Some children and young people with physical disabilities, such as cerebral palsy, are more prone to idiopathic constipation as a result of impaired mobility. Children and young people with Down's syndrome or autism are also more prone to the condition. It is important that assessment and ongoing management for these children and young people happen in the same way as is recommended for all children and young people.
Without early diagnosis and treatment, an acute episode of constipation can lead to anal fissure and become chronic. By the time the child or young person is seen they may be in a vicious cycle. Children and young people and their families are often given conflicting advice and practice is inconsistent, making treatment potentially less effective and frustrating for all concerned. Early identification of constipation and effective treatment can improve outcomes for children and young people. This guideline provides strategies based on the best available evidence to support early identification, positive diagnosis and timely, effective management. Implementation of this guideline will provide a consistent, coordinated approach and will improve outcomes for children and young people.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
# History-taking and physical examination
Establish during history-taking whether the child or young person has constipation. Two or more findings from table 1 indicate constipation.
Key components
Potential findings in a child younger than 1 year
Potential findings in a child/young person older than 1 year
Stool patterns
Fewer than three complete stools per week (type 3 or 4, see Bristol Stool Form Scale – appendix B) (this does not apply to exclusively breastfed babies after 6 weeks of age)
Hard large stool
'Rabbit droppings' (type 1, see Bristol Stool Form Scale – appendix B)
Fewer than three complete stools per week (type 3 or 4, see Bristol Stool Form Scale – appendix B)
Overflow soiling (commonly very loose , very smelly , stool passed without sensation. Can also be thick and sticky or dry and flaky.)
'Rabbit droppings' (type 1, see Bristol Stool Form Scale – appendix B)
Large, infrequent stools that can block the toilet
Symptoms associated with defecation
Distress on stooling
Bleeding associated with hard stool
Straining
Poor appetite that improves with passage of large stool
Waxing and waning of abdominal pain with passage of stool
Evidence of retentive posturing: typical straight legged, tiptoed, back arching posture
Straining
Anal pain
History
Previous episode(s) of constipation
Previous or current anal fissure
Previous episode(s) of constipation
Previous or current anal fissure
Painful bowel movements and bleeding associated with hard stools
If the child or young person has constipation take a history using table 2 to establish a positive diagnosis of idiopathic constipation by excluding underlying causes. If a child or young person has any 'red flag' symptoms, do not treat them for constipation. Instead, refer them urgently to a healthcare professional with experience in the specific aspect of child health that is causing concern.
Key components
Findings and diagnostic clues that indicate idiopathic constipation
'Red flag' findings and diagnostic clues that indicate an underlying disorder or condition: not idiopathic constipation
Timing of onset of constipation and potential precipitating factors
In a child younger than 1 year:
Starts after a few weeks of life
Obvious precipitating factors coinciding with the start of symptoms: fissure, change of diet, infections
In a child/young person older than 1 year:
Starts after a few weeks of life
Obvious precipitating factors coinciding with the start of symptoms: fissure, change of diet, timing of potty/toilet training or acute events such as infections, moving house, starting nursery/school, fears and phobias, major change in family, taking medicines
Reported from birth or first few weeks of life
Passage of meconium
Normal (within 48 hours after birth )
Failure to pass meconium/delay (more than 48 hours after birth )
Stool patterns
'Ribbon stools' (more likely in a child younger than 1 year)
Growth and general wellbeing (for faltering growth, see recommendation 1.1.4)
In a child younger than 1 year:
Generally well, weight and height within normal limits
In a child/young person older than 1 year:
Generally well, weight and height within normal limits, fit and active
No 'red flag', but 'amber flag' (possible idiopathic constipation)
Symptoms in legs/locomotor development
No neurological problems in legs (such as falling over in a child/young person older than 1 year), normal locomotor development
Previously unknown or undiagnosed weakness in legs, locomotor delay
Abdomen
Abdominal distension with vomiting
Diet and fluid intake
In a child younger than 1 year:
Changes in infant formula, weaning, insufficient fluid intake
In a child/young person older than 1 year:
History of poor diet and/or insufficient fluid intake
Note that for personal, familial or social factors, such as disclosure or evidence that raises concerns over possibility of child maltreatment, see recommendation 1.1.5.
Do a physical examination. Use table 3 to establish a positive diagnosis of idiopathic constipation by excluding underlying causes. If a child or young person has any 'red flag' symptoms do not treat them for constipation. Instead, refer them urgently to a healthcare professional with experience in the specific aspect of child health that is causing concern.
Key components
Findings and diagnostic clues that indicate idiopathic constipation
'Red flag' findings and diagnostic clues that indicate an underlying disorder or condition: not idiopathic constipation
Inspection of perianal area: appearance, position, patency, etc
Normal appearance of anus and surrounding area
Abnormal appearance/position/patency of anus: fistulae, bruising, multiple fissures, tight or patulous anus, anteriorly placed anus, absent anal wink
Abdominal examination
Soft abdomen. Flat or distension that can be explained because of age or excess weight
Gross abdominal distension
Spine/lumbosacral region/gluteal examination
Normal appearance of the skin and anatomical structures of lumbosacral/gluteal regions
Abnormal: asymmetry or flattening of the gluteal muscles, evidence of sacral agenesis, discoloured skin, naevi or sinus, hairy patch, lipoma, central pit (dimple that you can't see the bottom of), scoliosis
Lower limb neuromuscular examination including tone and strength
Normal gait. Normal tone and strength in lower limbs
Deformity in lower limbs such as talipes
Abnormal neuromuscular signs unexplained by any existing condition, such as cerebral palsy
Lower limb neuromuscular examination: reflexes (perform only if 'red flags' in history or physical examination suggest new onset neurological impairment)
Reflexes present and of normal amplitude
Abnormal reflexes
If the history-taking and/or physical examination show evidence of faltering growth treat for constipation and test for coeliac disease (see the NICE guideline on coeliac disease) and hypothyroidism.
If either the history-taking or the physical examination show evidence of possible maltreatment treat for constipation and refer to the NICE guideline on child maltreatment: when to suspect maltreatment in under 18s.
If the physical examination shows evidence of perianal streptococcal infection, treat for constipation and also treat the infection.
Inform the child or young person and his or her parents or carers of a positive diagnosis of idiopathic constipation and also that underlying causes have been excluded by the history and/or physical examination. Reassure them that there is a suitable treatment for idiopathic constipation but that it may take several months for the condition to be resolved.
# Digital rectal examination
A digital rectal examination should be undertaken only by healthcare professionals competent to interpret features of anatomical abnormalities or Hirschsprung's disease.
If a child younger than 1 year has a diagnosis of idiopathic constipation that does not respond to optimum treatment within 4 weeks, refer them urgently to a healthcare professional competent to perform a digital rectal examination and interpret features of anatomical abnormalities or Hirschsprung's disease.
Do not perform a digital rectal examination in children or young people older than 1 year with a 'red flag' (see tables 2 and 3) in the history-taking and/or physical examination that might indicate an underlying disorder. Instead, refer them urgently to a healthcare professional competent to perform a digital rectal examination and interpret features of anatomical abnormalities or Hirschsprung's disease.
For a digital rectal examination ensure:
privacy
informed consent is given by the child or young person, or the parent or legal guardian if the child is not able to give it, and is documented
a chaperone is present
the child or young person's individual preferences about degree of body exposure and gender of the examiner are taken into account
all findings are documented.
# Clinical investigations
## Endoscopy
Do not use gastrointestinal endoscopy to investigate idiopathic constipation.
## Coeliac disease and hypothyroidism
Test for coeliac disease (see the NICE guideline on coeliac disease) and hypothyroidism in the ongoing management of intractable constipation in children and young people if requested by specialist services.
## Manometry
Do not use anorectal manometry to exclude Hirschsprung's disease in children and young people with chronic constipation.
## Radiography
Do not use a plain abdominal radiograph to make a diagnosis of idiopathic constipation.
Consider using a plain abdominal radiograph only if requested by specialist services in the ongoing management of intractable idiopathic constipation.
## Rectal biopsy
Do not perform rectal biopsy unless any of the following clinical features of Hirschsprung's disease are or have been present:
delayed passage of meconium (more than 48 hours after birth in term babies)
constipation since first few weeks of life
chronic abdominal distension plus vomiting
family history of Hirschsprung's disease
faltering growth in addition to any of the previous features.
## Transit studies
Do not use transit studies to make a diagnosis of idiopathic constipation.
Consider using transit studies in the ongoing management of intractable idiopathic constipation only if requested by specialist services.
## Ultrasound
Do not use abdominal ultrasound to make a diagnosis of idiopathic constipation.
Consider using abdominal ultrasound in the ongoing management of intractable idiopathic constipation only if requested by specialist services.
# Clinical management
## Disimpaction
Assess all children and young people with idiopathic constipation for faecal impaction, including children and young people who were originally referred to the relevant services because of 'red flags' but in whom there were no significant findings following further investigations (see tables 2 and 3). Use a combination of history-taking and physical examination to diagnose faecal impaction – look for overflow soiling and/or faecal mass palpable abdominally and/or rectally if indicated.
Start maintenance therapy if the child or young person is not faecally impacted.
Offer the following oral medication regimen for disimpaction if indicated:
Polyethylene glycol 3350 + electrolytes, using an escalating dose regimen, as the first-line treatment. (November 2021: Not all macrogol preparations are licensed for chronic constipation and faecal impaction. Of those that are licensed for these indications, not all of them are licensed for use in children under 12, and those that are may have different licence starting ages. See individual summaries of product characteristics for further detail. See NICE's information on prescribing medicines.)
Polyethylene glycol 3350 + electrolytes may be mixed with a cold drink.
Add a stimulant laxative if polyethylene glycol 3350 + electrolytes does not lead to disimpaction after 2 weeks.
Substitute a stimulant laxative singly or in combination with an osmotic laxative such as lactulose if polyethylene glycol 3350 + electrolytes is not tolerated.
Inform families that disimpaction treatment can initially increase symptoms of soiling and abdominal pain.
Do not use rectal medications for disimpaction unless all oral medications have failed and only if the child or young person and their family consent.
Administer sodium citrate enemas only if all oral medications for disimpaction have failed.
Do not administer phosphate enemas for disimpaction unless under specialist supervision in hospital/health centre/clinic, and only if all oral medications and sodium citrate enemas have failed.
Do not perform manual evacuation of the bowel under anaesthesia unless optimum treatment with oral and rectal medications has failed.
Review children and young people undergoing disimpaction within 1 week.
## Maintenance therapy
Start maintenance therapy as soon as the child or young person's bowel is disimpacted.
Reassess children frequently during maintenance treatment to ensure they do not become reimpacted and assess issues in maintaining treatment such as taking medicine and toileting. Tailor the frequency of assessment to the individual needs of the child and their families (this could range from daily contact to contact every few weeks). Where possible, reassessment should be provided by the same person/team.
Offer the following regimen for ongoing treatment or maintenance therapy:
Polyethylene glycol 3350 + electrolytes as the first-line treatment. (November 2021: Not all macrogol preparations are licensed for chronic constipation and faecal impaction. Of those that are licensed for these indications, not all of them are licensed for use in children under 12, and those that are may have different licence starting ages. See individual summaries of product characteristics for further detail. See NICE's information on prescribing medicines).
Adjust the dose of polyethylene glycol 3350 + electrolytes according to symptoms and response. As a guide for children and young people who have had disimpaction the starting maintenance dose might be half the disimpaction dose.
Add a stimulant laxative if polyethylene glycol 3350 + electrolytes does not work.
Substitute a stimulant laxative if polyethylene glycol 3350 + electrolytes is not tolerated by the child or young person. Add another laxative such as lactulose or docusate if stools are hard.
Continue medication at maintenance dose for several weeks after regular bowel habit is established – this may take several months. Children who are toilet training should remain on laxatives until toilet training is well established. Do not stop medication abruptly: gradually reduce the dose over a period of months in response to stool consistency and frequency. Some children may require laxative therapy for several years. A minority may require ongoing laxative therapy.
# Diet and lifestyle
Do not use dietary interventions alone as first-line treatment for idiopathic constipation.
Treat constipation with laxatives and a combination of:
Negotiated and non-punitive behavioural interventions suited to the child or young person's stage of development. These could include scheduled toileting and support to establish a regular bowel habit, maintenance and discussion of a bowel diary, information on constipation, and use of encouragement and rewards systems.
Dietary modifications to ensure a balanced diet and sufficient fluids are consumed.
Advise parents and children and young people (if appropriate) that a balanced diet should include:
Adequate fluid intake (see table 4).
Adequate fibre. Recommend including foods with a high fibre content (such as fruit, vegetables, high-fibre bread, baked beans and wholegrain breakfast cereals) (not applicable to exclusively breastfed infants). Do not recommend unprocessed bran, which can cause bloating and flatulence and reduce the absorption of micronutrients.
Total water intake per day, including water contained in food
Water obtained from drinks per day
Infants 0 to 6 months
ml assumed to be from breast milk
to 12 months
ml from milk and complementary foods and beverages
ml
to 3 years
,300 ml
ml
to 8 years
,700 ml
,200 ml
Boys 9 to 13 years
,400 ml
,800 ml
Girls 9 to 13 years
,100 ml
,600 ml
Boys 14 to 18 years
,300 ml
,600 ml
Girls 14 to 18 years
,300 ml
,800 ml
The above recommendations are for adequate intakes and should not be interpreted as a specific requirement. Higher intakes of total water will be required for those who are physically active or who are exposed to hot environments. It should be noted that obese children may also require higher total intakes of water. (Institute of Medicine, 2005). Dietary reference intakes for water, potassium, sodium chloride and sulfate. Washington DC: The National Academies Press.
Provide children and young people with idiopathic constipation and their families with written information about diet and fluid intake.
In children with idiopathic constipation, start a cows' milk exclusion diet only on the advice of the relevant specialist services.
Advise daily physical activity that is tailored to the child or young person's stage of development and individual ability as part of ongoing maintenance in children and young people with idiopathic constipation.
# Psychological interventions
Do not use biofeedback for ongoing treatment in children and young people with idiopathic constipation.
Do not routinely refer children and young people with idiopathic constipation to a psychologist or child and adolescent mental health services unless the child or young person has been identified as likely to benefit from receiving a psychological intervention.
# Antegrade colonic enema procedure
Refer children and young people with idiopathic constipation who still have unresolved symptoms on optimum management to a paediatric surgical centre to assess their suitability for an antegrade colonic enema (ACE) procedure.
Ensure that all children and young people who are referred for an ACE procedure have access to support, information and follow-up from paediatric healthcare professionals with experience in managing children and young people who have had an ACE procedure.
# Information and support
Provide tailored follow-up to children and young people and their parents or carers according to the child or young person's response to treatment, measured by frequency, amount and consistency of stools. Use the Bristol Stool Form Scale to assess this (see appendix B). This could include:
telephoning or face-to-face talks
giving detailed evidence-based information about their condition and its management, using, for example, NICE's information for the public for this guideline
giving verbal information supported by (but not replaced by) written or website information in several formats about how the bowels work, symptoms that might indicate a serious underlying problem, how to take their medication, what to expect when taking laxatives, how to poo, origins of constipation, criteria to recognise risk situations for relapse (such as worsening of any symptoms, soiling etc.) and the importance of continuing treatment until advised otherwise by the healthcare professional.
Offer children and young people with idiopathic constipation and their families a point of contact with specialist healthcare professionals, including school nurses, who can give ongoing support.
Healthcare professionals should liaise with school nurses to provide information and support, and to help school nurses raise awareness of the issues surrounding constipation with children and young people and school staff.
Refer children and young people with idiopathic constipation who do not respond to initial treatment within 3 months to a practitioner with expertise in the problem.
# Terms used in this guideline
## Chronic constipation
Constipation lasting longer than 8 weeks.
## Digital rectal examination
Examination of the lower rectum using a gloved, lubricated finger to check for abnormalities.
## Idiopathic constipation
Constipation that cannot (currently) be explained by any anatomical, physiological, radiological or histological abnormalities.
## Intractable constipation
Constipation that does not respond to sustained, optimum medical management.
## Optimum management
Management as set out in this guideline.
## Specialist
Healthcare professional with either interest, experience and/or training in the diagnosis and treatment of constipation in children and young people. Examples: specialist continence nurse, community paediatrician with an interest in the diagnosis and treatment of constipation.
## Specialist services
Services for children and young people that include constipation management.
A larger glossary of terms can be found in the full guideline.# Recommendations for research
The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The GDG's full set of recommendations for research are detailed in the full guideline.
# Polyethylene glycol 3350 + electrolytes in children under 1
What is the effectiveness of polyethylene glycol 3350 + electrolytes in treating idiopathic constipation in children younger than 1 year old, and what is the optimum dosage?
## Why this is important
There is some evidence that treatment of constipation is less effective if faecal impaction is not dealt with first. Disimpaction with oral macrogols is recommended for children and their use avoids the need for rectal treatments.
Rectal treatments are used more commonly in hospital than at home. Although relatively few infants are admitted to hospital, there would be savings if initially all children were disimpacted at home.
Polyethylene glycol 3350 + electrolytes, an oral macrogol, is licensed for disimpaction in children older than 5 years. Increasing experience has shown that it is effective in infants younger than 1 year old, but evidence is limited to small case series. If dosage guidelines and evidence on macrogol use in infants were obtained and published, more healthcare professionals might be encouraged to try macrogols in this age group. It would also allow the guideline to be applicable across the whole paediatric age group.
# Age-specific information
Is age-specific information more effective than non-age-specific information in increasing children's knowledge and understanding of constipation and its treatment, and what information should be given?
## Why this is important
When treating idiopathic constipation it is helpful if children and young people understand how the bowel works, what can go wrong and what they can do about it. Younger children (pre toilet training) need to allow stools to come out. Older children and young people have a more active role and need to develop a habit of taking all prescribed medication, sitting on the toilet each day and pushing stools out. Volition from the child or young person is vital to establish and sustain a regular toilet habit. Intended learning outcomes are similar for all age groups.
Theory-based research has led to the development of some materials such as 'Sneaky-poo' that are not appropriate for young children. To help clinicians and parents motivate children and young people to fully participate in managing their constipation it is important to discover how best to communicate information to them, what materials are most effective and, specifically, what works at different ages.
# Specialist services
Do specialist nurse-led children's continence services or traditional secondary care services provide the most effective treatment for children with idiopathic constipation (with or without faecal incontinence) that does not respond fully to primary treatment regimens? This should consider clinical and cost effectiveness, and both short-term (16 weeks) and long-term (12 months) resolution.
## Why this is important
By the time children reach tertiary care they have often suffered years of constipation with or without faecal incontinence and have intractable constipation.
Findings from one trial have suggested that children referred to a tertiary gastroenterology service and diagnosed as having idiopathic constipation are managed as effectively by nurse-led follow-up as by a consultant paediatric gastroenterology service. Parent satisfaction was improved by the nurse-led service. However, the nurse-led service may require increased resources because many more contacts are made. Several services with a similar model of care have been established but cost effectiveness has not been formally assessed.
For coherent services to develop across the UK, the cost effectiveness of specialist nurse-led services provided as first referral point if primary treatment regimens have not worked needs to be examined.
# Colonic washouts
What is the effectiveness of different volumes and types of solutions used for colonic washouts in children who have undergone an antegrade colonic enema (ACE) procedure for intractable chronic idiopathic constipation?
## Why this is important
The ACE procedure has a role in the management of people with treatment-resistant symptoms. Close follow-up is integral to the effectiveness of this technique to allow safe and effective administration of washout solutions.
The choice of washout solutions and frequency of administration differs between centres. Outcomes may be improved by evaluating how experienced centres choose washout solutions and by comparing techniques.
Centres offering the ACE procedure as treatment for children with chronic idiopathic constipation should be surveyed for their choice of washout solution. To determine the perceived strengths and weaknesses of each solution, the survey should cover enema, choice of washout fluid, volumes and frequency of administration.
# Models of service
What is the impact of specific models of service on both clinical and social outcomes to deliver timely diagnosis and treatment interventions in children with chronic idiopathic constipation and their families?
## Why this is important
There has been no research to explore the social impact on children with constipation and their families, and many of the clinical studies have been of mediocre quality. A comprehensive study is needed that investigates the effectiveness of specific models of care, and that takes into consideration both the clinical and social impact of this complex condition.# Appendix A: The algorithms
A care pathway can be found on page 22 to 32 of the full guideline.# Appendix B: Bristol Stool Form Scale
The Bristol Stool Form Scale can be found on page 32 of the full guideline.
|
{'Introduction': "Constipation is common in childhood. It is prevalent in around 5% to 30% of the child population, depending on the criteria used for diagnosis. Symptoms become chronic in more than one third of patients and constipation is a common reason for referral to secondary care. Morbidity may be under-reported because people may not seek advice because they are embarrassed.\n\nThe exact cause of constipation is not fully understood but factors that may contribute include pain, fever, dehydration, dietary and fluid intake, psychological issues, toilet training, medicines and familial history of constipation. Constipation is referred to as 'idiopathic' if it cannot be explained by anatomical or physiological abnormalities.\n\nMany people don't recognise the signs and symptoms of constipation and few relate the presence of soiling to constipation. The signs and symptoms of childhood idiopathic constipation include: infrequent bowel activity, foul smelling wind and stools, excessive flatulence, irregular stool texture, passing occasional enormous stools or frequent small pellets, withholding or straining to stop passage of stools, soiling or overflow, abdominal pain, distension or discomfort, poor appetite, lack of energy, an unhappy, angry or irritable mood and general malaise.\n\nPainful defecation is an important factor in constipation but it is not always recognised; withholding behaviours to prevent passage of painful stools are often confused with straining to pass stools. Families may delay seeking help for fear of a negative response from healthcare professionals. It has been suggested that some healthcare professionals underestimate the impact of constipation on the child or young person and their family. This may contribute to the poor clinical outcomes often seen in children and young people with constipation.\n\nSoiling is debilitating but rarely life threatening so it might be expected to have little impact on healthcare provision. But many children and young people experience social, psychological and educational consequences that require prolonged support.\n\nSome children and young people with physical disabilities, such as cerebral palsy, are more prone to idiopathic constipation as a result of impaired mobility. Children and young people with Down's syndrome or autism are also more prone to the condition. It is important that assessment and ongoing management for these children and young people happen in the same way as is recommended for all children and young people.\n\nWithout early diagnosis and treatment, an acute episode of constipation can lead to anal fissure and become chronic. By the time the child or young person is seen they may be in a vicious cycle. Children and young people and their families are often given conflicting advice and practice is inconsistent, making treatment potentially less effective and frustrating for all concerned. Early identification of constipation and effective treatment can improve outcomes for children and young people. This guideline provides strategies based on the best available evidence to support early identification, positive diagnosis and timely, effective management. Implementation of this guideline will provide a consistent, coordinated approach and will improve outcomes for children and young people.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# History-taking and physical examination\n\nEstablish during history-taking whether the child or young person has constipation. Two or more findings from table 1 indicate constipation.\n\nKey components\n\nPotential findings in a child younger than 1 year\n\nPotential findings in a child/young person older than 1 year\n\nStool patterns\n\nFewer than three complete stools per week (type 3 or 4, see Bristol Stool Form Scale – appendix B) (this does not apply to exclusively breastfed babies after 6\xa0weeks of age)\n\nHard large stool\n\n'Rabbit droppings' (type 1, see Bristol Stool Form Scale – appendix B)\n\nFewer than three complete stools per week (type 3 or 4, see Bristol Stool Form Scale – appendix B)\n\nOverflow soiling (commonly very loose [no form], very smelly [smells more unpleasant than normal stools], stool passed without sensation. Can also be thick and sticky or dry and flaky.)\n\n'Rabbit droppings' (type 1, see Bristol Stool Form Scale – appendix B)\n\nLarge, infrequent stools that can block the toilet\n\nSymptoms associated with defecation\n\nDistress on stooling\n\nBleeding associated with hard stool\n\nStraining\n\nPoor appetite that improves with passage of large stool\n\nWaxing and waning of abdominal pain with passage of stool\n\nEvidence of retentive posturing: typical straight legged, tiptoed, back arching posture\n\nStraining\n\nAnal pain\n\nHistory\n\nPrevious episode(s) of constipation\n\nPrevious or current anal fissure\n\nPrevious episode(s) of constipation\n\nPrevious or current anal fissure\n\nPainful bowel movements and bleeding associated with hard stools\n\nIf the child or young person has constipation take a history using table 2 to establish a positive diagnosis of idiopathic constipation by excluding underlying causes. If a child or young person has any 'red flag' symptoms, do not treat them for constipation. Instead, refer them urgently to a healthcare professional with experience in the specific aspect of child health that is causing concern.\n\nKey components\n\nFindings and diagnostic clues that indicate idiopathic constipation\n\n'Red flag' findings and diagnostic clues that indicate an underlying disorder or condition: not idiopathic constipation\n\nTiming of onset of constipation and potential precipitating factors\n\nIn a child younger than 1 year:\n\nStarts after a few weeks of life\n\nObvious precipitating factors coinciding with the start of symptoms: fissure, change of diet, infections\n\nIn a child/young person older than 1 year:\n\nStarts after a few weeks of life\n\nObvious precipitating factors coinciding with the start of symptoms: fissure, change of diet, timing of potty/toilet training or acute events such as infections, moving house, starting nursery/school, fears and phobias, major change in family, taking medicines\n\nReported from birth or first few weeks of life\n\nPassage of meconium\n\nNormal (within 48 hours after birth [in term baby])\n\nFailure to pass meconium/delay (more than 48 hours after birth [in term baby])\n\nStool patterns\n\n-\n\n'Ribbon stools' (more likely in a child younger than 1 year)\n\nGrowth and general wellbeing (for faltering growth, see recommendation 1.1.4)\n\nIn a child younger than 1 year:\n\nGenerally well, weight and height within normal limits\n\nIn a child/young person older than 1 year:\n\nGenerally well, weight and height within normal limits, fit and active\n\nNo 'red flag', but 'amber flag' (possible idiopathic constipation)\n\nSymptoms in legs/locomotor development\n\nNo neurological problems in legs (such as falling over in a child/young person older than 1 year), normal locomotor development\n\nPreviously unknown or undiagnosed weakness in legs, locomotor delay\n\nAbdomen\n\n-\n\nAbdominal distension with vomiting\n\nDiet and fluid intake\n\nIn a child younger than 1 year:\n\nChanges in infant formula, weaning, insufficient fluid intake\n\nIn a child/young person older than 1 year:\n\nHistory of poor diet and/or insufficient fluid intake\n\n-\n\nNote that for personal, familial or social factors, such as disclosure or evidence that raises concerns over possibility of child maltreatment, see recommendation 1.1.5.\n\nDo a physical examination. Use table 3 to establish a positive diagnosis of idiopathic constipation by excluding underlying causes. If a child or young person has any 'red flag' symptoms do not treat them for constipation. Instead, refer them urgently to a healthcare professional with experience in the specific aspect of child health that is causing concern.\n\nKey components\n\nFindings and diagnostic clues that indicate idiopathic constipation\n\n'Red flag' findings and diagnostic clues that indicate an underlying disorder or condition: not idiopathic constipation\n\nInspection of perianal area: appearance, position, patency, etc\n\nNormal appearance of anus and surrounding area\n\nAbnormal appearance/position/patency of anus: fistulae, bruising, multiple fissures, tight or patulous anus, anteriorly placed anus, absent anal wink\n\nAbdominal examination\n\nSoft abdomen. Flat or distension that can be explained because of age or excess weight\n\nGross abdominal distension\n\nSpine/lumbosacral region/gluteal examination\n\nNormal appearance of the skin and anatomical structures of lumbosacral/gluteal regions\n\nAbnormal: asymmetry or flattening of the gluteal muscles, evidence of sacral agenesis, discoloured skin, naevi or sinus, hairy patch, lipoma, central pit (dimple that you can't see the bottom of), scoliosis\n\nLower limb neuromuscular examination including tone and strength\n\nNormal gait. Normal tone and strength in lower limbs\n\nDeformity in lower limbs such as talipes\n\nAbnormal neuromuscular signs unexplained by any existing condition, such as cerebral palsy\n\nLower limb neuromuscular examination: reflexes (perform only if 'red flags' in history or physical examination suggest new onset neurological impairment)\n\nReflexes present and of normal amplitude\n\nAbnormal reflexes\n\nIf the history-taking and/or physical examination show evidence of faltering growth treat for constipation and test for coeliac disease (see the NICE guideline on coeliac disease) and hypothyroidism.\n\nIf either the history-taking or the physical examination show evidence of possible maltreatment treat for constipation and refer to the NICE guideline on child maltreatment: when to suspect maltreatment in under 18s.\n\nIf the physical examination shows evidence of perianal streptococcal infection, treat for constipation and also treat the infection.\n\nInform the child or young person and his or her parents or carers of a positive diagnosis of idiopathic constipation and also that underlying causes have been excluded by the history and/or physical examination. Reassure them that there is a suitable treatment for idiopathic constipation but that it may take several months for the condition to be resolved.\n\n# Digital rectal examination\n\nA digital rectal examination should be undertaken only by healthcare professionals competent to interpret features of anatomical abnormalities or Hirschsprung's disease.\n\nIf a child younger than 1\xa0year has a diagnosis of idiopathic constipation that does not respond to optimum treatment within 4\xa0weeks, refer them urgently to a healthcare professional competent to perform a digital rectal examination and interpret features of anatomical abnormalities or Hirschsprung's disease.\n\nDo not perform a digital rectal examination in children or young people older than 1\xa0year with a 'red flag' (see tables 2 and 3) in the history-taking and/or physical examination that might indicate an underlying disorder. Instead, refer them urgently to a healthcare professional competent to perform a digital rectal examination and interpret features of anatomical abnormalities or Hirschsprung's disease.\n\nFor a digital rectal examination ensure:\n\nprivacy\n\ninformed consent is given by the child or young person, or the parent or legal guardian if the child is not able to give it, and is documented\n\na chaperone is present\n\nthe child or young person's individual preferences about degree of body exposure and gender of the examiner are taken into account\n\nall findings are documented.\n\n# Clinical investigations\n\n## Endoscopy\n\nDo not use gastrointestinal endoscopy to investigate idiopathic constipation.\n\n## Coeliac disease and hypothyroidism\n\nTest for coeliac disease (see the NICE guideline on coeliac disease) and hypothyroidism in the ongoing management of intractable constipation in children and young people if requested by specialist services.\n\n## Manometry\n\nDo not use anorectal manometry to exclude Hirschsprung's disease in children and young people with chronic constipation.\n\n## Radiography\n\nDo not use a plain abdominal radiograph to make a diagnosis of idiopathic constipation.\n\nConsider using a plain abdominal radiograph only if requested by specialist services in the ongoing management of intractable idiopathic constipation.\n\n## Rectal biopsy\n\nDo not perform rectal biopsy unless any of the following clinical features of Hirschsprung's disease are or have been present:\n\ndelayed passage of meconium (more than 48 hours after birth in term babies)\n\nconstipation since first few weeks of life\n\nchronic abdominal distension plus vomiting\n\nfamily history of Hirschsprung's disease\n\nfaltering growth in addition to any of the previous features.\n\n## Transit studies\n\nDo not use transit studies to make a diagnosis of idiopathic constipation.\n\nConsider using transit studies in the ongoing management of intractable idiopathic constipation only if requested by specialist services.\n\n## Ultrasound\n\nDo not use abdominal ultrasound to make a diagnosis of idiopathic constipation.\n\nConsider using abdominal ultrasound in the ongoing management of intractable idiopathic constipation only if requested by specialist services.\n\n# Clinical management\n\n## Disimpaction\n\nAssess all children and young people with idiopathic constipation for faecal impaction, including children and young people who were originally referred to the relevant services because of 'red flags' but in whom there were no significant findings following further investigations (see tables 2 and 3). Use a combination of history-taking and physical examination to diagnose faecal impaction – look for overflow soiling and/or faecal mass palpable abdominally and/or rectally if indicated.\n\nStart maintenance therapy if the child or young person is not faecally impacted.\n\nOffer the following oral medication regimen for disimpaction if indicated:\n\nPolyethylene glycol 3350 + electrolytes, using an escalating dose regimen, as the first-line treatment. (November 2021: Not all macrogol preparations are licensed for chronic constipation and faecal impaction. Of those that are licensed for these indications, not all of them are licensed for use in children under 12, and those that are may have different licence starting ages. See individual summaries of product characteristics for further detail. See NICE's information on prescribing medicines.)\n\nPolyethylene glycol 3350 + electrolytes may be mixed with a cold drink.\n\nAdd a stimulant laxative if polyethylene glycol 3350 + electrolytes does not lead to disimpaction after 2 weeks.\n\nSubstitute a stimulant laxative singly or in combination with an osmotic laxative such as lactulose if polyethylene glycol 3350 + electrolytes is not tolerated.\n\nInform families that disimpaction treatment can initially increase symptoms of soiling and abdominal pain.\n\nDo not use rectal medications for disimpaction unless all oral medications have failed and only if the child or young person and their family consent.\n\nAdminister sodium citrate enemas only if all oral medications for disimpaction have failed.\n\nDo not administer phosphate enemas for disimpaction unless under specialist supervision in hospital/health centre/clinic, and only if all oral medications and sodium citrate enemas have failed.\n\nDo not perform manual evacuation of the bowel under anaesthesia unless optimum treatment with oral and rectal medications has failed.\n\nReview children and young people undergoing disimpaction within 1 week.\n\n## Maintenance therapy\n\nStart maintenance therapy as soon as the child or young person's bowel is disimpacted.\n\nReassess children frequently during maintenance treatment to ensure they do not become reimpacted and assess issues in maintaining treatment such as taking medicine and toileting. Tailor the frequency of assessment to the individual needs of the child and their families (this could range from daily contact to contact every few weeks). Where possible, reassessment should be provided by the same person/team.\n\nOffer the following regimen for ongoing treatment or maintenance therapy:\n\nPolyethylene glycol 3350 + electrolytes as the first-line treatment. (November 2021: Not all macrogol preparations are licensed for chronic constipation and faecal impaction. Of those that are licensed for these indications, not all of them are licensed for use in children under 12, and those that are may have different licence starting ages. See individual summaries of product characteristics for further detail. See NICE's information on prescribing medicines).\n\nAdjust the dose of polyethylene glycol 3350 + electrolytes according to symptoms and response. As a guide for children and young people who have had disimpaction the starting maintenance dose might be half the disimpaction dose.\n\nAdd a stimulant laxative if polyethylene glycol 3350 + electrolytes does not work.\n\nSubstitute a stimulant laxative if polyethylene glycol 3350 + electrolytes is not tolerated by the child or young person. Add another laxative such as lactulose or docusate if stools are hard.\n\nContinue medication at maintenance dose for several weeks after regular bowel habit is established – this may take several months. Children who are toilet training should remain on laxatives until toilet training is well established. Do not stop medication abruptly: gradually reduce the dose over a period of months in response to stool consistency and frequency. Some children may require laxative therapy for several years. A minority may require ongoing laxative therapy.\n\n# Diet and lifestyle\n\nDo not use dietary interventions alone as first-line treatment for idiopathic constipation.\n\nTreat constipation with laxatives and a combination of:\n\nNegotiated and non-punitive behavioural interventions suited to the child or young person's stage of development. These could include scheduled toileting and support to establish a regular bowel habit, maintenance and discussion of a bowel diary, information on constipation, and use of encouragement and rewards systems.\n\nDietary modifications to ensure a balanced diet and sufficient fluids are consumed.\n\nAdvise parents and children and young people (if appropriate) that a balanced diet should include:\n\nAdequate fluid intake (see table 4).\n\nAdequate fibre. Recommend including foods with a high fibre content (such as fruit, vegetables, high-fibre bread, baked beans and wholegrain breakfast cereals) (not applicable to exclusively breastfed infants). Do not recommend unprocessed bran, which can cause bloating and flatulence and reduce the absorption of micronutrients.\n\n\n\n\n\nTotal water intake per day, including water contained in food\n\nWater obtained from drinks per day\n\nInfants 0 to 6 months\n\nml assumed to be from breast milk\n\n-\n\nto 12 months\n\nml from milk and complementary foods and beverages\n\nml\n\nto 3 years\n\n,300 ml\n\nml\n\nto 8 years\n\n,700 ml\n\n,200 ml\n\nBoys 9 to 13 years\n\n,400 ml\n\n,800 ml\n\nGirls 9 to 13 years\n\n,100 ml\n\n,600 ml\n\nBoys 14 to 18 years\n\n,300 ml\n\n,600 ml\n\nGirls 14 to 18 years\n\n,300 ml\n\n,800 ml\n\nThe above recommendations are for adequate intakes and should not be interpreted as a specific requirement. Higher intakes of total water will be required for those who are physically active or who are exposed to hot environments. It should be noted that obese children may also require higher total intakes of water. (Institute of Medicine, 2005). Dietary reference intakes for water, potassium, sodium chloride and sulfate. Washington DC: The National Academies Press.\n\nProvide children and young people with idiopathic constipation and their families with written information about diet and fluid intake.\n\nIn children with idiopathic constipation, start a cows' milk exclusion diet only on the advice of the relevant specialist services.\n\nAdvise daily physical activity that is tailored to the child or young person's stage of development and individual ability as part of ongoing maintenance in children and young people with idiopathic constipation.\n\n# Psychological interventions\n\nDo not use biofeedback for ongoing treatment in children and young people with idiopathic constipation.\n\nDo not routinely refer children and young people with idiopathic constipation to a psychologist or child and adolescent mental health services unless the child or young person has been identified as likely to benefit from receiving a psychological intervention.\n\n# Antegrade colonic enema procedure\n\nRefer children and young people with idiopathic constipation who still have unresolved symptoms on optimum management to a paediatric surgical centre to assess their suitability for an antegrade colonic enema (ACE) procedure.\n\nEnsure that all children and young people who are referred for an ACE procedure have access to support, information and follow-up from paediatric healthcare professionals with experience in managing children and young people who have had an ACE procedure.\n\n# Information and support\n\nProvide tailored follow-up to children and young people and their parents or carers according to the child or young person's response to treatment, measured by frequency, amount and consistency of stools. Use the Bristol Stool Form Scale to assess this (see appendix B). This could include:\n\ntelephoning or face-to-face talks\n\ngiving detailed evidence-based information about their condition and its management, using, for example, NICE's information for the public for this guideline\n\ngiving verbal information supported by (but not replaced by) written or website information in several formats about how the bowels work, symptoms that might indicate a serious underlying problem, how to take their medication, what to expect when taking laxatives, how to poo, origins of constipation, criteria to recognise risk situations for relapse (such as worsening of any symptoms, soiling etc.) and the importance of continuing treatment until advised otherwise by the healthcare professional.\n\nOffer children and young people with idiopathic constipation and their families a point of contact with specialist healthcare professionals, including school nurses, who can give ongoing support.\n\nHealthcare professionals should liaise with school nurses to provide information and support, and to help school nurses raise awareness of the issues surrounding constipation with children and young people and school staff.\n\nRefer children and young people with idiopathic constipation who do not respond to initial treatment within 3 months to a practitioner with expertise in the problem.\n\n# Terms used in this guideline\n\n## Chronic constipation\n\nConstipation lasting longer than 8 weeks.\n\n## Digital rectal examination\n\nExamination of the lower rectum using a gloved, lubricated finger to check for abnormalities.\n\n## Idiopathic constipation\n\nConstipation that cannot (currently) be explained by any anatomical, physiological, radiological or histological abnormalities.\n\n## Intractable constipation\n\nConstipation that does not respond to sustained, optimum medical management.\n\n## Optimum management\n\nManagement as set out in this guideline.\n\n## Specialist\n\nHealthcare professional with either interest, experience and/or training in the diagnosis and treatment of constipation in children and young people. Examples: specialist continence nurse, community paediatrician with an interest in the diagnosis and treatment of constipation.\n\n## Specialist services\n\nServices for children and young people that include constipation management.\n\nA larger glossary of terms can be found in the full guideline.", 'Recommendations for research': "The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The GDG's full set of recommendations for research are detailed in the full guideline.\n\n# Polyethylene glycol 3350 + electrolytes in children under 1\n\nWhat is the effectiveness of polyethylene glycol 3350 + electrolytes in treating idiopathic constipation in children younger than 1\xa0year old, and what is the optimum dosage?\n\n## Why this is important\n\nThere is some evidence that treatment of constipation is less effective if faecal impaction is not dealt with first. Disimpaction with oral macrogols is recommended for children and their use avoids the need for rectal treatments.\n\nRectal treatments are used more commonly in hospital than at home. Although relatively few infants are admitted to hospital, there would be savings if initially all children were disimpacted at home.\n\nPolyethylene glycol 3350 + electrolytes, an oral macrogol, is licensed for disimpaction in children older than 5 years. Increasing experience has shown that it is effective in infants younger than 1\xa0year old, but evidence is limited to small case series. If dosage guidelines and evidence on macrogol use in infants were obtained and published, more healthcare professionals might be encouraged to try macrogols in this age group. It would also allow the guideline to be applicable across the whole paediatric age group.\n\n# Age-specific information\n\nIs age-specific information more effective than non-age-specific information in increasing children's knowledge and understanding of constipation and its treatment, and what information should be given?\n\n## Why this is important\n\nWhen treating idiopathic constipation it is helpful if children and young people understand how the bowel works, what can go wrong and what they can do about it. Younger children (pre toilet training) need to allow stools to come out. Older children and young people have a more active role and need to develop a habit of taking all prescribed medication, sitting on the toilet each day and pushing stools out. Volition from the child or young person is vital to establish and sustain a regular toilet habit. Intended learning outcomes are similar for all age groups.\n\nTheory-based research has led to the development of some materials such as 'Sneaky-poo' that are not appropriate for young children. To help clinicians and parents motivate children and young people to fully participate in managing their constipation it is important to discover how best to communicate information to them, what materials are most effective and, specifically, what works at different ages.\n\n# Specialist services\n\nDo specialist nurse-led children's continence services or traditional secondary care services provide the most effective treatment for children with idiopathic constipation (with or without faecal incontinence) that does not respond fully to primary treatment regimens? This should consider clinical and cost effectiveness, and both short-term (16 weeks) and long-term (12 months) resolution.\n\n## Why this is important\n\nBy the time children reach tertiary care they have often suffered years of constipation with or without faecal incontinence and have intractable constipation.\n\nFindings from one trial have suggested that children referred to a tertiary gastroenterology service and diagnosed as having idiopathic constipation are managed as effectively by nurse-led follow-up as by a consultant paediatric gastroenterology service. Parent satisfaction was improved by the nurse-led service. However, the nurse-led service may require increased resources because many more contacts are made. Several services with a similar model of care have been established but cost effectiveness has not been formally assessed.\n\nFor coherent services to develop across the UK, the cost effectiveness of specialist nurse-led services provided as first referral point if primary treatment regimens have not worked needs to be examined.\n\n# Colonic washouts\n\nWhat is the effectiveness of different volumes and types of solutions used for colonic washouts in children who have undergone an antegrade colonic enema (ACE) procedure for intractable chronic idiopathic constipation?\n\n## Why this is important\n\nThe ACE procedure has a role in the management of people with treatment-resistant symptoms. Close follow-up is integral to the effectiveness of this technique to allow safe and effective administration of washout solutions.\n\nThe choice of washout solutions and frequency of administration differs between centres. Outcomes may be improved by evaluating how experienced centres choose washout solutions and by comparing techniques.\n\nCentres offering the ACE procedure as treatment for children with chronic idiopathic constipation should be surveyed for their choice of washout solution. To determine the perceived strengths and weaknesses of each solution, the survey should cover enema, choice of washout fluid, volumes and frequency of administration.\n\n# Models of service\n\nWhat is the impact of specific models of service on both clinical and social outcomes to deliver timely diagnosis and treatment interventions in children with chronic idiopathic constipation and their families?\n\n## Why this is important\n\nThere has been no research to explore the social impact on children with constipation and their families, and many of the clinical studies have been of mediocre quality. A comprehensive study is needed that investigates the effectiveness of specific models of care, and that takes into consideration both the clinical and social impact of this complex condition.", 'Appendix A: The algorithms': 'A care pathway can be found on page 22 to 32 of the full guideline.', 'Appendix B: Bristol Stool Form Scale': 'The Bristol Stool Form Scale can be found on page 32 of the full guideline.'}
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https://www.nice.org.uk/guidance/cg99
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This guideline covers diagnosing and managing constipation in children and young people up to 18. It provides strategies to support the early identification and timely, effective treatment of constipation which will help improve outcomes for patients. It does not cover constipation caused by a specific condition.
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9768adc470bbb43d568a145b2cd41cf225b9f4ad
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nice
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Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people
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Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people
Evidence-based recommendations on adalimumab (Humira), etanercept (Enbrel) and ustekinumab (Stelara) for plaque psoriasis in children and young people.
# Recommendations
Adalimumab is recommended as an option for treating plaque psoriasis in children and young people aged 4 years or older, only if the disease:
is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and
has not responded to standard systemic therapy, such as ciclosporin, methotrexate or phototherapy, or these options are contraindicated or not tolerated.
Etanercept is recommended as an option for treating plaque psoriasis in children and young people aged 6 years or older, only if the disease:
is severe, as defined by a total PASI of 10 or more and
has not responded to standard systemic therapy, such as ciclosporin, methotrexate or phototherapy, or these options are contraindicated or not tolerated.
Ustekinumab is recommended as an option for treating plaque psoriasis in children and young people aged 12 years or older, only if the disease:
is severe, as defined by a total PASI of 10 or more
has not responded to standard systemic therapy, such as ciclosporin, methotrexate or phototherapy, or these options are contraindicated or not tolerated.
Stop etanercept treatment at 12 weeks, and adalimumab and ustekinumab treatment at 16 weeks, if the psoriasis has not responded adequately. An adequate response is defined as a 75% reduction in the PASI score from the start of treatment.
The choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their parents or carers, about the advantages and disadvantages of the treatments available. Where a biosimilar product is available, start treatment with the least expensive option, taking into account administration costs, the dose needed and the product cost per dose.
When using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.
These recommendations are not intended to affect treatment with adalimumab, etanercept or ustekinumab that was started in the NHS before this guidance was published. Children and young people having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician and the child or young person or the child's or young person's parents or carers.# The technologies
Description of the technologies
Adalimumab (Humira, AbbVie) is a fully human immunoglobulin G1 monoclonal antibody that inhibits the activity of tumour necrosis factor alpha (TNF‑alpha).
Etanercept (Enbrel, Pfizer) is a recombinant human TNF‑alpha receptor fusion protein that inhibits the activity of TNF‑alpha. Biosimilars for etanercept are also available.
Ustekinumab (Stelara, Janssen) is a fully human monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin‑12 and interleukin‑23.
Marketing authorisations
Adalimumab has marketing authorisation for treating 'severe chronic plaque psoriasis in children and adolescents from 4 years of age who have an inadequate response to or are inappropriate candidates for topical therapy and phototherapies'.
Etanercept has a marketing authorisation for treating 'chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies'.
Ustekinumab has a marketing authorisation for treating 'moderate to severe plaque psoriasis in adolescent patients from the age of 12 years and older who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies'.
Adverse reactions
For full details of adverse reactions and contraindications, see the summary of product characteristics for adalimumab, etanercept and ustekinumab.
Recommended doses and schedules
Adalimumab: subcutaneous; initially 0.8 mg/kg every week (maximum per dose 40 mg) for 2 doses, then 0.8 mg/kg every 2 weeks (maximum per dose 40 mg).
Etanercept: subcutaneous; 0.8 mg/kg up to a maximum of 50 mg weekly for up to 24 weeks.
Ustekinumab: subcutaneous; 0.75 mg/kg for a body weight less than 60 kg; 45 mg for a body weight of between 60 kg and 100 kg; 90 mg for a body weight of above 100 kg at weeks 0 and 4, then every 12 weeks thereafter.
Prices
Costs may vary in different settings because of negotiated procurement discounts. Costs may vary for biosimilars.
The list prices (excluding VAT; 'British national formulary' online, March 2017) are: £352.14 for 40 mg adalimumab in a prefilled pen or prefilled syringe or vial for paediatric use; £35.75 for 10 mg etanercept in a vial (with solvent), powder for reconstitution, for injection; £2,147 for 45 mg ustekinumab in a prefilled syringe.# Evidence
The appraisal committee (section 7) considered evidence from a number of sources. See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of adalimumab, etanercept and ustekinumab, having considered evidence on the nature of psoriasis and the value placed on the benefits of adalimumab, etanercept and ustekinumab by people with the condition, those who represent them, and clinical experts. The data on the clinical evidence was submitted by the assessment group, AbbVie (adalimumab) and Janssen (ustekinumab). The data on the cost-effectiveness evidence was submitted by the assessment group. It also took into account the effective use of NHS resources.
The committee heard from the patient and clinical experts about the experience of people with psoriasis. It heard that the disease results in itchy, dry, red, scaly plaques on the skin, which can be physically and psychologically debilitating. Psoriasis may be unpredictable, with flare‑ups and remissions. The committee heard that, because psoriasis is visible, it can make children and young people feel isolated and lonely, which could lead to them losing self-confidence and avoiding social situations. The committee agreed that severe plaque psoriasis reduces quality of life.
# Treatment pathway
The committee heard from the clinical expert that the aim of treatment for people with psoriasis is to reduce the area of skin covered with psoriatic lesions and improve symptoms such as redness, flaking and itching. The committee was aware that, although there is a NICE guideline on psoriasis: assessment and management, treatment varies in practice. It heard from the clinical expert that children and young people have topical treatments first line. It heard that, if there is an inadequate response to treatment or if it is not tolerated or contraindicated, they can have systemic non-biological therapies (such as methotrexate, ciclosporin and phototherapy) second line. Clinicians then offer children and young people biological therapies or best supportive care third line. The clinical expert informed the committee that, if the disease no longer responds to a biological treatment, clinicians offer patients another biological therapy. The committee was aware that if patients could not have biological therapy they would have best supportive care, which would be non-biological systemic treatment. These treatments can be associated with frequent hospital visits for monitoring or treatment administration that can be inconvenient. These treatments can also be associated with adverse effects, for example, people who have phototherapy have an increased risk of developing skin cancer. The committee understood from the clinical expert that biological treatments have had a positive effect on patients over recent years because there is no longer a need to be hospitalised for long periods for treatment or monitoring. The committee concluded that it is valuable to have a range of biological treatment options that have different mechanisms of action.
## Position of technologies in the treatment pathway and comparators
The committee was aware that the marketing authorisations were different for adalimumab, etanercept and ustekinumab (see section 2). It was aware that adalimumab could be given as an alternative to non-biological systemic therapies but heard from the clinical expert that in clinical practice all 3 drugs are used as third line after topical therapies, phototherapy and non-biological systemic agents. It heard however, that patients and clinicians would welcome the opportunity to offer biologicals earlier in the treatment pathway. The committee concluded that the most appropriate comparator for adalimumab as a second-line treatment was non-biological systemic therapy (such as methotrexate). It also concluded that the most appropriate comparators for adalimumab, etanercept and ustekinumab as third-line treatment were each other and best supportive care, and that this was the point at which biologicals would most likely be used in the NHS.
# Clinical effectiveness
The committee considered the randomised controlled trial evidence for adalimumab, etanercept and ustekinumab submitted by the companies and reviewed by the assessment group:
M04‑717 compared adalimumab with methotrexate in children and young people (n=114) aged 4 years to 17 years. At 16 weeks adalimumab had improved Psoriasis Area and Severity Index 75 (PASI 75; a 75% reduction in PASI response) more than methotrexate (relative risk 1.79, 95% confidence interval 1.04 to 3.06).
compared etanercept with placebo in children and young people (n=211) aged 6 years to 17 years. At 12 weeks, etanercept had improved PASI 75 more than placebo (RR 4.95, 95% CI 2.84 to 8.65).
CADMUS compared ustekinumab with placebo in children and young people (n=110) aged 12 years to 17 years. At 12 weeks, ustekinumab had improved PASI 75 more than placebo (RR 7.5, 95% CI 2.9 to 19.1).
## Generalisability of the clinical trials to clinical practice
The committee considered the severity of psoriasis and the way it was defined in clinical practice and in the trials. It heard from the clinical experts that clinicians use both the PASI and the Children's Dermatology Life Quality Index (CDLQI; a questionnaire designed for use in children aged 5 years to 16 years) when monitoring disease and choosing who to offer biological therapies. The committee noted that percentage reduction in PASI score was the primary end point in M04‑717 and 20030211, and a secondary end point in CADMUS. It heard from the clinical expert that a 75% reduction in PASI (PASI 75) is a broadly used assessment method in children and young people. The committee agreed that the appropriate outcomes were captured in the trials. The committee concluded that PASI was a relevant measure used in clinical practice in the NHS and that PASI 75 was a clinically relevant definition of response to treatment.
The committee discussed the baseline characteristics of the patients in the trials:
Severity: the committee noted that the definition of severity varied between trials (notably, the inclusion criteria differed). It heard from the clinical expert that in practice clinicians use the definitions outlined in existing NICE guidance for biological treatments in adults. It heard that 'severe' disease is generally defined as a PASI of 10 or more. The committee noted that the trials mostly used a PASI at or above a score of 10.
Age: the committee noted that the mean age between the trials differed. It understood that this reflected the marketing authorisation for each technology (see section 4.9).The committee heard from clinical experts that the trials broadly reflected children and young people with severe plaque psoriasis in the NHS. It agreed that 'severe' disease should be defined as a PASI of 10 or more. It concluded that the clinical trial evidence was appropriate for decision-making and generalisable to NHS practice in England.
## Network meta-analysis results
The committee heard from the assessment group that it was not possible to connect the interventions and comparators together using direct evidence from children and young people alone because the trials did not use a common comparator. The committee understood that the assessment group's preferred analysis included all available adult data, because of the lack of evidence in children and young people. The committee understood that the assessment group adjusted for differences in population response rates and placebo response rates because they differed between trials and between children and adults. It agreed with the assessment group that all available adult evidence should be included in the network, and that it was appropriate to adjust the data for population characteristics and placebo response rates.
The results of the network meta-analyses are presented in table 1. The results for PASI 75 showed that the effectiveness of ustekinumab and adalimumab were similar, and that ustekinumab and adalimumab were more effective than etanercept. The committee heard from the clinical expert that this reflected clinical practice because clinicians are unlikely to offer etanercept as a first biological therapy. The committee was concerned that using adult data could potentially bias the effect estimates, but agreed that this was mitigated by the assessment group having adjusted for population and placebo effects. The committee concluded that, despite the uncertainty associated with the network meta-analyses (see section 4.7), the results showed adalimumab, etanercept and ustekinumab to be more clinically effective than placebo. In addition, the committee concluded that ustekinumab and adalimumab had broadly similar effectiveness, and that both were more clinically effective than etanercept.
Table 1 Network meta-analyses results
%, PASI 75 (95% CrI)
PASI 75 relative risk at 12 weeks, mean (95% CrI)
Versus placebo
Versus etanercept
Versus ustekinumab
Versus adalimumab
Etanercept
(39 to 69)
(3.30 to 8.05)
Ustekinumab
(71 to 90)
(4.46 to 14.14)
(1.28 to 1.92)
Adalimumab
(64 to 90)
(4.37 to 12.98)
(1.23 to 1.79)
(0.85 to 1.05)
Methotrexate
(31 to 68)
(3.01 to 6.94)
(0.66 to 1.15)
(0.41 to 0.77)
(0.44 to 0.78)
Placebo
(5 to 20)
Abbreviation: CrI, credible interval; PASI, Psoriasis Area and Severity Index.
# Cost effectiveness
## Model structure
The committee considered the assessment group's de novo Markov model. It noted the assessment group had done analyses for 3 different populations based on the position of the technology in the treatment pathway, and the different ages specified in the marketing authorisations for each intervention:
Population 1 included:
children and young people aged 4 years to 17 years
people with severe plaque psoriasis eligible for second-line treatment (that is, an alternative to a non-biological systemic treatment)
adalimumab and non-biological systemic treatment (methotrexate) as interventions or comparators.
Population 2 included:
children and young people aged 6 years to 17 years
people with severe plaque psoriasis eligible for third-line treatment (that is, as an alternative to another biological treatment or best supportive care)
adalimumab, etanercept and best supportive care as interventions or comparators.
Population 3 included:
children and young people aged 12 years to 17 years
people with severe plaque psoriasis eligible for third-line treatment (that is, as an alternative to another biological treatment or best supportive care)
adalimumab, etanercept, ustekinumab and best supportive care as interventions or comparators. The assessment group's model had 4 health states: 'trial period', 'continued use', 'best supportive care' and 'death'. Patients entered the model in the 'trial period' and had 1 of the 3 biological interventions or a relevant comparator. The modelled PASI response rates were from the assessment group's preferred network meta-analysis. The committee appreciated that young people continue taking biological treatments into adulthood, and may switch treatment, but understood from the assessment group that modelling these treatment sequences was not possible because the relevant data do not exist. The committee was aware that the marketing authorisation for adalimumab included children aged 4 to 6 years and was concerned that population 2 did not include this group of children. It therefore agreed to apply the results from population 2 to children aged between 4 and 6 years, in considering the comparison with best supportive care at third-line therapy (after non-biological systemic treatments). The committee accepted that the assessment group's modelling approach was acceptable for decision-making.
The committee discussed the length of the time horizon used in the assessment group's model. The assessment group assumed that at the age of 18 years, NICE technology appraisal guidance on etanercept, adalimumab and ustekinumab for biologicals in adults would apply. In the model, the time horizon varied according to population: 14 years for population 1 (aged 4 to 17 years); 12 years for population 2 (aged 6 to 17 years); and 6 years for population 3 (aged 12 to 17 years). The committee heard from one of the companies that a lifetime time horizon was needed to capture the full benefits and costs of treatment because the effects of psoriasis continue into adulthood. It heard from the assessment group that, in its model, most people had withdrawn from biological treatment after 14 years. It also noted that the time horizon did not have a large effect on the incremental cost-effectiveness ratios (ICERs). The committee concluded that, although a lifelong time horizon would better reflect the treated natural history of disease, given the data available, the assessment group's approach was acceptable.
The committee considered the stopping rules used by the assessment group in its model, that is, that clinicians should assess and stop treatment in patients whose disease has not responded by week 12 for etanercept, and week 16 for adalimumab and for ustekinumab. It agreed that this was consistent with the guidance in the summary of product characteristics for etanercept and adalimumab, but not for ustekinumab, which states that response should be assessed at 28 weeks, rather than 16 weeks. The committee understood that 16 weeks was used in NICE's technology appraisal guidance for ustekinumab for treating moderate to severe plaque psoriasis in adults. The committee agreed that it was desirable to have similar stopping rules for children and adults to avoid unnecessary changes in care during the transition from children to adult services. In addition, the committee agreed it was appropriate to use PASI 75 to assess response to treatment (see section 4.5). The committee concluded that the assessment group's approach and stopping rules based on PASI 75 were appropriate.
## Utilities
The committee discussed the challenges of measuring health-related quality of life in children and young people with psoriasis. The committee appreciated that the assessment group assumed that biological therapies improve quality of life but do not extend life. The committee noted that the trials did not collect data on EuroQol‑5 Dimension‑Youth (EQ‑5D‑Y, a generic preference-based measure for quality of life in people aged 8 years to 15 years), and reported only CDLQI and Pediatric Quality of Life Inventory (PedsQL, an approach to measuring health-related quality of life in healthy children and young people, and those with acute and chronic health conditions). In its model, the assessment group mapped PedsQL scores from the CADMUS trial to EQ‑5D‑Y using a mapping algorithm.
The committee noted that, when using this mapping algorithm, the quality of life in children and young people at the beginning of the trials was higher than in adults with severe plaque psoriasis (such as in NICE technology appraisal guidance on etanercept, adalimumab and ustekinumab). It also noted that the utility gain associated with an improvement in PASI response in children and young people was lower than in adults. The committee heard that it was implausible that children benefit less than adults, particularly because children experience similar physical symptoms, but some might feel more socially stigmatised than adults. The committee acknowledged that the gain in quality of life associated with an improvement in psoriasis was uncertain. It agreed that it was likely that the increase in quality of life in children and young people would be higher than estimated by the assessment group in its model. The committee concluded that it was appropriate to apply the most optimistic adult utility gains to children and young people.
The committee heard from the clinical and patient experts that carer disutility should be considered when appraising treatments for severe plaque psoriasis in children. The committee heard that children need help administering their treatments (such as applying emollients) and this can be time consuming, especially for best supportive care. The committee appreciated that it was difficult to estimate the disutility associated with psoriasis for carers and that, in the absence of quantitative estimates of these, the assessment group had not been able to incorporate carer disutilities in its analyses. The committee concluded that it would take into account the reduced disutility to carers with biological treatments in its decision-making.
## Resource use and costs
The committee considered costs used by the assessment group in its model:
Number of days in hospital with best supportive care: the committee noted that the assessment group assumed that there were 0 days in hospital with best supportive care after advice from its clinical expert in the absence of evidence. The committee noted comments from the companies that this was too conservative and that the assumption was inconsistent with previous NICE guidance (NICE guideline on psoriasis: 26.60 bed days; and a study on initiation of biological therapy in adults by Fonia et al. : 6.49 bed days). It heard from the clinical expert that hospitalisation was not common in the paediatric setting and was probably less than 6.49 bed days per year. The committee acknowledged that, because few children and young people with severe plaque psoriasis have best supportive care (with the availability of biologicals) in practice, it was difficult for clinicians to estimate the rate of hospitalisation in these patients. The committee acknowledged that the number of days in hospital was highly uncertain, but also that it had an important effect on the ICER. It agreed that the likely value was between 0 (as assumed by the assessment group) and 6.49 (as in the paper by Fonia et al.).
In its base case, the assessment group used costs for hospitalisation (£295.80) and for treatment at day centres (£472.55) from cost codes based on both adults and children. This was because it was not clear to them whether the costs only for children (£520.68 for hospitalisation and £622.29 for day centres) included the cost of the treatment. Following stakeholder comments on the appraisal consultation document, the assessment group also provided analyses using costs based only on children. The committee heard from the assessment group that using the costs only for children could potentially double-count costs of treatment. The committee noted consultation comments from a company, which pointed out that using costs based on both adults and children underestimated the cost of care for children and young people. The committee agreed that it was likely that children's costs would be higher than in adults, but acknowledged that the costs of hospitalisation and day centres for children were uncertain. Based on these uncertainties, the committee concluded that the likely costs for hospitalisation and treatment at day centres would be between the assessment group's base-case costs and the costs only for children.
## Cost-effectiveness results and conclusions
The committee recalled that its preferred assumptions included:
using adult utilities for children and young people (see section 4.13)
incorporating carer utilities (see section 4.14)
assuming the likely number of days in hospital with best supportive care was between 0 and 6.49 (see section 4.15)
assuming the likely costs for hospitalisation and for treatment at day centres were between costs based on both adults and children and just children (see section 4.15).
The committee agreed that the scenario analysis that most closely matched these assumptions was the assessment group's scenario analysis that combined the effect of using adult EQ‑5D data from NICE technology appraisal guidance on adalimumab, and which assumed 6.49 days in hospital per year for children and young adults having best supportive care from Fonia et al. (2010). However, the committee noted that some of its preferred assumptions were not fully reflected in the scenario analysis and took into account the potential for bias in the ICERs:
Including carer disutility: the committee agreed that including disutility might reduce the ICERs for more effective treatments.
Using higher costs for hospitalisation and for treatment at day centres: the committee agreed that these higher costs reduce the ICERs for more effective treatments.
Assuming the likely number of days in hospital with best supportive care was lower than 6.49: the committee agreed that a lower number of days in hospital would increase the ICERs for more effective treatments.
The ICER for adalimumab compared with methotrexate using costs for adults and children was £95,527 per quality-adjusted life year (QALY) gained. The ICER only using costs only for children was £85,170 per QALY gained. Taking into account potential biases (see section 4.16), the committee concluded that the most plausible ICER was unlikely to be at a level at which adalimumab could be considered a cost-effective use of NHS resources for this population.
The committee considered the cost-effectiveness estimates for populations 2 and 3:
Population 2:
Using adult and paediatric costs:
The ICER for etanercept compared with best supportive care was £8,897 per QALY gained.
The ICERs for adalimumab compared with etanercept and best supportive care were £49,274 and £25,657 per QALY gained respectively.
Using only paediatric costs:
Etanercept dominated best supportive care.
The ICERs for adalimumab compared with etanercept and best supportive care were £39,410 and £12,466 per QALY gained respectively.
Population 3:
Using adult and paediatric costs:
Etanercept was extendedly dominated by adalimumab. The ICER for etanercept compared with best supportive care was £29,177 per QALY gained.
The ICER for adalimumab compared with best supportive care was £23,861 per QALY gained.
The ICERs for ustekinumab compared with adalimumab and best supportive care were £61,722 and £26,253 per QALY gained respectively.
Using only paediatric costs:
Etanercept was extendedly dominated by adalimumab. The ICER for etanercept compared with best supportive care was £13,324 per QALY gained.
The ICER for adalimumab compared with best supportive care was £10,624 per QALY gained.
The ICERs for ustekinumab compared with adalimumab and best supportive care were £54,381 and £13,368 per QALY gained respectively.
The committee discussed whether a fully incremental approach was appropriate for decision-making. The committee was aware that NICE's guide to the methods of technology appraisal states that 'standard decision rules should be followed' and 'when appropriate, these should reflect when dominance or extended dominance exists'. The committee agreed that although a fully incremental approach was desirable, it was not appropriate for this appraisal because:
Using a fully incremental approach could result in different recommendations by age. That is, different technologies would be cost effective in children up to 11 years compared with children and young people from 12 to 17 years. The committee was aware that NICE's Social Value Judgement states that 'patients should not be denied, or have restricted access to, treatment simply because of their age'. The committee agreed that it had not been presented with any evidence to suggest that plaque psoriasis in children of different ages responds differently to the treatment.
The incremental difference in QALYs was uncertain:
The relative effectiveness estimates used in the assessment group's model were based on both direct and indirect comparisons using evidence from adults (see section 4.7).
The quality of life associated with an improvement in psoriasis was uncertain and the assessment group's model was based on adult utilities (see sections 4.12 and 4.13). The committee agreed that the incremental QALYs between all the technologies were uncertain.On balance, the committee concluded that a pairwise comparison of each technology with best supportive care was more appropriate for its decision-making.
The committee considered the cost effectiveness of the 3 biologicals. It took into account the potential biases associated with the ICERs (see section 4.17):
Etanercept: the most plausible ICER for etanercept compared with best supportive care was between dominance and £29,177 per QALY gained.
Adalimumab: the most plausible ICER for adalimumab compared with best supportive care was between £10,624 and 25,657 per QALY gained.
Ustekinumab: the most plausible ICER for ustekinumab compared with best supportive care was between £13,368 and £26,253 per QALY gained. The committee concluded that etanercept, adalimumab and ustekinumab could all be considered a cost-effective use of NHS resources for treating plaque psoriasis in children and young people.
The committee understood that it was valuable to have a range of biological treatment options that have different mechanisms of action (see section 4.2). It was also aware that a biosimilar for etanercept was now available. The committee agreed that the choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their parents or carers, about the advantages and disadvantages of the treatments available. Where a biosimilar product is available, start treatment with the least expensive option, taking into account administration costs, the dose needed and the product cost per dose.
# Innovation
The committee discussed whether adalimumab, etanercept and ustekinumab could be considered as innovative technologies. The committee heard from the clinical expert that these drugs were not novel to the NHS in England. The committee agreed that carer disutilities had not been included in the modelling but should be taken into account (see section 4.14). The committee concluded that there were QALYs that were not fully captured in the modelling.
# Equality issues
The committee was aware of the potential equality issue raised in previous NICE technology appraisals for adults that the PASI can underestimate disease severity in those with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make any adjustments they consider appropriate.
# Pharmaceutical Price Regulation Scheme 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.
# Summary of appraisal committee's key conclusions
TA455
Appraisal title: Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people
Section
Key conclusion
Adalimumab is recommended as an option for treating plaque psoriasis in children and young people aged 4 years or older. Etanercept is recommended as an option for treating plaque psoriasis in children and young people aged 6 years or older. Ustekinumab is recommended as an option for treating plaque psoriasis in children and young people aged 12 years or older. The committee concluded that adalimumab, etanercept and ustekinumab could all be considered a cost-effective use of NHS resources as a treatment for severe plaque psoriasis in children and young people.
to 1.3; 4.20 to 4.25
Current practice
Clinical need of patients, including the availability of alternative treatments
Children and young people have topical treatments as a first line. If their disease responds inadequately to treatment or if the previous treatment is not tolerated or contraindicated, they can have systemic non-biological therapies (such as methotrexate, ciclosporin and phototherapy) second line. Clinicians then offer children and young people biological therapies or best supportive care third line. If their disease no longer responds to a biological treatment, clinicians offer patients another biological therapy.
The technologies
Proposed benefits of the technologies
How innovative are the technologies in their potential to make a significant and substantial impact on health-related benefits?
Adalimumab and etanercept inhibit the activity of tumour necrosis factor alpha (TNF‑alpha), which is associated with psoriasis. Ustekinumab acts as a cytokine inhibitor by targeting interleukin‑12 and interleukin‑23, which are associated with psoriasis.
The committee concluded that the drugs were not novel to the NHS in England and that there were quality-adjusted life years (QALYs) that were not fully captured in the modelling.
What is the position of the treatments in the pathway of care for the condition?
The committee concluded that adalimumab, etanercept and ustekinumab would be offered as third-line treatments for children and young people with psoriasis.
Adverse reactions
Adverse reactions are described in the summary of product characteristics for each drug.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee considered evidence from the randomised controlled trials:
M04‑717 compared adalimumab with methotrexate in children and young people (n=114) aged 4 to 17 years.
compared etanercept with placebo in children and young people (n=211) aged 4 to 17 years.
CADMUS compared ustekinumab with placebo in children and young people (n=110) aged 12 to 17 years.
Relevance to general clinical practice in the NHS
The committee concluded that clinical trial evidence was appropriate for decision-making and generalisable to NHS practice in England.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The effectiveness of ustekinumab and adalimumab were similar based on relative effectiveness estimates for Psoriasis Area and Severity Index (PASI 75; adalimumab compared with ustekinumab, relative risk 0.96, 95% credible interval 0.85 to 1.05). In children and young people, ustekinumab (RR 1.54, 95% CrI 1.28 to 1.92) and adalimumab (RR 1.47, 95% CrI 1.23 to 1.79) are more effective than etanercept.
to 4.8
Evidence for cost effectiveness
Availability and nature of evidence
The committee considered the assessment group's de novo Markov model. It accepted that the model was appropriate for decision-making.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee identified the key uncertainties in the assumptions in the economic model, which include:
costs for hospitalisation and for treatment at day centres
not including carers' disutility
number of days in hospital.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee acknowledged that gain in quality of life associated with an improvement in psoriasis was uncertain. It agreed that it was likely that the increase in quality of life in children and young people would be higher than that estimated by the assessment group in its model. The committee concluded that it was appropriate to apply the most optimistic adult utility gains to children and young people.
Are there specific groups of people for whom the technologies are particularly cost effective?
No.
What are the key drivers of cost effectiveness?
The committee agreed that:
including carers' disutility might reduce the ICERs for more effective treatments
using higher costs for hospitalisation and for treatment at day centres might reduce the ICERs for more effective treatments
fewer days in hospital would increase the ICERs for more effective treatments.
Most likely cost-effectiveness estimate (given as an ICER)
Etanercept: the most plausible ICER for etanercept compared with best supportive care was between dominance and £29,177 per QALY gained.
Adalimumab: the most plausible ICER for adalimumab compared with best supportive care was between £10,624 and 25,657 per QALY gained.
Ustekinumab: the most plausible ICER for ustekinumab compared with best supportive care was between £13,368 and £26,253 per QALY gained.
Additional factors taken into account
Patient access schemes (PPRS)
The PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.
Equalities considerations and social value judgements
The committee was aware that the PASI can underestimate disease severity in those with darker skin. It concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make any adjustments they consider appropriate.
# Recommendations for research
Trials that evaluate utility values (using generic preference-based measures) in children and young people with severe psoriasis are needed to better inform future cost–utility analyses.
|
{'Recommendations': "Adalimumab is recommended as an option for treating plaque psoriasis in children and young people aged 4\xa0years or older, only if the disease:\n\nis severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and\n\nhas not responded to standard systemic therapy, such as ciclosporin, methotrexate or phototherapy, or these options are contraindicated or not tolerated.\n\nEtanercept is recommended as an option for treating plaque psoriasis in children and young people aged 6\xa0years or older, only if the disease:\n\nis severe, as defined by a total PASI of\xa010 or more and\n\nhas not responded to standard systemic therapy, such as ciclosporin, methotrexate or phototherapy, or these options are contraindicated or not tolerated.\n\nUstekinumab is recommended as an option for treating plaque psoriasis in children and young people aged 12\xa0years or older, only if the disease:\n\nis severe, as defined by a total PASI of\xa010 or more\n\nhas not responded to standard systemic therapy, such as ciclosporin, methotrexate or phototherapy, or these options are contraindicated or not tolerated.\n\nStop etanercept treatment at 12\xa0weeks, and adalimumab and ustekinumab treatment at 16\xa0weeks, if the psoriasis has not responded adequately. An adequate response is defined as a 75% reduction in the PASI score from the start of treatment.\n\nThe choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their parents or carers, about the advantages and disadvantages of the treatments available. Where a biosimilar product is available, start treatment with the least expensive option, taking into account administration costs, the dose needed and the product cost per dose.\n\nWhen using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make the clinical adjustments they consider appropriate.\n\nThese recommendations are not intended to affect treatment with adalimumab, etanercept or ustekinumab that was started in the NHS before this guidance was published. Children and young people having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician and the child or young person or the child's or young person's parents or carers.", 'The technologies': "Description of the technologies\n\nAdalimumab (Humira, AbbVie) is a fully human immunoglobulin\xa0G1 monoclonal antibody that inhibits the activity of tumour necrosis factor alpha (TNF‑alpha).\n\nEtanercept (Enbrel, Pfizer) is a recombinant human TNF‑alpha receptor fusion protein that inhibits the activity of TNF‑alpha. Biosimilars for etanercept are also available.\n\nUstekinumab (Stelara, Janssen) is a fully human monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin‑12 and interleukin‑23.\n\nMarketing authorisations\n\nAdalimumab has marketing authorisation for treating 'severe chronic plaque psoriasis in children and adolescents from 4\xa0years of age who have an inadequate response to or are inappropriate candidates for topical therapy and phototherapies'.\n\nEtanercept has a marketing authorisation for treating 'chronic severe plaque psoriasis in children and adolescents from the age of 6\xa0years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies'.\n\nUstekinumab has a marketing authorisation for treating 'moderate to severe plaque psoriasis in adolescent patients from the age of 12\xa0years and older who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies'.\n\nAdverse reactions\n\nFor full details of adverse reactions and contraindications, see the summary of product characteristics for adalimumab, etanercept and ustekinumab.\n\nRecommended doses and schedules\n\nAdalimumab: subcutaneous; initially 0.8\xa0mg/kg every week (maximum per dose 40\xa0mg) for 2\xa0doses, then 0.8\xa0mg/kg every 2\xa0weeks (maximum per dose 40\xa0mg).\n\nEtanercept: subcutaneous; 0.8\xa0mg/kg up to a maximum of 50\xa0mg weekly for up to 24\xa0weeks.\n\nUstekinumab: subcutaneous; 0.75\xa0mg/kg for a body weight less than 60\xa0kg; 45\xa0mg for a body weight of between 60\xa0kg and 100\xa0kg; 90\xa0mg for a body weight of above 100\xa0kg at weeks\xa00 and\xa04, then every 12\xa0weeks thereafter.\n\nPrices\n\nCosts may vary in different settings because of negotiated procurement discounts. Costs may vary for biosimilars.\n\nThe list prices (excluding VAT; 'British national formulary' [BNF] online, March\xa02017) are: £352.14 for 40\xa0mg adalimumab in a prefilled pen or prefilled syringe or vial for paediatric use; £35.75 for 10\xa0mg etanercept in a vial (with solvent), powder for reconstitution, for injection; £2,147 for 45\xa0mg ustekinumab in a prefilled syringe.", 'Evidence': 'The appraisal committee (section\xa07) considered evidence from a number of sources. See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of adalimumab, etanercept and ustekinumab, having considered evidence on the nature of psoriasis and the value placed on the benefits of adalimumab, etanercept and ustekinumab by people with the condition, those who represent them, and clinical experts. The data on the clinical evidence was submitted by the assessment group, AbbVie (adalimumab) and Janssen (ustekinumab). The data on the cost-effectiveness evidence was submitted by the assessment group. It also took into account the effective use of NHS resources.\n\nThe committee heard from the patient and clinical experts about the experience of people with psoriasis. It heard that the disease results in itchy, dry, red, scaly plaques on the skin, which can be physically and psychologically debilitating. Psoriasis may be unpredictable, with flare‑ups and remissions. The committee heard that, because psoriasis is visible, it can make children and young people feel isolated and lonely, which could lead to them losing self-confidence and avoiding social situations. The committee agreed that severe plaque psoriasis reduces quality of life.\n\n# Treatment pathway\n\nThe committee heard from the clinical expert that the aim of treatment for people with psoriasis is to reduce the area of skin covered with psoriatic lesions and improve symptoms such as redness, flaking and itching. The committee was aware that, although there is a NICE guideline on psoriasis: assessment and management, treatment varies in practice. It heard from the clinical expert that children and young people have topical treatments first line. It heard that, if there is an inadequate response to treatment or if it is not tolerated or contraindicated, they can have systemic non-biological therapies (such as methotrexate, ciclosporin and phototherapy) second line. Clinicians then offer children and young people biological therapies or best supportive care third line. The clinical expert informed the committee that, if the disease no longer responds to a biological treatment, clinicians offer patients another biological therapy. The committee was aware that if patients could not have biological therapy they would have best supportive care, which would be non-biological systemic treatment. These treatments can be associated with frequent hospital visits for monitoring or treatment administration that can be inconvenient. These treatments can also be associated with adverse effects, for example, people who have phototherapy have an increased risk of developing skin cancer. The committee understood from the clinical expert that biological treatments have had a positive effect on patients over recent years because there is no longer a need to be hospitalised for long periods for treatment or monitoring. The committee concluded that it is valuable to have a range of biological treatment options that have different mechanisms of action.\n\n## Position of technologies in the treatment pathway and comparators\n\nThe committee was aware that the marketing authorisations were different for adalimumab, etanercept and ustekinumab (see section\xa02). It was aware that adalimumab could be given as an alternative to non-biological systemic therapies but heard from the clinical expert that in clinical practice all 3\xa0drugs are used as third line after topical therapies, phototherapy and non-biological systemic agents. It heard however, that patients and clinicians would welcome the opportunity to offer biologicals earlier in the treatment pathway. The committee concluded that the most appropriate comparator for adalimumab as a second-line treatment was non-biological systemic therapy (such as methotrexate). It also concluded that the most appropriate comparators for adalimumab, etanercept and ustekinumab as third-line treatment were each other and best supportive care, and that this was the point at which biologicals would most likely be used in the NHS.\n\n# Clinical effectiveness\n\nThe committee considered the randomised controlled trial evidence for adalimumab, etanercept and ustekinumab submitted by the companies and reviewed by the assessment group:\n\nM04‑717 compared adalimumab with methotrexate in children and young people (n=114) aged 4\xa0years to 17\xa0years. At 16\xa0weeks adalimumab had improved Psoriasis Area and Severity Index\xa075 (PASI\xa075; a 75% reduction in PASI response) more than methotrexate (relative risk [RR] 1.79, 95% confidence interval [CI] 1.04 to\xa03.06).\n\ncompared etanercept with placebo in children and young people (n=211) aged 6\xa0years to 17\xa0years. At 12\xa0weeks, etanercept had improved PASI\xa075 more than placebo (RR\xa04.95, 95%\xa0CI 2.84 to\xa08.65).\n\nCADMUS compared ustekinumab with placebo in children and young people (n=110) aged 12\xa0years to 17\xa0years. At 12\xa0weeks, ustekinumab had improved PASI\xa075 more than placebo (RR\xa07.5, 95%\xa0CI 2.9 to\xa019.1).\n\n## Generalisability of the clinical trials to clinical practice\n\nThe committee considered the severity of psoriasis and the way it was defined in clinical practice and in the trials. It heard from the clinical experts that clinicians use both the PASI and the Children's Dermatology Life Quality Index (CDLQI; a questionnaire designed for use in children aged 5\xa0years to 16\xa0years) when monitoring disease and choosing who to offer biological therapies. The committee noted that percentage reduction in PASI score was the primary end point in M04‑717 and 20030211, and a secondary end point in CADMUS. It heard from the clinical expert that a 75% reduction in PASI (PASI\xa075) is a broadly used assessment method in children and young people. The committee agreed that the appropriate outcomes were captured in the trials. The committee concluded that PASI was a relevant measure used in clinical practice in the NHS and that PASI\xa075 was a clinically relevant definition of response to treatment.\n\nThe committee discussed the baseline characteristics of the patients in the trials:\n\nSeverity: the committee noted that the definition of severity varied between trials (notably, the inclusion criteria differed). It heard from the clinical expert that in practice clinicians use the definitions outlined in existing NICE guidance for biological treatments in adults. It heard that 'severe' disease is generally defined as a PASI of 10\xa0or more. The committee noted that the trials mostly used a PASI at or above a score of\xa010.\n\nAge: the committee noted that the mean age between the trials differed. It understood that this reflected the marketing authorisation for each technology (see section\xa04.9).The committee heard from clinical experts that the trials broadly reflected children and young people with severe plaque psoriasis in the NHS. It agreed that 'severe' disease should be defined as a PASI of 10\xa0or more. It concluded that the clinical trial evidence was appropriate for decision-making and generalisable to NHS practice in England.\n\n## Network meta-analysis results\n\nThe committee heard from the assessment group that it was not possible to connect the interventions and comparators together using direct evidence from children and young people alone because the trials did not use a common comparator. The committee understood that the assessment group's preferred analysis included all available adult data, because of the lack of evidence in children and young people. The committee understood that the assessment group adjusted for differences in population response rates and placebo response rates because they differed between trials and between children and adults. It agreed with the assessment group that all available adult evidence should be included in the network, and that it was appropriate to adjust the data for population characteristics and placebo response rates.\n\nThe results of the network meta-analyses are presented in table\xa01. The results for PASI\xa075 showed that the effectiveness of ustekinumab and adalimumab were similar, and that ustekinumab and adalimumab were more effective than etanercept. The committee heard from the clinical expert that this reflected clinical practice because clinicians are unlikely to offer etanercept as a first biological therapy. The committee was concerned that using adult data could potentially bias the effect estimates, but agreed that this was mitigated by the assessment group having adjusted for population and placebo effects. The committee concluded that, despite the uncertainty associated with the network meta-analyses (see section\xa04.7), the results showed adalimumab, etanercept and ustekinumab to be more clinically effective than placebo. In addition, the committee concluded that ustekinumab and adalimumab had broadly similar effectiveness, and that both were more clinically effective than etanercept.\n\nTable 1 Network meta-analyses results\n\n\n\n%, PASI\xa075 (95% CrI)\n\nPASI\xa075 relative risk at 12\xa0weeks, mean (95% CrI)\n\nVersus placebo\n\nVersus etanercept\n\nVersus ustekinumab\n\nVersus adalimumab\n\nEtanercept\n\n\n\n(39 to 69)\n\n\n\n(3.30 to 8.05)\n\n–\n\n–\n\n–\n\nUstekinumab\n\n\n\n(71 to 90)\n\n\n\n(4.46 to 14.14)\n\n\n\n(1.28 to 1.92)\n\n–\n\n–\n\nAdalimumab\n\n\n\n(64 to 90)\n\n\n\n(4.37 to 12.98)\n\n\n\n(1.23 to 1.79)\n\n\n\n(0.85 to 1.05)\n\n–\n\nMethotrexate\n\n\n\n(31 to 68)\n\n\n\n(3.01 to 6.94)\n\n\n\n(0.66 to 1.15)\n\n\n\n(0.41 to 0.77)\n\n\n\n(0.44 to 0.78)\n\nPlacebo\n\n\n\n(5 to 20)\n\n–\n\n–\n\n–\n\n–\n\nAbbreviation: CrI, credible interval; PASI, Psoriasis Area and Severity Index.\n\n# Cost effectiveness\n\n## Model structure\n\nThe committee considered the assessment group's de novo Markov model. It noted the assessment group had done analyses for 3\xa0different populations based on the position of the technology in the treatment pathway, and the different ages specified in the marketing authorisations for each intervention:\n\nPopulation\xa01 included:\n\n\n\nchildren and young people aged 4\xa0years to 17\xa0years\n\npeople with severe plaque psoriasis eligible for second-line treatment (that is, an alternative to a non-biological systemic treatment)\n\nadalimumab and non-biological systemic treatment (methotrexate) as interventions or comparators.\n\n\n\nPopulation\xa02 included:\n\n\n\nchildren and young people aged 6\xa0years to 17\xa0years\n\npeople with severe plaque psoriasis eligible for third-line treatment (that is, as an alternative to another biological treatment or best supportive care)\n\nadalimumab, etanercept and best supportive care as interventions or comparators.\n\n\n\nPopulation\xa03 included:\n\n\n\nchildren and young people aged 12\xa0years to 17\xa0years\n\npeople with severe plaque psoriasis eligible for third-line treatment (that is, as an alternative to another biological treatment or best supportive care)\n\nadalimumab, etanercept, ustekinumab and best supportive care as interventions or comparators. The assessment group's model had 4\xa0health states: 'trial period', 'continued use', 'best supportive care' and 'death'. Patients entered the model in the 'trial period' and had 1\xa0of the 3\xa0biological interventions or a relevant comparator. The modelled PASI response rates were from the assessment group's preferred network meta-analysis. The committee appreciated that young people continue taking biological treatments into adulthood, and may switch treatment, but understood from the assessment group that modelling these treatment sequences was not possible because the relevant data do not exist. The committee was aware that the marketing authorisation for adalimumab included children aged 4\xa0to 6\xa0years and was concerned that population\xa02 did not include this group of children. It therefore agreed to apply the results from population\xa02 to children aged between 4\xa0and 6\xa0years, in considering the comparison with best supportive care at third-line therapy (after non-biological systemic treatments). The committee accepted that the assessment group's modelling approach was acceptable for decision-making.\n\n\n\nThe committee discussed the length of the time horizon used in the assessment group's model. The assessment group assumed that at the age of 18\xa0years, NICE technology appraisal guidance on etanercept, adalimumab and ustekinumab for biologicals in adults would apply. In the model, the time horizon varied according to population: 14\xa0years for population\xa01 (aged 4\xa0to 17\xa0years); 12\xa0years for population\xa02 (aged 6\xa0to 17\xa0years); and 6\xa0years for population\xa03 (aged 12\xa0to 17\xa0years). The committee heard from one of the companies that a lifetime time horizon was needed to capture the full benefits and costs of treatment because the effects of psoriasis continue into adulthood. It heard from the assessment group that, in its model, most people had withdrawn from biological treatment after 14\xa0years. It also noted that the time horizon did not have a large effect on the incremental cost-effectiveness ratios (ICERs). The committee concluded that, although a lifelong time horizon would better reflect the treated natural history of disease, given the data available, the assessment group's approach was acceptable.\n\nThe committee considered the stopping rules used by the assessment group in its model, that is, that clinicians should assess and stop treatment in patients whose disease has not responded by week\xa012 for etanercept, and week\xa016 for adalimumab and for ustekinumab. It agreed that this was consistent with the guidance in the summary of product characteristics for etanercept and adalimumab, but not for ustekinumab, which states that response should be assessed at 28\xa0weeks, rather than 16\xa0weeks. The committee understood that 16\xa0weeks was used in NICE's technology appraisal guidance for ustekinumab for treating moderate to severe plaque psoriasis in adults. The committee agreed that it was desirable to have similar stopping rules for children and adults to avoid unnecessary changes in care during the transition from children to adult services. In addition, the committee agreed it was appropriate to use PASI\xa075 to assess response to treatment (see\xa0section 4.5). The committee concluded that the assessment group's approach and stopping rules based on PASI\xa075 were appropriate.\n\n## Utilities\n\nThe committee discussed the challenges of measuring health-related quality of life in children and young people with psoriasis. The committee appreciated that the assessment group assumed that biological therapies improve quality of life but do not extend life. The committee noted that the trials did not collect data on EuroQol‑5 Dimension‑Youth (EQ‑5D‑Y, a generic preference-based measure for quality of life in people aged 8\xa0years to 15\xa0years), and reported only CDLQI and Pediatric Quality of Life Inventory (PedsQL, an approach to measuring health-related quality of life in healthy children and young people, and those with acute and chronic health conditions). In its model, the assessment group mapped PedsQL scores from the CADMUS trial to EQ‑5D‑Y using a mapping algorithm.\n\nThe committee noted that, when using this mapping algorithm, the quality of life in children and young people at the beginning of the trials was higher than in adults with severe plaque psoriasis (such as in NICE technology appraisal guidance on etanercept, adalimumab and ustekinumab). It also noted that the utility gain associated with an improvement in PASI response in children and young people was lower than in adults. The committee heard that it was implausible that children benefit less than adults, particularly because children experience similar physical symptoms, but some might feel more socially stigmatised than adults. The committee acknowledged that the gain in quality of life associated with an improvement in psoriasis was uncertain. It agreed that it was likely that the increase in quality of life in children and young people would be higher than estimated by the assessment group in its model. The committee concluded that it was appropriate to apply the most optimistic adult utility gains to children and young people.\n\nThe committee heard from the clinical and patient experts that carer disutility should be considered when appraising treatments for severe plaque psoriasis in children. The committee heard that children need help administering their treatments (such as applying emollients) and this can be time consuming, especially for best supportive care. The committee appreciated that it was difficult to estimate the disutility associated with psoriasis for carers and that, in the absence of quantitative estimates of these, the assessment group had not been able to incorporate carer disutilities in its analyses. The committee concluded that it would take into account the reduced disutility to carers with biological treatments in its decision-making.\n\n## Resource use and costs\n\nThe committee considered costs used by the assessment group in its model:\n\nNumber of days in hospital with best supportive care: the committee noted that the assessment group assumed that there were 0\xa0days in hospital with best supportive care after advice from its clinical expert in the absence of evidence. The committee noted comments from the companies that this was too conservative and that the assumption was inconsistent with previous NICE guidance (NICE guideline on psoriasis: 26.60\xa0bed days; and a study on initiation of biological therapy in adults by Fonia et al. : 6.49\xa0bed days). It heard from the clinical expert that hospitalisation was not common in the paediatric setting and was probably less than 6.49\xa0bed days per year. The committee acknowledged that, because few children and young people with severe plaque psoriasis have best supportive care (with the availability of biologicals) in practice, it was difficult for clinicians to estimate the rate of hospitalisation in these patients. The committee acknowledged that the number of days in hospital was highly uncertain, but also that it had an important effect on the ICER. It agreed that the likely value was between 0\xa0(as assumed by the assessment group) and 6.49\xa0(as in the paper by Fonia et al.).\n\nIn its base case, the assessment group used costs for hospitalisation (£295.80) and for treatment at day centres (£472.55) from cost codes based on both adults and children. This was because it was not clear to them whether the costs only for children (£520.68 for hospitalisation and £622.29 for day centres) included the cost of the treatment. Following stakeholder comments on the appraisal consultation document, the assessment group also provided analyses using costs based only on children. The committee heard from the assessment group that using the costs only for children could potentially double-count costs of treatment. The committee noted consultation comments from a company, which pointed out that using costs based on both adults and children underestimated the cost of care for children and young people. The committee agreed that it was likely that children's costs would be higher than in adults, but acknowledged that the costs of hospitalisation and day centres for children were uncertain. Based on these uncertainties, the committee concluded that the likely costs for hospitalisation and treatment at day centres would be between the assessment group's base-case costs and the costs only for children.\n\n## Cost-effectiveness results and conclusions\n\nThe committee recalled that its preferred assumptions included:\n\nusing adult utilities for children and young people (see section\xa04.13)\n\nincorporating carer utilities (see section\xa04.14)\n\nassuming the likely number of days in hospital with best supportive care was between 0\xa0and\xa06.49 (see section\xa04.15)\n\nassuming the likely costs for hospitalisation and for treatment at day centres were between costs based on both adults and children and just children (see section\xa04.15).\n\nThe committee agreed that the scenario analysis that most closely matched these assumptions was the assessment group's scenario analysis that combined the effect of using adult EQ‑5D data from NICE technology appraisal guidance on adalimumab, and which assumed 6.49\xa0days in hospital per year for children and young adults having best supportive care from Fonia et al. (2010). However, the committee noted that some of its preferred assumptions were not fully reflected in the scenario analysis and took into account the potential for bias in the ICERs:\n\nIncluding carer disutility: the committee agreed that including disutility might reduce the ICERs for more effective treatments.\n\nUsing higher costs for hospitalisation and for treatment at day centres: the committee agreed that these higher costs reduce the ICERs for more effective treatments.\n\nAssuming the likely number of days in hospital with best supportive care was lower than\xa06.49: the committee agreed that a lower number of days in hospital would increase the ICERs for more effective treatments.\n\nThe ICER for adalimumab compared with methotrexate using costs for adults and children was £95,527 per quality-adjusted life year (QALY) gained. The ICER only using costs only for children was £85,170 per QALY gained. Taking into account potential biases (see section\xa04.16), the committee concluded that the most plausible ICER was unlikely to be at a level at which adalimumab could be considered a cost-effective use of NHS resources for this population.\n\nThe committee considered the cost-effectiveness estimates for populations\xa02 and\xa03:\n\nPopulation\xa02:\n\nUsing adult and paediatric costs:\n\n\n\nThe ICER for etanercept compared with best supportive care was £8,897 per QALY gained.\n\nThe ICERs for adalimumab compared with etanercept and best supportive care were £49,274 and £25,657 per QALY gained respectively.\n\n\n\nUsing only paediatric costs:\n\n\n\nEtanercept dominated best supportive care.\n\nThe ICERs for adalimumab compared with etanercept and best supportive care were £39,410 and £12,466 per QALY gained respectively.\n\n\n\nPopulation\xa03:\n\nUsing adult and paediatric costs:\n\n\n\nEtanercept was extendedly dominated by adalimumab. The ICER for etanercept compared with best supportive care was £29,177 per QALY gained.\n\nThe ICER for adalimumab compared with best supportive care was £23,861 per QALY gained.\n\nThe ICERs for ustekinumab compared with adalimumab and best supportive care were £61,722 and £26,253 per QALY gained respectively.\n\n\n\nUsing only paediatric costs:\n\n\n\nEtanercept was extendedly dominated by adalimumab. The ICER for etanercept compared with best supportive care was £13,324 per QALY gained.\n\nThe ICER for adalimumab compared with best supportive care was £10,624 per QALY gained.\n\nThe ICERs for ustekinumab compared with adalimumab and best supportive care were £54,381 and £13,368 per QALY gained respectively.\n\n\n\nThe committee discussed whether a fully incremental approach was appropriate for decision-making. The committee was aware that NICE's guide to the methods of technology appraisal states that 'standard decision rules should be followed' and 'when appropriate, these should reflect when dominance or extended dominance exists'. The committee agreed that although a fully incremental approach was desirable, it was not appropriate for this appraisal because:\n\nUsing a fully incremental approach could result in different recommendations by age. That is, different technologies would be cost effective in children up to 11\xa0years compared with children and young people from 12\xa0to 17\xa0years. The committee was aware that NICE's Social Value Judgement states that 'patients should not be denied, or have restricted access to, treatment simply because of their age'. The committee agreed that it had not been presented with any evidence to suggest that plaque psoriasis in children of different ages responds differently to the treatment.\n\nThe incremental difference in QALYs was uncertain:\n\n\n\nThe relative effectiveness estimates used in the assessment group's model were based on both direct and indirect comparisons using evidence from adults (see section\xa04.7).\n\nThe quality of life associated with an improvement in psoriasis was uncertain and the assessment group's model was based on adult utilities (see sections\xa04.12 and 4.13). The committee agreed that the incremental QALYs between all the technologies were uncertain.On balance, the committee concluded that a pairwise comparison of each technology with best supportive care was more appropriate for its decision-making.\n\n\n\nThe committee considered the cost effectiveness of the 3\xa0biologicals. It took into account the potential biases associated with the ICERs (see section\xa04.17):\n\nEtanercept: the most plausible ICER for etanercept compared with best supportive care was between dominance and £29,177 per QALY gained.\n\nAdalimumab: the most plausible ICER for adalimumab compared with best supportive care was between £10,624 and 25,657 per QALY gained.\n\nUstekinumab: the most plausible ICER for ustekinumab compared with best supportive care was between £13,368 and £26,253 per QALY gained. The committee concluded that etanercept, adalimumab and ustekinumab could all be considered a cost-effective use of NHS resources for treating plaque psoriasis in children and young people.\n\nThe committee understood that it was valuable to have a range of biological treatment options that have different mechanisms of action (see section\xa04.2). It was also aware that a biosimilar for etanercept was now available. The committee agreed that the choice of treatment should be made on an individual basis after discussion between the responsible clinician and the patient, or their parents or carers, about the advantages and disadvantages of the treatments available. Where a biosimilar product is available, start treatment with the least expensive option, taking into account administration costs, the dose needed and the product cost per dose.\n\n# Innovation\n\nThe committee discussed whether adalimumab, etanercept and ustekinumab could be considered as innovative technologies. The committee heard from the clinical expert that these drugs were not novel to the NHS in England. The committee agreed that carer disutilities had not been included in the modelling but should be taken into account (see section\xa04.14). The committee concluded that there were QALYs that were not fully captured in the modelling.\n\n# Equality issues\n\nThe committee was aware of the potential equality issue raised in previous NICE technology appraisals for adults that the PASI can underestimate disease severity in those with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make any adjustments they consider appropriate.\n\n# Pharmaceutical Price Regulation Scheme 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA455\n\nAppraisal title: Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people\n\nSection\n\nKey conclusion\n\nAdalimumab is recommended as an option for treating plaque psoriasis in children and young people aged 4\xa0years or older. Etanercept is recommended as an option for treating plaque psoriasis in children and young people aged 6\xa0years or older. Ustekinumab is recommended as an option for treating plaque psoriasis in children and young people aged 12\xa0years or older. The committee concluded that adalimumab, etanercept and ustekinumab could all be considered a cost-effective use of NHS resources as a treatment for severe plaque psoriasis in children and young people.\n\nto 1.3; 4.20 to 4.25\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nChildren and young people have topical treatments as a first line. If their disease responds inadequately to treatment or if the previous treatment is not tolerated or contraindicated, they can have systemic non-biological therapies (such as methotrexate, ciclosporin and phototherapy) second line. Clinicians then offer children and young people biological therapies or best supportive care third line. If their disease no longer responds to a biological treatment, clinicians offer patients another biological therapy.\n\n\n\nThe technologies\n\nProposed benefits of the technologies\n\nHow innovative are the technologies in their potential to make a significant and substantial impact on health-related benefits?\n\nAdalimumab and etanercept inhibit the activity of tumour necrosis factor alpha (TNF‑alpha), which is associated with psoriasis. Ustekinumab acts as a cytokine inhibitor by targeting interleukin‑12 and interleukin‑23, which are associated with psoriasis.\n\n\n\nThe committee concluded that the drugs were not novel to the NHS in England and that there were quality-adjusted life years (QALYs) that were not fully captured in the modelling.\n\n\n\nWhat is the position of the treatments in the pathway of care for the condition?\n\nThe committee concluded that adalimumab, etanercept and ustekinumab would be offered as third-line treatments for children and young people with psoriasis.\n\n\n\nAdverse reactions\n\nAdverse reactions are described in the summary of product characteristics for each drug.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee considered evidence from the randomised controlled trials:\n\nM04‑717 compared adalimumab with methotrexate in children and young people (n=114) aged 4\xa0to 17\xa0years.\n\ncompared etanercept with placebo in children and young people (n=211) aged 4\xa0to 17\xa0years.\n\nCADMUS compared ustekinumab with placebo in children and young people (n=110) aged 12\xa0to 17\xa0years.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that clinical trial evidence was appropriate for decision-making and generalisable to NHS practice in England.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe effectiveness of ustekinumab and adalimumab were similar based on relative effectiveness estimates for Psoriasis Area and Severity Index (PASI\xa075; adalimumab compared with ustekinumab, relative risk [RR] 0.96, 95% credible interval [CrI] 0.85 to 1.05). In children and young people, ustekinumab (RR 1.54, 95% CrI 1.28 to 1.92) and adalimumab (RR 1.47, 95% CrI 1.23 to 1.79) are more effective than etanercept.\n\nto 4.8\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe committee considered the assessment group's de novo Markov model. It accepted that the model was appropriate for decision-making.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee identified the key uncertainties in the assumptions in the economic model, which include:\n\ncosts for hospitalisation and for treatment at day centres\n\nnot including carers' disutility\n\nnumber of days in hospital.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee acknowledged that gain in quality of life associated with an improvement in psoriasis was uncertain. It agreed that it was likely that the increase in quality of life in children and young people would be higher than that estimated by the assessment group in its model. The committee concluded that it was appropriate to apply the most optimistic adult utility gains to children and young people.\n\n\n\nAre there specific groups of people for whom the technologies are particularly cost effective?\n\nNo.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee agreed that:\n\nincluding carers' disutility might reduce the ICERs for more effective treatments\n\nusing higher costs for hospitalisation and for treatment at day centres might reduce the ICERs for more effective treatments\n\nfewer days in hospital would increase the ICERs for more effective treatments.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nEtanercept: the most plausible ICER for etanercept compared with best supportive care was between dominance and £29,177 per QALY gained.\n\nAdalimumab: the most plausible ICER for adalimumab compared with best supportive care was between £10,624 and 25,657 per QALY gained.\n\nUstekinumab: the most plausible ICER for ustekinumab compared with best supportive care was between £13,368 and £26,253 per QALY gained.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe PPRS payment mechanism was not relevant in considering the cost effectiveness of any of the technologies in this appraisal.\n\n\n\nEqualities considerations and social value judgements\n\nThe committee was aware that the PASI can underestimate disease severity in those with darker skin. It concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score, and make any adjustments they consider appropriate.\n\n", 'Recommendations for research': 'Trials that evaluate utility values (using generic preference-based measures) in children and young people with severe psoriasis are needed to better inform future cost–utility analyses.'}
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https://www.nice.org.uk/guidance/ta455
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Evidence-based recommendations on adalimumab (Humira), etanercept (Enbrel) and ustekinumab (Stelara) for plaque psoriasis in children and young people.
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e6f27d9a9bc991c06f3bfb8a614a550ac9c79c19
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nice
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Ustekinumab for moderately to severely active Crohn's disease after previous treatment
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Ustekinumab for moderately to severely active Crohn's disease after previous treatment
Evidence-based recommendations on ustekinumab (Stelara) for previously treated moderately to severely active Crohn’s disease in adults.
# Recommendations
Ustekinumab is recommended, within its marketing authorisation, as an option for treating moderately to severely active Crohn's disease, that is, for adults who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF‑alpha inhibitor or have medical contraindications to such therapies.
The choice of treatment between ustekinumab or another biological therapy should be made on an individual basis after discussion between the patient and their clinician about the advantages and disadvantages of the treatments available. If more than 1 treatment is suitable, the least expensive should be chosen (taking into account administration costs, dosage and price per dose).
Ustekinumab should be given until treatment failure (including the need for surgery) or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed in accordance with NICE's recommendations for infliximab and adalimumab for the treatment of Crohn's disease to see whether treatment should continue.# The technology
Description of the technology
Ustekinumab (Stelara, Janssen) is a human monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin‑12 (IL‑12) and interleukin‑23 (IL‑23).
Marketing authorisation
Ustekinumab has a marketing authorisation in the UK for treating 'adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF‑alpha inhibitor or have medical contraindications to such therapies:
Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose may receive a second subcutaneous dose at this time.
Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing frequency to every 8 weeks.
Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment'.
Adverse reactions
The most common adverse reactions for ustekinumab include arthralgia, headache, nausea, pyrexia, nasopharyngitis, abdominal pain, upper respiratory tract infection, diarrhoea and fatigue. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
Ustekinumab is given as intravenous infusion at induction and as subcutaneous injection at maintenance:
intravenous induction treatment (dose depends on body weight and is approximately 6 mg/kg).
Maintenance subcutaneous treatment at week 8 (90 mg), then every 12 weeks.
Price
The list price for ustekinumab is £2,147 per 130‑mg vial concentrate for solution for infusion and per 90‑mg vial solution for injection (excluding VAT; Monthly Index of Medical Specialties).
A confidential pricing arrangement has been agreed with the Commercial Medicines Unit.# Evidence
The appraisal committee (section 6) considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of moderately to severely active Crohn's disease and the value placed on the benefits of ustekinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
# Clinical effectiveness
## Clinical need of people with Crohn's disease
The committee understood that Crohn's disease follows an unpredictable, relapsing and remitting course with many debilitating symptoms. It heard from the patient experts that the disease can present a major barrier to a person's ability to participate in daily life, severely affecting their self-esteem, social functioning, engagement in work and other activities, personal relationships and family life. The patient experts recounted their experience of current treatments including conventional non-biological therapy and TNF‑alpha inhibitors, and their intolerance to, or subsequent loss of response to these treatments. The committee heard that patients fear loss of remission and exacerbations of the disease because of the major impact these have on quality of life. It also heard that it is very important to have a range of treatment options to enable patients to regain remission. The committee noted that both the patient experts had ustekinumab as part of a clinical trial after losing response to TNF‑alpha inhibitors. Both recounted a positive response to treatment with ustekinumab and emphasised its life-changing effects, with good control of symptoms allowing them to resume work and everyday activities as well as avoiding the need for surgery. One patient expert explained that ustekinumab had left him feeling 'wonderfully normal again' while the other highlighted the immense improvement to her quality of life, enabling her to start a family. The patient experts also emphasised that maintenance treatment with ustekinumab is a subcutaneous injection rather than an intravenous infusion, which is greatly valued by patients because it means they can take the treatment at home with no need for hospital visits. The committee acknowledged that ustekinumab is a convenient and well-tolerated treatment that has considerably improved the quality of life of the patient experts. It concluded that the availability of a further treatment option to improve symptoms and bring the disease into remission would be highly valued by people with Crohn's disease.
## Current clinical management of Crohn's disease
The committee heard from the clinical experts that initial treatment for people with Crohn's disease is conventional non-biological treatment but if this fails, patients are offered a TNF‑alpha inhibitor (infliximab or adalimumab). If this fails or is unsuitable, patients may switch to an alternative TNF‑alpha inhibitor or have vedolizumab in line with NICE technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy. It was the clinical experts' opinion that only when all other options have been exhausted, including dose escalation of a TNF‑alpha inhibitor despite it becoming less effective, would various non-biological approaches including surgery be considered. The committee heard from the clinical experts that ustekinumab is a novel treatment with a different mechanism of action to existing treatments, and that it can be used either in place of a TNF‑alpha inhibitor after conventional non-biological treatment has failed, or instead of vedolizumab (or a subsequent TNF‑alpha inhibitor, for which there is very limited evidence) after a first TNF‑alpha inhibitor has failed. It acknowledged that the clinical experts value using TNF‑alpha inhibitors first‑line, after failure of conventional non-biological treatment, because there is considerable clinical experience in using them. It is likely therefore that ustekinumab would predominantly be used later in the treatment pathway, although there may be some individual patients for whom ustekinumab would be considered earlier. The committee concluded that ustekinumab would be used as an option where other biological treatments would be considered appropriate, and hence that these are the relevant comparators in the appraisal.
The committee considered the duration of treatment with current biological therapies in clinical practice. It heard from the clinical experts that in line with current guidelines the benefit of these agents is assessed after induction to ensure a primary response and then at 1 year to see whether treatment should continue. The clinical experts emphasised that, when there is evidence of clinical benefit, therapy usually continues beyond 1 year in order to avoid complications and exacerbations that can result in life-changing surgery. However, the clinical experts acknowledged that there are currently no clinical data to support the long-term effectiveness of biological therapies. The committee also heard from the clinical experts that evidence from the UK Inflammatory Bowel Disease Audit shows that most patients continue on biological therapy for more than 1 year and that initial results suggest that continuous use is associated with better outcomes. The committee concluded that there is uncertainty about the appropriate duration of treatment with biological therapy but that evidence from current practice suggests there may be a benefit to continuing treatment beyond 1 year.
## Clinical trial evidence
The committee noted that the clinical evidence for ustekinumab came from 2 induction trials (UNITI‑1 and UNITI‑2) and 1 maintenance trial (IM‑UNITI) that included patients who had had a clinical response to ustekinumab in either of the 2 induction trials. It was aware that the UNITI‑1 and -2 trials were identical in design except for the trial populations. In UNITI‑1, patients had had TNF‑alpha inhibitor therapy but did not respond, lost response or were intolerant to it ('the TNF‑alpha-inhibitor failure population'). In UNITI‑2, patients had had conventional non-biological treatment that had failed ('the conventional-care failure population'). The committee noted the evidence review group (ERG's) comments that the induction trials were generally well conducted with high internal validity and were reasonably generalisable to the UK Crohn's disease population, although the committee was aware of some issues worthy of further consideration. For example, clinical advice to the ERG suggested that the Crohn's disease activity index (CDAI; a measurement of clinical, biochemical and physical parameters of disease activity) on which the primary outcome in the trials was based, is not used in clinical practice in the UK. The committee heard from the clinical experts present at the meeting that outcomes based on the CDAI have historically been used in studies of biological treatments in Crohn's disease to assess response, and therefore it was not unreasonable that they were used in the current trials. However they explained that there is now a move towards more objective assessment of disease activity, such as endoscopic evaluation of ulceration. The committee accepted that the use of the CDAI was acceptable given its historic use in assessing response to other biological treatments. The committee also noted that the trial excluded patients with the most severe disease (defined by a CDAI score higher than 450). The committee heard from the clinical experts that the trial populations were generally representative of patients seen in clinical practice and that the exclusion of some groups of patients, such as those with the most severe disease, was a limitation of trials generally. The committee concluded that the studies were of a good quality and broadly generalisable to the population likely to have ustekinumab in clinical practice in England.
## Clinical effectiveness results from induction trials
The committee noted that in both of the induction trials, the proportion of patients with a clinical response at 6 weeks (the primary outcome, defined as a reduction from baseline in CDAI score of 100 points or more) was significantly greater in patients randomised to ustekinumab compared with placebo. In UNITI‑1, 33.7% of patients in the ustekinumab group at the licensed dose of approximately 6 mg/kg had a clinical response compared with 21.5% in the placebo group (p=0.003). In UNITI‑2, 55.5% of patients in the ustekinumab group had a clinical response compared with 28.7% in the placebo group (p=0.001). The committee also noted that there were statistically significant differences between ustekinumab and placebo in the rates of clinical remission (defined as attaining a CDAI score of less than 150 points) and other secondary outcomes. The committee noted that the results were more favourable for the conventional-care failure population in UNITI‑2 than for the TNF‑alpha-inhibitor failure population in UNITI‑1. However, it understood from the clinical experts that patients in whom TNF‑alpha inhibitors have failed are likely to respond less well to all biological treatments than patients who are naive to TNF‑alpha inhibitors. The committee concluded that the results from the induction studies suggest that ustekinumab is associated with higher rates of response and clinical remission compared with placebo in both populations of patients.
## Clinical effectiveness results from maintenance trials
The committee noted that at 44‑week follow-up in the IM‑UNITI maintenance trial, the proportion of patients in clinical remission (the primary outcome) was significantly greater in both the 90 mg every 12 weeks (48.8%) and 90 mg every 8 weeks (53.1%) ustekinumab groups than in the placebo group (35.9%, p=0.040 and p=0.005 respectively). It also noted that there were statistically significant differences between ustekinumab and placebo for clinical response at 44 weeks. The committee acknowledged that the company had submitted some additional results up to week 92 but that no statistical comparisons between ustekinumab and placebo were presented. It concluded that the results from the maintenance study suggest that ustekinumab is associated with higher rates of clinical remission and response at 44 weeks compared with placebo but that the longer-term effects are uncertain because limited data are available.
## Relative effectiveness of ustekinumab and other biological therapies
The committee noted that the company had presented indirect comparisons to provide comparative efficacy estimates for ustekinumab compared with other biological treatments. It understood that analyses were performed separately for induction trials and maintenance trials and for the conventional-care failure population and the TNF‑alpha-inhibitor failure population. For the induction phase, the company provided a network meta-analysis. The committee noted that the ERG considered that the trials included in the network meta-analysis were generally conducted to a high-standard. However there were some limitations with the analysis because of variability in the time at which primary outcomes were assessed in the trials and differences in treatment history and previous exposure to TNF‑alpha inhibitors. It also noted that only 1 small study of infliximab was included in the analysis and that the company had highlighted the need to interpret the results of the study with caution because of missing data, and because a smaller magnitude of effect was observed with higher doses of infliximab than with smaller doses. The committee acknowledged that the network meta-analysis suggested significantly higher rates of response and remission in the induction phase with infliximab compared with ustekinumab but no statistically significant differences between ustekinumab and the other biological therapies. However, it concluded that the results were associated with uncertainty and that the comparison between infliximab and ustekinumab in particular should be interpreted with caution.
For the maintenance phase, the company carried out a treatment sequence analysis instead of a conventional network meta-analysis because of the multiple sources of heterogeneity between the maintenance trials. The committee noted that the company's aim was to evaluate treatment effects over the entire treatment sequence to reduce bias inherently associated with the analysis of long-term relative treatment effect estimates for ustekinumab. The committee also noted that the company stated that this was a complex analysis and the results should be viewed with caution. The committee was aware that the ERG had identified a number of issues with the company's analysis, and believed the results were highly uncertain. The ERG's concerns included the comparability of the trials included in the treatment sequence analysis. It also considered that the methods used to construct the control arm for biological therapies had considerable potential for confounding of results, because the analysis was based on placebo-data from IM‑UNITI and not on randomised comparisons. The committee acknowledged that both the company and the ERG had reservations about the reliability of the treatment sequence analysis. It agreed that the treatment sequence analysis had many limitations and that the results should be interpreted with caution.
# Cost effectiveness
## Company's economic model
The company presented a model consisting of a short-term induction phase (a decision tree) and a long-term maintenance phase (a Markov state transition model) comparing ustekinumab with conventional non-biological therapies and other biological therapies (infliximab, adalimumab and vedolizumab) in patients with moderately to severe active Crohn's disease. The committee recalled that ustekinumab would be used in place of other biological treatments (see section 4.2) and therefore the comparison of ustekinumab with other biological treatments is the most relevant to the appraisal.
The committee acknowledged comments from the ERG about the general weaknesses of the model structure. It heard that it did not fully characterise the chronic life-long relapsing-remitting nature of Crohn's disease because it did not allow patients to cycle through multiple biological therapies. It also heard that the impact of surgery on future prognosis, including the need for further surgery, and health-related quality of life were not appropriately incorporated. The committee acknowledged that similar models had been used in other technology appraisals for Crohn's disease and, while noting its limitations, concluded that the structure of the model was acceptable for decision making. However it also noted the ERG's comment that research is needed to develop a new and more appropriately structured decision-analytic model for Crohn's disease, which could be used in future appraisals.
## Cost-effectiveness results
The committee noted that in the company's base-case analysis ustekinumab dominated other biological treatments (that is, it cost less and resulted in higher quality adjusted life years ), both in the conventional-care failure population and in the TNF‑alpha-inhibitor failure population. It also noted that ustekinumab remained dominant compared with other biological treatments in the ERG's exploratory analyses using the company's model structure. The committee observed that there were only small differences in the QALY estimates between the different biological therapies as estimated by the company and the ERG. It recognised that this leads to instability in the cost-effectiveness results and therefore further considered the company's suggestion that a cost-minimisation analysis may be more appropriate. The committee heard from the ERG that it is not unreasonable to assume similar efficacy between the biological therapies based on the available evidence. It also recalled that the clinical experts had commented that the absence of direct comparative data meant that it was unknown whether there were any differences in efficacy. The committee was therefore persuaded that cost minimisation was not an unreasonable approach. It noted that in the company analysis, which used the confidential pricing arrangement for ustekinumab agreed with the Commercial Medicines Unit, ustekinumab appeared to have lower total costs in year 1 than comparator treatments when considered at their list price, and therefore ustekinumab could be considered a cost-effective option for use in the NHS. However, the committee was mindful that different prices may be available in the NHS for different biological treatments and it concluded that the total cost of the treatments should be taken into account when deciding which one to use in clinical practice.
## Innovation
The committee discussed the innovative aspects of ustekinumab, recognising that it offered less frequent dosing in the maintenance stage than the other biological treatment administered by subcutaneous injection. The committee accepted that the positive impact this can have on minimising the interruption of patients' daily living, including work activities, may not be fully captured in the cost-effectiveness modelling. The committee concluded that ustekinumab is an innovative and cost-effective treatment for treating moderately to severely active Crohn's disease and should be recommended for use in the NHS.
# Pharmaceutical Price Regulation Scheme (PPRS) 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
# Summary of appraisal committee's key conclusions
TA456
Appraisal title: Ustekinumab for moderately to severely active Crohn's disease after previous treatment
Section
Key conclusion
Ustekinumab is recommended, within its marketing authorisation, as an option for treating moderately to severely active Crohn's disease, that is, for adults who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF‑alpha inhibitor or have medical contraindications to such therapies.
The committee concluded that the results from the ustekinumab studies suggest that it is associated with higher rates of response and clinical remission compared with placebo.
The committee considered that the company's treatment sequence analysis comparing ustekinumab with other biological treatments had many limitations and that the results should be interpreted with caution.
The committee was persuaded that cost minimisation was not an unreasonable approach. It noted that in the company analysis, which used the confidential pricing arrangement for ustekinumab agreed with the Commercial Medicines Unit, ustekinumab appeared to have lower total costs in year 1 than comparator treatments when considered at their list price, and therefore ustekinumab could be considered a cost-effective option for use in the NHS.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee acknowledged that ustekinumab is a convenient treatment that had considerably improved the quality of life of the patient experts. It concluded that the availability of a further treatment option to improve symptoms and bring the disease into remission would be highly valued by people with Crohn's disease.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee concluded that ustekinumab is an innovative and cost-effective treatment.
What is the position of the treatment in the pathway of care for the condition?
The committee concluded that ustekinumab would be used in place of other biological treatments and hence that these are the relevant comparators in the appraisal.
Adverse reactions
The committee acknowledged that ustekinumab is a well-tolerated treatment.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that the clinical evidence for ustekinumab came from 2 induction trials (UNITI-1 and UNITI-2) and 1 maintenance trial (IM-UNITI) that included patients who had had a clinical response to ustekinumab in either of the 2 induction trials. The committee concluded that the studies were of a good quality.
Relevance to general clinical practice in the NHS
The committee concluded that the studies were broadly generalisable to the population likely to have ustekinumab in clinical practice in England.
Uncertainties generated by the evidence
The committee concluded that there is uncertainty about the appropriate duration of treatment with biological therapy but that evidence from current practice suggests there may be a benefit to continuing treatment beyond 1 year.
The committee considered that the company's treatment sequence analysis comparing ustekinumab with other biological treatments should be interpreted with caution.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee noted that the results were more favourable for the conventional-care failure population in UNITI-2 than for the TNF‑alpha-inhibitor failure population in UNITI-1. However, it understood from the clinical experts that patients in whom TNF‑alpha inhibitors have failed are likely to respond less well to all biological treatments than patients who are naive to TNF‑alpha inhibitors.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee concluded that the results from the ustekinumab studies suggest that it is associated with higher rates of response and clinical remission compared with placebo.
Evidence for cost effectiveness
Availability and nature of evidence
The company presented a model consisting of a short-term induction phase (a decision tree) and a long-term maintenance phase (a Markov state transition model) comparing ustekinumab with conventional non-biological care and other biological therapies (infliximab, adalimumab and vedolizumab) in patients with moderately to severe active Crohn's disease. The committee recalled that ustekinumab would be used in place of other biological treatments and hence that the comparison of ustekinumab with other biological treatments is the most relevant to the appraisal.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee acknowledged comments from the ERG about the general weaknesses of the model structure.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee accepted that the positive impact of the reduced administrative burden of ustekinumab in the maintenance phase, minimising the interruption of patients' daily living and work activities, may not be fully captured in the cost-effectiveness modelling.
Are there specific groups of people for whom the technology is particularly cost effective?
None.
What are the key drivers of cost effectiveness?
The committee was persuaded that cost minimisation was not an unreasonable approach.
Most likely cost-effectiveness estimate (given as an ICER)
The committee noted that in the company's cost-minimisation analysis, which used the confidential pricing arrangement for ustekinumab agreed with the Commercial Medicines Unit, ustekinumab appeared to have lower total costs in year 1 than comparator treatments when considered at their list price, and therefore ustekinumab could be considered a cost-effective option for use in the NHS. However the committee was mindful that different prices may be available in the NHS for different biological treatments and it concluded that the total cost of the treatments should be taken into account when deciding which one to use in clinical practice.
Additional factors taken into account
Patient access schemes (PPRS)
The contract prices used for decision-making in this appraisal are the relevant prices the NHS pays for ustekinumab. These prices are based on contract pricing arrangements between the company and the Commercial Medicines Unit.
Equalities considerations and social value judgements
No equalities issues were identified.
|
{'Recommendations': "Ustekinumab is recommended, within its marketing authorisation, as an option for treating moderately to severely active Crohn's disease, that is, for adults who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF‑alpha inhibitor or have medical contraindications to such therapies.\n\nThe choice of treatment between ustekinumab or another biological therapy should be made on an individual basis after discussion between the patient and their clinician about the advantages and disadvantages of the treatments available. If more than 1\xa0treatment is suitable, the least expensive should be chosen (taking into account administration costs, dosage and price per dose).\n\nUstekinumab should be given until treatment failure (including the need for surgery) or until 12\xa0months after the start of treatment, whichever is shorter. People should then have their disease reassessed in accordance with NICE's recommendations for infliximab and adalimumab for the treatment of Crohn's disease to see whether treatment should continue.", 'The technology': "Description of the technology\n\nUstekinumab (Stelara, Janssen) is a human monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin‑12 (IL‑12) and interleukin‑23 (IL‑23).\n\nMarketing authorisation\n\nUstekinumab has a marketing authorisation in the UK for treating 'adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF‑alpha inhibitor or have medical contraindications to such therapies:\n\nPatients who have not shown adequate response at 8\xa0weeks after the first subcutaneous dose may receive a second subcutaneous dose at this time.\n\nPatients who lose response on dosing every 12\xa0weeks may benefit from an increase in dosing frequency to every 8\xa0weeks.\n\nPatients may subsequently be dosed every 8\xa0weeks or every 12\xa0weeks according to clinical judgment'.\n\nAdverse reactions\n\nThe most common adverse reactions for ustekinumab include arthralgia, headache, nausea, pyrexia, nasopharyngitis, abdominal pain, upper respiratory tract infection, diarrhoea and fatigue. For full details of adverse reactions and contraindications, see the summary of product characteristics.\n\nRecommended dose and schedule\n\nUstekinumab is given as intravenous infusion at induction and as subcutaneous injection at maintenance:\n\nintravenous induction treatment (dose depends on body weight and is approximately 6\xa0mg/kg).\n\nMaintenance subcutaneous treatment at week\xa08 (90\xa0mg), then every 12\xa0weeks.\n\nPrice\n\nThe list price for ustekinumab is £2,147 per 130‑mg vial concentrate for solution for infusion and per 90‑mg vial solution for injection (excluding VAT; Monthly Index of Medical Specialties).\n\nA confidential pricing arrangement has been agreed with the Commercial Medicines Unit.", 'Evidence': 'The appraisal committee (section\xa06) considered evidence submitted by Janssen and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.', 'Committee discussion': "The appraisal committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of moderately to severely active Crohn's disease and the value placed on the benefits of ustekinumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\n## Clinical need of people with Crohn's disease\n\nThe committee understood that Crohn's disease follows an unpredictable, relapsing and remitting course with many debilitating symptoms. It heard from the patient experts that the disease can present a major barrier to a person's ability to participate in daily life, severely affecting their self-esteem, social functioning, engagement in work and other activities, personal relationships and family life. The patient experts recounted their experience of current treatments including conventional non-biological therapy and TNF‑alpha inhibitors, and their intolerance to, or subsequent loss of response to these treatments. The committee heard that patients fear loss of remission and exacerbations of the disease because of the major impact these have on quality of life. It also heard that it is very important to have a range of treatment options to enable patients to regain remission. The committee noted that both the patient experts had ustekinumab as part of a clinical trial after losing response to TNF‑alpha inhibitors. Both recounted a positive response to treatment with ustekinumab and emphasised its life-changing effects, with good control of symptoms allowing them to resume work and everyday activities as well as avoiding the need for surgery. One patient expert explained that ustekinumab had left him feeling 'wonderfully normal again' while the other highlighted the immense improvement to her quality of life, enabling her to start a family. The patient experts also emphasised that maintenance treatment with ustekinumab is a subcutaneous injection rather than an intravenous infusion, which is greatly valued by patients because it means they can take the treatment at home with no need for hospital visits. The committee acknowledged that ustekinumab is a convenient and well-tolerated treatment that has considerably improved the quality of life of the patient experts. It concluded that the availability of a further treatment option to improve symptoms and bring the disease into remission would be highly valued by people with Crohn's disease.\n\n## Current clinical management of Crohn's disease\n\nThe committee heard from the clinical experts that initial treatment for people with Crohn's disease is conventional non-biological treatment but if this fails, patients are offered a TNF‑alpha inhibitor (infliximab or adalimumab). If this fails or is unsuitable, patients may switch to an alternative TNF‑alpha inhibitor or have vedolizumab in line with NICE technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy. It was the clinical experts' opinion that only when all other options have been exhausted, including dose escalation of a TNF‑alpha inhibitor despite it becoming less effective, would various non-biological approaches including surgery be considered. The committee heard from the clinical experts that ustekinumab is a novel treatment with a different mechanism of action to existing treatments, and that it can be used either in place of a TNF‑alpha inhibitor after conventional non-biological treatment has failed, or instead of vedolizumab (or a subsequent TNF‑alpha inhibitor, for which there is very limited evidence) after a first TNF‑alpha inhibitor has failed. It acknowledged that the clinical experts value using TNF‑alpha inhibitors first‑line, after failure of conventional non-biological treatment, because there is considerable clinical experience in using them. It is likely therefore that ustekinumab would predominantly be used later in the treatment pathway, although there may be some individual patients for whom ustekinumab would be considered earlier. The committee concluded that ustekinumab would be used as an option where other biological treatments would be considered appropriate, and hence that these are the relevant comparators in the appraisal.\n\nThe committee considered the duration of treatment with current biological therapies in clinical practice. It heard from the clinical experts that in line with current guidelines the benefit of these agents is assessed after induction to ensure a primary response and then at 1\xa0year to see whether treatment should continue. The clinical experts emphasised that, when there is evidence of clinical benefit, therapy usually continues beyond 1\xa0year in order to avoid complications and exacerbations that can result in life-changing surgery. However, the clinical experts acknowledged that there are currently no clinical data to support the long-term effectiveness of biological therapies. The committee also heard from the clinical experts that evidence from the UK Inflammatory Bowel Disease Audit shows that most patients continue on biological therapy for more than 1 year and that initial results suggest that continuous use is associated with better outcomes. The committee concluded that there is uncertainty about the appropriate duration of treatment with biological therapy but that evidence from current practice suggests there may be a benefit to continuing treatment beyond 1\xa0year.\n\n## Clinical trial evidence\n\nThe committee noted that the clinical evidence for ustekinumab came from 2 induction trials (UNITI‑1 and UNITI‑2) and 1\xa0maintenance trial (IM‑UNITI) that included patients who had had a clinical response to ustekinumab in either of the 2\xa0induction trials. It was aware that the UNITI‑1 and -2 trials were identical in design except for the trial populations. In UNITI‑1, patients had had TNF‑alpha inhibitor therapy but did not respond, lost response or were intolerant to it ('the TNF‑alpha-inhibitor failure population'). In UNITI‑2, patients had had conventional non-biological treatment that had failed ('the conventional-care failure population'). The committee noted the evidence review group (ERG's) comments that the induction trials were generally well conducted with high internal validity and were reasonably generalisable to the UK Crohn's disease population, although the committee was aware of some issues worthy of further consideration. For example, clinical advice to the ERG suggested that the Crohn's disease activity index (CDAI; a measurement of clinical, biochemical and physical parameters of disease activity) on which the primary outcome in the trials was based, is not used in clinical practice in the UK. The committee heard from the clinical experts present at the meeting that outcomes based on the CDAI have historically been used in studies of biological treatments in Crohn's disease to assess response, and therefore it was not unreasonable that they were used in the current trials. However they explained that there is now a move towards more objective assessment of disease activity, such as endoscopic evaluation of ulceration. The committee accepted that the use of the CDAI was acceptable given its historic use in assessing response to other biological treatments. The committee also noted that the trial excluded patients with the most severe disease (defined by a CDAI score higher than 450). The committee heard from the clinical experts that the trial populations were generally representative of patients seen in clinical practice and that the exclusion of some groups of patients, such as those with the most severe disease, was a limitation of trials generally. The committee concluded that the studies were of a good quality and broadly generalisable to the population likely to have ustekinumab in clinical practice in England.\n\n## Clinical effectiveness results from induction trials\n\nThe committee noted that in both of the induction trials, the proportion of patients with a clinical response at 6\xa0weeks (the primary outcome, defined as a reduction from baseline in CDAI score of 100\xa0points or more) was significantly greater in patients randomised to ustekinumab compared with placebo. In UNITI‑1, 33.7% of patients in the ustekinumab group at the licensed dose of approximately 6\xa0mg/kg had a clinical response compared with 21.5% in the placebo group (p=0.003). In UNITI‑2, 55.5% of patients in the ustekinumab group had a clinical response compared with 28.7% in the placebo group (p=0.001). The committee also noted that there were statistically significant differences between ustekinumab and placebo in the rates of clinical remission (defined as attaining a CDAI score of less than 150 points) and other secondary outcomes. The committee noted that the results were more favourable for the conventional-care failure population in UNITI‑2 than for the TNF‑alpha-inhibitor failure population in UNITI‑1. However, it understood from the clinical experts that patients in whom TNF‑alpha inhibitors have failed are likely to respond less well to all biological treatments than patients who are naive to TNF‑alpha inhibitors. The committee concluded that the results from the induction studies suggest that ustekinumab is associated with higher rates of response and clinical remission compared with placebo in both populations of patients.\n\n## Clinical effectiveness results from maintenance trials\n\nThe committee noted that at 44‑week follow-up in the IM‑UNITI maintenance trial, the proportion of patients in clinical remission (the primary outcome) was significantly greater in both the 90\xa0mg every 12\xa0weeks (48.8%) and 90\xa0mg every 8\xa0weeks (53.1%) ustekinumab groups than in the placebo group (35.9%, p=0.040 and p=0.005 respectively). It also noted that there were statistically significant differences between ustekinumab and placebo for clinical response at 44\xa0weeks. The committee acknowledged that the company had submitted some additional results up to week\xa092 but that no statistical comparisons between ustekinumab and placebo were presented. It concluded that the results from the maintenance study suggest that ustekinumab is associated with higher rates of clinical remission and response at 44\xa0weeks compared with placebo but that the longer-term effects are uncertain because limited data are available.\n\n## Relative effectiveness of ustekinumab and other biological therapies\n\nThe committee noted that the company had presented indirect comparisons to provide comparative efficacy estimates for ustekinumab compared with other biological treatments. It understood that analyses were performed separately for induction trials and maintenance trials and for the conventional-care failure population and the TNF‑alpha-inhibitor failure population. For the induction phase, the company provided a network meta-analysis. The committee noted that the ERG considered that the trials included in the network meta-analysis were generally conducted to a high-standard. However there were some limitations with the analysis because of variability in the time at which primary outcomes were assessed in the trials and differences in treatment history and previous exposure to TNF‑alpha inhibitors. It also noted that only 1\xa0small study of infliximab was included in the analysis and that the company had highlighted the need to interpret the results of the study with caution because of missing data, and because a smaller magnitude of effect was observed with higher doses of infliximab than with smaller doses. The committee acknowledged that the network meta-analysis suggested significantly higher rates of response and remission in the induction phase with infliximab compared with ustekinumab but no statistically significant differences between ustekinumab and the other biological therapies. However, it concluded that the results were associated with uncertainty and that the comparison between infliximab and ustekinumab in particular should be interpreted with caution.\n\nFor the maintenance phase, the company carried out a treatment sequence analysis instead of a conventional network meta-analysis because of the multiple sources of heterogeneity between the maintenance trials. The committee noted that the company's aim was to evaluate treatment effects over the entire treatment sequence to reduce bias inherently associated with the analysis of long-term relative treatment effect estimates for ustekinumab. The committee also noted that the company stated that this was a complex analysis and the results should be viewed with caution. The committee was aware that the ERG had identified a number of issues with the company's analysis, and believed the results were highly uncertain. The ERG's concerns included the comparability of the trials included in the treatment sequence analysis. It also considered that the methods used to construct the control arm for biological therapies had considerable potential for confounding of results, because the analysis was based on placebo-data from IM‑UNITI and not on randomised comparisons. The committee acknowledged that both the company and the ERG had reservations about the reliability of the treatment sequence analysis. It agreed that the treatment sequence analysis had many limitations and that the results should be interpreted with caution.\n\n# Cost effectiveness\n\n## Company's economic model\n\nThe company presented a model consisting of a short-term induction phase (a decision tree) and a long-term maintenance phase (a Markov state transition model) comparing ustekinumab with conventional non-biological therapies and other biological therapies (infliximab, adalimumab and vedolizumab) in patients with moderately to severe active Crohn's disease. The committee recalled that ustekinumab would be used in place of other biological treatments (see section\xa04.2) and therefore the comparison of ustekinumab with other biological treatments is the most relevant to the appraisal.\n\nThe committee acknowledged comments from the ERG about the general weaknesses of the model structure. It heard that it did not fully characterise the chronic life-long relapsing-remitting nature of Crohn's disease because it did not allow patients to cycle through multiple biological therapies. It also heard that the impact of surgery on future prognosis, including the need for further surgery, and health-related quality of life were not appropriately incorporated. The committee acknowledged that similar models had been used in other technology appraisals for Crohn's disease and, while noting its limitations, concluded that the structure of the model was acceptable for decision making. However it also noted the ERG's comment that research is needed to develop a new and more appropriately structured decision-analytic model for Crohn's disease, which could be used in future appraisals.\n\n## Cost-effectiveness results\n\nThe committee noted that in the company's base-case analysis ustekinumab dominated other biological treatments (that is, it cost less and resulted in higher quality adjusted life years [QALYs]), both in the conventional-care failure population and in the TNF‑alpha-inhibitor failure population. It also noted that ustekinumab remained dominant compared with other biological treatments in the ERG's exploratory analyses using the company's model structure. The committee observed that there were only small differences in the QALY estimates between the different biological therapies as estimated by the company and the ERG. It recognised that this leads to instability in the cost-effectiveness results and therefore further considered the company's suggestion that a cost-minimisation analysis may be more appropriate. The committee heard from the ERG that it is not unreasonable to assume similar efficacy between the biological therapies based on the available evidence. It also recalled that the clinical experts had commented that the absence of direct comparative data meant that it was unknown whether there were any differences in efficacy. The committee was therefore persuaded that cost minimisation was not an unreasonable approach. It noted that in the company analysis, which used the confidential pricing arrangement for ustekinumab agreed with the Commercial Medicines Unit, ustekinumab appeared to have lower total costs in year\xa01 than comparator treatments when considered at their list price, and therefore ustekinumab could be considered a cost-effective option for use in the NHS. However, the committee was mindful that different prices may be available in the NHS for different biological treatments and it concluded that the total cost of the treatments should be taken into account when deciding which one to use in clinical practice.\n\n## Innovation\n\nThe committee discussed the innovative aspects of ustekinumab, recognising that it offered less frequent dosing in the maintenance stage than the other biological treatment administered by subcutaneous injection. The committee accepted that the positive impact this can have on minimising the interruption of patients' daily living, including work activities, may not be fully captured in the cost-effectiveness modelling. The committee concluded that ustekinumab is an innovative and cost-effective treatment for treating moderately to severely active Crohn's disease and should be recommended for use in the NHS.\n\n# Pharmaceutical Price Regulation Scheme (PPRS) 2014\n\nThe committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.\n\n# Summary of appraisal committee's key conclusions\n\nTA456\n\nAppraisal title: Ustekinumab for moderately to severely active Crohn's disease after previous treatment\n\nSection\n\nKey conclusion\n\nUstekinumab is recommended, within its marketing authorisation, as an option for treating moderately to severely active Crohn's disease, that is, for adults who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF‑alpha inhibitor or have medical contraindications to such therapies.\n\nThe committee concluded that the results from the ustekinumab studies suggest that it is associated with higher rates of response and clinical remission compared with placebo.\n\nThe committee considered that the company's treatment sequence analysis comparing ustekinumab with other biological treatments had many limitations and that the results should be interpreted with caution.\n\nThe committee was persuaded that cost minimisation was not an unreasonable approach. It noted that in the company analysis, which used the confidential pricing arrangement for ustekinumab agreed with the Commercial Medicines Unit, ustekinumab appeared to have lower total costs in year\xa01 than comparator treatments when considered at their list price, and therefore ustekinumab could be considered a cost-effective option for use in the NHS.\n\n, 4.5, 4.8, 4.11\n\nCurrent practice\n\nClinical need of patients, including the availability of alternative treatments\n\nThe committee acknowledged that ustekinumab is a convenient treatment that had considerably improved the quality of life of the patient experts. It concluded that the availability of a further treatment option to improve symptoms and bring the disease into remission would be highly valued by people with Crohn's disease.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nThe committee concluded that ustekinumab is an innovative and cost-effective treatment.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe committee concluded that ustekinumab would be used in place of other biological treatments and hence that these are the relevant comparators in the appraisal.\n\n\n\nAdverse reactions\n\nThe committee acknowledged that ustekinumab is a well-tolerated treatment.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThe committee noted that the clinical evidence for ustekinumab came from 2 induction trials (UNITI-1 and UNITI-2) and 1 maintenance trial (IM-UNITI) that included patients who had had a clinical response to ustekinumab in either of the 2 induction trials. The committee concluded that the studies were of a good quality.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe committee concluded that the studies were broadly generalisable to the population likely to have ustekinumab in clinical practice in England.\n\n\n\nUncertainties generated by the evidence\n\nThe committee concluded that there is uncertainty about the appropriate duration of treatment with biological therapy but that evidence from current practice suggests there may be a benefit to continuing treatment beyond 1\xa0year.\n\nThe committee considered that the company's treatment sequence analysis comparing ustekinumab with other biological treatments should be interpreted with caution.\n\n, 4.8\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nThe committee noted that the results were more favourable for the conventional-care failure population in UNITI-2 than for the TNF‑alpha-inhibitor failure population in UNITI-1. However, it understood from the clinical experts that patients in whom TNF‑alpha inhibitors have failed are likely to respond less well to all biological treatments than patients who are naive to TNF‑alpha inhibitors.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe committee concluded that the results from the ustekinumab studies suggest that it is associated with higher rates of response and clinical remission compared with placebo.\n\n, 4.6\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe company presented a model consisting of a short-term induction phase (a decision tree) and a long-term maintenance phase (a Markov state transition model) comparing ustekinumab with conventional non-biological care and other biological therapies (infliximab, adalimumab and vedolizumab) in patients with moderately to severe active Crohn's disease. The committee recalled that ustekinumab would be used in place of other biological treatments and hence that the comparison of ustekinumab with other biological treatments is the most relevant to the appraisal.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe committee acknowledged comments from the ERG about the general weaknesses of the model structure.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nThe committee accepted that the positive impact of the reduced administrative burden of ustekinumab in the maintenance phase, minimising the interruption of patients' daily living and work activities, may not be fully captured in the cost-effectiveness modelling.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone.\n\n–\n\nWhat are the key drivers of cost effectiveness?\n\nThe committee was persuaded that cost minimisation was not an unreasonable approach.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe committee noted that in the company's cost-minimisation analysis, which used the confidential pricing arrangement for ustekinumab agreed with the Commercial Medicines Unit, ustekinumab appeared to have lower total costs in year\xa01 than comparator treatments when considered at their list price, and therefore ustekinumab could be considered a cost-effective option for use in the NHS. However the committee was mindful that different prices may be available in the NHS for different biological treatments and it concluded that the total cost of the treatments should be taken into account when deciding which one to use in clinical practice.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nThe contract prices used for decision-making in this appraisal are the relevant prices the NHS pays for ustekinumab. These prices are based on contract pricing arrangements between the company and the Commercial Medicines Unit.\n\n\n\nEqualities considerations and social value judgements\n\nNo equalities issues were identified.\n\n–"}
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https://www.nice.org.uk/guidance/ta456
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Evidence-based recommendations on ustekinumab (Stelara) for previously treated moderately to severely active Crohn’s disease in adults.
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